Does the environment affect menopause? A review of the effects of endocrine disrupting chemicals on menopause.

Endocrine disrupting chemicals are widely distributed in our environment. Humans are exposed to these compounds not only through their occupations, but also through dietary consumption and exposure to contaminated water, personal care products and textiles. Chemicals that are persistent in the body and in our environment include dioxins and polychlorinated biphenyls. Non-persistent chemicals including bisphenol A, phthalates and parabens are equally as important because they are ubiquitous in our environment. Heavy metals, including lead and cadmium, can also have endocrine disrupting properties. Although difficult to study due to their variety of sources of exposures and mechanisms of action, these chemicals have been associated with early menopause, increased frequency of vasomotor symptoms, altered steroid hormone levels and markers of diminished ovarian reserve. Understanding the impacts of these exposures is important given the potential for epigenetic modification, which can alter gene function and result in multi-generational effects. This review summarizes findings in humans and animals or cell-based models from the past decade of research. Continued research is needed to assess the effects of mixtures of chemicals, chronic exposures and new compounds that are continuously being developed as replacements for toxic chemicals that are being phased out.

Intratumoral delivery of tavokinogene telseplasmid yields systemic immune responses in metastatic melanoma patients.

BACKGROUND: Interleukin 12 (IL-12) is a pivotal regulator of innate and adaptive immunity. We conducted a prospective open-label, phase II clinical trial of electroporated plasmid IL-12 in advanced melanoma patients (NCT01502293). PATIENTS AND METHODS: Patients with stage III/IV melanoma were treated intratumorally with plasmid encoding IL-12 (tavokinogene telseplasmid; tavo), 0.5 mg/ml followed by electroporation (six pulses, 1500 V/cm) on days 1, 5, and 8 every 90 days in the main study and additional patients were treated in two alternative schedule exploration cohorts. Correlative analyses for programmed death-ligand 1 (PD-L1), flow cytometry to assess changes in immune cell subsets, and analysis of immune-related gene expression were carried out on pre- and post-treatment samples from study patients, as well as from additional patients treated during exploration of additional dosing schedules beyond the pre-specified protocol dosing schedule. Response was measured by study-specific criteria to maximize detection of latent and potentially transient immune responses in patients with multiple skin lesions and toxicities were graded by the Common Terminology Criteria for Adverse Events version 4.0 (CTCAE v4.0). RESULTS: The objective overall response rate was 35.7% in the main study (29.8% in all cohorts), with a complete response rate of 17.9% (10.6% in all cohorts). The median progression-free survival in the main study was 3.7 months while the median overall survival was not reached at a median follow up of 29.7 months. A total of 46% of patients in all cohorts with uninjected lesions experienced regression of at least one of these lesions and 25% had a net regression of all untreated lesions. Transcriptomic and immunohistochemistry analysis showed that immune activation and co-stimulatory transcripts were up-regulated but there was also increased adaptive immune resistance. CONCLUSIONS: Intratumoral Tavo was well tolerated and led to systemic immune responses in advanced melanoma patients. While tumor regression and increased immune infiltration were observed in treated as well as untreated/distal lesions, adaptive immune resistance limited the response.

Topographic Measurement of Individual Laser Tracks in Alloy 625 Bare Plates.

Additive manufacturing (AM) combines all of the complexities of materials processing and manufacturing into a single process. The digital revolution made this combination possible, but the commercial viability of these technologies for critical parts may depend on digital process simulations to guide process development, product design, and part qualification. For laser powder bed fusion (LPBF), one must be able to model the behavior of a melt pool produced by a laser moving at a constant velocity over a smooth bare metal surface before taking on the additional complexities of this process. To provide data on this behavior for model evaluations, samples of a single-phase nickel-based alloy were polished smooth and exposed to a laser beam at 3 different power and speed settings in the National Institute of Standards and Technology (NIST) Additive Manufacturing Metrology Testbed (AMMT) and a commercial AM machine. The solidified track remaining in the metal surface after the passing of the laser is a physical record of the position of the air-liquid-solid interface of the melt pool trailing behind the laser. The surface topography of these tracks was measured and quantified using confocal laser scanning microscopy (CLSM) for use as benchmarks in AM model development and validation. These measurements are part of the Additive Manufacturing Benchmark Test Series (AM-Bench).

