Search

Background: Cannabis use is highly prevalent and detrimental among people with HIV (PWH). Legislative changes in several states altered the legality and accessibility of cannabis. We examined pre-post legislative changes in current, daily, and severe use in PWH in clinical care. Methods: PWH engaged in the Centers for AIDS Research Network of Integrated Clinical Systems (CNICS) cohort from 3 sites/states were asked about past 3-month cannabis use on a routine clinical assessment of health behavior before and after legalization. A fourth site in a state without legalization served as a comparator. We used linear regression to estimate changes in use prevalence from 1 year before to 1 year after legalization. Results: Among PWH (n=7885), from 1 year before to 1 year after legalization, cannabis use prevalence increased slightly in Boston, MA (32–38 %), Birmingham, AL (26–27 %), and San Diego, CA (25–29 %); and decreased in Seattle, WA (44–41 %). Contemporaneously, daily cannabis use increased modestly (less than 5 %) at all sites. Severe use (cannabis-specific ASSIST score ≥27) decreased or plateaued at all sites. No site showed significant change in prevalence trends of current, daily, or severe use 1 year before and after legalization in linear regression (p >0.05). Conclusion: Few changes prevailed in cannabis use patterns around dates of legalization among PWH in care in the U.S. Relaxation of cannabis policy does not appear to result in an immediate increase in use among PWH.

The enhancement of associative synaptic plasticity often results in impaired rather than enhanced learning. Previously, we proposed that such learning impairments can result from saturation of the plasticity mechanism (Nguyen-Vu et al., 2017), or, more generally, from a history-dependent change in the threshold for plasticity. This hypothesis was based on experimental results from mice lacking two class I major histocompatibility molecules, MHCI H2-Kb and H2-Db (MHCI KbDb−/−), which have enhanced associative long-term depression at the parallel fiber-Purkinje cell synapses in the cerebellum (PF-Purkinje cell LTD). Here, we extend this work by testing predictions of the threshold metaplasticity hypothesis in a second mouse line with enhanced PF-Purkinje cell LTD, the Fmr1 knockout mouse model of Fragile X syndrome (FXS). Mice lacking Fmr1 gene expression in cerebellar Purkinje cells (L7-Fmr1 KO) were selectively impaired on two oculomotor learning tasks in which PF-Purkinje cell LTD has been implicated, with no impairment on LTD-independent oculomotor learning tasks. Consistent with the threshold metaplasticity hypothesis, behavioral pre-training designed to reverse LTD at the PF-Purkinje cell synapses eliminated the oculomotor learning deficit in the L7-Fmr1 KO mice, as previously reported in MHCI KbDb−/−mice. In addition, diazepam treatment to suppress neural activity and thereby limit the induction of associative LTD during the pre-training period also eliminated the learning deficits in L7-Fmr1 KO mice. These results support the hypothesis that cerebellar LTD-dependent learning is governed by an experience-dependent sliding threshold for plasticity. An increased threshold for LTD in response to elevated neural activity would tend to oppose firing rate stability, but could serve to stabilize synaptic weights and recently acquired memories. The metaplasticity perspective could inform the development of new clinical approaches for addressing learning impairments in autism and other disorders of the nervous system.

Authors are often faced with the decision of whether to maximize traditional impact metrics or minimize costs when choosing where to publish the results of their research. Many subscription-based journals now offer the option of paying an article processing charge (APC) to make their work open. Though such “hybrid” journals make research more accessible to readers, their APCs often come with high price tags and can exclude authors who lack the capacity to pay to make their research accessible. Here, we tested if paying to publish open access in a subscription-based journal benefited authors by conferring more citations relative to closed access articles. We identified 146,415 articles published in 152 hybrid journals in the field of biology from 2013–2018 to compare the number of citations between various types of open access and closed access articles. In a simple generalized linear model analysis of our full dataset, we found that publishing open access in hybrid journals that offer the option confers an average citation advantage to authors of 17.8 citations compared to closed access articles in similar journals. After taking into account the number of authors, Journal Citation Reports 2020 Quartile, year of publication, and Web of Science category, we still found that open access generated significantly more citations than closed access (p

OBJECTIVES/GOALS: Partnering with the Housing Authority of Los Angeles, we launched a place-based initiative in the Nickerson Gardens housing development in South Los Angeles, where we apply our community engagement approach of listening and learning, and trust and relationship building, to deliver public health interventions in a discrete community. METHODS/STUDY POPULATION: Nickerson Gardens is the largest housing development in Los Angeles, with 1,066 units and over 3,000 residents. 58% and 40% of the residents are Hispanic and Black/African American respectively with an average yearly income of less than $30,000. To build trust and establish relationships, our team began attending community events, holding weekly educational workshops, and participating in the summer program for youth. We also held listening sessions in English and Spanish that asked aboutthe overall health of the Nickerson Gardens community, environment and public space, access and barriers to care, needed healthcare services, and the lived experience within Nickerson Gardens. RESULTS/ANTICIPATED RESULTS: To date, we have held eight 90-minute listening sessions in English and Spanish with 59 participants. The sessions provided insight into theneeded health and educational resources and services, the organizational structure of the housing development and how that impacts access to information and services, as well as the nuanced and area-specific transportation issues and the connection to safety concerns. These findings will inform the next phase of this initiative which includes convening a Coordinating Council composed of service providers and Nickerson Gardens residents. This council will oversee the coordination and implementation of needed services, help maintain accountability of the providers, and offer residents the opportunity to take ownership of the process. DISCUSSION/SIGNIFICANCE: Academic-community partnerships are an effective strategy to deliver public health interventions and promote health equity in under-resourced communities. We tested and measured impact in a distinct community to reinforce a widely-applicable place-based model.

