Monthly Archives: July 2018

Results from application of scripted based, algorithmic approach to multi-target SRS planning, evaluation and characterization of volume dependent metrics

DOI: 10.31038/CST.2018335

Abstract

Purpose: Transitioning away from fixed beam toward VMAT approach for multi-target SRS, we developed a standardized algorithmic approach for treatment planning, and a script-based evaluation application characterizing high, intermediate and low dose regions proximal to targets and throughout the brain. The evaluation script was used to compare metrics for clinically treated fixed- and VMAT-based plans to quantify benchmark norms.

Methods and Materials: Plans were examined for 79 patients (37 Fixed/47 VMAT) treating 179 (120 fixed/59 VMAT) targets. Dual purpose structures used for optimization and evaluation include 5 mm thick shells around the PTV (HDRing) and around the HDRing (MDRing) to control/measure dose fall off around the targets, and Brain – (PTV + 5 mm) to quantify for low dose regions. Effective gradients (GrEff) were calculated using V100% [cc] and V50% [cc] in HDRing and MDRings. Volume dependence of metric value distributions were characterized with quantile regression.

Results: Conformity index (CI) decreased rapidly toward unity with increasing volume, plateauing near 0. 5 cc. Conformity index was significantly improved for VMAT plans (1. 19 ± 0. 17 vs 1. 40 ± 0. 46, p<0. 001) whereas effective gradients (%/cm) were reduced (117. 55 ± 17. 26 vs 137. 62 ± 26. 50, p<0. 001). Gradients decreased with increasing target volume (TV) converging near 4 cc for fixed field plans. Quantiles for volumes outside the PTVs receiving 12 Gy or more were smaller for VMAT than fixed beams, increasing as smaller powers of volume (e. g. 0. 45 vs 0. 51). Doses 5-10 mm from targets were similar. Volume of Brain – (PTV+05) receiving at least 5 Gy depended on cumulative PTV volumes and were less for fixed vs VMAT beams. Automation of metric collection improved evaluation of newly generated treatment plans and expedited the transition to multi-target VMAT-based SRS.

Conclusions: Development of standardized algorithmic approach to optimization plus script based metrics calculation improved the SRS planning process and evaluation.

Introduction

The process of transitioning from single target to volumetric modulated arc therapy (VMAT)-based multi-target SRS is underway in many clinics. Conformity and gradient metrics of VMAT-based approaches have been demonstrated by several authors to match or exceed those achieved with other technologies [1-6]. In addition, these VMAT-based approaches reduce treatment time and improve clinical flow by utilizing the same planning and delivery technologies used for other treatments.

In making a transition for treatment planning we focused on two main themes. First, the ability to quantify achieved versus expected values for dosimetric measures in the context of historical experience is an important touchstone. We know that plans will vary in high, intermediate and low dose regions of the distributions, dependent on a range of parameters (e. g. technology used, planner experience, etc. ). Placing those quantified differences in the context of historical norms enables better informed judgements on treatment options. Second, in busy clinics, as the volume of multi-target SRS treatments increases, the number of planners involved may also increase. Standardized, algorithmic approaches for planning and evaluation are valuable for ensuring consistent, objectively demonstrable plan quality and efficiency.

For standardized comparison metrics to be clinically useful, they must be calculable with reasonable effort as part of routine practice so that statistics can be consistently reported and recorded for all treated patients and analyzed. We developed an approach combining a standardized contouring and structure nomenclature, with a script calculating a set of standardized metrics. For VMAT plans, an algorithmic approach to optimization was implemented. The approach was designed to be extensible to implementation with write-enabled scripting that enables programmatic creation of plans, structures and optimization, when that functionality becomes available in clinical systems. With that ability, these algorithmic approaches can be implemented as software applications to enable automation as part of planning processes to improve efficiency and plan quality.

Our objective here is to report on results from the application of this approach, demonstrating the ability of the metrics to provide quantified, clinically comprehensible comparisons of treatment planning approaches. Detailed values and regression parameters characterizing distribution of metrics values quantifying high, intermediate and low dose regions are reported. In particular, we focus on differences between the application of a standardized, algorithmic VMAT planning approach and a more conventional fixed beam approach using static MLCs.

Methods

The approach was applied for patients treated as we transitioned from the use of fixed static beams to VMAT arcs for stereotactic treatment of single and multiple brain lesions. Over this period, both VMAT and fixed beam approaches were used with volume based prescribed doses. All patients were treated on a Varian Edge accelerator outfitted with a high definition multi-leaf collimator (HDMLC). All planning was carried out with the Eclipse (Varian Medical Systems) planning system version 13. 6. Plans were calculated using 1 mm resolution.

Standardized Contouring

The standardized approach to target naming and contouring was defined (Figure 1). Gross tumor volumes (GTVs) and planning target volumes (PTVs) were numbered sequentially, with numbering continuing if patients return for future treatments (e. g. PTV01, PTV02…PTV12). PTV margins are typically 1 mm. Other organs at risk (OARs) are included as necessary with our standardized nomenclature. As described in Table 1, seven structure classes were contoured for use in optimization and evaluation.

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Figure 1. Structures utilized in algorithmic VMAT plan optimization and in treatment plan evaluation with a custom Eclipse API based script are illustrated: (a) PTVaa, HDRingxx, MDRingxx, (b) zBrain-PTV+05, (c) zBuffxxyy, (d) a dose distribution produced with the method.

Low dose spillage in the brain was measured using the brain structure with PTV targets and 0. 5 mm region around each PTV subtracted i. e. Brain – (PTV + 5 mm). To accommodate character restrictions in the planning system this structure was labeled zBrain-PTV+05.

Table 1. Structure classes were contoured for use in optimization and evaluation

Structure	Purpose	Construction comments
GTVxx	Gross tumor volume delineation	Number targets with two digits. For subsequent treatments continue numbering in sequence.
PTVxx	Planning target volume delineation	PTV numbers are matched to corresponding GTV
zHDRingxx	Used to optimize/measure intermediated dose region proximal to PTVs	Ring 0-5 mm from PTVxx, crop all PTVxx’s out
zMDRingxx	Used to measure low dose region proximal to PTVs	Ring 5-10 mm from PTVxx, crop all PTVxx’s out
zBufxxyy	Used to control fall off between close (< 1 cm) targets	When two or more zHDRings overlap (e. g. zHDRingxx, zHDRingyy) create as Boolean AND of zHDRings. Crop PTVs out by by 0. 1 cm.
zBrain-PTV+05	Used to monitor dose to normal brain	Brain minus PTVs with 5 mm margin i. e. Brain-(PTV+ 5mm)

Beam selection and optimization

Isocenter is placed by inspection of PTVs and OARs to a) minimize the distance to targets and b) minimize the potential of angular variations to negatively impact critical organs at risk, e. g. brainstem, optic nerves, optic chiasm. Thus, if one target abuts the brainstem, the isocenter placement is biased to be close to the brainstem.

A separate isocenter and plan was used for each PTV for fixed beam planning. For VMAT plans, a single isocenter was typically used to treat all PTVs. However, two isocenters/plans were used if separation and clustering of targets revealed improved ability to reduce low dose MLC transmission to normal brain with smaller collimator openings.

For VMAT planning, non-coplanar arcs corresponding to at least two minimally overlapping arc trajectories were used. Beams eye views (BEVs) were used to select table/gantry angle combinations minimizing transmission to organs at risk. BEVs were used to select optimal collimator rotations and groups with two principal goals: 1) minimize low dose contribution of leaf transmission and 2) optimize the ability of leaves to conformally minimize dose to OARs including normal brain. For example, if targets were clustered in both the left and right hemispheres of the brain with a large (> 3cm) separation, then two sagittal arcs could be used with collimator groups treating the left and right clusters separately. Collimator angles for each group would be selected to maximize the ability of leaves to block regions between the targets over the range of the arc. We note that other authors have shown that single isocenters are adequate in these circumstances [2, 6]

A standardized set of optimization constraints, listed in Table 2, were entered as the starting point for all optimizations. During optimization, constraint values were adjusted from start values to achieve the desired coverage. The Progressive Resolution Optimizer (PRO) (Varian Medical Systems) was used for all optimizations.

Table 2. Standardized optimization objectives and methods for using the standardized structures.

Structure	Type	Volume [%]	Dose	Priority	Comment
PTVxx	Lower	100	Rx[Gy]	120
	Upper	0	Rx[Gy] + 25%	50	–
GTVxx	Lower	50	Rx[Gy] + 8%	50	Push dose higher if needed to reduce horns in dose profile
HDRingxx	Upper	2	Rx[Gy]	80
	Upper	70	0.5 * Rx[Gy]	100	Push Volume[%] to < 70% as optimization allows
zBrain-PTV+05	Upper	0	0.5*Rx[Gy]	120	–
	Upper	3	0.25*Rx[Gy]	50	Push dose to < 0.25*Rx[Gy] as optimization allows
zBufxxyy	Upper	20	0.9* Rx[Gy]	50	Push volume[%] to < 20% as optimization allows
Orbit_L Orbit_R	Upper	0%	5 Gy	50	Push dose as lower, as optimization allows, to minimize dose

Scripted DVH Metrics Calculation and Recording

A script was written using C#. Net (version 15) and the Eclipse Application Programming Interface (ESAPI, version 13. 6) that is run from within the plan evaluation session to calculate a set of standardized DVH metrics using the standardized contours/nomenclature outlined in Table 1.

The script allows entry of the prescribed doses for each target. It operates on single plans and on plan sums. When multiple plans are used in a single course of treatment (e. g. two SRS isocenters/plans and one multi-fraction SBRT plan) the script is run on the plan sum so that the metrics reflect the composite dose.

Metrics collected included a series of those describing the PTVs (volume[cc] and RxDose[Gy]), dose achieved in each PTV (V100%[cc], Min[Gy], and Max[Gy]) as well as dose falloff around each PTV (V100%[cc], V50%[cc], V12Gy[cc], DC5%[Gy], and D5%[Gy] for both the HDRingxx and MDRingxx structures). Conformity index and effective gradient were also calculated as described below. Here we have used the standardized DVH nomenclature defined by AAPM Task Group 263.

The ICRU conformity index (CI) was calculated for each PTVxx using the zHDRingxx to restrict DVH measures to the region within 5 mm of each target. These are written as

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The PTVxx, zHDRingxx and zMDRingxx structures were also used to calculate the effective gradient index, GrEff, described by Mayo et al [1]. With these structures GrEff constructs a volume- based average of the dose fall off within 10 mm of the PTV in units of %/cm.

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Where

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Ratios of prescribed dose to doses covering the hottest (D5% [cc]) and coldest (DC5% [cc]) five percent of the zHDRingxx and zMDRingxx structures were calculated to characterize dose falloff in intermediate and low dose regions.

Low dose spillage to brain tissue not adjacent to the PTVxx’s (i. e. outside the HRingxx’s) was characterized using the zBrain-PTV+05 structure by measuring: Volume [cc], V12Gy[cc], V10Gy[cc] and V5Gy[cc]. Delivering 12 Gy in 1 fraction has the same BED as 30Gy in 10 fractions assuming an α/β equal to 3. V12Gy [cc] has been used by several authors as a metric for gauging intermediate dose spread.

Significance of differences in means for distributions were assessed with the Student’s t test, p < 0. 05. Volume dependence of metrics was checked with Kendall’s tau (kt) correlations with a threshold, |kt|>0. 05. Quantile regression was carried out for volume dependent metrics evaluating median (50% quantile) and 50% confidence intervals (25% and 75% quantiles). Low dose spillage metrics in zBrain- PTV+05 were characterized with respect to cumulative target volumes. Target coverage metrics computed with PTVxx and HDRingxx structures were fit with respect to individual target volumes. All computations were carried out in R (3. 3. 6). Fit functional forms were selected empirically.

Results

A total of 79 patients with 179 SRS targets (120-VMAT and 59-fixed) were included in this study. Patients were treated between January and July of 2017. In this cohort there were 37 VMAT and 47 fixed plans. Fixed beam plans were typically used for patients with smaller numbers of targets. Average numbers of targets per plan were 3. 2 and 1. 2 for VMAT and fixed beam plans, respectively. There were no significant differences between the target volumes in the two sets of patients (2. 49 ± 4. 03 cc for VMAT and 3. 06 ± 3. 89 for fixed).

Conformity indices were regressed with the functional form

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Regressions are illustrated in Figure 2 a and b. Coefficient values (CI0, a, b) were (1. 03, 0. 052, 0. 68), (1. 07, 0. 053, 0. 88) and (1. 06, 0. 13, 0. 60) for 25%, 50%, 70% quantiles of VMAT beams, respectively. For fixed beams coefficients for the same respective quantiles were (1. 19, 0. 0008, 3. 6), (1. 21, 0. 046, 1. 81) and (1. 32, 0. 11, 1. 4). At 1 cc, median and 50% CI were 1. 12 (1. 09-1. 17) and 1. 25 (1. 19-1. 43) for VMAT and Fixed beams, respectively. At 10 cc values were 1. 07 (1. 04-1. 09) and 1. 21 (1. 19-1. 32) for VMAT and Fixed beams. VMAT was significantly (p< 0. 001) more conformal than fixed beams.

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Figure 2. Conformity index for all target volumes (a). The same data are shown in part (b) with the x-axis zoomed in for clarity. GrEff for all target volumes (c). The same data are shown in part (d) with the x-axis zoomed in for clarity. Quantile regressions enable prediction of expectation values based on history and PTV volumes.

Effective gradients were regressed with the function

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Regressions are illustrated in Figures 2 c and d. Coefficient values (GrEff0, a, b) were (139, 27, 0. 30), (143, 23. 6, 0. 34) and (140, 12. 1, 0. 50) for 25%, 50%, 70% quantiles of VMAT beams respectively. For fixed beams coefficients for the same respective quantiles were (192, 50. 6, 0. 30), (294, 143, 0. 15) and (210, 52. 4, 0. 33). At 1 cc, median and 50% CI were 119 (114-129) and 150 (142 – 158) %/cm for VMAT and Fixed beams. At 10 cc values were 91. 7 (88. 4-103) and 92 (90. 6-99. 0) %/cm for VMAT and fixed beams. Fixed beams demonstrated steeper dose gradients than VMAT beams for PTV target volumes < 10 cc.

Fall off of dose adjacent to the target volumes were examined with the HDRingxx and MDRingxx structures. In the HDRingxxs, V12Gy[cc] was regressed with respect to PTV volume using

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Regressions are illustrated in Figure 3. Coefficients (a, b) for VMAT beams were (2. 37, 0. 411), (2. 84, 0. 456), (3. 14, 0. 484) for 25%, 50% and 75% quantiles, respectively. For fixed beams coefficients were (1. 92, 0. 537), (2. 81, 0. 507), (3. 23, 0. 563). Median and 50% CI at 1 cc were 2. 8 92. 4-3. 1) cc and 2. 8 (1. 9-3. 2) cc for VMAT and fixed beams, respectively. Respective values at 10 cc were 8. 1 (6. 8-9. 0) cc and 9. 0 (6. 2-10. 4) cc. Volumes outside the PTVs receiving 12 Gy or more were smaller for VMAT than fixed beams.

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Figure 3. Volume receiving 12Gy or more in the HDRingxx structures surrounding PTV structures. Quantile regressions enable prediction of expectation values based on history and PTV volumes.

The dose falloff ratio (DFR) in the HD and MD rings was measured as the ratio of the difference in dose encompassing the “hottest” and “coldest” 5% of the ring structure to the prescribed dose. Steeper gradients imply larger DFR values.

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The high dose (HD) in the HD and MD rings was measured as the ratio of dose encompassing the “hottest” 5% of the ring to the prescribed dose. Higher values of RHD are less desirable than lower.

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Distributions of DRF and RHD are illustrated in Figure 4. In the HDRingxx structures, DFR was less variable for VMAT than fixed beams, but smaller consistent with the higher GrEff values.

RHD was smaller for VMAT than fixed beams consistent with VMAT being more conformal. In the MDRingxx structures, DRF and HD distributions were similar.

Distributions of low dose spread in the brain proximal to the targets (zBrain-PTV+05) showed significant (p<0. 001) difference for V5Gy [cc], V10Gy [cc] but not for V12Gy [cc] (p = 0. 13). Median and 50% CI for VMAT and fixed beams respectively were 62 (35. 4-131) cc and 11. 60 (4. 75-21. 1) cc for V5Gy [cc], 1. 0 (0. 4-3. 1) and 0. 2 (0. 0 – 0. 95) cc for V10Gy [cc]. For V12Gy [cc] values were 0. 0 (0-0. 1) cc for both VMAT and fixed. Both V5Gy [cc] and V10Gy [cc] demonstrated dependence on cumulative volume of PTVs in the multi-target plan.

For V5Gy [cc], using the functional form in equation 7 for quantile regression, coefficients (a, b) were (12. 5, 0. 317), (26. 5, 0. 29), (31. 3, 0. 5) for the 25%, 50% and 75% quantiles respectively. For fixed beams, respective coefficients were (4. 14, 0. 62), (5. 89, 5. 64) and (8. 69, 0. 65). Median and 50% CI at 3 cc cumulative PTV volume were 18 (9-36) cc and 11 (8-18) for VMAT and fixed beams. For 13 cc cumulative PTV volume respective values were 56 (28-113) and 25 (20-51). Fixed beam V5Gy [cc] values were significantly (p<< 0. 0001) lower than VMAT.

For V10Gy [cc], coefficients (a, b) were (0. 102, 0. 056), (0. 401, 0. 089), (0. 771, 0. 531) for the 25%, 50% and 75% quantiles respectively. For fixed beams, respective coefficients were (0. 005, 0. 844), (0. 108, 0. 768) and (0. 374, 0. 761). Median and 50% CI at 3 cc cumulative PTV volume were 0. 44 (0. 11 – 1. 4) cc and 0. 25 (0. 01-0. 86) cc for VMAT and fixed beams. For 13 cc cumulative PTV volume, respective values were 0. 50 (0. 12-3. 0) cc and 0. 78 (0. 05-2. 6) cc. For 10Gy [cc] fixed beam values were similar overall between VMAT and fixed beams.

Discussion

Automated analysis of SRS planning metrics provides a number of insights into the planning process and assists with ongoing quality assurance of plans. The metrics derived enable quantitative vs qualitative distinctions between plans such as VMAT and fixed field plans for multi-target SRS.

