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ObjectiveTo determine the reproducibility of the World Health Organization Fifth Edition (WHO5) strict grading methodology by comparing the percentage of morphologically normal sperm (PNS) recorded by the core laboratory with results obtained at the fertility centers participating in a multisite clinical trial.DesignSecondary cohort analysis of data from the Males, Antioxidants, and Infertility trial.SettingFertility centers.PatientsSemen values of 171 men participating in a multicenter, double-blind, randomized, placebo-controlled trial evaluating the effect of antioxidants on male fertility.InterventionsNot applicable.Main outcome measuresStrict morphology expressed as PNS as determined at each fertility center and the core central laboratory for the same semen sample.ResultsNo correlation was found in the PNS values for the same semen sample between the core laboratory and fertility center laboratories either as a group or by individual site. Interobserver agreement was similarly low (κ = 0.05 and 0.15) between the core and fertility laboratories as a group for strict morphology, categorized by the WHO5 lower reference limits of 4% and 0, respectively. Moderate agreement was found between the core and 2 individual fertility laboratories for the cutoff value of 0 (κ = 0.42 and 0.57). The remainder of the comparisons demonstrated poor to fair agreement.ConclusionsStrict morphology grading using the WHO5 methodology demonstrated overall poor reproducibility among a cohort of experienced fertility laboratories. This lack of correlation and agreement in the PNS values calls into question the reproducibility, and thereby the potential applicability, of sperm strict morphology testing.

ObjectiveTo assess attitudes and factors that influence public opinion in the general US population toward insurance coverage and provision of infertility care to lower income patients.DesignCross-sectional survey.SettingOnline.PatientsA nationally representative sample of US residents.InterventionsQuestionnaire with multiple choice and open response questions.Main outcome measuresPublic attitudes toward in vitro fertilization and infertility care coverage for lower income patients.ResultsA total of 1,027 (90.2%) participants completed the survey, among whom 620 (60.4%) had private insurance, 275 (26.8%) had Medicare/Medicaid, and 56 (5.5%) were uninsured. The majority (916, 89.2%) did not consider infertility a disease. Over half of the respondents (568, 55.3%) supported private insurance coverage of infertility services, including for in vitro fertilization. Most respondents, 735 (71.6%) believed that the prevalence and psychosocial impact of infertility were equal among the lower and higher income people. The majority of respondents with an opinion (512, 67.6%) believed that doctors should provide infertility treatments regardless of the income level of the patients. Of supporters, 40.1% believed in the right to have a family regardless of income, and 38.2% believed that doctors had a social responsibility to provide infertility services. After adjusting for covariates, age

ObjectiveTo examine the factors associated with increased deoxyribonucleic acid fragmentation index (DFI), evaluate the pregnancy outcomes of men with increased DFI, and compare three independent DFI assays.DesignSecondary analysis.SettingNine US-based fertility centers.PatientsInfertile men (N = 147) with sperm concentration ≤15 × 106/mL, motility ≤40%, or normal morphology ≤4% were enrolled. The female partners were ovulatory, ≤40 years old, and had documented tubal patency.InterventionsAt a baseline visit, the men provided a semen sample. The couples attempted conception without assistance for 3 months and with ovarian stimulation and intrauterine insemination in the subsequent 3 months.Main outcome measuresThe DFI was analyzed using the sperm chromatin structure assay (SCSA) with increased DFI defined as >30%. The predictors of increased DFI were determined by a multivariable linear regression model. The pregnancy outcomes were compared using the χ2 test. The independent DFI assays (SCSA, deoxynucleotidyl transferase-mediated dUTP nick end labeling, and Comet) were compared with Pearson and Spearman correlations.ResultsThe 19% of men with increased DFI were older (36.0 vs. 33.0 years) and had lower total sperm motility (38.2% ± 20.5% vs. 45.2% ± 15.6%). Increased male age was found to be a significant predictor of DFI (0.75, 95% confidence interval [0.06, 1.45]). Increased DFI was not associated with conception or live birth. There was a modest correlation of the deoxynucleotidyl transferase-mediated dUTP nick end labeling assay with the SCSA (r = 0.34) and Comet assay (r = 0.19).ConclusionsOlder age was associated with increased DFI among infertile men. The DFI assays were only weakly correlated, indicating a standard definition of DFI is needed to truly interrogate how sperm deoxyribonucleic acid fragmentation impacts male fertility.