Abstract Obesity induces a chronic inflammatory state associated with changes in adipose tissue macrophages (ATMs). Macrophage scavenger receptor 1 (MSR1) has been implicated in the regulation of adipose tissue inflammation and diabetes pathogenesis; however, reports have been mixed on the contribution of MSR1 in obesity and glucose intolerance. We observed increased MSR1 expression in VAT of obese diabetic individuals compared to non-diabetic and single nuclear RNA sequencing identified macrophage-specific expression of MSR1 in human adipose tissue. We examined male Msr1 −/− (Msr1KO) and WT controls and observed protection from obesity and AT inflammation in non-littermate Msr1KO mice. We then evaluated obese littermate Msr1 +/− (Msr1HET) and Msr1KO mice. Both Msr1KO mice and Msr1HET mice became obese and insulin resistant when compared to their normal chow diet counterparts, but there was no Msr1-dependent difference in body weight, glucose metabolism, or insulin resistance. Flow cytometry revealed no significant differences between genotypes in ATM subtypes or proliferation in male and female mice. We observed increased frequency of proliferating ATMs in obese female compared to male mice. Overall, we conclude that while MSR1 is a biomarker of diabetes status in human adipose tissue, in mice Msr1 is not required for obesity-associated insulin resistance or ATM accumulation.

Abstract Background Huntington’s disease is a complex neurodegenerative hereditary disease with symptoms in all domains of a person’s functioning. It begins after a healthy start in life and leads through the relentless progression over many years to complete care dependency and finally death. To date, the disease is incurable. The long progressive complex nature of the disease demands multiple disciplines for treatment and care of patient and family. These health care providers need inter- and multidisciplinary collaboration to persevere and be efficacious in this devastating disease trajectory. Discussion The position paper outlines current knowledge and experience alongside the experience and consensus of a recognised group of HD multidisciplinary experts. Additionally the patient’s voice is clear and calls for health care providers with a holistic view on patient and family. Building long-term trust is a cornerstone of the network around the patient. This paper describes a managed care network comprising all the needed professionals and services. In the health care system, the role of a central coordinator or case manager is of key importance but lacks an appropriate guideline. Other disciplines currently without guidelines are general practitioners, nurses, psychologists, and social workers. Guidelines for neurologists, psychiatrists, geneticists, occupational therapists, speech and language therapists, physiotherapists, dieticians, and dentists are being discussed. Apart from all these profession-specific guidelines, distinctive inter- and multidisciplinary collaboration requirements must be met. Conclusions and recommendations The complex nature of Huntington's disease demands multidisciplinary treatment and care endorsed by international regulations and the lay association. Available guidelines as reviewed in this paper should be used, made available by a central body, and updated every 3–5 years. Time needs to be invested in developing missing guidelines but the lack of this ‘proof’ should not prevent the ‘doing’ of good care.

BackgroundThe prevalence of substance use in people with HIV (PWH) in the United States is higher than in the general population and is an important driver of HIV-related outcomes. We sought to assess if previously identified genetic associations that contribute to substance use are also observed in a population of PWH.MethodsWe performed genome-wide association studies (GWAS) of alcohol, smoking, and cannabis use phenotypes in a multi-ancestry population of 7,542 PWH from the Center for AIDS Research Network of Integrated Clinical Systems (CNICS). We conducted multi-ancestry GWAS for individuals of African (n = 3,748), Admixed American (n = 1,334), and European (n = 2,460) ancestry. Phenotype data were self-reported and collected using patient reported outcomes (PROs) and three questions from AUDIT-C, an alcohol screening tool. We analyzed nine phenotypes: 1) frequency of alcohol consumption, 2) typical number of drinks on a day when drinking alcohol, 3) frequency of five or more alcoholic drinks in a 30-day period, 4) smoking initiation, 5) smoking cessation, 6) cigarettes per day, 7) cannabis use initiation, 8) cannabis use cessation, 9) frequency of cannabis use during the previous 30 days. For each phenotype we considered a) variants previously identified as associated with a substance use trait and b) novel associations.ResultsWe observed evidence for effects of previously reported single nucleotide polymorphisms (SNPs) related to alcohol (rs1229984, p = 0.001), tobacco (rs11783093, p = 2.22E-4), and cannabis use (rs2875907, p = 0.005). We also report two novel loci (19p13.2, p = 1.3E-8; and 20p11.21, p = 2.1E-8) associated with cannabis use cessation.ConclusionsOur analyses contribute to understanding the genetic bases of substance use in a population with relatively higher rates of use compared to the general population.