Simulation of TTT Curves for Additively Manufactured Inconel 625.

The ability to use common computational thermodynamic and kinetic tools to study the microstructure evolution in Inconel 625 (IN625) manufactured using the additive manufacturing (AM) technique of laser powder-bed fusion is evaluated. Solidification simulations indicate that laser melting and re-melting during printing produce highly segregated interdendritic regions. Precipitation simulations for different degrees of segregation show that the larger the segregation, i.e., the richer the interdendritic regions are in Nb and Mo, the faster the δ-phase (Ni3Nb) precipitation. This is in accordance with the accelerated d precipitation observed experimentally during post-build heat treatments of AM IN625 compared to wrought IN625. The δ-phase may be undesirable since it can lead to detrimental effects on the mechanical properties. The results are presented in the form of a TTT diagram and agreement between the simulated diagram and the experimental TTT diagram demonstrate how these computational tools can be used to guide and optimize post-build treatments of AM materials.

Grafts for Peyronie's disease: a comprehensive review.

The difficulty implicit in combining all the characteristics that an ideal patch to treat Peyronie's disease with a lengthening procedure should have, together with the challenges of comparing results from different series, means that the ideal patch has yet to be determined. Our objective with this review was to determine whether any given patch type is preferable to the others based on the evaluation of the results of published studies. A systematic search of the literature was conducted from PubMed until December 2016. Articles reporting basic research, animal research, reviews or meta-analyses and studies in children were eliminated. Series with patients undergoing some kind of other surgical intervention were only included if results were reported separately. Case reports and series of five patients were excluded. Five variables were selected to evaluate the results: number of patients, follow-up period, straightening rate, shortening rate and post-operative ED rate. For this purpose, 69 papers were included for review, and the outcomes of the use of autologous dermis, tunica vaginalis, dura mater, fascia, saphenous vein, tunica albuginea, buccal mucosa, porcine intestinal submucosa, pericardium, TachoSil® and synthetic materials were presented and analysed separately. The different series published are extremely variable and heterogeneous in terms of the number of patients included, patient selection, follow-up periods, and in the measurement and interpretation of the outcomes analysed. Given these facts, it is not possible to draw any definitive conclusion, homogeneous, prospective studies using validated tools are required to determine which the ideal graft is.

The Influence of Annealing Temperature and Time on the Formation of δ-Phase in Additively-Manufactured Inconel 625.

This research evaluated the kinetics of δ-phase growth in laser powder bed additively-manufactured (AM) Inconel 625 during post-build stress-relief heat treatments. The temperatures ranged between 650°C and 1050°C, and the times from 0.25 to 168 hours. The presence of δ-phase was verified for each temperature/time combination through multiple techniques. A conventional time-temperature-transformation diagram was constructed from the time-temperature data. Comparison to the growth in wrought IN625 with a similar nominal composition revealed that δ-phase formation occurred at least two orders of magnitude faster in the AM IN625. The results of this study also revealed that the segregated microstructure in the as-built condition has a strong influence on the kinetics of δ-phase formation in AM IN625 as compared to a homogenized material. Since control of the δ-phase growth is essential for reliable prediction of the performance of IN625 components in service, avoiding heat treatments that promote the formation of δ-phase in AM components that are not homogenized is highly recommended. This will be particularly true at elevated temperatures where the microstructural stability and the consistency of mechanical properties are more likely to be affected by the presence of δ-phase.

The Influence of Post-Build Microstructure on the Electrochemical Behavior of Additively Manufactured 17-4 PH Stainless Steel.