PurposeToday, male and female adult and pediatric cancer patients, individuals transitioning between gender identities, and other individuals facing health extending but fertility limiting treatments can look forward to a fertile future. This is, in part, due to the work of members associated with the Oncofertility Consortium.MethodsThe Oncofertility Consortium is an international, interdisciplinary initiative originally designed to explore the urgent unmet need associated with the reproductive future of cancer survivors. As the strategies for fertility management were invented, developed or applied, the individuals for who the program offered hope, similarly expanded. As a community of practice, Consortium participants share information in an open and rapid manner to addresses the complex health care and quality-of-life issues of cancer, transgender and other patients. To ensure that the organization remains contemporary to the needs of the community, the field designed a fully inclusive mechanism for strategic planning and here present the findings of this process.ResultsThis interprofessional network of medical specialists, scientists, and scholars in the law, medical ethics, religious studies and other disciplines associated with human interventions, explore the relationships between health, disease, survivorship, treatment, gender and reproductive longevity.ConclusionThe goals are to continually integrate the best science in the service of the needs of patients and build a community of care that is ready for the challenges of the field in the future.

BackgroundFew studies have examined health literacy and fertility knowledge among women from low income, socio-culturally diverse communities presenting for fertility care in the United States. Our study sought to examine demographic predictors of fertility-related knowledge among infertile women from low and high-resource communities in two major metropolitan centers in the United States.MethodsFertility Knowledge Assessments were administered to women presenting for fertility care at county medical centers serving low-resource, largely immigrant patients and to women from largely affluent populations presenting to comprehensive fertility centers in two cities. The influence of demographic predictors on fertility knowledge was examined through regression analysis.ResultsA total of 143 women were included in our analysis. In the county hospital/low resource clinic (LR, n = 70), the mean age was 32.8 ± 6.1 years vs 35.0 ± 5.0 years in the fee-for-service/high resource clinic (HR, n = 73). Among the LR patients, 74% were immigrants, 71% had an annual income $100,000, and 95% had some college or above. On average, women from HR settings scored 3.0 points higher on the Fertility Knowledge Assessment than their LR counterparts (p

Once unimaginable, fertility management is now a nationally established part of cancer care in institutions, from academic centers to community hospitals to private practices. Over the last two decades, advances in medicine and reproductive science have made it possible for men, women and children to be connected with an oncofertility specialist or offered fertility preservation soon after a cancer diagnosis. The Oncofertility Consortium's National Physicians Cooperative is a large-scale effort to engage physicians across disciplines - oncology, urology, obstetrics and gynecology, reproductive endocrinology, and behavioral health - in clinical and research activities to enable significant progress in providing fertility preservation options to children and adults. Here, we review the structure and function of the National Physicians Cooperative and identify next steps.

Extracellular microRNAs (miRNAs) and other small RNAs are implicated in cellular communication and may be useful as disease biomarkers. We systematically compared small RNAs in 12 human biofluid types using RNA sequencing (RNA-seq). miRNAs and tRNA-derived RNAs (tDRs) accounted for the majority of mapped reads in all biofluids, but the ratio of miRNA to tDR reads varied from 72 in plasma to 0.004 in bile. miRNA levels were highly correlated across all biofluids, but levels of some miRNAs differed markedly between biofluids. tDR populations differed extensively between biofluids. Y RNA fragments were seen in all biofluids and accounted for >10% of reads in blood plasma, serum, and cerebrospinal fluid (CSF). Reads mapping exclusively to Piwi-interacting RNAs (piRNAs) were very rare, except in seminal plasma. These results demonstrate extensive differences in small RNAs between human biofluids and provide a useful resource for investigating extracellular RNA biology and developing biomarkers.