BackgroundNigeria has been consistently targeted in sub-Saharan Africa as an HIV-priority country. Its main mode of transmission is heterosexual, and consequently, a key population of interest is female sex workers (FSWs). While HIV prevention services are increasingly implemented by community-based organizations (CBOs) in Nigeria, there is a paucity of evidence on the implementation costs of these organizations. This study seeks to fill this gap by providing new evidence about service delivery unit cost for HIV education (HIVE), HIV counseling and testing (HCT), and sexually transmitted infection (STI) referral services.MethodsIn a sample of 31 CBOs across Nigeria, we calculated the costs of HIV prevention services for FSWs taking a provider-based perspective. We collected 2016 fiscal year data on tablet computers during a central data training in Abuja, Nigeria, in August 2017. Data collection was part of a cluster-randomized trial examining the effects of management practices in CBOs on HIV prevention service delivery. Staff costs, recurrent inputs, utilities, and training costs were aggregated and allocated to each intervention to produce total cost calculations, and then divided by the number of FSWs served to produce unit costs. Where costs were shared across interventions, a weight proportional to intervention outputs was applied. All cost data were converted to US dollars using the mid-year 2016 exchange rate. We also explored the cost variation across the CBOs, particularly the roles of service scale, geographic location, and time.ResultsThe average annual number of services provided per CBO was 11,294 for HIVE, 3,326 for HCT, and 473 for STI referrals. The unit cost per FSW tested for HIV was 22 USD, the unit cost per FSW reached with HIV education services was 19 USD, and the unit cost per FSW reached by STI referrals was 3 USD. We found heterogeneity in total and unit costs across CBOs and geographic location. Results from the regression models show that total cost and service scale were positively correlated, while unit costs and scale were consistently negatively correlated; this indicates the presence of economies of scale. By increasing the annual number of services by 100 percent, the unit cost decreases by 50 percent for HIVE, 40 percent for HCT, and 10 percent for STI. There was also evidence that indicates that the level of service provision was not constant over time across the fiscal year. We also found unit costs and management to be negatively correlated, though results were not statistically significant.ConclusionsEstimates for HCT services are relatively similar to previous studies. There is substantial variation in unit costs across facilities, and evidence of a negative relationship between unit costs and scale for all services. This is one of the few studies to measure HIV prevention service delivery costs to female sex workers through CBOs. Furthermore, this study also looked at the relationship between costs and management practices-the first of its kind to do so in Nigeria. Results can be leveraged to strategically plan for future service delivery across similar settings.

Introduction: No nomogram exists to predict maximum achievable neovaginal depth before penile inversion vaginoplasty (PIV) based on available penile & scrotal skin (SS). Maximal depth is important to patients and is determined by available skin and available anatomic space within the pelvis and varies with surgical technique. Aim: We endeavored to create a nomogram to predict expected postoperative vaginal depth. Methods: Retrospective review of all patients undergoing primary PIV at a single institution from June 2017 to February 2020 (n = 60). Pre-op: Dorsal penile and midline scrotal skin length were measured. Intra-op: Tubularized scrotal skin length measured on a dilator. Immediate post-op: Final vaginal depth measured with a dilator. Outcomes: The amount of available penile and scrotal skin was not associated with vaginal depth. The only variable that did significantly increase depth was the use of penile + scrotal skin, as compared to penile skin alone. (P < .001) Results: In patients who underwent PIV-SS, the final vaginal depth (13.3 ± 1.9 cm) was 87% of pre-op measured penile skin length (15.3 ±- 3.0 cm). In patients who underwent PIV+SS, pre-op penile skin length was 11.1 ± 4.7±cm and pre-op midline scrotal length was 22.8 ± 2.6 cm. with a final post-op vaginal canal depth of 15.2 ± 1.3 cm. In 45/46 (98%) surgeries utilizing SS grafts, SS tube length exceeded the length necessary to achieve maximal vaginal depth, and required trimming and discard. Given that in most cases there was an excess of SS, final post-op depth equaled the maximal vaginal depth that could be surgically dissected, and was not limited by the amount of available skin. Clinical Implications: Our findings suggest that for most patients it should not be necessary to include additional tissue sources (eg, peritoneum) to create a vaginal canal during primary vaginoplasty. Strengths and Limitations: Any penile skin that was discarded due to poor quality (eg, tight phimosis, poor viability) was not measured and accounted for. This likely resulted in a slight overestimation of the contribution of the penile skin to the final vaginal depth, but did not change the overall finding that final depth was not limited by available skin. Conclusion: SS grafts, when harvested and tubularized using optimized technique, supplied an excess of skin necessary to line a vaginal canal space of maximal achievable depth. We found that additional tissue sources can, instead, be reserved for future salvage surgery if it becomes necessary to augment depth.Smith SM, Yuan N, Stelmar J, et al. Penile and Scrotal Skin Measurements to Predict Final Vaginal Depth With Penile Inversion Vaginoplasty. Sex Med 2022;10:100569.