The additive manufacturing (AM) build process produces a segregated microstructure with significant variations in composition and phases that are uncommon in traditional wrought materials. As such, the relationship between the post-build microstructure and the corrosion resistance is not well understood. Stainless steel alloy 17-4PH is an industrially-relevant alloy for applications requiring high-strength and good corrosion resistance. A series of potentiodynamic scans conducted in a deaerated 0.5 mol/L NaCl solution evaluated the influence of these microstructural differences on the pitting behavior of SS17-4. The pitting potentials were found to be higher in the samples of additively-processed material than in samples of the alloy in wrought form. This indicates that the additively-processed material is more resistant to localized corrosion and pitting in this environment than the wrought alloy. The results also suggest that after homogenization, the additively-produced SS17-4 could be more resistant to pitting than wrought SS17-4 in an actual service environment.

Surgical outcomes from limiting the use of nonabsorbable suture in tunica albuginea plication for Peyronie's disease.

Tunica albuginea plication (TAP) surgery for Peyronie's disease (PD) is classically described using nonabsorbable suture. Many patients are aware of nodularity at the suture sites (50-88%), and some find them painful (10-33%). We explore whether limiting permanent sutures provides a durable correction of curve and report the incidence of bothersome nodules. Beginning in 2007, we modified our TAP procedure to limit the use of permanent sutures. We reviewed all patients who underwent TAP procedures from 2007 to 2014 at our institution. Patients were contacted to complete a previously published survey regarding postoperative satisfaction. In total, 142 PD patients underwent the TAP procedure and 81/142 (57%) completed the postoperative survey. Mean office follow-up and survey follow-up were 17.3 and 56.3 months, respectively. Of the surveyed patients, 6.2% complained of a bothersome residual curve, 19.8% experienced nodularity and 4.9% reported bothersome nodules. Men with dorsal curves experienced less painful nodularity than those with ventral (P=0.047) or lateral curves (P=0.017). In total, 4/142 (2.8%) of men underwent repeat intervention. At long-term follow-up, limiting permanent sutures during TAP procedures for PD is durable with respect to curvature correction and has encouragingly low levels of nodularity and bother at suture sites.

Designing a Uniaxial Tension/Compression Test for Springback Analysis in High-Strength Steel Sheets.

We describe an innovative design for an in-plane measurement technique that subjects thin sheet metal specimens to bidirectional loading. The goal of this measurement is to provide the critical performance data necessary to validate complex predictions of the work hardening behavior during reversed uniaxial deformation. In this approach, all of the principal forces applied to the specimen are continually measured in real-time throughout the test. This includes the lateral forces that are required to prevent out of plane displacements in the specimen that promote buckling. This additional information will, in turn, improve the accuracy of the compensation for the friction generated between the anti-bucking guides and the specimen during compression. The results from an initial series of experiments not only demonstrate that our approach is feasible, but that it generates data with the accuracy necessary to quantify the directionally-dependent changes in the yield behavior that occur when the strain path is reversed (i.e., the Bauschinger Effect).

Factors associated with postpartum follow-up and persistent hypertension among women with severe preeclampsia.

OBJECTIVE: To determine factors associated with lower 6-week postpartum follow-up rates and persistent hypertension among women with preeclampsia with severe features (PEC-S). STUDY DESIGN: Planned secondary analysis of a retrospective cohort study of women with PEC-S. Outcomes were (1) attendance at the 6-week postpartum visit and (2) persistent hypertension. RESULTS: One hundred ninety-three women were in the final cohort. The 6-week follow-up rate was 52.3%. Factors associated with lower follow-up were African-American race (OR 0.37 (0.18-0.77)) and <5 prenatal visits (OR 0.44 (0.20-0.97)). Women with diabetes and women with a cesarean had higher follow-up (OR 4.00 (1.09-14.66) and 2.61 (1.40-4.88), respectively). Among those with 6-week follow-up, 21% had persistent hypertension. Obese women, women diagnosed with PEC-S by severe range blood pressure (BP) and women discharged home on BP medication were more likely to have persistent hypertension (OR 3.50 7 (1.06-11.58), 3.58 (1.11-11.54) and 3.04 (1.12-8.23), respectively). CONCLUSION: We identified a subgroup of women at higher risk for poor postpartum follow-up and those at risk for persistent hypertension.