BackgroundInfertility is a prevalent disease of reproductive health that exerts an impact on an estimated 80 million people worldwide. For many, involuntary childlessness becomes a central and preoccupying issue in their lives, the impact of which is exacerbated by lack of access to basic care and treatment. These effects maybe further magnified among immigrant communities, a growing but highly marginalized population that has been shown in other areas of reproductive health to experience worse health outcomes and delays in access to care. To date, few studies have examined the unique medical and sociocultural considerations of infertility among immigrant populations in the United States.MethodsOur study is a cross-sectional analysis of women presenting for infertility evaluation at a county hospital serving a low resource, socioculturally diverse largely immigrant communities in comparison to infertile women from a largely affluent population presenting to a high resource, comprehensive fertility center. We employed surveys to evaluate demographics and socioeconomic parameters as well as abstracted data from medical records to obtain infertility diagnoses. Multivariate regression analysis was applied to examine impact of sociocultural factors as predictors of duration of untreated infertility disease burden experienced by patients.ResultsEighty-seven women were included in our analysis. In the county hospital/low resource clinic (LR), the mean age was 32.9 ± 4.9 vs 36.4 ± 6.3 years in the fee-for-service/high resource clinic (HR). The mean reported duration of infertility in LR and HR patients was 3.4 ± 3.0 vs 2.3 ± 1.5 years. 70% of LR patients were monolingual non-English speakers vs 5.4% of HR patients. 59% of LR patients reported an annual household income of less than $25,000 and 70% did not have a college degree. 81.1% of HR patients reported an income of higher than $100,000, and 81.1% had completed college or graduate school. The most common infertility diagnosis in the LR was anovulation (38%) and tubal factor (28%) compared to diminished ovarian reserve (37.8%) and male factor (51.4%) in the HR. After controlling for age at the initiation of pregnancy attempt, lower education level, lower income, and immigrant status were significantly correlated with a longer duration of infertility.ConclusionsWomen presenting for infertility care to a low resource county medical center represent immigrant communities and are generally of younger age, but with a longer duration of infertility. This study identifies lower educational level, income, and immigrant status as barriers in access to care.

Unlike other human biological fluids, semen contains multiple types of amyloid fibrils in the absence of disease. These fibrils enhance HIV infection by promoting viral fusion to cellular targets, but their natural function remained unknown. The similarities shared between HIV fusion to host cell and sperm fusion to oocyte led us to examine whether these fibrils promote fertilization. Surprisingly, the fibrils inhibited fertilization by immobilizing sperm. Interestingly, however, this immobilization facilitated uptake and clearance of sperm by macrophages, which are known to infiltrate the female reproductive tract (FRT) following semen exposure. In the presence of semen fibrils, damaged and apoptotic sperm were more rapidly phagocytosed than healthy ones, suggesting that deposition of semen fibrils in the lower FRT facilitates clearance of poor-quality sperm. Our findings suggest that amyloid fibrils in semen may play a role in reproduction by participating in sperm selection and facilitating the rapid removal of sperm antigens.

IntroductionInfertility affects approximately 6.7 million women in the United States. Couples with infertility have significantly more anxiety, depression, and stress. This is compounded by the fact that almost 40% of couples undergoing assisted reproduction technology still cannot conceive, which can have an ongoing effect on quality of life, marital adjustment, and sexual impact.AimTo assess the sexual impact of infertility in women undergoing fertility treatment.MethodsThis study is a cross-sectional analysis of women in infertile couples seeking treatment at academic or private infertility clinics. Basic demographic information was collected. Respondents were surveyed regarding sexual impact and perception of their infertility etiology. Multivariate regression analyses were used to identify factors independently associated with increased sexual impact.Main outcome measureSexual impact of perceived fertility diagnosis.ResultsIn total, 809 women met the inclusion criteria, of whom 437 (54%) agreed to participate and 382 completed the sexual impact items. Most of the infertility was female factor only (58.8%), whereas 30.4% of infertility was a combination of male and female factors, 7.3% was male factor only, and 3.5% was unexplained infertility. In bivariate and multivariate analyses, women who perceived they had female factor only infertility reported greater sexual impact compared with woman with male factor infertility (P = .01). Respondents who were younger than 40 years experienced a significantly higher sexual impact than respondents older than 40 years (P < .01). When stratified by primary and secondary infertility, respondents with primary infertility overall reported higher sexual impact scores.ConclusionIn women seeking fertility treatment, younger age and female factor infertility were associated with increased sexual impact and thus these women are potentially at higher risk of sexual dysfunction. Providers should consider the role young age and an infertility diagnosis plays in a women's sexual well-being.