Introduction: Gender-affirming peritoneal vaginoplasty has been described, and previous descriptions are modifications of the Davydov technique. Aim: To describe our alternative technique for gender-affirming peritoneal vaginoplasty (PV) using a single-pedicled, urachus-peritoneal hinge flap, discussing proposed advantages. Methods: Retrospective review of all consecutive transfeminine patients with neovaginal shortening after prior penile inversion vaginoplasty (PIV) who underwent our PV technique from May 2019 to July 2022. PV was performed via combined transperineal and laparoscopic (robot-assisted) approaches. After spatulation of the neovaginal remnant, a midline, inferiorly based urachus-peritoneal hinge flap was elevated craniocaudally from the umbilicus to the mid-posterior bladder. The free end of the flap was flipped posteriorly and sutured to posterior edge of the open canal remnant, forming a peritoneal pouch. The lateral edges of the pouch were sutured together for water-tight closure. Patients resumed dilation on POD 6 and douching on POD 10. Main Outcome Measures: Ten transfeminine patients underwent PV, with good outcomes. We measured: Pre-op penile and scrotal skin lengths, intra-op tubularized scrotal skin length, pre and post-op vaginal depth and width (immediate and at last follow-up). Results: Pre-op: mean neovaginal depth was 9.2cm (SD 1.5); width was 12cm. Immediate post-op: mean depth was 15.1 cm (SD 2.2 cm, mean net increase: 5.9 cm). At mean follow-up of 18.3 months, mean depth was 12.5 cm (SD 2.1 cm, mean net increase: 3.3 cm) and width was 12 cm. There were no immediate post-op complications. Eight (80%) of the 10 patients report satisfactory vaginal receptive intercourse. The other 2 have not yet attempted vaginal receptive intercourse. Clinical Implications: Advantages of the proposed technique over existing techniques include no tension on peritoneal suture lines and total exclusion of the rectum. Strengths and Limitations: Strengths include a short learning curve for urologic surgeons with robotic experience. The study is limited by small sample size. Conclusions: Our PV technique is a safe and effective option for salvage peritoneal vaginoplasty after primary PIV.Smith SM, Yuan N, Stelmar J, et al. An Alternative Option for Gender-Affirming Revision Vaginoplasty: The Tubularized Urachus-Peritoneal Hinge Flap. Sex Med 2022;10:100572.

Mitochondria harbor an independent genome, called mitochondrial DNA (mtDNA), which contains essential metabolic genes. Although mtDNA mutations occur at high frequency, they are inherited infrequently, indicating that germline mechanisms limit their accumulation. To determine how germline mtDNA is regulated, we examined the control of mtDNA quantity and quality in C. elegans primordial germ cells (PGCs). We show that PGCs combine strategies to generate a low point in mtDNA number by segregating mitochondria into lobe-like protrusions that are cannibalized by adjacent cells, and by concurrently eliminating mitochondria through autophagy, reducing overall mtDNA content twofold. As PGCs exit quiescence and divide, mtDNAs replicate to maintain a set point of ~200 mtDNAs per germline stem cell. Whereas cannibalism and autophagy eliminate mtDNAs stochastically, we show that the kinase PTEN-induced kinase 1 (PINK1), operating independently of Parkin and autophagy, preferentially reduces the fraction of mutant mtDNAs. Thus, PGCs employ parallel mechanisms to control both the quantity and quality of the founding population of germline mtDNAs.