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Figure 4. Characterizing dose distributions near to the PTVxx structures. Distributions of DFR and RHD values are illustrated with box and whisker plots for HDRingxx (a, c) and MDRingxx (b, d) structures.

Figure 2 shows the differences in conformity index and effective gradient (GrEff) between the two groups of plans. The quantile fits of these data show similar behavior between the two planning strategies. Conformity index is relatively constant for larger volumes but increases dramatically below a target volume of 0. 5-1. 0 cc. There is an improvement in conformity index with VMAT plans but a reduction in effective gradient compared to fixed field plans. The quantile analysis aids in providing a range of acceptable metric values for use in evaluating plan quality.

As expected, VMAT plans tend to spread more low dose to normal brain compared to fixed field plans because of the rotational nature of this treatment technique (see Figure 2a-c). However, this effect plateaus near 12 Gy. Figure 2d shows the V12Gy for normal brain for all plans included in this study, illustrating the similarities between the two techniques at this dose level. During the transition to multi-target VMAT treatment techniques, it is essential to closely monitor low-dose spread to minimize potential for cumulative low dose effects when patients return for additional treatment.

Figure 3 further investigates the distribution of dose outside of the target in the HDRingxx (within 0. 5 cm of the target) and the MDRingxx (0. 5 – 1. 0 cm from the target). The HDRingxx has a higher hotspot in fixed field plans however, the dose complement (hottest dose to the coldest 5% in this case) is in fact lower in the fixed field plans. One reason for this reversal is that the fixed field plans tend to be more asymmetrical due to the limited number of beam angles.

In their study of 6 patients with a total of 19 targets, Liu et al noted conformity indices of 1. 19 ±0. 14 for VMAT based SRS (RapidArc) compared to 1. 5 ± 0. 16 for Gamma Knife [3]. Mean V12Gy [cc] and V4. 5Gy [cc] values were 9. 7± 5. 1 cc and 10. 9± 7. 2cc for VMAT compared to Gamma Knife. Mean V4. 5Gy [cc] was 99 ± 27. 3 cc and 86. 7 ± 7. 2 cc VMAT and Gamma Knife respectively. Volume dependence of metrics was not investigated in that study. Similarly, Thomas et al re-planned 28 Gamma Knife cases with VMAT [2]. They reported in conformity index median of 1. 29 with ranging from 0. 99 to 4. 31 for VMAT compared to 1. 94 ranging from 1. 21 to 6. 10 for Gamma Knife plans. In an early (2010) study of VMAT (RapidArc) based SRS, for 12 patients and 14 targets (5. 2 ± 6. 0cc), Mayo et al. reported a mean conformity index of 1. 1 ± 0. 11 and a mean GrEff of 80 ± 0. 11 [1].

Our metrics compare favorably with those of prior authors demonstrating the viability of the algorithmic planning approach. By using the script to incorporate metric evaluation into the routine planning workflow, we were able to gather a much larger dataset than prior studies. This provided sufficient information to extend analysis to characterize volume dependence. Expansion of the amount of clinically relevant data produced by integrating analysis can collection into clinical processes further demonstrates value of the standardized, algorithm approach to planning and evaluation.

With quantification of distributions by quantiles, including regressions to account for PTV volume dependence, the evaluation script can be further enhanced to highlight values for individual plans that are outside the historic norms of our practice. This provides the basis for actively incorporating statistics on historic experience back into routine clinical planning processes. Further, the standardized approach for grouping individual constraints and historical context into a single plan evaluation metric, recently described by Mayo et al, will be incorporated into the script for overall plan evaluation using the set described [7].

The ability to efficiently create and evaluate treatment plans is an enormous asset in such a time-limited and work-intensive process as stereotactic radiosurgery. When write-enabled scripting becomes available for clinical use in Eclipse, the process of creating the structures and optimization constraints a described in this study could be made considerably faster. To demonstrate this potential, we created a set of ESAPI scripts in our non-clinical development environment to automate structure creation and plan optimization. These were run on plans transferred into the development environment to check the accuracy of the scripts and the time to execute. Automating these steps ensures consistency in creation and evaluation of plans, with the ability to easily identify outliers a compare plan quality across planners as well as institutions. These types of scripts could also be combined with knowledge-based planning strategies to further automate the planning process.

Conclusions

We believe the future of treatment planning is increased utilization of automation using statistically-based quantifications of experience to guide design and evaluation. Creation of algorithmically based planning approaches that also produce clinically meaningful quantified metrics is an important enabling step. Such metrics provide quantitative basis for defining differences between plans. By characterizing distributions of these metrics from clinically acceptable plans, expectation values for subsequent plans can be established. Our objective here is to report a method we have implemented as part of our transition to multi-target VMAT based SRS and demonstrate the utility of the method for making quantitative comparisons that can be incorporated into routine clinical practice

Acknowledgements: The work described was supported in part by a grant from Varian Medical Systems. We wish to thank Drs. Xxxxx and xxxxx at the xxxxx and yyyyy of yyyyy for sharing their insights and methods used in multi-target SRS VMAT planning.

References

Mayo CS, Ding L, Moser R et al. Initial experience with volumetric IMRT (RapidArc) for intracranial stereotactic radiosurgery Int. J. Radiat. Oncol. Biol. Phys. 78: 1457–1466,
Thomas EM, Popple RA, Fiveash JB, et al. (2014) Comparison of plan quality and delivery time between volumetric arc therapy (RapidArc) and Gamma Knife radiosurgery for multiple cranial metastases. Neurosurgery. 75:409–17.
Liu H, Andrews DW, Shi W et al. (2016) PlanQuality and Treatment Efficiency for Radiosurgery to Multiple Brain Metastases:Non-Coplanar RapidArc vs. Gamma Knife. Front Oncol 11;6:26.
Fiorentino A, Giaj-Levra N, Tebano U, Mazzola R, Ricchetti F, et al. (2017) Stereotactic ablative radiation therapy for brain metastases with volumetric modulated arc therapy and flattening filter free delivery: feasibility and early clinical results. Radiol Med 122: 676–682. [crossref]
Clark GM, Popple RA, Fiveash JB, et al . (2012) Plan quality and treatment planning techniquefor single isocenter cranial radiosurgery with volumetric modulated arc therapy. Pract Radiat Oncol 2:306–13.
Clark GM, Popple RA, Young PE, Fiveash JB (2010) Feasibility of single-isocenter volumetric modulated arc radiosurgery for treatment of multiple brain metastases. Int J Radiat Oncol Biol Phys 76:296–302.
Mayo CS, Yao J, Eisbruch A et al. (2017) Incorporating big data into treatment plan evaluation: Development of statistical DVH metrics and visualization dashboards, Advances in Radiation.

Women’s Experiences of Gynaecological Consultations – Uncovering Its Technological Toolboxes: Challenges in a Brazilian context

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DOI: 10.31038/AWHC.2018111

Abstract

Historically, the medical definition of women as an object of biomedical knowledge has restricted the way by which gynecology is understood. In Brazil’s Unified Health System (Sistema Unificado de Saúde – SUS, in Portuguese), it is the responsibility of gynaecological care services to identify, diagnose and treat reproductive related conditions. However, gynaecological consultations are based predominantly on a medicalised model of diagnosis, treatment and disease management which often fails to address the wider determinants of women’s reproductive health and its impact on their general health and life chances. This paper is focused on the way the Brazilian health system has responded to women’s health needs in gynaecological consultations, given its central role in maintaining and promoting women’s health. it explores variations between “what should be” and “what is” offered to Brazilian women in gynaecological consultations. The authors argue that while gynaecological consultations in Brazil (and elsewhere) are currently restricted to programmatic targets, complaints and symptoms associated with sexual and reproductive functions; consultations could be used to respond to women’s needs, using a broader life course approach if a combination of health technologies ‘toolboxes’ are employed. Implementation of care services utilising a ‘toolbox’ approach provides an opportunity to truly follow the principle of ‘integrality’, one of the doctrinal principles of the Brazilian health system, which furthermore could have application in women’s health care services elsewhere.

Keywords

Gynaecology, women’s health, integrality, health toolboxes

Introduction

Over the last three decades demographic changes, lifestyle and environmental factors have brought about profound changes in morbidity and mortality profiles worldwide. This epidemiological transition has been marked by a decrease in the rates of infectious diseases and a raise in the occurrence of non-comunicable diseases. In such a scenario, scientific developments and associated increases in the availability of diagnosis tools and treatment have not been able to completely eradicate the global burden non-communicable diseases such as cancer, which remains among the most common cause of death, especially in low and middle-income countries [1]. The WHO report that cancer is the second leading cause of death globally, and was responsible for 8. 8 million deaths in 2015. Globally, with approximately 70% of deaths from cancer occuring in low- and middle-income countries (World Health Organization 2018).

In relation to women’s cancers population-based interventions can be largely effective in reducing the impact of cervical and breast cancer on women`s morbidity and mortality, however, rates have continued to rise in the past 30 years [2]. Globally, breast cancer is the most frequently diagnosed cancer and the leading cause of cancer death among women, accounting for 23% of the total cancer cases and 14% of the cancer deaths [3]. With approximately 530 000 new cases per year worldwide, cervical cancer is the fourth most common type of cancer among women, being responsible for the death of 265 thousand women per year [2].

Women`s health is a Brazilian government priority [4]. Breast and cervical cancer, together with contraception, sexually transmitted diseases and AIDS, maternal health, abortion, chronic diseases, domestic violence, are all categorized in the Brazilian public health agenda as concerning to “women`s health” [5]. Even though there is recognition of the importance of this range of problems, programmatic actions are focused on reproduction with interventions across the ‘reproductive cycle’ from gynaecological to maternal care. Gynaecological services in Brazil are the only part of the system specifically directed towards responding to women’s health needs as maternal care includes also care for the baby. It is therefore, in gynaecological services, which are identified as the main provision, responsible for providing health care to women, that they should find responses to their needs.

The term “gynecology”, has its origin in the Greek roots “gyneco” meaning “woman”, and “logia” meaning “study”, so gynecology literally is the study of women. Despite the broaden scope of its literal meaning, historically, the medical definition of women as an object of biomedical knowledge has restricted the way by which gynecology is understood as something strictly concerning reproductive related conditions [6].

In Brazil’s Unified Health System (Sistema Unificado de Saúde – SUS, in Portuguese), it is the responsibility of gynaecological care services to identify, diagnose and treat reproductive related conditions, like cervical and breast cancer and sexually transmitted diseases, as well as provide guidance on reproductive planning [7–9]. To meet these aims the system relies on gynaecological consultations delivered by primary care services based predominantly on a medicalised model of diagnosis, treatment and disease management. This approach often fails to address the wider determinants of women’s reproductive health and its impact on their general health and life chances. There is the need therefore, as stressed by The WHO, to address women’s health comprehensively in order to extend the agenda beyond reproduction and provide care to new women’s health related problems, like the chronic diseases. The approach to be taken would be one that considered women’s health as a continuum during her life course with lifechances and health impacted by social determinants as well as availability of medical care [2].

This paper is focused on the way the Brazilian health system has responded to women’s health needs in gynaecological consultations, given its central role in maintaining and promoting women’s health. Exploring how gynaecological care has been delivered in Brazil, this paper will contribute to analyses of variations between “what should be” and “what is” offered to Brazilian women in gynaecological consultations.

The authors argue that while currently gynaecological consultations in Brazil are restricted to programmatic targets, complaints and symptoms associated with sexual and reproductive functions; they still have potential to respond comprehensively to women’s needs, depending on the combination of health technologies being employed. We point out that such potential could be achieved through implementation of care services that truly follow the principle of ‘integrality’, one of the doctrinal principles of the Brazilian health system.

The paper begins by describing the Brazilian context, with regard to the organization of the health system and epidemiological data. It goes on to present the discussion standpoints taking into account the proposal of an enlargement of the boundaries of the healthcare offered in gynaecological consultations. Health as a positive resource, rather than simply treatment of illness is the theoretical standpoint which underpins this paper. The relevance of this to the practice of health professionals, in particular of nurses is used as a reference point to explore the issues raised.

Overview of the Brazilian Health System and Primary Care Services

Brazil is the fifth largest country in the world with a population of over 200 million people in 2016 (www. statistica. com 2018). Despite the challenges represented by regional diversities and social inequalities Brazil has experienced increasing economic development, [10, 11] In addition, the past ten years has seen changes in the country’s demographic profile with an age range weighted more towards adults and elderly rather than children [12]. In Brazil, as elsewhere, economic growth has been accompanied by a reduction in the rates of infectious diseases and a need to prioritize the care for non-communicable diseases in an ageing population [12].

The last few decades have seen important improvements in the health status of the Brazilian population, which can be ascribed to initiatives resulting in positive changes in the social determinants of health. A radical institutional change in the Brazilian health system with the offering of universal and free access to health care services was one of the changes associated with those improvements [13, 14]. Although the public services can be accessed by everyone, it is mostly used by people on lower [13].

In 1988, after a period of nearly 20 years of military dictatorship, a new federal constitution was promulgated, starting a period of redemocratisation of the country. For the first time in Brazilian history a constitution established that health was a citizen’s right and a governments’ duty. In 1989, a national health system funded by taxes and social contributions – unique in Latin America – was established, guaranteeing equal and free access to health care at primary, secondary and tertiary level [14]. Since then, the SUS has represented a landmark in the overcoming of health inequities, although the old public health problems have not been eliminated yet and new ones, like the rise of non-communicable diseases, have been adding pressure to the system [13, 14].

The system is organized on the basis of the following doctrinal principles: universality, integrality, equity and social control. It foresees the delivery of healthcare according to levels of complexity (primary, secondary and tertiary), through a network of integrated services coordinated by federal, state and municipal government. It works on the basis of decentralization and regionalization processes, with priority given to prevention [4, 13]. The National Policy of Basic Attention (in Portuguese, Política Nacional de Atenção Básica), which establishes the guidelines for actions in primary care, highlights its importance as the main gateway and communication center with the whole healthcare network. The Policy stresses that it is therefore essential to take universality, integrality of attention, equity and social participation as the actions orienting principles [15].

Primary care has been key to the expansion of access to health services. It is the entry level of the Health System. It is responsible for providing universal and comprehensive care and coordinates the flow and continuity of care by referring service users to other levels of care, like specialist services and hospital care [11]. It has also been important in the implementation of intersectorial actions for health promotion and disease prevention [10].

The Brazilian primary care network is constituted by two principal sets of services: Basic Health Units and Family Health Clinics. Although both work with overlapping care offers, much attention has been given to the expansion of the Family Health Program (in Portuguese, Programa de Saúde da Família – PSF) coverage. The Program was created to organize the decentralization process from federal to municipal healthcare management. The relevance of the PSF to the system lies on its importance for the restructuration of municipal health systems and reorganization of primary care. It is focused on family and community health, targets to be met by the work of family care teams composed by a minimum of one doctor, one nurse, one auxiliary nurse, oral health professionals and community health agents (who live in the same community of the service users) [15] . Each team works in a specific geographic area and with its respective population, which facilitates the effectiveness of the actions and the potential of the services to understand and respond to the users` needs.

Women’s Health in the Brazilian Context

In 1989, a health reform introduced new goals to the Brazilian context of women’s healthcare, taking into account a broadening perspective of women’s health with the intent of overcoming the traditional focus on reproduction. New health policies were created such as the National Program of Comprehensive Care to Women’s Health (Programa Nacional de Atenção Integral à Saúde da Mulher, PNAISM, in Portuguese). Despite the declared intentions and the development of some coherent actions, the definition of women as reproductive beings remains significantly influential in the care women receive. In addition, the restriction of women’s health to reproduction has not always included consideration of their general well-being [16].

The care offered to women in Brazil is commonly associated with the competence of women’s bodies to produce and maintain healthy babies [17, 18]. Pre-natal and post-natal care, breastfeeding check-outs and education are amongst the services provided. In this arena other issues, concerning women’s health and well-being, such as those associated with the menopause (post reproductive years) or conditions commonly experienced post menopausally like urinary incontinence, high blood pressure and cardiovascular diseases, remain neglected [2, 19].

As previously mentioned, in Brazil, the areas of focus for women’s health care are closely related to governmental programmatic goals which are aligned with epidemiological measures of incidence and prevalence. However, this emphasis raises a problem with regards to women’s health as not everything concerning the impact of health, womanhood and gynaecological conditions can be identified solely on the basis of objective and measurable data. Women’s health, reproductive system and gynaecological needs retain their close association with the cultural, sociological and psychological situation in which health and wellbeing are experienced and understood by the women themselves. It therefore follows that in a data driven, medically orientated environment, such as Brazilian health contexts, it would be unsurprising to find situations that impact on women’s health which would remain hidden.

For example, despite the universal and free access to health care and the government initiatives to promote preventive consciousness, the percentage of smear test beneficiaries is still very low, considering a coverage that does not exceed 8% of women aged over 20 years. This percentage is far short of the recommendations of the WHO, which recommends coverage of 85% of the female population at (World Health Organization 2015). Also, it has been observed that the majority of women undergoing a smear test are less than 35 years, suggesting that their access to prevention is related to their attendance at the health clinics in order to receive care for birth control [4, 20] .

The consequences of this situation in the Brazilian context can be seen in the case of cervical cancer. In 2012, the disease was the third highest cause of death from cancer among Brazilian women, representing a mortality rate adjusted to the world population of 4. 72 deaths for every 100 thousand women [20]. In the year 2014, 15. 590 new cases of cervical cancer were predicted, with an estimated risk of 15. 33 cases per 100. 000 women [20]. The estimated cervical cancer incidence rates and mortality in Brazil are in the ‘intermediate’ range compared to other countries with a similar GDP, but are high when compared to high-income countries with early detection well-structured programs [20]. This suggests that health and life chances in cervical cancer are not simply a question of the disease itself as a physical entity. This is further borne out by the fact that cervical cancer rates are highest in the poorest Brazilian regions, like the Northern territories where the incidence is 23. 6 cases per 100. 000 inhabitants compared with 10. 15 cases in the Southeast [20].

Early diagnosis and treatment has shown to be key strategies in the fight against the burden women’s cancers such as breast and cervical cancer (World Health Organization 2015). In both cases, the success of the interventions depends not only on the quality of specific primary care offers – screening and first access to treatment – but also on the competence of the health system to intervene in the social and cultural determinants of health which are largely linked to equity and social justice [2, 12, 13, 21].