Steroids regulate cell proliferation, tissue development, and cell signaling via two pathways: a nuclear receptor mechanism and genome-independent signaling. Sperm activation, egg maturation, and steroid-induced anesthesia are executed via the latter pathway, the key components of which remain unknown. Here, we present characterization of the human sperm progesterone receptor that is conveyed by the orphan enzyme α/β hydrolase domain-containing protein 2 (ABHD2). We show that ABHD2 is highly expressed in spermatozoa, binds progesterone, and acts as a progesterone-dependent lipid hydrolase by depleting the endocannabinoid 2-arachidonoylglycerol (2AG) from plasma membrane. The 2AG inhibits the sperm calcium channel (CatSper), and its removal leads to calcium influx via CatSper and ensures sperm activation. This study reveals that progesterone-activated endocannabinoid depletion by ABHD2 is a general mechanism by which progesterone exerts its genome-independent action and primes sperm for fertilization.

Prepubertal boys treated with high-dose chemotherapy do not have an established means of fertility preservation because no established in vitro technique exists to expand and mature purified spermatogonial stem cells (SSCs) to functional sperm in humans. In this study, we define and characterize the unique testicular cellular niche required for SSC expansion using testicular tissues from men with normal spermatogenesis. Highly purified SSCs and testicular somatic cells were isolated by fluorescence-activated cell sorting using SSEA-4 and THY1 as markers of SSCs and somatic cells. Cells were cultured on various established niches to assess their role in SSC expansion in a defined somatic cellular niche. Of all the niches examined, cells in the SSEA-4 population exclusively bound to adult testicular stromal cells, established colonies, and expanded. Further characterization of these testicular stromal cells revealed distinct mesenchymal markers and the ability to undergo differentiation along the mesenchymal lineage, supporting a testicular multipotent stromal cell origin. In vitro human SSC expansion requires a unique niche provided exclusively by testicular multipotent stromal cells with mesenchymal properties. These findings provide an important foundation for developing methods of inducing SSC growth and maturation in prepubertal testicular tissue, essential to enabling fertility preservation for these boys.

UnlabelledSemen enhances HIV infection in vitro, but how long it retains this activity has not been carefully examined. Immediately postejaculation, semen exists as a semisolid coagulum, which then converts to a more liquid form in a process termed liquefaction. We demonstrate that early during liquefaction, semen exhibits maximal HIV-enhancing activity that gradually declines upon further incubation. The decline in HIV-enhancing activity parallels the degradation of peptide fragments derived from the semenogelins (SEMs), the major components of the coagulum that are cleaved in a site-specific and progressive manner upon initiation of liquefaction. Because amyloid fibrils generated from SEM fragments were recently demonstrated to enhance HIV infection, we set out to determine whether any of the liquefaction-generated SEM fragments associate with the presence of HIV-enhancing activity. We identify SEM1 from amino acids 86 to 107 [SEM1(86-107)] to be a short, cationic, amyloidogenic SEM peptide that is generated early in the process of liquefaction but that, conversely, is lost during prolonged liquefaction due to the activity of serine proteases. Synthetic SEM1(86-107) amyloids directly bind HIV-1 virions and are sufficient to enhance HIV infection of permissive cells. Furthermore, endogenous seminal levels of SEM1(86-107) correlate with donor-dependent variations in viral enhancement activity, and antibodies generated against SEM1(86-107) recognize endogenous amyloids in human semen. The amyloidogenic potential of SEM1(86-107) and its virus-enhancing properties are conserved among great apes, suggesting an evolutionarily conserved function. These studies identify SEM1(86-107) to be a key, HIV-enhancing amyloid species in human semen and underscore the dynamic nature of semen's HIV-enhancing activity.ImportanceSemen, the most common vehicle for HIV transmission, enhances HIV infection in vitro, but how long it retains this activity has not been investigated. Semen naturally undergoes physiological changes over time, whereby it converts from a gel-like consistency to a more liquid form. This process, termed liquefaction, is characterized at the molecular level by site-specific and progressive cleavage of SEMs, the major components of the coagulum, by seminal proteases. We demonstrate that the HIV-enhancing activity of semen gradually decreases over the course of extended liquefaction and identify a naturally occurring semenogelin-derived fragment, SEM1(86-107), whose levels correlate with virus-enhancing activity over the course of liquefaction. SEM1(86-107) amyloids are naturally present in semen, and synthetic SEM1(86-107) fibrils bind virions and are sufficient to enhance HIV infection. Therefore, by characterizing dynamic changes in the HIV-enhancing activity of semen during extended liquefaction, we identified SEM1(86-107) to be a key virus-enhancing component of human semen.