Introduction: Permanent genital hair removal is required before gender-affirming vaginoplasty to prevent hair-related complications. No previous studies have directly compared the relative efficacy, costs, and patient experiences with laser hair removal (LHR) vs electrolysis treatments. Food and Drug Administration (FDA) oversight of medical devices is poorly understood and commonly misrepresented, adversely affecting patient care. Aim: This study compares treatment outcomes of electrolysis and LHR for genital hair removal and investigates FDA regulation of electrolysis and LHR devices. Methods: Penile-inversion vaginoplasty and shallow-depth vaginoplasty patients completed surveys about their preoperative hair removal, including procedure type, number/frequency of sessions, cost, and discomfort. Publicly available FDA-review documents and databases were reviewed. Main Outcomes Measure: Compared to electrolysis, LHR was associated with greater efficiency, decreased cost, decreased pain, and improved patient satisfaction. Results: Of 52 total (44 full-depth and 8 shallow-depth) vaginoplasty patients, 22 of 52 underwent electrolysis only, 15 of 52 underwent laser only, and 15 of 52 used both techniques. Compared to patients that underwent LHR only, patients that underwent only electrolysis required a significantly greater number of treatment sessions (mean 24.3 electrolysis vs 8.1 LHR sessions, P < .01) and more frequent sessions (every 2.4 weeks for electrolysis vs 5.3 weeks for LHR, P < .01) to complete treatment (defined as absence of re-growth over 2 months). Electrolysis sessions were significantly longer than LHR sessions (152 minutes vs 26 minutes, P < .01). Total treatment costs for electrolysis ($5,161) were significantly greater than for laser ($981, P < .01). Electrolysis was associated with greater pain and significantly increased need for pretreatment analgesia, which further contributed to higher net costs for treatment with electrolysis vs laser. Many LHR and electrolysis devices have been FDA-cleared for safety, but the FDA does not assess or compare clinical efficacy or efficiency. Clinical Implications: For patients with dark-pigmented hair, providers should consider LHR as the first-line treatment option for preoperative hair removal before gender-affirming vaginoplasty. Strength and Limitations: This is the first study to compare electrolysis and LHR for genital hair removal. The discussion addresses FDA review/oversight of devices, which is commonly misrepresented. Limitations include the survey format for data collection. Conclusion: When compared with electrolysis, LHR showed greater treatment efficiency (shorter and fewer treatment sessions to complete treatment), less pain, greater tolerability, and lower total cost. Our data suggests that, for patients with dark genital hair, providers should consider recommending laser as the first-line treatment for permanent genital hair removal before vaginoplasty.Yuan N, Feldman A, Chin P, et al. Comparison of Permanent Hair Removal Procedures before Gender-Affirming Vaginoplasty: Why We Should Consider Laser Hair Removal as a First-Line Treatment for Patients Who Meet Criteria. Sex Med 2022;10:100545.

Abstract Central nervous system (CNS) injury and infection can result in profound tissue remodeling in the brain, the mechanism and purpose of which is poorly understood. Infection with the protozoan parasite Toxoplasma gondii causes chronic infection and inflammation in the brain parenchyma. Control of parasite replication requires the continuous presence of IFNγ-producing T cells to keep T. gondii in its slowly replicating cyst form. During infection, a network of extracellular matrix fibers, revealed using multiphoton microscopy, forms in the brain. The origin and composition of these structures are unknown but the fibers have been observed to act as a substrate for migrating T cells. In this study, we show a critical regulator of extracellular matrix (ECM) remodeling, Secreted Protein, Acidic, Rich in Cysteine (SPARC), is upregulated in the brain during the early phases of infection in the frontal cortex. In the absence of SPARC, a reduced and disordered fibrous network, increased parasite burden, and reduced antigen-specific T cell entry into the brain points to a role for SPARC in T cell recruitment to and migration within the brain. We also report SPARC can directly bind to CCR7 ligands CCL19 and CCL21 but not CXCL10, and enhance migration toward a chemokine gradient. Measurement of T cell behavior points to tissue remodeling being important for access of immune cells to the brain and facilitating cellular locomotion. Together, these data identify SPARC as an important regulatory component of immune cell trafficking and access to the inflamed CNS.

Introduction: While providers generally counsel patients about possible effects of gender affirming treatments, such as gender affirming hormone therapy (GAHT) and gender affirming surgery (GAS), on sexual function – the effects of these treatments on orgasm function and quality are not well understood. Aim: To develop a gender transition orgasm quality inventory based on orgasm function domains transgender patients communicated were important to them. Methods: We conducted a series of interviews in which we asked transgender patients to describe which factors related to orgasm (ie, orgasm quality and orgasm-related sexual function) were most important to them. This work generated a list of 6 domains which we incorporated into a survey instrument. The 6 domains that our work generated are: (1) Lead-time to reach orgasm, (2) Duration of orgasm, (3) Body location of orgasm sensation; (4) Description of orgasm as either a single or multiple-peak event, (5) Duration of postorgasm refractory period, and (6) Overall satisfaction with orgasm quality. Using this new questionnaire, we queried potential changes in orgasm function before and after commencing GAHT (minimum 1 year) among 130 consecutive transgender women (TW) and 33 transgender men (TM) as a pilot study. Results: Within groups by gender, TW and TM cohorts reported similar responses to our inventory before starting GAHT. After commencing GAHT, TW reported notable changes in orgasm function: increase in lead-time necessary to reach orgasm, orgasm duration, and overall orgasm satisfaction; and decrease in post-orgasm refractory period. Similarly, TM reported an increase in duration of orgasm and increased overall satisfaction with orgasm quality; and a decrease in post-orgasm refractory period. Over half of the TW reported experiencing orgasms in new/additional body locations. Additionally, prior to commencing GAHT, the majority of TM and TW patients reported their orgasms as a short, single-peak event but following GAHT these same patients reported longer and protracted multiple-peak orgasms. Conclusion: We have developed a novel questionnaire with the purpose of assessing patient self-reported changes in orgasm function following gender affirming treatments. Findings from our pilot study shows that GAHT has the potential to positively improve sexual function and orgasm quality for transgender patients undergoing gender transition. We encourage future studies to utilize our novel questionnaire to assess potential changes in orgasm function related to various gender affirming procedures.Zaliznyak M, Lauzon M, Stelmar J, et al. A Proposed Inventory to Assess Changes in Orgasm Function of Transgender Patients Following Gender Affirming Treatments: Pilot Study. Sex Med 2022;10:100510.