Induction, labor length and mode of delivery: the impact on preeclampsia-related adverse maternal outcomes.

OBJECTIVE: The objectives were to evaluate whether induction, specifically prolonged labor, was associated with adverse maternal outcomes related to preeclampsia with severe features (PEC-S) and whether cesarean affected the rate. STUDY DESIGN: This was a retrospective cohort study of women with PEC-S ⩾34 weeks who were diagnosed either before planned cesarean or before induction/latent labor. The primary outcome was a composite adverse maternal outcome related to PEC-S. RESULTS: The final cohort comprised 193 women (n=172 with labor and n=21 with planned cesarean). The prevalence of the outcome was 15.5%. Women exposed to labor did not have a higher rate compared with planned cesarean (16.3% vs 9.5%, P=0.4). Adjusting for confounders, women with a cesarean after prolonged labor had a 10-fold higher adverse outcome risk compared with women with a planned cesarean (adjusted odds ratio (aOR) 9.7 (1.2 to 78.6), P=0.03) or with a vaginal delivery <24 h (aOR 9.7 (1.4 to 67.4), P=0.02). CONCLUSION: Prolonged labor and cesarean in labor were both associated with an increase in our outcome.

Clinical factors associated with readmission for postpartum hypertension in women with pregnancy-related hypertension: a nested case control study.

OBJECTIVE: To evaluate the association between mode of delivery and length of labor on readmission for postpartum hypertension in women with pregnancy-related hypertension. STUDY DESIGN: Nested case control study within a cohort of 99 women with pregnancy-related hypertension who delivered at our institution between 2005 and 2009. Data were abstracted for clinical and labor information. Mode of delivery and length of labor were compared between women with previously diagnosed pregnancy-related hypertension readmitted within 4 weeks post partum (25 cases) and those not readmitted (74 controls). Categorical and continuous variables were compared using χ(2) and T-tests, respectively. Multivariable logistic regression controlled for confounders. RESULT: Hypertension readmission was not associated with mode of delivery (cases: 10(40%) spontaneous vaginal delivery, 15(60%) cesarean delivery; controls: 38(51%) spontaneous vaginal delivery, 36(49%) cesarean delivery, P=0.33). Length of labor appeared longer in cases, with a trend toward significance (median: 15.5 [7,28] h vs 10.75 [5.8,15.9] h, P=0.12) and was significantly associated with readmission after controlling for delivery mode, induction and parity (adjusted odds ratio=1.06 [1 to 1.12], P=0.048). Readmitted patients were less likely to have initially been started on antihypertensive medications after controlling for age, race and chronic hypertension (adjusted odds ratio=0.23 [0.06 to 0.88], P=0.03). CONCLUSION: Postpartum readmission for hypertension in women with known pregnancy-related hypertension is not associated with mode of delivery, appears increased in those with longer length of labor and decreased in those initially started on antihypertensive medications. This provides targets for future research to continue to improve transitions of care and reduce preventable readmissions.

Topical treatment for acute phase Peyronie's disease utilizing a new gel, H-100: a randomized, prospective, placebo-controlled pilot study.