ObjectiveTo determine the time that infertile couples spend seeking and utilizing fertility care.DesignProspective cohort.SettingEight community and academic infertility practices.Patient(s)A total of 319 couples presenting for a fertility evaluation.Intervention(s)Face-to-face and telephone interviews and questionnaires.Main outcome measure(s)Participants recorded diaries of time spent on provider visits, travel, telephone, and miscellaneous activities. Participants also recorded time off from work due to the physical and mental stress related to fertility care. Linear regression was used to assess relationship between fertility characteristics and time spent pursuing care.Result(s)Diaries were completed by 319 subjects. Over an 18-month time period, the average time spent on fertility care was 125 hours, equating to 15.6 days, assuming an 8-hour workday. For couples utilizing cycle-based treatments (CBT), overall time spent pursuing care averaged 142 hours, versus 58 hours for couples using other therapies, with the majority of time spent on provider visits (73 hours). After multivariable adjustment for clinical and sociodemographic characteristics, possessing a college degree and intensity of fertility treatment were independently associated with increased time spent pursuing fertility care. Furthermore, couples that spent the most time on care were significantly more likely to experience fertility-related stress.Conclusion(s)Over the course of 18 months of observation, couples pursuing fertility treatment dedicated large amounts of time to attaining their family-building goals. This burden on couples adds to the already significant financial and emotional burdens of fertility treatment and provides new insight into the difficulties that these couples face.

IntroductionThe prevalence and associations of sexual bother in male medical students has not been extensively studied.AimsThe aim of this study is to analyze predictors of sexual bother in a survey of male North American medical students.MethodsStudents enrolled in allopathic and osteopathic medical schools in North America between February 2008 and July 2008 were invited to participate in an internet-based survey of sexuality and sexual function.Main outcome measuresThe principle outcome measure was a single-item question inquiring about global satisfaction with sexual function. The survey also consisted of a questionnaire that included ethnodemographic factors, student status, sexual history, and a validated scale for the assessment of depression. Respondents completed the International Index of Erectile Function, the premature ejaculation diagnostic tool, and the Self-Esteem and Relationship Quality survey (SEAR). Descriptive statistics, analysis of variance, and multivariable logistic regression were utilized to analyze responses.ResultsThere were 480 male subjects (mean age 26.3 years) with data sufficient for analysis. Forty-three (9%) reported sexual bother. Sexual bother was significantly more common in men with erectile dysfunction (ED), high risk of premature ejaculation (HRPE), depressive symptoms, and lower sexual frequency. However, after multivariate analysis including SEAR scores, ED, and HRPE were no longer independently predictive of sexual bother. Higher scores for all domains of the SEAR were associated with lower odds of sexual bother.ConclusionsED and HRPE are associated with sexual bother in this young and presumably healthy population. However, after controlling for relationship factors neither ED nor HRPE independently predicted sexual bother. It is plausible to hypothesize that sexual dysfunction from organic causes is rare in this population and is seldom encountered outside of relationship perturbations. Attention to relationship and psychological factors is likely of key importance in addressing sexual concerns in this population.