Background: Most complications after masculinizing genital gender-affirming surgery (gGAS) are associated with urethral lengthening (+UL). While many transmasculine patients desire +UL for standing urination, not all patients prioritize this benefit over the significantly increased risk of complications. Currently, phalloplasty without UL (−UL) appears to be seldom offered, and previous −UL techniques create genital anatomy that is visibly different from the anatomy created by phallourethroplasty+UL (P+UL). Aim: To describe a novel surgical technique to create a normal-appearing phallus tip, scrotum, and perineal urethral opening that avoids urethral complications associated with +UL. Methods: We describe our surgical technique and approach to patient counseling. We report patient satisfaction outcomes from the first cohort of patients to undergo this ‘modified phallourethroplasty’ (−UL) approach to date. Outcomes: Among patients who elected phalloplasty over metoidioplasty, 13/40 (32.5%) patients elected P−UL. Prior to 1/2020, before we standardized how we presented this option to patients, 17.4% elected this option. Of the patients that elected P−UL, 8 have completed first-stage and 7 have completed second-stage surgeries. Results: All patients that have undergone P−UL have expressed satisfaction with body image and urinary function. Among patients asked to rank which of 14 preoperative factors were most important (1 = most important, 14 = least important), having a normal-appearing phallus (mean rank 4.14) and minimizing complications (mean rank 8.14) were ranked more highly than ability to urinate in a standing position (mean rank 9.14). When asked what factors most influenced their choice to have −UL (ranked from 1 to 9), elimination of risks was rated the most important (mean rank 2.71) and expected decrease in risk of needing revision surgery was rated the second most important (mean rank 3.57). Clinical Implications: The significant reduction in +UL-related complications decrease morbidity, urgent revision surgeries, and cost to our healthcare system. Strengths and Limitations: Strengths include a novel technique that provides a surgical alternative to P+UL that eliminates the majority of phalloplasty related postoperative complications. Limitations include the small number of patients who have completed first and second stage surgery, and short follow up time. Conclusion: It is important to understand what factors drive individual patients’ choices. Patients considering masculinizing gGAS should be offered both +UL and −UL options. The costs and benefits of each option should be presented objectively and in the context of each patient's unique priorities and needs.Smith SM, Yuan N, Lee G, et al. ‘Modified Phallourethroplasty’ as a Surgical Alternative to Phalloplasty With Urethral Lengthening: Technique, How We Present This Option to Patients, and Clinical Outcomes. Sex Med 2022;10:100495.

ObjectiveTo compare maternal and infant outcomes with different antihypertensive medications in pregnancy.DesignRetrospective cohort study.SettingKaiser Permanente, a large healthcare system in the United States.PopulationWomen aged 15-49 years with a singleton birth from 2005-2014 treated for hypertension.MethodsWe identified medication exposure from automated pharmacy data based on the earliest dispensing after the first prenatal visit. Using logistic regression, we calculated weighted outcome prevalences, adjusted odds ratios (aORs) and 95% confidence intervals, with inverse probability of treatment weighting to address confounding.Main outcome measuresSmall for gestational age, preterm delivery, neonatal and maternal intensive care unit (ICU) admission, preeclampsia, and stillbirth or termination at > 20 weeks.ResultsAmong 6346 deliveries, 87% with chronic hypertension, the risk of the infant being small for gestational age (birthweight < 10th percentile) was lower with methyldopa than labetalol (prevalence 13.6% vs. 16.6%; aOR 0.77, 95% CI 0.63 to 0.92). For birthweight < 3rd percentile the aOR was 0.57 (0.39 to 0.80). Compared with labetalol (26.0%), risk of preterm delivery was similar for methyldopa (26.5%; aOR 1.10 [0.95 to 1.27]) and slightly higher for nifedipine (28.5%; aOR 1.25 [1.06 to 1.46]) and other β-blockers (31.2%; aOR 1.58 [1.07 to 2.23]). Neonatal ICU admission was more common with nifedipine than labetalol (25.9% vs. 23.3%, aOR 1.21 [1.02 to 1.43]) but not elevated with methyldopa. Risks of other outcomes did not differ by medication.ConclusionsRisk of most outcomes was similar comparing labetalol, methyldopa and nifedipine. Risk of the infant being small for gestational age was substantially lower for methyldopa, suggesting this medication may warrant further consideration.