Breast and cervical screening and treatments are provided through gynaecological services, part of the primary care services in Brazil. In relation to breast cancer; self-examination, clinical breast examination and mammography screening are the main strategies used to reduce breast cancer mortality rates [21, 22]. While for cervical cancer, reduction in mortality and morbidity follows the WHO recommendations (World Health Organization 2015) in providing periodical cytological screening, cervix examination after applying acetic acid, vaccination of girls against the Human Papilloma Virus (HPV) infection and treatment for precancerous lesions or invasive cancer. These actions are among the interventions that have been currently put in place by the Ministry of Health.

The highly medicalised approach used in both breast and cervical cancer care illustrates how the prioritized intervention strategies for women’s health in Brazil, rely on scientific and technological knowledge to provide for all care needs. The services provided are therefore based on two assumptions; the professionals’ competence to make use of the available technical tools to identify and ‘treat’ women’s conditions and the government’s commitment to provide the services necessary for those needed conditions [23, 24].

Meeting the Challenge of Women’s Health Integrality in Gynaecological Consultations

We propose a broader interpretation of “gynaecological consultations” in Brazil, beyond the focus on pathology and its biomedical origins. This interpretation puts forward a notion that gynaecological consultation should encompass more than a pathological focus and related issues, such as clinical diagnosis and treatment. Instead, we propose an expansion of its traditional conceptualization in Brazil to include cultural, social and personal aspects of care. This proposed concept is anchored in an amplified notion of health (taking into account social, religious, economic, racial and gender issues, etc. ), in line with the assumptions of health promotion and the meanings of integral health. Those assumptions are also highlighted in the National Program of Comprehensive Care to Women’s Health [4]. By going beyond the usual, predominantly focused on women’s diseases and the biology of the reproductive system, this new conceptualization of gynaecological consultation allows for the opening of other possibilities to meet women’s needs.

Adopting this perspective we define “gynaecological consultation” as an interactive encounter between at least one health professional and one woman, which is carried out with the aim of understanding and meeting this woman’s health care needs. Such needs are to be assessed not only considering the demands posed by health policies and programs but also by valuing more personal demands that can possibly be hidden behind usual programmatic priorities.

In addition to physical examination, medical history and conducting smear tests, there are other components that should equally constitute gynaecological consultations. These components include listening, dialogue, and bond development, discussion to promote ways of addressing problems, etc. These act as key health practices as well as products of the caring relationship. Adopting this approach requires a change in the Brazilian tradition of predetermined medicalized definitions to establish in advance of consultations, the actions and expected outcomes of each gynaecological consultation.

Integrality, rights and responsibilities

Our argument for a change on the way women’s health needs are addressed in gynecological consultations is based on two theoretical constructs. The first is integrality, a central principle of the Brazilian health system. Although it has been pointed out in the literature that “integrality” cannot be defined absolutely, mainly because it can incorporate multiple meanings, some authors have argued that it can be seen as an ethical value [25, 26, 27].

Considered as a value, integrality embodies the idea of health as a right and health needs as marked by a high level of subjectivity, unpredictability and complexity (Pinheiro et al. 2012). The right is not only envisioned in the right of access to health services, but also refers to a person’s set of rights as a whole. Taking into account its legitimacy as constituent of the operational logic of the Brazilian health system, integrality shall be the orienting line for all the actions undertaken in health services. In that sense, health policies/programs and the derived actions should be aimed at guaranteeing the rights of people living with certain diseases to the assistance they need as well as the rights of those without the disease, to benefit from preventative actions [26]. As a driving force of the system, integrality requires that healthcare includes more than simply actions to reduce the burden of diseases in terms of suffering, risk of death or possible complications. Healthcare integrality demands the broadening of the assistance response by providing a broad range of support for the people so that, despite the disease, they can have the best life possible.

Integrality is taken here as an image-aim or an idea-force, as something to fight for. It is not the same as utopia, which in essence describes an ideal that may never be reached. Integrality, in contrast, encompasses a goal believed to become real in the future. It is personally and contextually determined within the ‘lived experience’ of the individual. In that sense, to propose an image-aim implies to make a distinction of what one wants to achieve from what already exists, based on a critique of the present reality [26].

The link between integrality and prevention is similar. One cannot prevent a disease by simply measuring and investigating it as an entity in isolation from human experience. There are a number of issues to be taken into consideration in the planning and implementation of diseases preventive strategies. These are not necessarily limited to the disease itself, but may impact on an individual’s ability to take advantage of the preventative or assistance actions available (Oliveira 2011, Victora et al 2011, Rossetto & Oliveira 2013, Blanchard et al. 2013, [16] . For example; a Brazilian housewife with a diagnosis of a lump in her breast was referred to a specialist service to undergo a mammography. The service was located far away from the place she lived and as the local services did not have mammography equipment she would need to travel to another city taking with her three children. The health professional who diagnosed the lump did not ask if she had any difficulty to attend the mammography appointment. He focused only on the physical breast examination and completion of the paperwork. In the end, the woman could not take up the referral in order to benefit from the care offered, risking her life, hence the well-being of herself and possibly future welfare of her children.

In order to make the most of the care available in gynecological consultations, the encounter between the professional and the service user must be guided by what we call an “amplified hearing” (Pinheiro et al. 2012). This requires the caregiver to facilitate within the consultation an environment which supports open dialogue with the woman, integrating the physical diagnosis and possible treatment or management options within the context of her wider needs.

It is important to highlight that, in such perspective; women should not be treated as a group but as individuals, a position that may have the potential to reconfigure their relation (as users) with the system, in the sense of defining the healthcare trajectory in particular terms. The care offers available to women in primary care settings are, usually, formatted according to specific programmatic goals limiting the practice to a restricted frame of morbidity and restricting the assistance to women’s health needs.

One cannot dispute the value of public health policies and programs focused on the control of certain epidemiologically relevant diseases, like cervix and breast cancers. The critique is that little attention has been given by them to women’s singularities, either in preventive or clinical assistance. The importance of epidemiology for the definition of public health targets has led women to be valued less for its unique demands and most particularly by its representation as a group with a certain “epidemiological profile” [16, 28].

Good quality relationship user-professional is essential for integrality oriented actions (Pinheiro et al. 2012) missed. Gynecological consultations guided by open conversations, can give woman the opportunity to express concerns or difficulties regarding sexual life, which are not necessarily definably as a clinical issue but may be equally a health need. Integrality in a gynecological consultation may illuminate situations of gender power imbalance, domestic and sexual violence, infertility, sexual pleasure or unpleasant sexual relations, reproductive rights, for example. Integrality opens a space to discuss a woman’s unique requirements, challenging the practice of configuring in advance the limits of the care to be offered.

‘technologies’, toolboxes and women’s health

The second construct which supports our discussion is the notion of ‘health technologies’ based on the work of Emerson Merhy and colleagues [29]. The authors draw on Marx’s theorization about “living and dead labor” and the understanding that labor is configured not only in terms of its operative dimension (as an activity), but as a praxis, which in its turn gives meaning to the work [30]. Human production activities are therefore undertaken through a mental construction of the product to be made, which precedes the work process itself. All products used in the production process, which are results of a previous human work, are called dead labor. Living labor is a process that makes use of the products of dead labor in a creative work, which ends up in the manufacture of a new product [29, 30].

‘Health technologies’ here does not only refer to the equipment or instruments needed in the delivery of particular health services, like in gynaecological consultations. It also encompasses technological knowledge, professional experience and components of the work process which combine to inform professional decision making [31]. The notion of “health technologies” has at its center a critique of the objectification of the healthcare subject – the transformation of the person into an object of the clinic -, which may be viewed as a product of the fragmentation and medicalization of the biological body [31, 32] . Life and its experiences are not only the result of the functioning of body parts, either taken individually or as a certain biological system. There are other elements and interactions involved in the processes of life production. As pointed out before, many of them have been neglected in gynaecological consultations when it comes to prevention or treatment of what may initially be seen as a physiological problem, reducing the actions potential to optimise women’s health and wellbeing.

Health technologies are constituents of technological toolboxes, which are brought by health professionals to their encounters with service users. At least three toolboxes are present in such context: toolbox of “hard technologies”, of “soft-hard technologies” and of “soft technologies” [29, 31]. Next, following the ideas of Merhy et al. (1997) and Merhy and Feuerwerker [29, 31], we take the notion of “technological toolbox” as applied to the care model of traditional gynaecological consultation undertaken in Brazilian primary care services.

The toolbox constituted by “hard technologies” allows for the health professional to make use of machines or equipments to carry out physical, laboratorial and imaging examination. In traditional gynaecological consultations this toolbox would include the speculum, the microscope, or other equipments used to examine, access physical information, perform laboratorial and imaging examination. Those tools made possible the development of a clinical reasoning and, in certain cases, to define therapeutical interventions. Such processes consume the dead labor (of the machines) and the living labor of their operators.

The second toolbox is based on the particular professional role of the caregiver, in the traditional gynecological consultations offered in primary care services, a position assumed by doctors or nurses. Such role guides the health professional’s way of understanding and approaching the woman’s gynaecological needs. While it may be based on professional knowledge about what are those needs and how to respond to them, there may always be a degree of tension generated by the professional’s uncertainty in the definition of “what to do”. It is through professional experience in clinical situations that the professional begins to develop the links between these first two boxes. Toolbox two therefore combines ‘hard’ tools and reflexive exercises through which the caregiver develops a professional reasoning. It is therefore conceptualized as constituted by “soft-hard technologies” [29, 31].

The third toolbox is constituted by tools that allow the professional to get a more accurate perception of the particular situation of the woman to be cared for. Her social and cultural context, experiences and values, support network, are all important aspects to be accessed in order to understand her singularities. To do that, interactive tools are to be used, like listening, developing a bond, getting to know the woman’s expectations and requests, familiarization with possible impacts of a certain condition and treatment regime to her life, are some tools that may facilitate the dialogue with that person and with her needs. These ‘tools’ enrich and broaden the professional’s clinical reasoning and, at the same time, increase the opportunities for the woman to be an active participant in such encounter. Those tools contained in toolboxes three are called “soft-technologies” [29, 31].

The configuration of models of health care depends on the way those three kinds of technologies are combined [31]. During the gynecological consultation, for example, the health professional embarks on a mediation process between approved procedures/test related to the symptoms presented in each case, their professional knowledge and the singularity of each woman’s experiences before deciding the best approach to take.

Final Reflections

This paper presents a reflexive standpoint to help guide thinking about how women’s health needs could be addressed in Brazil. The decision to develop this reflexive paper arises from our belief that there is much to be gained from examining health technologies’ potential for integrality in gynaecological consultations in Brazil, where women’s individual needs are not commonly considered, is problematic. In addition, while focused on the Brazilian context, gynaecological consultations are not unique to this country and exist in some form in most countries. The concept of integrality and the use of ‘toolboxes’ in gynaecological consultations therefore has potential benefits to improving the effectiveness of such consultations for women in other countries.

In the way we conceptualize it, a gynaecological consultation should be guided by an integrated approach combining what are known as ‘soft’ and ‘hard’ technologies. This requires an acceptance of the importance of a range of skills involving more than the prioritized use of equipment and procedures. From this standpoint, any professional decision in relation to gynaecological care will acquire a degree of individualised meaning and negotiated management, actions that make sense in the particular situation of each woman.

To expand the definition of Brazilian gynaecological consultations in such a way would require consideration of the possibility of expanding its structural limits, e. g. , to accept that it may include actions and procedures of different professionals, depending on the nature of the woman`s health needs. In such perspective the healthcare offered by gynaecological consultations to Brazilian women will be the result of the articulation of a network of health services on a continuous basis, considered the needs expressed by each woman`s request to the services. It will be set by particular therapeutic projects, and therefore will count on a health services network that has flexible configurations and is centred on the needs of the women requiring care.

The WHO classical definition of health puts forward a positive view of health as a state of well-being, not merely an absence of disease [33]. This infers that even when services are focused on treating illness, promoting future health cannot be achieved by limiting care to pathology identification, diagnosis and treatment [34–37]. In addition, as care is also delivered during consultative interactions between women and their health caregiver, it is unlikely that, considering only technical knowledge of health care professionals will be sufficient to also address the subjective and diverse needs of the women involved.

In the current Brazilian context gynaecological consultations do not usually have the necessary scope for the promotion of women’s health, with priority given to complaints and symptoms associated with sexual and reproductive functions. In such context other possible health needs are disregarded, such as the ones related to contextual factors (social, relational and affective, for example) that impact upon their health. Along with smear test procedures, breast examination and the diagnosis of sexually transmitted infections, for example, gynaecological consultations should take into consideration other important health related issues like access to health care offers, the possibility to exercise self-care and make informed decisions related to personal health, and so on. These are all aspects of women’s health that should be valued in such encounters [23].

In addition to their diagnostic purposes, the smear test and breast examination may provide opportunities for establishing dialogue, connection and affirmation of women’s sexual and reproductive rights. By taking into account social determinants of health, gender perspectives and valuing women’s decisions regarding sexual and reproductive health, the health professional may optimise the health promotion potential of each consultation. This has the potential to bring about important changes in the way women’s healthcare is provided in Brazilian primary health care settings. This in turn could contribute to maximizing women’s wellbeing while contributing to a reduction in women’s morbidity and mortality.

Even when the theoretical background suggests that this possibility exists (and we believe that), to actual see that potential in Brazil; will depend on professionals’ capacity to be open to other ways of configuring healthcare. To successfully engage with possibilities of change in women’s services, Brazilian health professionals and service providers need to be supported to overcome “taken for granted’ assumptions of how health care, in this case gynaecological consultations, are provided. This paper is the first stage in challenging those assumptions of what is “natural” in such consultations. Without presenting this ‘alternative’ view of reality of women’s healthcare in Brazil there will be little chance of successfully achieving our aim of identifying and exploring factors that may facilitate changes in policy or processes to support the practice of integrality. The reflections developed here, may help health professionals to begin to visualize a more individualized approach to women’s health and the associated combinations of health technologies that make up the toolboxes used in the consultations.

Acknowledgements: The authors would like to thank Capes (Coordination for the Improvement of Higher Education Personnel), a Foundation affiliated with the Ministry of Education of Brazil, for the grant awarded to one of them as a Visiting Scholar at the University of Wolverhampton, UK (Proc. BEX 1793/14–4).

Conflict of interest: No conflict of interest has been declared by the authors.

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The Use of Ultrasound in Detecting Urogenital Schistosomiasis

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DOI: 10.31038/UGFM.2018112

Commentary

Scientists have been interested in the interior of the human body for millennia. Effectively, the history of ancient anatomy [1] shows that: (i) in Egypt, the study of this science began at least as early as 1600 BC, the date of “Edwin Smith Surgical Papyrus” where kidneys, uterus and bladder, amongst others, were recognized, and that the blood vessels were known to emanate from the heart [1]; (ii) the first use of human cadavers for anatomical research occurred later in the 4th Century BCE, when Herophilos and Erasistratus gained permission to perform live dissections, or vivisections, on : criminals in Alexandria under the auspices of the Ptolemaic Dynasty. Herophilos was the first physician to dissect human bodies and he is considered to be the founder of Anatomy. With the passage of time, new technologies were being created in different scientific disciplines and were also used in other areas. An example is Sonography: (i) in 1942, the neurologist Karl Dussik was credited with the first use of sonography for medical diagnosis; (ii) in 1949–1951, Douglas Howry and Joseph Holmes, from the University of Colorado, were some of the leading pioneers of B-mode ultrasound equipment, including the 2D B-mode linear compound scanner, and John Reid and John Wild invented a hand-held B- mode device to detected breast tumors; (iii) in 1958, Ian Donald incorporated this in the obstetrics and gynaecology field of medicine; (iv) in the 1970s many developments occurred, including the continuous wave Doppler spectral and color Doppler ultrasound instruments; (v) in the 1980s, K. Baba of the University of Tokyo developed 3D ultrasound technology and captured three- dimensional images of a fetus in 1986; (vi) in the 1990s, starting in 1980s ultrasound technology became more sophisticated with improved image quality and 3 D imaging capabilities These improvements continued into the 1990s with the adaption of 4 D (real time) capabilities. Ultrasound guided biopsies (endoscopic ultrasounds) also began in the 1990s; (vii) in the 2000s, the medical ultrasound technologies are continuously evolving.

Another article [2] on “the history of sonographers” related also that since the early days of medicine, there has been a great desire to “see” inside the body. This is what drove Roentgen to develop X rays in 1895, Helmholtz the ophthalmoscope in 1851, Garcia the laryngoscope in 1854, and Nitze the cystoscope in 1876.

Sound was first applied to the human body through auscultation in 1761 and the stethoscope in 1819, and interpreting these sounds required imagination, as did interpreting the early sonographic images.

On sonography in obstetrics and gynaecology [3], commented that the history of sonography and gynaecology dates from the classic 1958 Lancet paper of Ian Donald and his team from Glasgow. On the other hand, fifty years on it is impossible to conceive of practicing obstetrics and gyanaecology without one of the many forms of ultrasound available today.

Concerning sonographers, the need of educate and elevate the level of competency was discussed as early as 1969 by those who founded the American society ASUTS. The society needed to establish a credentialing method, thus an Examination Committee was formed, which in 1975 became the American Registry of Diagnostic Medical Sonoygraphers (ARDMS). The work of these two key Committees would become the centerpiece of activities for many years [4].

As to urogenital schistosomiasis, which etiological agent is the digenetic trematode Schistosoma haematobium, that is recorded in Africa, the Middle East, and in Corsica (France) [5]. S. haematobium had been recorded in Portugal, with several foci occurring in the Algarve – southern Portugal [6,7] and more recently, the record of a new locality for intermediate hosts of S. haematobium underlines the risk of expansion of this parasite in the European continent [8, 9]. The adults, female and male, are elongated and superficially resemble roundworms, what is an adaptation to their habitat – inside blood vessels, and oviposition normally occurs in around the vesical plexus, and occasionally in the rectal region, the mesenteric portal system and ectopic sites. The eggs have a shell within prominent terminal spine, that is responsible by haematuria observed in the patients, and the its presence in the different part of the body results in a variety of lesions [10] In 1996 and 2000 [11, 12] considering the importance of the ultrasonography, were published practical guides to the standardized use of schistosomiasis for assessment schistosomiasis related morbidity. More recently in [13] the authors review the use of ultrasound to assess the morbidity due to schistosomiasis with emphasis one easy, quick and reproducible ways that can be used in the field.