This retrospective cohort study from a single clinical practice enrolled patients with evidence of calcified Peyronie's disease (PD) plaques detected on penile ultrasound at the time of initial presentation. The primary objective was to describe the effect of pentoxifylline (PTX) treatment on subtunical calcifications in men with PD. A PD-specific questionnaire was administered and sonographic evaluations were performed at baseline and follow-up visits. Descriptive statistics and χ(2) analysis were used to characterize the effect of PTX on calcified tunical plaques. In all, 71 men (mean age: 51.9 years) with PD and sonographic evidence of calcification were identified. Of them, 62 of these men were treated with PTX for a mean duration of 1 year, and nine with vitamin E or no treatment. Improvement or stabilization in calcium burden at follow-up was noted in 57 (91.9%) of men treated with PTX versus four (44.4%) of those not treated with PTX (P

IntroductionThe role of sexuality as an association of medical student well-being has not been extensively studied.AimWe explored the relationship between depressive symptoms, sexuality, and sexual dysfunction in male North American medical students.Main outcome measureNorth American medical students were invited to participate in an Internet-based survey. The Center for Epidemiological Studies Depression Scale (CES-D) was utilized to screen for depressive symptoms.MethodsSubjects completed an ethnodemographic survey, a sexuality survey, and instruments for the quantification of anxiety, sexuality, and psychosocial function. Descriptive statistics, odds ratios (ORs), and logistic regression were used to analyze our data.ResultsThere were 844 male subjects with complete data on the CES-D and the Spielberger State-Trait Anxiety Index. Depressive symptoms (CES-D ≥ 16) were present in 37% of respondents and were more common in subjects with greater levels of anxiety. Subjects who were in sexual relationships and/or had frequent sexual activity were less likely to be depressed compared to other subjects. Erectile dysfunction (ED) was associated with significantly greater likelihood of depressive symptoms (OR 2.90 and 9.27 for depressive symptoms in men with mild or moderate/severe ED relative to men without ED, P < 0.01). After adjusting for ethnodemographic and sexual history factors, ED remained significantly positively associated with depressive symptoms (OR 2.87 and 6.59 for depressive symptoms in men with mild or moderate/severe ED relative to men without ED after adjustment, P ≤ 0.01). Inclusion of data related to psychosocial/relationship factors in the multivariate model eliminated the significant association between ED and depressive symptoms (OR 1.59 and 2.29 for depressive symptoms in men with mild or moderate/severe ED relative to men without ED after adjustment with the Self-Esteem and Relationship quality instrument, P > 0.05), suggesting that psychosocial factors were more strongly associated with depressive symptoms than erectile function.ConclusionHealthy sexuality and relationships may be protective against depressive symptoms in medical students. Attention to these factors may enhance medical student well-being.

PurposeTo determine factors associated with students' comfort in addressing patients' sexuality in the clinical context.MethodThe authors invited students enrolled in MD-degree-granting and osteopathic medical schools in the United States and Canada to participate in an anonymous Internet survey between February and July 2008. The survey assessed ethnodemographic factors and sexual history. Respondents also completed the Center for Epidemiologic Studies Depression Scale. Male respondents completed the International Index of Erectile Function and the Premature Ejaculation Diagnostic Tool. Female respondents completed the Female Sexual Function Index and the Index of Sex Life. The authors used descriptive statistics, ANOVA, and multivariable logistic regression to analyze responses.ResultsThe authors' analyses included 2,261 completed survey responses: 910 from men, 1,343 from women, and 8 from individuals who self-identified as "other" gendered. Over 53% of respondents (n = 1,206) stated that they felt they had not received sufficient training in medical school to address sexual concerns clinically. Despite this, 81% of students (n = 1,827) reported feeling comfortable dealing with their patients' sexuality issues. Students with limited sexual experience, students at risk for sexual problems, and students who felt that they had not been trained adequately were less likely to report being comfortable talking to patients about sexual health issues.ConclusionsPerception of inadequate sexuality training in medical school and personal issues pertaining to sex may be associated with students' difficulty in addressing patients' sexuality. Adequate training is preeminently associated with feeling comfortable addressing patients' sexuality and should be a priority for medical education.

Return on investment (ROI) has long been accepted as a primary tool for decision‐making for capital investments and even choices among competing operational budget lines. Applying ROI to investments intended to prevent or mitigate future risks and hazards can be very difficult, as benefits are typically arduous to define and calculate while risk probabilities can be very small. This paper uses examples from recent research concerning law enforcement, airport security, and airport resiliency to illustrate the feasibility of computing ROI and resiliency ROI (RROI) for such investments and to suggest methodology to approach these computations. [ABSTRACT FROM AUTHOR]