Safety and efficacy of topically applied gel H-100 composed of Nicardipine, superoxide dismutase and emu oil for treatment of acute phase Peyronie's disease (PD) was evaluated. Twenty-two patients (PD <12 months duration) were studied in a prospective, randomized, double-blind, placebo-controlled study. Eleven patients received H-100 and 11 patients received placebo for 3 months. All 22 patients then received H-100 for the final 3 months. Flaccid-stretched penile length, degree of penile curvature, pain level and side effects were assessed monthly. H-100 showed significant improvement in all PD parameters at 6 months: mean stretched penile length increase (22.6%, P=0.0002), mean curvature reduction (40.8%, P=0.0014), and mean pain level reduction (85.7%, P=0.004). Placebo group showed no significant improvement except for mean stretched penile length increase (6.8%, P=0.009). Crossover patients from placebo to H-100 showed significant improvement in all parameters: mean stretched penile length increase (17.5%, P=0.000007), mean curvature reduction (37.1%, P=0.006), and mean pain level reduction (40%, P=0.17). Treatment was well tolerated. A self-limited rash was the only side effect in three patients. Statistically significant improvements in flaccid-stretched penile length, curvature and pain suggest that H-100 is a safe and possibly effective non-invasive, topically applied treatment for acute phase Peyronie's Disease.

Peyronie's disease: urologist's knowledge base and practice patterns.

Peyronie's disease (PD) is a poorly understood clinical entity. We performed an in-depth analysis of the knowledge base and current practice patterns of urologists in the United States. A 46-question instrument was created by two experienced PD practitioners and emailed to current American Urology Association members nationally. Questions were either multiple-choice or used a visual analogue scale. Responses regarding treatment options were answered by ranking a list of utilized therapies by preference. Data were aggregated and mean values for each category compiled. Responses were received from 639 urologists (67% in private practice). Almost all (98%) reported seeing PD patients with regularity. Twenty-six percent believed PD prevalence is ≤1%, a small fraction (5%) reporting prevalence as ≥10%. Only 3% referred patients to a subspecialist in PD. Twenty-six percent believed PD is a condition that does not warrant any treatment. The preferred initial management was with oral agents (81%). Of those who used intralesional injections as first line, verapamil was most commonly selected (67%). Seventy-nine percent perform surgery for PD with 86% reporting the optimal timing at ≥12 months after onset of symptoms. Seventy percent perform penile plication, most commonly the Nesbit technique (54%), 61% perform implant surgery and 37% reported performing plaque incision/excision and grafting. Although PD is now a more recognized condition, there are still large variances in knowledge and management strategies. Prospective clinical studies are needed to elucidate standardized management guidelines and a more cohesive strategy to manage this common disease.

Ab initio study of the mechanical and transport properties of pure and contaminated silver nanowires.

The mechanical properties and conductance of contaminated and pure silver nanowires were studied using density functional theory (DFT) calculations. Several nanowires containing O2 on their surfaces were elongated along two different directions. All of the NWs thinned down to single atom chains. In most simulations, the breaking force was not affected by the presence of the O2, and similar fracture strengths of ≈1 nN were computed for the pure and impure NWs. When the O2 became incorporated in the single atom chain, the fracture occurred at the Ag-O bond and a lower fracture strength was found. All of the simulations showed that the impurity interacted with the silver atoms to reduce the electron density in its nearby vicinity. A variety of conductance effects were observed depending on the location of the impurity. When the impurity migrated during the elongation to the thinnest part of the NW, it reduced the conductance significantly, and an ≈1 G0 conductance (usually associated with a single atom chain) was calculated for three- and two-dimensional structures. When the impurity was adjacent to the single atom chain, the conductance reduced almost to zero. However, when it stayed far from the thinnest part of the NW, the impurity had only a small influence on the conductance.

Review of non-surgical treatment options for Peyronie's disease.

Non-surgical treatment of Peyronie's disease (PD) has come a long way since it was first described in 1743. A myriad of treatment options are currently available, including oral, intralesional and external energy therapies. The purpose of this article is to review the contemporary literature on non-surgical therapies for PD, and where possible, focus on randomized, placebo-controlled trials, as well as review the latest guidelines for the management of PD from the International Committee on Sexual Medicine, which conveyed its findings in July 2009. At this time, it appears that a combination of oral agents and/or intralesional injection with traction therapy may provide a synergy between the chemical effects of the drugs and the mechanical effects of traction. Until a reliable treatment emerges, it does appear that some of the non-surgical treatments discussed can be used to stabilize the scarring process and may result in some reduction of deformity with improved sexual function.