Here we go give three examples of the use of ultrasounds in studies on urogenital schistosomiasis in Angolan people:

In a study [14] of primary sterility in Angolan women which biopsy of the bladder wall had revealed calcified S. haematobium ova, the ultrasonographic study showed bilateral upper urinary track obstruction, and hypertrophy and irregularity of the bladder wall.
In a study [15], in an Angolan patient which prostatic gland biopsy shows calcified eggs of S haematobium, the prostate ultrasonography shows a heterogeneous structure with an irregular and nodular capsule.
In a study [16] carried out in 104 Angolan patients, the ultrasonographic examination showed urinary changes, namely hyperechogenicitis of the bladder wall (in 55.8%), bladder masses (in 23.1%), and upper urinary tract obstruction (in 54.8%).

In conclusion, it is demonstrated that urogenital schistosomiasis is a serious problem in the human health, as much as in its normal and ectopic localizations. Then, to avoid or at least to attenuate this situation it is necessary: (1) that urogenital schistosomiasis is included in the group of priority disease to be controlled and in training of people in the health services, concerning its diagnostic and treatment; (2) health education programs have to implemented with the objective of to explain the population on the conducts to adopt for avoid the infection by S haematobium; (3) that the diagnostic is made in the first time of the infection; (4) the use of ultrasonography in the diagnostic of schistosomiasis have to implemented in all health services (hospitals, health centers, etc).

Finally, according to [17] “ultrasonography is a major imaging tool in the diagnosis of schistosomiasis. Its ability to provide direct information about lesions in target organs, their pattern and regression, after treatment makes it a valuable imaging modality. Most importantly, it is inexpensive, non- invasive, radiation-free and portable”.

References

Ancient Anatomy. Wikipedia en. Wikipedia.org.
Baker JP (2015) The history of sonographers. Journal of Ultrasound in Medicina, Wiley online Library, 2015
Campbell S (2013) A short history of sonography in obstetrics and gynaecology. Facts Views Vis Obgyn 5: 213–229. [crossref]
Baker JP (1995) The society of diagnostic medical sonographers. Focus on the future. The history of SDMS! First 25 years. Philadelphia, PA: Lippincott-Raven.
WHO. Schistosomiasis WWW.who.int 20 February 2018
Azevedo JF de, Silva JB de, Coito AM, Coelho MF, Colaço A (1948) O foco português de schistosomiase. Anais Inst. Med. Trop. Lisboa 5: 275–222.
Grácio MA (1983) Distribution and habitats do six species of freshwater pulmonate snails in Algarve, southern Portugal. Malacological Review 16: 27–23.
Grácio MA, Richter J (2015) Risk of expansion of Schistosoma haematobium in Europe. XIX SOCEPA- II Encuentro International de Parasitólogos de España, Francia, Italia, Portugal – Vitória, Gasteiz.
Dana, EO, Garcia-de-Lomss J, Juan Baños JL et al. (2015) New location for Bulinus truncatus (Audouin, 1827. Gastropoda: Planorbidae) in Iberian Peninsula. Graelllsia, 71: e030, Julio-Deciembre. ISSN-L: 0367–5041.
Eddington GM, Nwabuelo I, Junaid TA (1975) The.pathology of schistosomiasis in Ibadan Nigeria with special reference to the appendix, brain, pancreas and genital organs.Trans, R Soc trop Med Hyg 69: 153–156.
Richter J et al. Practical Guide to the Standardized use of Ultrasonography for assessment of schistosomiasis related morbidity. TDR/ STR/ SCH/ 001: 49 pgs.
WHO (2000) Ultrasound in schistosomiasis. A practical guide to the standardized use of ultrasonography for assessment of schistosomiasis related morbidity.
Richter J, Botelho MC, Holtfreter MC, Akpata R, El Scheich T, et al. (2016) Ultrasound assessment of schistosomiasis. Z Gastroenterol 54: 653–660. [crossref]
Figueiredo J, Richter J, Belo S, Grácio MA (2013) Urogenital schistosomiasis presenting genital and urinary tract lesions and abdominal discomfort in a sterile Angolan woman. J Genit Syst Disor 2: 1–4.
Figueiredo J, Richter J, Borja N, Balaca A, Costa S, Belo S, Grácio MA (2014) Prostate adenocarcinoma associated with prostatic infection due to S. haematobium. Case report and systematic review. Parasitol Rev 114: 351–358.
Figueiredo J, Videira M, Guilherme M, Nilo B, Grácio MA, Richter J, Belo S (2013) Urinary tract morbidity due to S haematobium in patients attending Américo Boavida hospital, Luanda , Angola. Trop Med Int Health 18: abstract 190
Sah VK, Min LW, Ragiv R, Zhaoyan F et al. (2015) Human schistosomiasis: a diagnostic focused review of a neglected disease. Radiology of Infectious Diseases: 150–157

The correlation of follicular fluid Anti Mullerian Hormone (AMH) and follicular fluid soluble receptor of Advanced Glycation End products (sRAGEs) with IVF outcome, in women with Polycystic Ovarian Syndrome

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DOI: 10.31038/IGOJ.2018122

Abstract

Aim: The aim of this study was to investigate the association between follicular fluid (FF) AMH and follicular fluid (FF) soluble receptor of Advanced Glycation End products (sRAGEs) in women with Polycystic Ovarian Syndrome (PCOS) regarding IVF outcome parameters.

Methods: FF AMH, serum AMH and FF sRAGEs were measured in 49 women undergoing IVF in the IVF Department of University Hospital of Alexandroupolis from December 2014 to May 2015. Women were divided in two groups, the PCOS women and the non PCOS women (Group A 38 non PCOS women and Group B 12 PCOS women). FF AMH, serum AMH and FF sRAGE values of Group A were compared to those of group B. The correlation of these values with IVF outcome parameters was investigated in both groups.

Results: We did not find a correlation among the factors studied (serum AMH, FF AMH and FF sRAGES). FF sRAGE levels were found to be higher in PCOS women (p-value <0,01). No correlation of FF sRAGE concentration and number of oocytes retrieved during IVF or number of embryos was noted in PCOS women. FF sRAGE levels were only found to be negatively correlated with the quality of the oocytes retrieved in non PCOS women (r= -0.484, p-value= 0.003). The higher the FF sRAGE concentration, the lower the quality of the oocytes was found to be. A negative correlation was also noted between FF sRAGE levels and BMI in non PCOS women (r= -0.401, p-value=0.014).

Conclusion: These findings support that FF sRAGEs could not be used combined with AMH measurements (serum and FF) to predict IVF outcome but could be used separately and only in non PCOS women.

Keywords

AMH, oxidative stress, sRAGEs, PCOS, ovarian reserve, IVF outcome

Introduction

Firstly described in 1935 by Stein Leventhal 1], Polycystic Ovary Syndrome (PCOS), is the most common endocrine disorder among reproductive-aged women and the main cause of female infertility due to anovulation, affecting the 19,9 % of Caucasian women under the Rotterdam criteria [2]. It is, therefore, understood that determining ovarian reserve- the quality and quantity of ovarian follicles at a given point in time and being able to predict total IVF outcome in women with PCOS is of great importance in Assisted Reproduction Technology (ART) [3].

Ovarian reserve markers

Up to date, many markers including FSH, estradiol, inhibin B, anti-Müllerian hormone (AMH), the antral follicle count (AFC), the ovarian volume (OVVOL) and the ovarian blood flow, have been studied and proposed as ovarian reserve markers [3].

Among them, the use of AMH seems to be widely accepted and has gained value in everyday clinical practice. AMH is a member of TGF-b glycoprotein superfamily, mainly expressed in granulosa cells of growing antral and pre-antral follicles in the gonadotropin independent phase [4]. AMH inhibits follicle sensitivity to follicle-stimulating hormone (FSH) and therefore affects follicular growth [5]. In clinical practice, AMH has been found to have high specificity and sensitivity in predicting ovarian response to Controlled Ovarian Stimulation (COS). Positive correlation with oocyte retrieval, role in poor responders’ prediction and a relation with life birth rate after IVF have also been noted [6–9]. AMH declines during reproductive age from puberty to menopause until it is almost undetectable [10, 11]. The idea of age related ovarian reserve diminishment and subsequent decline of ovarian function and reproductive potential have led scientist to seek for ovarian aging markers that could be used in practice as ovarian reserve markers.

Oxidative stress and ovarian aging

It is known that aerobic organisms develop the ability to use oxygen to efficiently emit energy. The prevention of oxidation during this procedure is controlled by antioxidant defense mechanisms and is of great importance. Any imbalance of the available antioxidant mechanisms combined with uncontrolled oxidation of biomolecules, mainly by the reactive oxygen species (ROS), results in oxidative stress. Many types of molecules like nucleic acids, proteins, lipids and carbohydrates may be damaged by oxidative stress suggesting that proteins, membranes and carbohydrate complexes could be victims of oxidative stress resulting in unrepaired DNA damage, telomerase loss, altered proteins and lipid destruction. These catastrophic oxidative events accumulate with age, cause tissue damage and in humans plays a significant role in the pathophysiology of many pathological situations and diseases, including the age related ovarian quality and quantity decline [12,13]. Thus, oxidative stress has been proposed to be involved in the pathogenesis of infertility. ROS concentrations have been proposed by many researchers to affect negatively fertilization and implantation [14]. More recently, the Advanced Glycation End products (AGEs) have been proposed to get involved in ovarian function decline [15, 16].

Advanced Glycation end products (AGEs), are the products of one of the most important modifications that occurs after translation, the nonenzymatic glycation of proteins, lipids, and nucleic acids [17, 18]. AGEs may either cause the formation of cross links between key molecules in the basement membrane of the extracellular matrix (ECM) or act via binding to receptors. Two types of receptors have been described. The first one is the multi-ligand transmembrane receptor, the RAGE (receptor for advanced glycation end products), known as the inflammatory receptor [17, 18]. RAGEs are expressed by several cell types, like endothelium, smooth muscle cells and ovaries and their activation may lead to unfavorable cellular conditions like proinflammation, cellular toxicity, and cellular damage via activating nuclear factor-κB [19, 20]. The second receptor that has been described is the soluble RAGE (sRAGE). sRAGE is an extracellular form of RAGE, lacking the cytosolic and transmembrane domains. It is able to adverse intracellular effects AGEs can cause and therefore is known as anti-inflammatory receptor [17, 18].

Prolonged exposure to AGEs, during reproductive life, has been shown to be able to cause subtle oxidative damage to the follicles of the ovary by altering ovarian microenvironment. These changes in the ovarian microenvironment may have adverse effects on granulosa cells’ metabolism, in antioxidant defense, and the development of inadequate follicle vascularization with subsequent follicle hypoxia. Follicle health and maturation may be negatively affected and age related oocyte dysfunction events may occur [21]. Additionally, it has been found that ff sRAGE levels were higher in younger women than in advanced aged women undergoing IVF treatment [22].The idea that sRAGEs may have a protective role in these unfavorable events have led scientist to investigate the correlation of sRAGEs with ovarian reserve markers.

Ovarian reserve markers in PCOS

AMH levels in women with PCOS have been shown to be two to three times higher than in healthy controls and levels of AMH are on average 75 times higher in granulosa cells from PCOS ovaries, compared to levels in granulosa cells from normal ovaries because of the increased development of antral follicles compared to normal women [23,24]. Serum AMH has been shown to be a diagnostic marker of high specificity (92%) and sensitivity (67%) for PCOS [24].

Serum AGE levels and AGE-RAGE expression in theca and granulosa cells have been found to be higher in PCOS women than in healthy controls. This has been attributed to hyperglycemia, oxidative stress and insulin resistance in PCOS women [25, 26] and is linked to diminished ovarian reserve and abnormal folliculogenesis [27]. On the contrary, follicular fluid sRAGEs have been found to be lower in women with PCOS compared to non-PCOS women [28, 29].

It has been shown, in vitro, that the inappropriate prolonged activation of ERK1/2 path, which is critical for normal follicle growth and the beginning of ovulation, by AGEs via intervention in the action of LH, could be responsible for the impaired follicle growth and the subsequent ovulation dysfunction that characterizes PCOS women. Moreover, it is understood that AGEs accumulation in FF of PCOS women could lead to premature ovarian aging [30].

Methods & Materials

49 women from different regions of Greece, mainly from Thrace, who received IVF treatment in the IVF Department of University Hospital of Alexandroupolis from December 2014 to May 2015 were recruited for this study and were divided in two groups (Group A and Group B) . Group A consisted of 38 non PCOS women, while Group B of 12 PCOS women diagnosed under the Rotterdam criteria. Written consent was signed by all women.

Controlled Ovarian Stimulation (COS) was offered to all women, after preliminary control and appropriate COS protocol was chosen for each after study and evaluation of parameters like age, day 3 serum FSH, day 3 serum LH, serum AMH and others. During COS period all women were offered serial ultrasound examinations and serum Estradiol (E2) measurements in order to evaluate respond to stimulation. I.M b-HCG administration was decided when at least 3 of developing follicles reached diameter of 18 mm and oocyte retrieval (OR) was planned for 36 hours post. During OR, FF needed to measure AMH and s RAGEs was collected.

Follicular Fluid collection

During oocyte retrieval, follicular fluid was aspired and collected in tubes. The embryologist separated the oocytes in FF and placed them in a plate with culture substances. Meanwhile, FF was collected in a falcon and labeled with woman’s name. Following FF was centrifuged for 15 minutes in 3000 rpm, to remove any unnecessary element, like cumulus cells. After centrifugation was completed, supernatant serum was transferred to another falcon (labeled with woman’s name) and refrigerated in -70 degree of Celsius. This procedure was followed in all cases in order to collect the samples.

Moreover, in order to be able to distinguish PCOS from non PCOS samples, falcons were labeled with respective labels. Therefore, the samples of Groups A and B could easily be evaluated and compared. AMH and sRAGE measurements were carried out simultaneously by the same kit, special for each parameter. AMH was measured by Elisa method, according to kit’s manufacturer (Anshlab) instructions (UltraSensitive AMH/MIS ELISA AL-105-i). The kit Quantikine ELISA/ Human RAGE was used for the measurements for the FF sRAGE levels according to manufacturer’s instructions(R & D Systems).

Statistical Analysis

The IBM SPSS Statistics for Windows Program, Version 21.0. Released 2012, Armonk, NY: IBM Corp. was used for the statistical analysis in our study.

Demographic characteristics and clinical data of women recruited were evaluated by descriptive statistic methods. The ratio of MII oocytes to the total number of oocytes retrieved for each woman was defined as simple quantitative expression of Oocyte quality. We consider that this ratio adequately represents oocyte quality and were used as quantitative variable during analysis. T-test for independent variables was used to compare the quantitative variables between two groups while χ² test was used to compare the qualitative variables. Significance levels for both cases was set at 0, 05.

The concentrations of the parameters studied (serum and FF AMH, FF sRAGE) were calculated and presented as mean values ± standard deviation for each group separately. The comparison of these concentrations between the two groups was made by t-test for independent variables with significance level of 0.05.

In each group, quantitative variables were examined for possible monofactor linear correlation among them by the Pearson correlation coefficient r and the relative p-values. Multifactor linear regression was applied to whole sample, in order to study the correlation of ff sRAGE, ff AMH and serum AMH levels, taking into consideration women’s age, BMI and PCOS presence. The results of this multifactor analysis were expressed via βήτα coefficient (βήτα mean value± standard error) and the relative p-values. In the mono factor and in the multifactor analysis the significance level was of 0.05.

Results

In the beginning, we completed the above analysis between the two groups, including all qualitative and quantitative variables we had collected. The demographic and clinical characteristics of all women are presented in Table 1. Infertility in non PCOS women was attributed to tubal factor (21, 6%), to male factor (24, 3%), to premature ovarian failure (8, 1%), to other factors (8, 1%), to more than one factors (18, 9%) or was unknown (18, 9%). PCOS women presented in great percentage more than one infertility factors (50%). PCOS women had higher E₂levels when compared to non PCOS women, had more growing follicles during stimulation, more oocytes after OR. They also had more MII oocytes and more embryos available for embryo transfer (p-value <0, 05). There were no other statistical significant differences between the two groups in the clinical and laboratory characteristics studied.

Table 1. Demographic and clinical characteristics of 49 recruited women (12 PCOS and 37 non PCOS). Quantitative variables: mean value± standard deviation, comparison with t-test for independent samples. Quantitative variables: number of patients, percentage within parenthesis, comparison with χ² test. NS: statistically non significant, significance level 0.05.

Characteristics	PCOS women	Non-PCOS women	p- value
Age	34,0 ± 4,2	36,3 ± 5,5	NS
ΒΜΙ	22,8 ± 5,3	25,9 ± 4,7	NS
Day 3 FSH (mIU/ml)	6,8 ± 2,1	8,9 ± 3,6	NS
Day 3 LH (mIU/ml)	5,4± 2,1	5,27 ± 1,91	NS
Smoking (cigarettes/day)	5,0± 7,6	7,2 ± 8,8	NS
Alcohol (glasses/week)	0,41 ± 1,44	0,55 ± 1,96	NS
Total Gonadotrophin administrated for COS (IU’s)	2636 ± 2048	3600 ± 1191	NS
E2 during COS	3875 ± 2826	2200 ± 2197	0,04
Number of follicles	9,8 ± 2,8	7,4 ± 3,7	0,04
Serum AMH (ng/ml)	13,8 ± 22,7	4,6 ± 4,7	NS
Follicular fluid AMH (ng/ml)	3,1 ± 4,0	2,3 ± 2,1	NS
Follicular fluid sRAGE (pg/ml)	6237 ± 2784	4058 ± 1907	<0,01
Number of oocytes	12,0 ± 5,9	5,2 ± 3,7	<0,01
Number of MII oocytes	8,7 ± 5,2	3,5 ± 3,2	<0,01
Number of MII oocytes/ number of oocytes	0,76 ± 0,22	0,62 ± 0,32	NS
Number of embryos suitable for embryo transfer	6,1 ± 3,7	2,5 ± 2,3	<0,01
Infertility Factor
PCOS	6 (50%)
Tubal		8 (21, 6%)
Male		9 (24, 3%)
Premature ovarian insufficiency		3 (8, 1%)
Unknown		7 (18, 9%)
Other (Age, uterine abnormality, endometriosis)		3 (8, 1%)
Combined(more than one factor)	6 (50%)	7 (18, 9%)
Pituitary Suppression			NS
GnRH agonist	4 (33, 3%)	12 (32, 4%)
GnRH antagonist	4 (33, 3%)	19 (51, 4%)
Cumulus-oocyte complex quality			NS
Normal	9 (75%)	25 (67, 6%)
IMMCC, PMCC, POCC	3 (25%)	12 (32, 4%)
Fertilization method			NS
IVF	4 (33, 3%)	6 (16, 2%)
ICSI	7 (58, 3%)	26 (70, 3%)
IVF- ICSI	1 (8, 3%)	3 (8, 1%)
PREGNANCY			NS
βhCG (+)	3 (25%)	4 (10, 8%)
Other IVF outcome	9 (75%)	33 (89, 2%)
Total	12 (100%)	37 (100%)

Following, we made the below analysis and the graphic with the data of serum AMH, FF AMH and FF sRAGEs.