ABSTRACT: Introduction: The age at which transgender women (TW) and men (TM) first experience gender dysphoria (GD) has not been reported in a U.S. population of adults seeking genital gender-affirming surgery (gGAS). Because gender is an innate part of identity, we hypothesized that untreated GD would be a part of individuals’ earliest memories. Understanding GD onset can help guide providers with when and how to focus care to patients not yet identified as “transgender Aim: (i) Determine the age at which transgender adults seeking gGAS first experience GD(ii) Determine the number of life-years that transgender adults spend living with untreated GD Methods: During initial consultation for gGAS, we asked patients the earliest age at which they experienced GD and the age at which they had their earliest episodic memory. We also queried history of anxiety, depression, and suicide attempt. Main Outcome Measures: Patients self-reported their earliest recollections of experiencing GD, earliest memories in general, and history of anxiety, depression, and suicide attempt. Results: Data from 155 TW (mean age 41.3; SD 16.3) and 55 TM (mean age 35.4; SD 10.8) were collected. Most patients (TM: 78%; TW: 73%) reported experiencing GD for the first time between ages 3 and 7 years. For TM the mean age of onset was 6.17 years; for TW it was 6.71 years. A total of 81% of TW and 80% of TM described their first recollection of GD as one of their earliest memories. Mean years of persistent GD before the start of gender transition were 22.9 (TM) and 27.1 (TW). Rates of depression, anxiety, and suicide ideation decreased following gender transition. Conclusion: Our findings suggest that GD typically manifests in early childhood and persists untreated for many years before individuals commence gender transition. Diagnosis and early management during childhood and adolescence can improve quality of life and survival.Zaliznyak M, Yuan N, Bresee C, et al. How Early in Life do Transgender Adults Begin to Experience Gender Dysphoria? Why This Matters for Patients, Providers, and for Our Healthcare System. Sex Med 2021;9:100448.

Health plan-based resources are promising avenues for decreasing cardiovascular disease risk. This study examined associations of lifestyle-related resource utilization within a healthcare delivery system and cardiovascular biomarkers among midlife women with low physical activity. Midlife women (45-55 years old) with

Lumen extension in intracellular tubes can occur when vesicles fuse with an invading apical membrane. Within the Caenorhabditis elegans excretory cell, which forms an intracellular tube, the exocyst vesicle-tethering complex is enriched at the lumenal membrane and is required for its outgrowth, suggesting that exocyst-targeted vesicles extend the lumen. Here, we identify a pathway that promotes intracellular tube extension by enriching the exocyst at the lumenal membrane. We show that PAR-6 and PKC-3/aPKC concentrate at the lumenal membrane and promote lumen extension. Using acute protein depletion, we find that PAR-6 is required for exocyst membrane recruitment, whereas PAR-3, which can recruit the exocyst in mammals, appears dispensable for exocyst localization and lumen extension. Finally, we show that CDC-42 and RhoGEF EXC-5/FGD regulate lumen extension by recruiting PAR-6 and PKC-3 to the lumenal membrane. Our findings reveal a pathway that connects CDC-42, PAR proteins, and the exocyst to extend intracellular tubes.

mRNA modification by N6-methyladenosine (m6A) is involved in many post-transcriptional regulation processes including mRNA stability, splicing and promotion of translation. Accordingly, the recently identified mRNA methylation complex containing METTL3, METTL14, and WTAP has been the subject of intense study. However, METTL16 (METT10D) has also been identified as an RNA m6A methyltransferase that can methylate both coding and noncoding RNAs, but its biological role remains unclear. While global studies have identified many potential RNA targets of METTL16, only a handful, including the long noncoding RNA MALAT1, the snRNA U6, as well as the mRNA MAT2A have been verified and/or studied to any great extent. In this study we identified/verified METTL16 targets by immunoprecipitation of both endogenous as well as exogenous FLAG-tagged protein. Interestingly, exogenously overexpressed METTL16 differed from the endogenous protein in its relative affinity for RNA targets which prompted us to investigate METTL16's localization within the cell. Surprisingly, biochemical fractionation revealed that a majority of METTL16 protein resides in the cytoplasm of a number of cells. Furthermore, siRNA knockdown of METTL16 resulted in expression changes of a few mRNA targets suggesting that METTL16 may play a role in regulating gene expression. Thus, while METTL16 has been reported to be a nuclear protein, our findings suggest that METTL16 is also a cytoplasmic methyltransferase that may alter its RNA binding preferences depending on its cellular localization. Future studies will seek to confirm differences between cytoplasmic and nuclear RNA targets in addition to exploring the physiological role of METTL16 through long-term knockdown.

Abstract Background In an attempt to increase the therapeutic potential for myocardial regeneration, there is a quest for new cell sources and types for cell therapy protocols. The pathophysiology of heart diseases may affect cellular characteristics and therapeutic results. Methods To study the proliferative and differentiation potential of mesenchymal stem cells (MSC), isolated from bone marrow (BM) of sternum, we made a comparative analysis between samples of patients with ischemic (IHD) or non-ischemic valvular (VHD) heart diseases. We included patients with IHD (n = 42) or VHD (n = 20), with average age of 60 years and no differences in cardiovascular risk factors. BM samples were collected (16.4 ± 6 mL) and submitted to centrifugation with Ficoll-Paque, yielding 4.5 ± 1.5 × 107 cells/mL. Results Morphology, immunophenotype and differentiation ability had proven that the cultivated sternal BM cells had MSC features. The colony forming unit-fibroblast (CFU-F) frequency was similar between groups (p = 0.510), but VHD samples showed positive correlation to plated cells vs. CFU-F number (r = 0.499, p = 0.049). The MSC culture was established in 29% of collected samples, achieved passage 9, without significant difference in expansion kinetics between groups (p > 0.05). Dyslipidemia and the use of statins was associated with culture establishment for IHD patients (p = 0.049 and p = 0.006, respectively). Conclusions Together, these results show that the sternum bone can be used as a source for MSC isolation, and that ischemic or valvular diseases do not influence the cellular yield, culture establishment or in vitro growth kinetics.