Serum AMH, FF AMH and FF sRAGEs levels of PCOS and non PCOS women are presented in Table 2 and in Figure 1. PCOS women were found to have higher FF sRAGE levels compared to non PCOS women (p-value <0, 01). On the contrary, the differences in serum and FF AMH levels were not found to be statistically significant between the two groups. Moreover, the deviation of the values (standard deviation) of the three factors studied is larger in PCOS women. This could be attributed to the small sample size (12 women) or could reflect the real heterogeneity of PCOS women, indeed.

Table 2. Serum AMH, FF AMH and FF sRAGE studied in 12 PCOS and in 27 non PCOS women. Mean values ± standard deviations are presented, comparison with t-test for independent samples. NS: statically non significant with significance value 0.05.

Factor	PCOS women	non PCOS women	p- value
Serum AMH (ng/ml)	13,8 ± 22,7	4,6 ± 4,7	NS
Follicular Fluid AMH (ng/ml)	3,1 ± 4,0	2,3 ± 2,1	NS
Follicular Fluid sRAGE (ng/ml)	6,2 ± 2,7	4,0 ± 1,9	<0,01

IGOJ 2018-108-Bachur Manav Greece_F1

Figure 1. AMH and sRAGEs concentrations studies in serum and FF of 12 PCOS and 37 non PCOS. Mean values with 95% confidential intervals are presented.

This data is presented in the graph below (Figure 1).

Additionally, a multifactor analysis, regarding the three variables was made. The results were as following:

The most significant results of the monofactor analysis are presented summarized in Table 3. In PCOS women serum AMH, ff AMH and FF sRAGE levels were not found to be correlated with the number of the oocytes retrieved, the number of MII oocytes, with the embryo number or the ratio of MII oocytes to the total number of the oocytes retrieved. Serum AMH but not ff AMH was found to be a better marker of ovarian response in non PCOS women because it was found to be correlated with the number of MII oocytes and the number of the embryos available for embryo transfer. Only in non PCOS women, ff sRAGE levels were found to be negatively correlated with the quality of the oocytes, as it is expressed in the above mentioned ratio (r= -0.484, p-value= 0.003). This correlation is the most important finding of our study and is presented as a graph in Figure 2. Specifically, elevated ff sRAGE concentrations have been found to lead to lower Oocyte quality in non PCOS women. In PCOS women a high degree linear correlation of serum AMH and ff AMH, something that is not seen in non PCOS women, is noted (r= 0,965, p-value <0.001) (Figure 3). Neither serum AMH, nor ff AMH was found to be correlated with ff sRAGE levels in the sample studied. Lastly, ff sRAGE was found to have a negative correlation with BMI in non PCOS women (r= -0.401, p-value=0.014, Figure 4).

IGOJ 2018-108-Bachur Manav Greece_F2

Figure 2. Graph of the correlation of number of MII oocytes/total Oocyte number with the concentration of ff sRAGE in 12 PCOS and 37 non PCOS women. Statistical significant correlation was noted only in non PCOS women (Pearson r = -0.484, p-value = 0.003).

IGOJ 2018-108-Bachur Manav Greece_F3

Figure 3. Graph of the correlation of serum AMH with ff AMH in 12 PCOS and in 37 non PCOS women. Statistical significant correlation only in PCOS women (Pearson r=0.965, p-value <0.001).

IGOJ 2018-108-Bachur Manav Greece_F4

Figure 4. Graph of the correlation of ff sRAGE with the BMI of 12 PCOS and 37 non PCOS women. Statistically significant correlation is noted only in non PCOS women (Pearson r = -0.484, p-value = 0.003).

Table 3. Results of correlation of serum AMH and FF AMH with oxidative stress factors (ff SRAGEs) and with other clinical and laboratory factors in 12 PCOS and in 37 non PCOS women. Mono factor linear correlation based on Pearson’s r. NS: statistically non significant with significance levels 0.05%.

Factor correlation	PCOS women		Non PCOS women
	Pearson r	p- value	Pearson r	p- value
Number of oocytes , serum AMH		NS	0,287	NS (0,08)
Number of oocytes, FF AMH		NS		NS
Number of oocytes , FF sRAGE		NS		NS
Number of MII oocytes, serum AMH		NS	0,413	0,011
Number of MII oocytes, FF AMH		NS		NS
Number of MII oocytes, FF sRAGE		NS		NS
Number of MII oocytes/ Number of oocytes, serum AMH		NS		NS
Number of MII oocytes/ Number of oocytes, FF AMH		NS		NS
Number of MII oocytes/ Number of oocytes, FF sRAGE		NS	-0,484	0,003
Number of embryos, serum AMH πλάσματος		NS	0,362	0,028
Number of embryos, FF AMH		NS		NS
Number of embryos, FF sRAGE		NS		NS
Serum AMH, FF AMH	0,965	<0,001		NS
Serum AMH, FF sRAGE		NS		NS
FF AMH, FF sRAGE		NS		NS
Seum AMH, IU’s gonadotrophins		NS	-0,387	0,018
FF AMH, IU’s gonadotrophins		NS	-0,387	0,022
FF sRAGE, ΒΜΙ		NS	-0,401	0,014
Number of oocytes, age		NS	-0,474	0,003
Number of oocytes, FSH		NS	-0,340	0,039
Number of oocytes, IU’s gonadotrophins	-0,550	NS (0,06)	-0,445	0,006
Number of oocytes, E2	0,577	0,049	0,293	NS (0,07)
Number of oocytes, number of follicles	0,610	0,035	0,545	<0,001
Number of MII ωαρίων, number of oocytes	0,812	0,001	0,874	<0,001
Number of MII ωαρίων/number of oocytes, FSH		NS	-0,336	0,049
Number of embryos, FSH		NS	-0,385	0,018
Number of embryos, ΒΜΙ	0,780	0,003		NS
Number of embryos, IU’s gonadotrophins	-0,579	0,049	-0,319	0,050
Number of embryos, number of oocytes	0,720	0,008	0,777	<0,001
Number of embryos,number of MII oocytes	0,758	0,004	0,917	<0,001
Number of embryos, Number of MII oocytes/ number of oocytes		NS	0,504	0,002
Number of follicles , age	-0,840	0,001	-0,448	0,005
IU’s gonadotrophins, age		NS	0,526	0,001
IU’s gonadotrophins, FSH		NS	0,361	0,028

Lastly, with multifactor linear regression in all women, taking into consideration the age, serum AMH and ff AMH levels, we found that ff sRAGE levels is independently correlated only with the BMI (β= -136.1, p-value =0.036) and the presence of PCOS(β= 1563.9, p-value = 0,045).

Discussion

In our study we tried to determine whether FF sRAGEs are correlated to serum AMH or FF AMH levels and to evaluate the association of these markers with IVF outcome parameters, in PCOS women receiving IVF treatment.

AHM has been widely used as an ovarian reserve marker in prediction of IVF outcome [8]. Additionally, many researchers have found that the severity of PCOS is positively correlated with the number of small antral follicles and that AMH plays a significant role in the pathogenesis of anovulation in women with PCOS. However, in our study, AMH values between PCOS and non PCOS women were not found to be statistically significant. Additionally, we did not find a correlation between ff AMH and serum AMH. Regarding the predictive value of AMH in IVF outcome, serum AMH was found to be correlated with the number of the number of MII oocytes and the number of the embryos only in non PCOS women. We did not find a correlation of ff AMH with the number of the oocytes retrieved or the number of the embryos available for embryo transfer neither in PCOS, nor in non PCOS women.

As above mentioned, AGEs have been incriminated for age-related ovarian dysfunction due to the effect of oxidative stress mechanisms in the ovarian microenvironment that results in insufficient vascularization, hypoxia of the ovary and malnutrition of the granulosa cells [21]. It is known that folliculogenesis is an inflammatory procedure and when combined with COS during IVF cycles large amounts of cytokines are produced and secreted into the follicular fluid. This environment could cause a huge AGE production and effect negatively oocyte quality. Jinno et al, in a study of 157 women undergoing IVF treatment (71 PCOS women included) reported that elevated AGE levels play a significant role in ovarian dysfunction and are associated with poor IVF outcome [31]. While, AGEs have been found to have negative correlation with follicular growth and IVF outcome, in 2014 Merhi et al was the first to report that FF sRAGEs are positively correlated with ovarian reserve, as measured by FF AMH (r=0.5, P = 0.0085) and the number of the oocytes retrieved (r=0,57, P=0.02) but only in non-PCOS women [16]. Recently Li et al, who studied 124 women undergoing IVF treatment, divided into two age groups, found that ff sRAGE levels are positively correlated with folliculogenesis and IVF outcome only in women of advanced age [22].

In our study, we did not find a statistically significant correlation between ff sRAGE levels and the number of the oocytes retrieved or the number of the embryos available for embryo transfer after the IVF treatment in none of the groups studied. But we did found that ff sRAGE levels seem to have an effect on the quality of the oocytes retrieved. In fact, we found that increased ff sRAGE levels are negatively correlated with the quality of the oocytes retrieved, as defined by the ratio of MII oocytes to the total number of the oocytes retrieved but only in non PCOS women(r= -0.484, p-value= 0.003). Given that the number of the embryos available for embryo transfer is correlated with the number and the quality of the oocytes retrieved, it seems that ff sRAGEs play a role in the IVF outcome, at least in non PCOS women. On the contrary to this hypothesis, it has been shown by Malickova et al, that FF sRAGE concentrations in women undergoing IVF were significantly higher in those having a positive IVF outcome [31].

We also found that PCOS women have higher FF sRAGE levels when compared to non PCOS women (p-value <0,01)but no correlation of these high FF sRAGE values with IVF outcome parameters were noted in this group as above mentioned. On the contrary to our study, Wang et al found that FF sRAGEs are significantly decreased in PCOS females compared to control groups and associated with lower total gonadotrophin doses. However, they did also not found a correlation o FF sRAGEs with other IVF outcome parameters (number of oocytes retrieved, fertilization rate, number of high quality embryos) [28].

Lastly, we found a negative correlation of FF sRAGE levels with BMI(r= -0.401, p-value=0.014). No correlation with FF sRAGE and women’s age was noted.

Therefore combining the above mentioned information and taking into consideration the small sample size, we can conclude that there is no correlation between the AMH protein and the oxidative stress agents. However, each of these factors could be used separately for the improvement and the prediction of IVF outcome. AMH can be used as an ovarian reserve marker and as a predictive marker of ovarian response during ovarian stimulation. On the other hand, FF oxidative stress agents (sRAGEs) could consist of a great marker of the quality of the oocytes retrieved during IVF treatment and an indirect marker of IVF outcome. The combination of both could be used, therefore, in order to improve the IVF outcome.

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The durability of oral diabetic medications: Time to A1c baseline and a review of common oral medications used by the primary care provider

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DOI: 10.31038/EDMJ.2018232

Abstract

Introduction Cost of generic medications has risen more in the past few years than any other time in history. While medical insurance covers much of these costs, health care professionals can better provide medications that have the longest duration of action when compared to placebo-treated controls. This will save health care costs and improve prescribing accuracy.

Methods Papers in PubMed were identified with keywords placebo. The study must be at least 2 years in length to evaluate the change in A1c over time. The primary endpoint was time to A1c neutrality (return of A1c to baseline at a maximum dose of single oral agent). A medication would be considered at neutrality if the 95% CI crossed baseline. Time to neutrality was averaged for each medication within the class and each summarized for class effect.

Results: Effective therapy for the DPP-4 and sulfonylurea classes of medications are 3–4 years as compared to a 5-year time to A1c neutrality for metformin usage. In comparison, the projected time to A1c neutrality was approximately 6–8 years for rosiglitazone and pioglitazone. While only a few studies have been published in the SGLT-2 class of medication, the time to A1c neutrality was also 6–8 years with Canagliflozin and full dosage of Empagliflozin.

Conclusion: Metformin appears to have a 5-year duration of effect before the A1c returns to baseline. The sulfonylureas and DPP-4 inhibitors class of medications have one of the shortest durability which ranges between 3.3 to 4.4 years. In contrast, the SGLT-2 class of medication and the TZD class of medications has a projected time to A1c neutrality from 6–8 years. Diabetic duration of therapy as compared to placebo should be listed with those medications tested so the provider can choose wisely.

Introduction

ADA and AACE suggest that metformin be the first line medication for type 2 diabetes mellitus with many choices for the second line agent (ADA 2018, AACE 2016). Primary care health care professionals would benefit from understanding the potential durability of the diabetic medications to help improve compliance and reduce cost. Historically, sulfonylureas have been added second to metformin, fortunately, over the last 15 years, many combination agents have been developed that include metformin as one of the combo medications. So, the decision to choose the best second agent should be based on the evidence of safety and durability provided.

Limited studies have evaluated the long-term durability of a single diabetic agent on A1c control. The ADOPT trial used monotherapy with Metformin, Glyburide or Rosiglitazone and evaluated A1c changes over a 5-year period. Since the potential risk of rosiglitazone causing CV disease in 2008, the FDA has regulated that all diabetic medications have a CV trial to demonstrate safety. Prior to this regulation by the FDA, the ADOPT trial was a landmark study to evaluate the durability of single diabetic agents [1]. Since the 2008 FDA requirement, all oral diabetic medications have been evaluated with a major endpoint being cardiovascular safety which requires large sample size and longer duration of therapy. Oral diabetic meds were evaluated in randomized, single agent, placebo-controlled clinical cardiovascular trials (with one exception being the TECOS trial) were used to also evaluate the durability of these oral medications based on baseline A1c nadir, return to baseline and compared to placebo treatment.

Methods

Based on the approach of the ADOPT [1] trial, where monotherapy was tried with three separate agents over an extended period of time (minimum 2 years), the study was designed to evaluate newer diabetic medications when given in placebo driven clinical trials for a minimum of 2 years. Trials with the several class of medications have recently been completed and the data summarized [2–9].

The ADOPT trial demonstrated what monotherapy with metformin, glyburide or rosiglitazone will reduce A1c levels over a 5-year period. Since DM-2 is considered a progressive disease with slow loss of the beta cell function, the waning effect of each medication was documented and projected time to A1c neutrality was documented over the 5-year study [1].

The purpose of the trial was to clarify the duration of action of the more commonly used classes of medications. Traditionally the choice of medications has been limited and now there are over 20 combination oral medications for use in the treatment of type 2 diabetes. If the provider appreciates the duration of action of these medications then more appropriate choices can be made which should reduce the cost of medications and improve overall diabetic control.

Results

Three of the five FDA approved DPP-4 medications have had CV safety tested in a double-blind and placebo-controlled design.

The first two agents’ saxagliptin (2) and alogliptin (8) were published on the same day (9/2/13) and they demonstrated a drop in A1c that was not significantly lower than baseline at the end of study. The Sitagliptin study showed a significant drop in A1c at 12 weeks but the difference from baseline was not significant after 34 weeks nor at the end of the 4-year study (Table 1 and Figure 1).

Table 1. Duration of A1c Effect over Time vs Placebo (Return to Baseline)

NAME	Dose (mg) Total Daily	Baseline A1c (%)	Early (Nadir)	Mid level	End of Study	Time to A1c Neutrality
Alogliptin (EXAMINE)	30	8.0	-0.7/12w*		-0.36/3yrs*	3.3yrs
Sitagliptin (Green)	100	7.2	-0.3/4w (NS)	-0.2/34w (NS)	-0.1%/4yrs	4.0 yrs
Saxagliptin (Scirica)	5	8.0	-0.5/104w		-0%/4yrs	4.0 yrs
Gliptins: (3–4 yrs)
Glipizide (Feinglos)	2.5	8.0	-0.5/14w			3.0 yrs
Glyburide (ADOPT)	20	7.3	-0.90/12w			3.7yrs
Sulfas: (3–4 yrs)
Metformin (ADOPT)	2500	7.3	-0.60/52w			5.0yrs
Metformin: (5 yrs)
Rosiglitazone (ADOPT)	4–8	7.3	-0.67/104w			8.0yrs
Pioglitazone (PROACTIVE)	45	7.8			-0.80/3yrs	6.0yrs
TZDs: (6–8 yrs)
Empagliflozin (EMPA)	10	8.1	-0.54/12w	-0.42/94w	-0.36/206w	5.0yrs
“	25	8.1	-0.60/12w	-0.47/94w	-0.42/206w	8.0yrs
Canaglifozin(CANVAS)	100/300	8.2	-0.70/26 w	-0.40/156w	-0.20/286w	7.0 yrs
SGLT-2: (5–7 yrs)

EDMJ 2018-105 - John A. Tayek USA_F1

Figure 1. Projected durability of diabetic medications.

The first of three DPP-4 clinical trials demonstrated that saxagliptin use for 2.1 years had no CV benefit and it reduced A1c from 8.0 to 7.7% which was 0.2% less than placebo [2]. Unfortunately, the SAVOR trial demonstrated that more saxagliptin-treated patients developed heart failure than placebo-treated patients (3.5% vs 2.8%; NNH = 143). This potential risk is listed with the FDA for health care professionals to evaluate and discuss with their patients [8]. Alogliptin treatment for 3 years dropped A1c from 8.0% to 7.67% which was 0.36% less than the placebo at the end of the 3 years but there was no cardiovascular benefit observed [3]. Sitagliptin was given for 3 years and it had no CV benefit and it reduced the A1c from 7.3% to 7.1% which was 0.29% less than the placebo at the end of the 3 years [4].

In comparison, monotherapy was provided with glyburide over 5 years and the results after 3 years demonstrated a significant drop in A1c from 7.3% to 7.1% (1). Low dose glipizide XL has 0.5% drop in A1c which nadirs, like glyburide at 12–14 weeks. Glipizide appears to have a shorter duration of action as it is projected to return to baseline at approximately 1 year. Likewise, metformin was given a monotherapy and the A1c dropped from 7.3% to 6.9% at 3 years. Rosiglitazone was also given and it dropped the A1c from 7.3% to 6.85% at 3 years [1]. The A1c returned to its baseline of 7.3% after 3.75 years of starting glyburide and after 5-years after starting metformin.

The TZD class of medications appears to provide for a longer duration of action. Interestingly, the A1c did not return to normal after 5 years of starting rosiglitazone as it remained significantly reduced at 7.1%. If you extend linear trend for A1c, it appears to take approximately 8 years for the A1c to return it to baseline of 7.3%. In the PROACTIVE trial, pioglitazone treatment for 3 years significantly reduced A1c from 7.8% to 7.0% at the end of 3 years [5]. The placebo-treated patients drop their A1c by 0.3% at the end of study which showed no difference from baseline.

Pioglitazone treatment in the PROACTIVE trial demonstrated a 0.8% drop in A1c at the end of the 3 years study with a predicted durability of 6.0 years [5]. In contrast, the Empagliflozin data demonstrated a 0.4% drop in A1c at the end of the 4-year study which projected to a 5-8 years durability of this therapy depend on the dose studied [6].

It would appear that the effective therapy for the DPP-4 class is approximately 3–4 years as compared to 5 years for the time for the A1c measurement to return the baseline level for metformin. The 5 year duration of action for metformin was confirmed in the Diabetes Prevention Trial where FBG was 106 mg/dl at baseline and returned to 106 mg/dl after 5 years [17]. In the placebo arm the FBG increased from 106 to 112 mg/dl over the 5-year period. In the 15 year follow up report the FBG increased to 117 mg/dl in the metformin arm, which is smaller then the projected change in A1c over time in Fig 1. In contrast, the projected time A1c baseline was approximately 6–8 years for rosiglitazone and pioglitazone. While only two large studies have been published in the SGLT-2 class of medication, it appears that the time to A1c neutrality was seen Canagliflozin was 7 years [7] and with Empagliflozin an estimated 5 years with a low dose and 8 years with high dose [6].

Discussion

The natural history of type 2 diabetes mellitus appears to be due to persistent loss of the beta-cell function over time. While there can be an increase in insulin resistance that can occur with aging or weight gain, the majority of the waning effect of diabetic medications are likely due to the natural loss of insulin secretion. Why this rate is different with different medication is unknown.

We know that fasting insulin levels are increased with glyburide treatment and remain neutral with both metformin and DPP-4 inhibitors. The mechanism of the DPP-4 inhibitors is to increase incretin levels (GLP-1 and GIP), which inhibits glucagon release, which in turn increases insulin secretion, decreases gastric emptying and decreases blood glucose levels. While metformin has a neutral effect, the administration of TZD medication and that of the SGLT-2 medication are associated with a significant reduction in the fasting insulin levels [10]. The reduction in the insulin levels is unlikely to play a major role in the durability because of the failure of Origins trial to delay the onset of DM-2, where basal insulin was administered for 5 years [11]. So, TZD and SGLT-2 class appear to have a direct drug effect on the beta cell and/or other pathways of insulin resistance. We know that liver fat, beta cell fat and selective muscle fat is reduced with TZD treatment [10]. Likewise, weight loss seen with the SGLT-2 inhibitors can be associated with similar changes in these tissues that could both reduce insulin resistance and increase insulin secretion.

Diabetes appears to be a progressive disease process with slow but consistent loss of control over 6 to 12 months of therapy in many patients. It is well known that the use of TZD reduces carotid intima thickness as compared to glimepiride [10], it reduces liver fat content by 54% [12] and improves insulin resistance and beta cell function [10]. Metformin prevents the production of glucose in both the liver and kidney which may reduce the insulin requirements associated with hormonal or metabolic factors that would otherwise rise insulin secretion.

This raises two interesting points: durability of each class of medications and potential mechanism of action of these medications. The best durability appears to be in the TZD and SGLT-2 classes which appears… to have a projected effect on A1c of greater than 6–8 years while metformin has limited benefit of approximately 5-years before the A1c returns to baseline [1]. The shortest durability is seen in the DPP-4 medications, which have 3–4 years projected time to A1c neutrality. Therefore, the time for A1c neutrality appears to be the shortest for the DPP-4 and sulfa classes of medications.

What to do about the waning effect of several classes of mediations: The current answer is unknown, but if the effective treatment benefit of a DPP-4 medication is approximately 3–4 years and metformin has 5 years, it seems clear that metformin has both durability and cost savings. The combinations agents with both metformin and DPP-4s may misleading health care professionals to its durability since metformin is likely doing the majority of the treatment effect. Interestingly, the use of rosiglitazone, the medication that caused the introduction of the FDA for Cardiovascular Outcome trials to confirm CV neutrality has been shown to have one of the two longest duration of benefit for A1c reduction over time.

Caution about the use of both Rosiglitazone and Pioglitazone exists in the medical literature. Rosiglitazone was put on restricted usage requiring REMS after Dr. Steve Nisson published his analysis of the increase CV risk that appears to be associated with rosiglitazone [15]. This REMS requirement for rosiglitazone was withdrawn by the FDA after publication of the RECORD trial where there was no CV risk associated with rosiglitazone [16]. This class of medications is contraindicated in CHF stage 3 or 4. They are known to cause intravascular fluid retention and also to cause lower extremity swelling which is likely due to pre-adipocyte differentiation into adipocytes. This class of medications lowers fasting insulin levels and also lower IGF-1 concentrations which likely explains the loss of bone mass over time. The TZD class of medications should be avoided in patients with significant osteoporosis.

In comparison to the downsides of using the TZD class of medication, there is growing evidence suggests that pioglitazone treatment has shown a 51% resolution of NASH and reduces fibrosis [13]. In addition, pioglitazone has been shown to help reduce recurrent CVA in diabetics [5] and pre-diabetics [14]. Similarly, the SGLT-2 medication Empagliflozin has been approved by the FDA to reduce CV risk and it has a projected long-term reduction in A1c levels. Based on the duration of action, potential CV risk reduction, this medication would be an excellent choice for diabetic patients at risk for CV events. Likewise, pioglitazone may be a wise choice for pre-diabetic or diabetic patients who have had a recent CVA event or have F3-F4 fibrosis or proven NASH. Additional CV outcome trials with newer diabetic medications will also provide the provider with duration of effect estimate which may help improve compliance and reduce health care costs.

In conclusion, the primary care provider should consider the durability of treatment in their treatment decision after starting metformin. The A1c durability of each agent should be included in treatment guidelines for ACP, ADA, AACE and European Diabetic Guidelines. In the time of abundant oral diabetic medications, effort should be used to educate health care professionals on the duration of action as well as potential non-diabetic risk and benefits of diabetic agents. More studies on the comprehensive effective long-term, placebo-controlled monotherapy treatment trials will allow the health care professionals can choose wisely for their patients.

In summary, the duration of A1c effect was 5 years for metformin and it appears to be a better choice over a sulfa and DPP-4 class of medications. A longer duration of action was seen with the SGLT-2 and TZD class of medications. These both have a long duration of action (6–8 yrs), and with their low cost may be considered in patients who would benefit from their use.

With the recent adoption by the ACP (American College of Physicians) that target A1c of < 8% is “at goal” for diabetic patients, then metformin should provide 5 years of acceptable diabetic control if stating at an A1c of 8%. Our data would suggest that mono-therapy with a SGLT-2 inhibitor or PPAR-gamma agonist (TZD) would keep someone at goal for approximately 7-8 years if the starting A1c was 8%. Using this stepwise triple therapy approach, it may be possible for a diabetic patient to maintain their A1c at goal for approximately 20 years.

Acknowledgement: The NIH Clinical Investigator Award KO8DK02083 and MO1-RR-00425 supported this grant

References

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Liver Honeycomb Sign

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DOI: 10.31038/CST.2018334

Case Report

A 40-year-old man with a 20-years history of hepatitis B virus infection was diagnosed as post-hepatitis cirrhosis a month ago. He sought to take Chinese Herbs (CH), aiming to softening the cirrhotic nodules. Unexpectedly, he experienced fever and diarrhea for 1 week and abdominal pain for 2 days after taking CH of 7 days. Blood investigations revealed severe leucocytosis and raised liver enzymes and bilirubinemia, elevated Alpha Fetal Protein (AFP) and incredible severe coagulation disorders that coincided with the diagnosis of Disseminated Intravascular Coagulation (DIC). Computed tomography revealed some cirrhotic liver with partial enhancement. Magnetic Resonance Imaging (MRI) for the first time unveiled multiple low-signal vaculoses throughout the liver (honeycomb sign) in its diffused weighted imaging phase (Figure 1), which were potentially made up of necrotic nodules of varying sizes but less than 1 centimeter. Unlike melioid liver abscesses, his inflammatory was soon cured after antibiotic (Meropenem) using of 10 days. In this case, DIC was a confusing issue about its definitive cause that was thought to be associated with the advanced liver cirrhosis or nodules carcinomarization or drug-related liver injury or other blood malignancy. In any way, CH may play a key role in inducing these changes. Strangingly, DIC didn’t significantly improved following improved liver function and cured infection. Further evaluation of petron emission tomography / computed tomography confirmed hepatic nodules carcinoma transformation and extensive abdominal peritoneum metastasis, which also clarified the initial conundrum of DIC cause, fluctuating value of AFP and honeycomb sign. On 3-month following-up visit, he seemed to obtain benefit from CH performance of promoting hard nodules-resolving because AFP began to go better and clotting disorder also improved gradually.

Consent statement: The patient has given his written informed consent for his data to be submitted or published.

Conflicts of Interest: All authors declare that they have no conflicts of interest concerning on this manuscript.

Authors’ Contributions: Zhong Jia and Jia-Qing Huang were involved in compilation of the data and drafting of the article. Both authors read and approved the final manuscript.

CST 2018-114 - Jia Zhong China_F1

Figure 1. Magnetic Resonance Imaging (MRI)

Accreditation in hospitals: Should we implement the same standards in different types of hospitals? The case of a mental health hospital

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DOI: 10.31038/ASMHS.2018232

Abstract

In the era of implementing quality standards as a mandatory process toward licensing, we raise the issue of implementing a generic standards for hospitals, or organizations, in general. Should we set different standards for different types of hospitals that implement to standards? This case study explores the specific issues that raise the dilemma. Regarding the fact that this hospital is the first mental health hospital in Israel to adopt the quality standards, it is crucial to understand the issue of adjusting the solutions for quality care.

Keywords

Accreditation, Quality service, Hospital types

Introduction

In the current era of globalization and the rapid changes that come with it, most governments are trying to improve management efficiency processes and performance [1, 2]. Since the 1980s, public reform has expanded around the world, in particular as a result of public pressure to improve services in exchange for the tax burden imposed on citizens [2, 3].

As we know, over the past several decades, Israel’s governments have adopted various reforms; the main one being privatized [4], which has led to competition in all areas of life, including healthcare services [5]. Healthcare organizations in Israel now face challenges such as reducing resources, narrowing the budget share, balancing the load in hospitals and improving quality of service. In light of this, the question of “how to provide quality care?” has been raised. In the next section, we will present the latest healthcare system reform in general and specifically in hospitals, in particular to Accreditation standards and the benefit to quality services [6].

Accreditation is a structured process of recognizing and promoting performance and adherence to standards either received from an authorized body or those that are newly developed, including updated existing standards. It is a system of organizational improvement centered on a certifying agency (or accrediting body) that assesses performance against pre-determined standards [7, 8].

Accreditation services in hospitals began around 1910 in the USA. The Association of American Surgeons has been promoting quality standards to increase safety and safety awareness in more than 16, 000 healthcare facilities in the USA. The organization has an international arm known as “Joint Commission International” (JCI), which currently operates in countries around the world and throughout Europe, South Africa, the Far East and Middle East [9].

Research shows that healthcare organizations benefit from increased quality service through the implementation of accreditation standards. The benefit of accreditation includes: patient safety and reduced clinical risk and others [10, 11], promotion of quality improvement activities, Implementation of processes that promote improvement, effective management [12], increased organizational learning [13, 14], improved organizational reputation [8, 15], improve organizational communication and cooperation between the staff and the community [10, 12, 13], and reduction in the cost of claims [16]. Studies shows that there is a correlation between clinical performances, safety and patient outcomes, and the implementation of accreditation [17].

At the national level, the agency responsible for carrying out quality improvement is the Ministry of Health’s Quality Assurance Department. They are tasked with overseeing quality assurance standards that meet national and accreditation-like system operations [6]. Due to the advantages of working in accordance with international standards for improving the quality and safety of care, the Health Ministry Director General decided at 2012 that hospital accreditation is a prerequisite for a licensing of all the general hospitals in Israel. For other hospitals (such as mental health hospitals) it is not mandatory. The JCI organization and their standards were selected by Israel’s Ministry of Health to be the competent authority for accreditation.

Case study

Accreditation standards exist for different types of health organizations such as hospitals, medical laboratories, home health care, nursing services, ambulatory services, medical transportation, etc. [18]. At the same time, we are not aware of specific standards for psychiatric hospitals. The Sha’ar Menashe Mental Health Center is the first psychiatric hospital in the world, to the best of our knowledge, to adopt the accreditation standard for all its departments.

The purpose of this article is to examine the decision of Sha’ar Menashe Hospital to fully implement the accreditation standard. It should be noted that the standard is adapted to general hospitals on the basis of their characteristics, which differ significantly from psychiatric hospitals. For example, in a general hospital, a patient is usually in need of treatment for a short period of time, several days to weeks. On the other hand, in a psychiatric hospital, a patient can stay in for treatment for a long period of time, which could last for months or even years. Treatment characteristics and the nature of patients are different and there is a long-standing acquaintance with patients in psychiatric hospitals [19].

The different characteristics of the types of organizations in addition to long-term acquaintance with the patient necessitate a different managerial approach [19]. In light of the above, we would like to examine whether the decision to adopt a standard intended for general hospitals in psychiatric hospitals is a correct decision and was it necessary to make adjustments before implementing the standard?

Regarding the attempt to implement the necessary standards of the JCI, Shaar Menashe mental health hospital’s managers have built a framework of standardization. The hospital had good work processes till that time, but the willing to adopt the new standards led to build the processes in the proper time constraints of the JCI. Most of the issues focused on schedule, oriented to the patient secure, such as: 5 day program for new patient, patient’ identification, mammography, patients’ discharge, summery of detailed disease within two weeks of discharge, ensuring continuity of treatment after release in the community for further treatment in the community.

After a process of more than a year in an attempt to meet the requirements of the accreditation standard at the Shaar Menashe Hospital and following the learning process, we have decided to present in this article as a case study the case of securing the patient through proper identification. In light of the general hospitals, clinical risks such as misidentification of patients that led to the wrong treatment, one of the major JCI standards is the proper patient identification clinical risk events. In order to reach the standard of this issue, the general hospital’s quality assurance solve the identification problem by adopting the process of attaching an identification handcuff on the patient’s hand. In an era in which we are required to use a variety of means to identify citizens (such as identification by means of a biometric ID), it is logical that this requirement will be a core requirement of an organization such as a hospital relative to its patients. It is known that in general hospitals, where there is a very high turnover rate of patients and attendants, and in order to prevent mistakes and unusual events (such as incorrect treatment of the patient), it is very important to attach an identification handcuff to the patient. On the other hand, in psychiatric hospitals where there are patients who stay for a long period of time and with minimum attendant’s turnover, the question arises whether there is a need to attach a handcuff or is there an alternative solution that can be used. It is important to note that examination of this requirement of the standard is not arbitrary. In fact, from the moment the decision was made at the Shaar Menashe Hospital, the therapists were forced to deal daily with patients who teared the handcuffs from their hands, wasting time on attaching a new handcuff to the patient’s hand and the economic costs incurred by the hospital in light of the widespread phenomenon. Every day, therapists face the challenge of spending precious time in preparing a patient plan, departmental activities for the patient, and more. Nevertheless, this financial expenditure to the hospital was available and it was possible to invest these resources, in infrastructure or in any means to improve the conditions of hospitalization and the level of treatment that patients receive. It seems that the same demands for organizations with different characteristics, even though they are in the same field, are an issue that needs to be considered. In other words, it is necessary to examine whether it was correct to create adjustments based on the characteristics of the organization.

Conclusions and Recommendations

A mental health hospital has to deal with unique issues which differ from the general hospital ones. For instance, one of the major issues of patients’ safety is seaside prevent. Yet, the need to meet the JCI standards under the health ministry regulations brought the quality assurance managers in the hospital to focus on those of the general hospital ones.

After examining this case and presenting the dilemma that arises from the requirement of the standard for attaching the patient’s handcuff identification, we bring the constant dilemma that arises when implementing generic standards – should the same standard be implemented in organizations with different characteristics? Organizational management standards are required for efficiency and organizational effectiveness, and mainly for managerial control. However, this issue should be examined in terms of organizational characteristics. In the present case, it could be more efficient, in our opinion, to examine the significance of the decision in light of the characteristics of the psychiatric hospital and to make adjustments. For example, we would recommend that the hospital, in the era of information technology, makes use of the digital medical record that each patient has and add the patient’s digital (or biometric) picture. Thus, at any time, the staff will be able to check the correlation between the patient in care and his record to which a picture was added. Even if we would assume that in most cases the staff is well acquainted with the patient, this implement provides a solution to situations in which there is no prior acquaintance. We can see that in many areas of our lives, we are required to meet the means of identification and today there are many technological means such as the biometric identification that could be adopted for this case. We must strive to introduce accreditation in managerial control, while adapting to the characteristics of unique organizations.

The health ministry encourages the hospitals to get the JCI accreditation (while in the general hospitals it is mandatory). Thus, it would be a benefit if the health ministry will present unique solutions for the mental health hospitals in a way that will help them to meet the JCI standards with solutions that meet their needs, while managing the resource utilization wisely, especially toward implementing the JCI standards in.

A quality care for the patients demands not only reaching the goal standards, but getting innovative solutions as well.

References

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Pollitt C, Bouckaert G (2004) Public management reform: a comparative analysis. Oxford: Oxford Press University, United Kingdom.
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Utility of Optical Density of Picrosirius Red Birefringence for Analysis of Cross-Linked Collagen in Remodeling of the Peripartum Cervix for Parturition

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DOI: 10.31038/IGOJ.2018121

Abstract

We report on development of a rapid, quantitative analysis technique of collagen fibers in cross-linked structures to assess remodeling of the cervix during the transition from soft to ripening in preparation for birth. Optical density analysis of picrosirius red stain tissue using circular polarized birefringence light from fixed paraffin-embedded or frozen cervix from pregnant mice during phases of remodeling prior to birth. Data were analyzed using NIH Image J and extended recently to include studies of prepartum cervix in peripartum women. Our results, developed a rapid, consistent, technique to quantify cervical organization. This approach assesses the structure of collagen organization (the principle component of the cervix) and is essential for analysis of experimental outcomes that disrupt cervical morphology in rodent models of preterm birth. The technique, in this report has, for the first time permitted rapid, accurate assessment of the stages that define cervical ripening with large numbers of slides from individual animals. The approach integrates analysis of collagen organization, with distensability and inflammation, processes associated with cervical change before birth. This analysis further holds promise to evaluate other tissues, but also fibrolytic and fibrogenic changes in collagen associated with physiological or pathophysiological conditions.

Key words

pregnancy, remodeling, ripening, inflammation

Introduction

Identification of large protein using various stains have been used as early as the 17^th century to label extracellular, cellular, and sub-cellular organ structures in tissue [1]. More recently, improved fixation and specificity of stains has allowed quantification of small cellular components and their structural organization. Collagens are the most abundant proteins in humans with type 1 the majority (98%) of the 28 identified types [2, 3], and common in all vertebrate species. The human cervix, composed predominately of collagen fibers, serves as a barrier to the vaginal biome and protects the developing contents of the uterus during pregnancy [4]. Junqueira’s group was the first to use picrosirius red stain to identify a reduction in collagen in cervix from intrapartum compared to nonpregnant women. Picrosirius red stains the principal forms of collagen in the cervix, mostly type 1, though type 3 is present to a lesser extent [5]. As Lattouf more recently concluded, picrosirius red stain is “simple, sensitive and specific for collagen staining….particularly useful to reveal the molecular order, organization and/or heterogeneity of collagen fiber orientation in different connective tissues” [6].

Evidence supporting this conclusion led our lab, well over a decade ago, to develop a protocol that uses birefringence of circular polarized light from picrosirius red stained cervix sections to study the progression of remodeling during the progression from phases of softening to ripening [7–11]. In multiple strains of mice and rats, and more recently in women at term and preterm delivery, this technique is reliable, consistent and essential to assess degradation of collagen organization during late term normal pregnancy or experimental manipulations.

Given the utility of picrosirius red stain with birefringence, physiological remodeling and inflammation-induced premature ripening of the cervix, the goal of this report was to document the current state of our method, which is likely to have broad value to accurately study collagen of other tissues and assess pathological or healing of fibrotic processes.

Methods

Cervix from pregnant mice were processed by immersion fixation in 4% paraformaldehyde, paraffin embedded, sectioned at 10 µm, heated at 60^o C for 45 minutes using a slide warmer, then subjected to xylene incubations to remove paraffin, and rehydrated through a graded series of ethanol. Sections were counterstained with hematoxylin to identify cell nuclei (for cell counting), and washed in distilled water to remove background stain. These tissue processing procedures have been previously detailed [7]. Collagen in cervix sections was stained using a picrosirius red kit (Polysciences Kit #24901-500, Warrington, PA, USA). Following instructions, slides were first placed into Solution-A (a phosphomolybdic acid hydrate solution from the kit) for two minutes and then into Solution-B (Picrosirius Red-F3BA) for 60 minutes. Variations in incubation times of ±20 min were not found to improve staining. Slides were placed into Solution-C (0.01 N HCL) for 2 minutes, dehydrated through an ascending series of ethanol, and placed in xylene before coverslipped with Permount (Fisher Scientific, #SP15-100).

For analysis of collagen structural organization during phases of cervix remodeling, a Zeiss Axio Imager A1 microscope with circular polarized light filters was used to evaluate sections at 250x. In early development of this technique an additional microscope (Nikon Optiphot, with Plan apochromat objectives and Nomarski optics) was similarly validated for this method. In both cases, a Spot Pursuit 4MP digital camera was used for micrographs (Diagnostic Instruments, Sterling Heights, MI). In dim room illumination, initial regions of interest were visually identified. A representative sample of 4–6 grey scale photomicrographs were taken from 2 sections/mouse (8–12 total). A similar process was used for human tissue. Care was taken to avoid distorted morphology, including blood vessels, epithelial lumen, and section artifacts, i.e. tissue folds or tears. To ensure consistency in analysis across sections, as well as individuals and groups, microscope properties (field aperture, condenser, light intensity) were optimized and unchanged across viewing each study session. Cells counts were verified using two to three independent observers.

For image analyses, grey scale photomicrographs were filed into a date-labeled folder and batch processed to evaluate optical density using Image J software (NIH, Bethesda, MD; macro plug-in attached in Appendix). At the outset, a global calibration macro was set with the first photomicrograph. The macro first digitized the photomicrograph into an 8-bit grayscale image (Figure. 1B). The program automatically and without bias centered a 9-square box cross region for analysis. An average optical density (OD) was calculated with Rodbard transformation (performed by the program) for each of the 9 boxed regions together with total OD then exported as an output file to a Excel worksheet for statistical analyses. Data were analyzed by ANOVA (p<0.05 level of significance) with Tukey’s post-hoc analysis following Levene’s test (GraphPad Prism Software, Inc., La Jolla, CA).

Results and Conclusions

In the cervix from a nonpregnant mouse, collagen fibers were observed as a dense, uniform fascicle, stained by picrosirius red collagen fibers (Figure. 1A). The birefringence values further quantified this initial impression with values indicative of aligned and organized cross-linked fibers and bundles/fascicles (i.e., low light transmission values) characteristic of an unremodeled cervix. In contrast, by day18 postbreeding (gestation term is 19 days, (Figure 1B), birefringence values were significantly altered, correlating with the presence of numerous gaps and disorganized, nonparallel collagen fibers. This morphology is characteristic of cervical ripening and consistent with early electron microscope studies [12, 13], as well as, consistent with ripening processes of hypertrophy, edema, and increased distensability of the cervix near term. Digitizing this image in grayscale combined with Rodbard transformation (performed by Image J), increased the sensitivity to discriminate the decline in picrosirius red-stained cross-linked collagen was enhanced (Figure 1C).

The utility of picrosirius red stain to understand structural remodeling of the cervix prior to parturition is illustrated by studies of two genetically modified (knockout, KO) mouse models (Figure 2). In mice lacking the progesterone receptor B isoform, picrosirius red stain identified reduced extracellular cross-linked collagen in a temporal pattern that was similar as ripening found in wild type controls before term [14]. Moreover, in a second modified strain of mice lacking the prostaglandin F2 α receptor, pregnancy progressed while collagen structure was reduced similar to wild-type pregnant controls, however, neither labor nor term birth occurred in these animals [11]. The softening and ripening phases of cervix remodelling occurred in similar phases for both knockout models. Moreover, the use of our picrosirius red protocol critically distinguished, for the first time, the phases of cervical ripening from labor to birth in genetic modified animals in which progesterone mechanisms, thought to be essential for normal delivery, were deleted. In both models, the ability to assess cervical phases and collagen organization in processes thought as essential for normal inflammatory processes for parturition, were rapidly, quantitatively, easily, and determined.

These findings demonstrate the value of a rapid and replicable technique in which assessment of picrosirius red birefringence light can benefit analysis of critical biological questions about cross-linked collagen organization in tissue undergoing physiological change. Although used in the cervix, this technique has potential applications in other tissues or pathologies where fiber organization is disrupted. For example, this analysis may be useful to track the progression of fibrotic diseases of lung, kidney, or liver, as well as, to quantify therapeutic interventions of relevance for diverse pathologies including atherosclerosis, tumor growth, and metastatic processes, e.g. cardiovascular, scleroderma [7, 15]. Additionally, the use of transmitted light to determine collagen organization has been usefully employed in a variety of tissues, including human optic nerve [16], biological cells [17], and human skin [18].

Beyond tissue histology or biology, industrial applications would similarly benefit from a rapid assessment of other fibrous structures such as fabrics including Kevlar [19, 20], colloidal organization in liquid suspensions where knowledge of density, quantitative measurement, or dispersion properties are required.

Although useful in many biological situations, limitations of the use of picrosirius red stain to quantify collagen include its use in aqueous permeable fixed material and relatively thick (~10um) sections [20, 21]. Additionally, oral mucous and oral cavity fibrosis [22, 23], luminal crypts [21], or understandably, nonhomogeneous tissues with differing sub-layers encountered within the same region are problematic for analysis with this technique.

Microsoft PowerPoint - _Kirby et al PSRms Figures.pptx

Figure 1A. Illustrative photomicrographs of Picrosirius Red stained, 10µm thick paraffin sections from the cervix of a non-pregnant (NP) and a day18 (d18) pregnant mouse cervix. Term gestation is 19–20 days. Note the ability to visualize individual collagen fibers and fascicles in both sections at this relatively low magnification (250X, using a 20 power objective). The NP section is substantially darker reflecting the denser collagen fiber organization and corresponding reduced light transmission of cross-polarized light through the tissue. In contrast, at d18, as term gestation approaches, the collagen fiber organization is less dense and less organized. Individual fascicles have increased spacing, allowing greater light transmission through the tissue. Within Individual fascicles there is less organization and numerous irregularities as denoted by the overall lighter appearance (increased transmitted light and increased disorganization of individual fibers. Scale bar=50µm.

Figure 1 B and C. Photomicrographs of from nonpregnant (NP) and late term (d18) cervix from wild-type (WT) and progesterone receptor B knockout mice (PRBko). White areas illustrate birefringent illumination and more easily depicts differences in collagen organization. Fibers from non-pregnant animals have more linear structure, in contrast to late term D18 fibers which are dispersed and lack defined structure. Scale bar is 50µm for the two color images and 50µm for all grey scale images and is the same for all grey scale images.

IGOJ 2018-107 - Mike Kirby USA-F2

Figure 2. Histograms obtained from photomicrographs of Figure 1 A and B. Cervix optical density histograms (mean±SEM) from pregnant Prostaglandin Receptor 2 knockout (Ptgfr^-/-) and PRB ^-/-) mice following picrosirius red processing (see methods). Optical density values denote an inverse relationship to collagen structure and organization. The more structured a tissue, the lower optical density values for that tissue. All statistical comparisons were performed using analysis of variance (ANOVA) with Tukey’s post-hoc analysis. “a” equals comparison to non-pregnant, “b” denotes comparison to D15. [11, 14]

In summary, the technique we have developed combining picrosirius red stain and birefringence analysis using circular cross polarized light has evolved over several years into an easy, rapid and essential technique, for our continued analysis in experimental manipulations of the rodent, human, and potentially other non-human primate cervical tissue. This technique is essential for rapid, accurate analysis of several hundred sections we commonly employ for each cervix. Our experimental manipulations are pivotal for understanding cervical processes promoting normal term delivery in rodent experimental models with our ultimate goal to understand the central and sometimes subtle process in humans.

Acknowledgements

This work was supported, in part, by NIH grant # R01-HD054931 (SY), and grateful support from the Department of Pediatrics, School of Medicine, Loma Linda University, and the John Mace Pediatric Research fund (MAK). All animal work was performed in accordance with an approved animal care protocol of the Loma Linda University Animal Care and Use Committee (IACUC), #89002.

Competing Interests: All authors declare and affirm the lack of competing interests, finical or otherwise, in this manuscript.

Abbreviations

ANOVA – analysis of variance

CA – State of California

DIH₂O – double distilled water

DXX – estimated day post-conception

Inc. – incorporated business

MI – State of Michigan

NP – nonpregnant

OD – optical density

PP – postpartum, day of delivery animal

PRB ko – Progesterone receptor, gene deleted animal

Ptgfr ko – prostaglandin-F2-genetic gene-deleted animal

ROI – region of interest

WT – wild type

250X – total optical magnification as viewed through microscope objective

References

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Mescher AL, Junqueira LCU (2016) Junqueira’s basic histology: Text and atlas (Fourteenth edition.). New York: McGraw-Hill Education.
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Junqueira LC, Zugaib M, Montes GS, Toledo OM, Krisztan RM, Shigihara KM (1980) Morphologic and histochemical evidence for the occurrence of collagenolysis and for the role of neutrophilic polymorphonuclear leukocytes during cervical dilation. Am J Obstet Gynecol. 138: 273–81.
Uldbjerg N, Ekman G, Malmstrom A, Olsson K, Ulmsten U (1983) Ripening of the human uterine cervix related to changes in collagen, glycosaminoglycans, and collagenolytic activity. Am J Obstet Gynecol 147: 662–6.
Lattouf R, Younes R, Lutomski D, Naaman N, Godeau G, et al. (2014) Picrosirius red staining: a useful tool to appraise collagen networks in normal and pathological tissues. J Histochem Cytochem 62: 751–758. [crossref]
Kirby MA, Heuerman AC, Custer M, et al. (2016) Progesterone Receptor-Mediated Actions Regulate Remodeling of the Cervix in Preparation for Preterm Parturition. Reprod Sci 23: 1473–83.
Dubicke A, Ekman-Ordeberg G, Mazurek P, Miller L, Yellon SM (2016) Density of Stromal Cells and Macrophages Associated With Collagen Remodeling in the Human Cervix in Preterm and Term Birth. Reprod Sci 23: 595–603.
Dobyns AE, Goyal R, Carpenter LG, Freeman TC, Longo LD, et al. (2015) Macrophage gene expression associated with remodeling of the prepartum rat cervix: microarray and pathway analyses. PLoS One 10: e0119782. [crossref]
Yellon SM, Burns AE, See JL, Lechuga TJ, Kirby MA (2009) Progesterone withdrawal promotes remodeling processes in the nonpregnant mouse cervix. Biol Reprod 81: 1–6.
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The Leg Length Discrepancies: Clinical and Radiographic Criteria for Evaluation

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DOI: 10.31038/IJOT.2018111

Summary

The heterometry of the lower limbs in the developmental age can influence the development of the rachis, generating axial deviations or not good adaptations in walking; in adulthood it can have an important role in low back pain. In general, a heterometry must always be compensated in the evolutionary age, in order to align the rachis-pelvis-lower limb system for an optimal mechanical equilibrium of the subject. The clinical iter that leads to highlight and quantify the heterometry of the lower limbs is based on a careful observation of clinical and radiographic features; from the integration of all the references comes a reliable value for the purpose of mechanical compensation.

Keywords

lower limbs, heterometry, clinical examination

Introduction

In the global kinesiological assessment of a child is necessary a preliminary identification of a possible heterometry of the lower limbs (h.l.l.), considering the anatomical-functional relationship that exists between the rachis and the lower limbs for balance and correct joint function. The iliac bones are correlated in synergy with the lower limbs, the sacrum with the vertebral column [1]. In the developmental age the lower limbs are frequently with length differences often underestimated or more frequently misunderstood, with disharmonic reflexes on the growth or rehabilitative programming of the small patient. The h.l.l., can be idiopathic in the absence of diseases that cause anatomical districts and articular alterations or secondary to congenital or acquired joint pathologies of the hip (Epiphysiolysis, Dysplasias, Osteochondrosis, etc.), of the knee (asymmetric axial deviations) and of the foot (outcomes of diseases congenital, asymmetric pronator syndromes, etc.) [2].

The lack of or insufficient correction or often the overcorrection of the heterogeneous limb in the developmental age can exert an influence on the mechanical arrangement of the pelvis and of the rachis. There is often a discrepancy between specialists, about the presence and the extent of h.l.l. not carefully measured or based only on an inaccurate radiographic report. There is a clinical study, a semiological iter for the definition of h.l.l., supported by a radiographic study. A group of patients in developmental age has been evaluated by more specialists to identify h.l.l., and study the incidence of detection errors and their degree of significance (Figure 1).

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Figure 1. a: Iliac Crest Line; b: Sincondrosis Sacroiliac Line; c: Heads Femur Line; d: Little Trochanter Line

Material and Method

Clinical Analysis

Evaluation of the patient with an h.l.l., must be done during walking, in orthostasis and in clinostasis, looking for repeatable reperiences for all the evaluators. They must be correlated with the radiographic data. The patient’s walking allows detecting disharmony in the step or lameness; in general, a heterometry is manifested in the ambulation when it is equal to or greater than 1.0 cm, if it is of an inferior value it finds an intrinsic compensation and cannot be documented in the passage [3].

Clinical observation in walking in a posterior view better demonstrates this, since the posterior and Superior Iliac Spines (SIPS) can be seen. In orthostasis barefoot, on a podoscope, the following are to be considered:

The level of Iliac Crests, assessed through the placement of the examiner’s hands on the same. This assessment may be imprecise, related to the experience of the examiner and disturbed by the presence of fat, the tickling of the patient, etc.
The examination of the Postero-Superior Iliac Spine (SIPS), particularly evident in the thin subjects.
The alignment of the gluteal folds and the poplite folds.
Plantar support and asymmetric pronator syndromes, due to h.l.l.

In clinostasis after having mobilized the hips to eliminate contractures and bad functional adaptations and aligned the limbs slightly dividing, we proceeded to measure:

The medial spino-malleolar distance, with limbs in full extension, from the antero-superior iliac spine up to the apex of the medial malleolus, in comparison with the contralateral limb.
The medial navel-malleolar distance from the amelic to the apex of the medial malleolus.
The unevenness of the knees flexed, at 90 °, with the feet juxtaposed and aligned on the back side of the heel; a repere on the knees records the difference in height of the rotule [3–7].

Radiographic Study

On the panoramic radiograph of the rachis in anterior-posterior projection the radiologist often reports the data of an heterometry, referring to the comparative level of the iliac crests projected on the radiographic grid. Considering the radiographic magnification (on average of 15%) and the symmetry of the pelvis in the radiography, the reading of an X-ray is based on the observation of the following features:

The level of the iliac crests, projected on the radiographic grid, is the most widely used or even the only one.
The tangent to the femoral heads, a true reference for the metric variations of the limbs.
The tangent to sacro-iliac synchondrosis, inferiorly, considered a fixed, little variable and therefore reliable.
The horizontal joining half of the small trochanters, if they appear symmetrical; this datum correlates with the tangent of the femoral heads (Figure 2).

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Figure 2. Heterometric values in study population.

Case Material

Twenty patients in the developmental age, 13 females and 7 males, aged between 10 and 16 years (average age of 12.8 years) who came to the observation for presumed scoliotic deficiency, were subjected to the examination of vertebral pathology, to clinical and radiographic evaluation for the recognition of an eventual h.l.l. Patients with pelvic dysmorphism and dysplastic hip disease were excluded. Each small patient was evaluated by 4 orthopaedic specialists (Table 1).

Table 1. Physician’s Evaluation in Study Population.

N°	sex	age	1° Physician	2° Physician	3° Physician	4° Physician
1	F	12	-1 cm	-1 cm	-1 cm	-1 cm
2	F	11	-0,5 cm	Non heter	Non heter	-0,5 cm
3	F	14	-0,8 cm	-0,5 cm	– 0,8 cm	-0,8 cm
4	M	14	-0,5 cm	-0,5 cm	– 0,8 cm	-0,5 cm
5	M	12	-1 cm	-1 cm	-1 cm	-1 cm
6	F	13	No heter.	Non heter.	Non heter.	Non heter.
7	F	13	-0,8 cm	– 1 cm	– 1 cm	– 1 cm
8	M	15	-0,8 cm	-0,5 cm	– 0,8 cm	-0,8 cm
9	F	10	-1 cm	-1 cm	-1 cm	-1 cm
10	M	12	No heter	-0,5 cm	-0,8	-1 cm
11	F	11	-0,5 cm	-0,5 cm	No heter	-0,8 cm
12	F	11	No heter	-0,5 cm	No heter	Non heter
13	M	15	-0,8 cm	-0,5 cm	– 0,8 cm	-0,8 cm
14	F	16	-0,5 cm	-0,5 cm	-0,5 cm	-0,5 cm
15	F	14	-0,5 cm	-0,5 cm	– 0,8 cm	-0,5 cm
16	F	13	No heter	No heter	-0,5 cm	No heter
17	M	12	-0,8 cm	-0,5 cm	– 1 cm	-0,8 cm
18	F	13	-0,5 cm	-0,5 cm	-0,5 cm	-0,5 cm
19	F	15	No heter	-0,5 cm	-0,5 cm	No heter
20	M	11	-1 cm	-1 cm	-1 cm	-1 cm

Results

The overall data on the 20 patients analyzed by 4 specialists are summarized in Table 1. Each specialist had evaluated 7 clinical parameters and 4 radiographic parameters. There was a unanimous correspondence between the 4 specialists for 7 cases (35%), a correspondence of 3 specialists on 4 for 10 cases (50%), a correspondence of 2 specialists on 4 in 2 cases (10%) and a complete discrepancy in 1 case (5%) (Figure 2). Among the clinical parameters the Spine-malleolar distance and the evaluation in clinostasis with flexed knees were very important, which for cases with h.l.l. they are constant results for all observers. The other data have meant confirmation for the former. About the radiographic data, the most significant and constant datum was the repere of the femoral heads, compared to the reticulum of the iliac crests, considered the main reference in the radiographic reports. In the group of study patients, according to the 4 different specialists, higher mean heterometric values were observed for the observer n ° 3 and n ° 4 with respect to the evaluation of the observer n ° 1 and n ° 2 (both with homogeneous heterometric values) resulting in a significant correlation of results, respectively: -0.6400 ± 0.3733 cm; -0.6250 ± 0.3726; – 0.5500 ± 0.3735cm; – 0.5500 ± 0.3204 cm. with p <0.0001 (Figure 3). No significant correlation was found between age and the evaluations of the 4 observers (respectively; p = 0.40; p = 0.28; p = 0.68; p = 0.13 = 0.13).

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Figure 3. The mean resulting in heterometric evaluation: study population.

Therefore the search for an h.l.l. it does not correlate with the patient’s age but with the accuracy of the clinical evaluation and with the observation of several semiological.

Discussion

An heterometry of the lower limbs causes a functional lumbar compensation curve; lumbar salience disappears both with the compensation of the same heterometry (equivalent rise) and with the Stagnara maneuver (deflection of the trunk in the discharge). The adaptive functional datum of the lumbar curve to the heterometry and its existence and existence. May be present in a patient with idiopathic scoliosis [4]. Preliminarily do not base the diagnosis of heterometry of the lower limbs on the sole radiographic reference, on presumed clockwise or anticorrosive rotations of the pelvis, without any anatomical-functional references. Some authors propose the use of QCT scans for data evaluation [5, 6]. The evaluation starts from the clinical examination in its entirety and is answered in the radiographic data; the sum of the evaluations concludes the clinical reasoning on the subject and expresses the extent of any heterometry. The search for heterometry on the radiograph of the panoramic spine should not only limit references on iliac crest.

On the frontal plane it is possible to detect asymmetries of a hemi-pelvis on the sagittal plane with alteration of the anteroversion or retroversion and on the transverse plane for modification of the intra-and extra-rotation. Total in the presence of retroversion of an emi-pelvis, h.l.l. is only apparent thanks to an posture adaptation of homologous lower limb, sometimes inducing a sub-division of contralateral hemi-pelvis. In such cases, this is a question before considering dismetric limbs [7]. The success has been more than ever positive among the clinical signs some have the value of greater reliability as precision of the spino-malleolar distance or the evaluation of an inflection compared to others. Among the radiographic signs, the tangent to the femoral heads represents the main reference point associated with the other three parameters. For all physicians were observed a correlation of the data, with no relation between the age and the evaluations of the specialists. Respect the search for h.l.l. is correlates with the accuracy of the clinical evaluation and with the examination of several semiological parameters, integrated for a diagnosis of probable certainty [8, 9].

References

Morscher E (1972) Etiology and pathophysiology of leg length discrepancies. Orthopade 1: 1–8.
Papaioannou T, Stokes I, Kenwright J (1982) Scoliosis associated with limb-length inequality. J Bone Joint Surg Am 64: 59–62. [crossref]
Song KM, Halliday SE, Little DG (1997) The effect of limb-length discrepancy on gait. J Bone Joint Surg Am 79: 1690–1698. [crossref]
Leali Tranquilli P, Valassina A “Le dismetria degli arti”, Argomenti di ortopedia e traumatologia Estratti, Verducci Editore.
GREEN WT, WYATT GM, ANDERSON M (1946) Orthoroentgenography as a method of measuring the bones of the lower extremities. J Bone Joint Surg Am 28: 60–65. [crossref]
Aaron A, Weinstein D, Thickman D, Eilert R (1992) Comparison of orthoroentgenography and computed tomography in the measurement of limb-length discrepancy. J Bone Joint Surg Am 74: 897–902. [crossref]
Stanitski DF (1999) Limb-length inequality: assessment and treatment options. J Am Acad Orthop Surg 7: 143–153. [crossref]
Goel A, Loudon J, Nazare A, Rondinelli R, Hassanein K (1997) Joint moments in minor limb length discrepancy: a pilot study. Am J Orthop (Belle Mead NJ) 26: 852–856. [crossref]
Shapiro F (1982) Developmental patterns in lower-extremity length discrepancies. J Bone Joint Surg Am 64: 639–651. [crossref]

Shedding Light on the Potential Implications of Solar Eclipse on Psychiatric Patients

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DOI: 10.31038/JNNC.2018115

Abstract

Astronomical phenomena have been purported to impact human behavior throughout history. Though literature regarding the potential influence of lunar phases on emotional status exists, reputable evidence based information detailing the impact of solar eclipses on psychiatric conditions is lacking. Our case study evaluates the potential psychiatric impact on patients in a state psychiatric hospital in Buffalo, NY that occurred on August 21^st, 2017. Our case study reports that although the lowest count of restraint and seclusion events, as measured by evaluation of previously collected, de-identified and analyzed routine facility performance improvement data, occured during the month of the solar eclipse which took place on August 21st 2017 when compared to any date within the previous 6 years, one patient experienced significant and unexpected psychiatric exacerbation. On April 28, 2024, another total solar eclipse will cross the United States. As Buffalo falls within the path of totality, this event would be an excellent opportunity for further analysis of these findings.

Key Words

Eclipse, behavior, restraint, seclusion, psychiatry

Introduction

Astronomical phenomena have been purported to impact human behavior throughout history. Historical perceptions of cosmic influences are predominantly based upon the beliefs that the moon can induce so- called “biological tides,” which are thought to provoke emotional disturbances [1]. Eclipses are one such event that has been suggested to impact human behavior. In a solar eclipse, the moon aligns directly between the sun and the earth, and seemingly blocks the light of the sun. A total solar eclipse is visible from the geographic location that is at the center of the moon’s shadow, while a partial solar eclipse may be seen in surrounding areas. As the sun, moon and earth are not in direct alignment in the areas that a partial eclipse is seen, the sun appears to have a dark shadow on part of its surface. Though unsubstantiated, several sources detailing the alleged impact of eclipses on the psyche are easily located with a simple Internet search. Literature regarding the potential influence of lunar phases on emotional status exists, however reputable information regarding the impacts of solar eclipses on psychiatric conditions is lacking [2]. Furthermore, the information that is available on solar eclipses is dated, focuses predominantly on suicide rates, and provides little insight into other psychiatric consequences of solar eclipses [3,4]. As “sun-gazing epidemics” in psychiatric hospitals have been described during these eclipses, further investigation into the impact of these phenomena on patients with mental illnesses is warranted [5].

On August 21, 2017, the first total solar eclipse in nearly four decades passed through the continental United States. As one of only fifteen total solar eclipses visible within the United States in the past century, the event was the subject of substantial media attention [6]. As the event date drew closer, speculation of the impact of the phenomenon on human behavior provoked debate and discussions within the scientific community. As previous publications suggest that psychiatric patients may be uniquely impacted by the event, curiosity over the potential implications of this upcoming event in psychiatric hospitals increased [7].

In an effort to provide further information on the role of a solar eclipse in psychiatric patient behavior, we present a case study evaluating trended data previously collected, de-identified and analyzed as part of routine facility performance improvement actvities, on restraint and seclusion (R&S) orders at an inpatient state psychiatric hospital in Buffalo, New York. Because Buffalo, New York was out of the path of totality of the 2017 solar eclipse, the impact of a partial solar eclipse is reported in our findings. Restraint and seclusion was identified as the marker of the most extreme psychiatric exacerbation often representing a failure of first line PRN/STAT medication(s) given as a first line lower level intervention.

Case Report

Data previously collected, de-identified and analyzed as part of a routine facility performance improvement activity on the number of R&S orders per month over the course of 6-years prior to the partial solar eclipse was compared to the quantity of orders during the month of August 2017. On average, 13.75 R&S orders per month were entered in the years leading up to the eclipse (range 3–47). The quantity of R&S orders reached the lowest point (nadir) of 1 in August 2017, the month of the partial solar eclipse.

Figure 1 highlights the trend observed. No correlation was noted between time of year and historical number of R&S orders. Figure 2 details trends in the number of R&S orders during the month of August during the 6-years preceding the eclipse event.

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Figure 1. R&S Trends January 2011 – September 2017 (arrow highlights the nadir recorded in August 2017)

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Figure 2. R&S Order Trends during the month of August years 2011–2017

The only patient restrained during the month of the solar eclipse was a 30-year-old African American male with schizophrenia who had been admitted to the psychiatric center since November 18, 2016. Between January and June of 2017, thirty-six R&S orders were entered for this patient (average 4.5 orders per month). He was subject to a manual restraint on August 29, 2017, 8 days after the eclipse. Prior to this event, the patient no R&S orders had been entered for the patient since June 2, 2017.

The event prompting the August 29^th restraint began with the patient’s sexual preoccupation with female staff and requests for these staff members to go into his room with him. He requested administration of as needed (PRN) oral lorazepam 2mg at 2040 and attempted to assault staff shortly afterwards. He was unable to be redirected or to follow simple directions, therefore a psychiatric emergency code was called. Patient was was subjected to a 2 person take down restraint without injury. Intramuscular chlorpromazine 100mg was ordered by the unit physician for acute treatment of this exacerbation episode. The patient attempted to grab the syringe from the administering nurse and stated that the staff member was the devil. Patient then received oral diphenhydramine 25mg at 2059 and was given an additional 25mg dose shortly afterwards per patient request. Patient responded to treatment with good effect. The patient did require PRN haloperidol and lorazepam during the month of August prior to his restraint, with a total of 12 administrations. Of note, PRN oral lorazepam 2mg, intramuscular lorazepam 2mg, and oral haloperidol 10mg were required on August 17^th. Prior to this, administration of PRN psychiatric medications occurred sporadically, with only 1 dose given per occurrence during the month of August. On the day of the eclipse, the patient received 1 dose of PRN oral lorazepam 2mg. Following the eclipse, PRN oral haloperidol 10mg and oral lorazepam 2mg were given on August 25^th and 29^th.

Discussion

When focusing on an individual patient, the pattern of behavior provides further insight into the implications of the eclipse. Previous authors have found similar results indicating that human behavior may be influenced by the anticipation of major events. Though previously the patient had several aggressive incidents requiring R&S, over 2 months had passed between the patient’s most recent behavioral episode and the restraint following the eclipse. When considering the contrast of monthly R&S orders prior to the eclipse and during the month of August in the institution, the potential effect becomes even more pronounced. Of note, other factors unrelated to the eclipse may have played a role in these findings. First, any differences in acuity of patient specific psychiatric conditions throughout the timeline in question cannot be ascertained as the R&S events were only available as a de-identified quality management indicator. Additionally, during the period evaluated, a performance improvement plan with a strategic emphasis to reduce the use of high risk interventions such as R&S was identified and implemented by the institution. While this may account for the overall reduced quantity of orders between 2011 and 2014, an uptick in R&S orders was noted in 2015.

A 2002 analysis conducted by Voracek and colleagues focused on the impact of a solar eclipse on suicide incidence in Austria. The investigation found a reduction in suicide rates at weeks 4, 3 and 1 prior to August 11, 1999 solar eclipse. prior to the August 11, 1999 solar eclipse. No significant changes in suicide incidence on the date of the eclipse were noted. The authors concluded that the anticipation of the event may have been protective against suicide. Of note, the timing of this eclipse also coincided with the turn of the millennium, which was another widespread media event. While it could be speculated that the reduction in suicide rate may have been partially related to a dual excitement surrounding both events, the temporal findings specifically leading up to the eclipse and immediately following the event suggest greater prominence of the eclipse in the findings observed [4].

In a follow-up to the 2002 analysis, Voracek and colleagues published a replication test providing information on suicide rates in Latvia and Romania during the 1999 solar eclipse. While no difference was noted in the incidence of suicide either 4-weeks before, during, or after the event in Latvia, the same trend in suicide reduction leading up to the eclipse was observed in Romania. Considering that Romania was within the path of totality while Latvia experienced a partial solar eclipse, the authors inferred that findings may be different in areas with varying degrees of salience. The findings in Romania thus provide further support for the hypothesis that anticipation of an eclipse may protect against suicide [4].

Although the psychological impact of anticipatory excitement cannot be excluded, confirmation of neurochemical changes may strengthen the hypothesis that solar eclipses may have psychiatric effects on humans. Boral et al, conducted a prospective evaluation of 13 psychiatric inpatients with the goal to evaluate the effects that a total solar eclipse may produce on behaviors and circulating hormones and to further identify potential correlations to the natural phenomenon. Hormones evaluated included Thyroxine (T4), Triiodothyronine (T3), Thyroid Stimulating Hormone (TSH), prolactin, and cortisol. Blood samples were collected twice daily for 6 days before and after the eclipse, during the event, and immediately after and behaviors were monitored 6 days prior to the eclipse, during the eclipse, and 6 days afterwards. Six patients experienced behavioral changes and in all cases, prolactin concentrations attained were significantly higher and abnormal behaviors became more pronounced immediately after the eclipse. Prolactin levels began gradually reducing in intensity to baseline over the 6 post eclipse days with no additional changes or abnormalities noted over the 6 post eclipse days with no additional changes or abnormalities noted [8]. This suggests a potential physiologic cause of peri-eclipse alterations in behavior.

Conclusion

The reduction in R&S utilization may suggest a positive impact of excitement associated with a solar eclipse on the behavior of psychiatric patients. Of note, the event described here was a partial solar eclipse based upon the location of the analyzed population. Therefore, results within the path of totality may provide different information. Nevertheless, these findings suggest that anticipation of a major event such as a solar eclipse may impact psychiatric behaviors. This may be in part due to a collective experience in which staff and patients interact on a different (common) level that what might be expected on any given day with institutional hierarchy and perceived imbalance of power. In addition, there is the possibility that patients may be on their best behavior in hopes of being granted privileges to witness the event firsthand. Lastly, as other authors have suggested neurochemical changes are likely associated with the potential psychiatric effects of solar eclipses, our analysis did not assess physiologic alterations.

On April 28, 2024, another total solar eclipse will cross the United States. As Buffalo falls within the path of totality, this event would be an excellent opportunity for further analysis of these findings.

References

Biermann T, Estel D, Sperling W et al. ( 2005) Influence of lunar phases on suicide: the end of a myth? A population-based study. Chronobiology International 22: 1137–1143.
Tejedor MJ, Etxabe MP, Aguirre-Jaime A (2010) Emergency psychiatric condition, mental illness behavior and lunar cycles: is there a real or an imaginary association?. Actas Esp Psiquiatr 38: 50–56.
Voracek M (2002) Solar eclipse and suicide. Am J Psychiatry 159: 1247–1248. [crossref]
Voracek M, Rancans E, Vintila M et al. (2004) Anticipation of total solar eclipse and suicide incidence. Psychiatria Danubina 16: 157–159. [crossref]
Anaclerio AM, Wicker HS (1970) Self-induced solar retinopathy by patients in a psychiatric hospital. American Journal of Ophthalmology 69: 731–736. [crossref]
Tran L. (2017 Aug 6) Preparing for the August 2017 total solar eclipse. Retrieved from: https://www.nasa.gov/feature/goddard/2016/preparing-for-the-august-2017-total-solar-eclipse
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Boral GC, Mishra DC, Pai SK, Ghosh KK (1981) Effects of total solar eclipse on mental patients: a clinicobiochemical correlation. Indian J Psychiat 23: 160–163.