Abstract Invasive pulmonary aspergillosis (IPA) is one of the major complications in immunocompromised patients. The mainstay of diagnostic imaging is non-enhanced chest-computed-tomography (CT), for which various non-specific signs for IPA have been described. However, contrast-enhanced CT pulmonary angiography (CTPA) has shown promising results, as the vessel occlusion sign (VOS) seems to be more sensitive and specific for IPA in hematologic patients. The aim of this study was to evaluate the diagnostic accuracy of CTPA in a larger cohort including non-hematologic immunocompromised patients. CTPA studies of 78 consecutive immunocompromised patients with proven/probable IPA were analyzed. 45 immunocompromised patients without IPA served as a control group. Diagnostic performance of CTPA-detected VOS and of radiological signs that do not require contrast-media were analyzed. Of 12 evaluable radiological signs, five were found to be significantly associated with IPA. The VOS showed the highest diagnostic performance with a sensitivity of 0.94, specificity of 0.71 and a diagnostic odds-ratio of 36.8. Regression analysis revealed the two strongest independent radiological predictors for IPA to be the VOS and the halo sign. The VOS is highly suggestive for IPA in immunocompromised patients in general. Thus, contrast-enhanced CTPA superior over non-contrast_enhanced chest-CT in patients with suspected IPA.

INTRODUCTION:Given constrained funding for Human Immunodeficiency Virus (HIV) programs across Sub-Saharan Africa, delivering services efficiently is paramount. Voluntary medical male circumcision (VMMC) is a key intervention that can substantially reduce heterosexual transmission-the primary mode of transmission across the continent. There is limited research, however, on what factors may contribute to the efficient and high-quality execution of such programs. METHODS:We analyzed a multi-country, multi-stage random sample of 108 health facilities providing VMMC services in sub-Saharan Africa in 2012 and 2013. The survey collected information on inputs, outputs, process quality and management practices from facilities providing VMMC services. We analyzed the relationship between management practices, quality (measured through provider vignettes) and efficiency (estimated through data envelopment analysis) using Generalized Linear Models and Mixed-effects Models. Applying multivariate regression models, we assessed the relationship between management indices and efficiency and quality of VMMC services. RESULTS:Across countries, both efficiency and quality varied widely. After adjusting for type of facility, country and scale, performance-base funding was negatively correlated with efficiency -0.156 (p < 0.05). In our analysis, we did not find any significant relationships between quality and management practices. CONCLUSIONS:No significant relationship was found between process quality and management practices across 108 VMMC facilities. This study is the first to analyze the potential relationships between management and service quality and efficiency among a sample of VMMC health facilities in sub-Saharan Africa and can potentially inform policy-relevant hypotheses to later test through prospective experimental studies.

Human semen contains trillions of extracellular vesicles (SEV) similar in size to sexually transmitted viruses and loaded with potentially bioactive miRNAs, proteins and lipids. SEV were shown to inhibit HIV and Zika virus infectivity, but whether SEV are able also to affect subsequent immune responses is unknown. We found that SEV efficiently bound to and entered antigen-presenting cells (APC) and thus we set out to further dissect the impact of SEV on APC function and the impact on downstream T cell responses. In an APC-T cell co-culture system, SEV exposure to APC alone markedly reduced antigen-specific cytokine production, degranulation and cytotoxicity by antigen-specific memory CD8+ T cells. In contrast, inhibition of CD4+ T cell responses required both APC and T cell exposure to SEV. Surprisingly, SEV did not alter MHC or co-stimulatory receptor expression on APCs, but caused APCs to upregulate indoleamine 2,3 deoxygenase, an enzyme known to indirectly inhibit T cells. Thus, SEV reduce the ability of APCs to activate T cells. We propose here that these immune-inhibitory properties of SEV may be intended to prevent immune responses against semen-derived antigens, but can be hi-jacked by genitally acquired viral infections to compromise adaptive cellular immunity.

An amendment to this paper has been published and can be accessed via the original article.

BackgroundCongenital diaphragmatic hernia (CDH) is a fetal defect comprising an incomplete diaphragm and the herniation of abdominal organs into the chest cavity that interfere with fetal pulmonary development. Though the most promising treatment for CDH is via interventional fetoscopic tracheal occlusion (TO) surgery in-utero, it has produced mixed results due to the static nature of the inserted occlusion. We hypothesize that a suitable noninvasively-actuatable, cyclic-release tracheal occlusion device can be developed to enable dynamic tracheal occlusion (dTO) implementation.ObjectiveTo conduct an in-vitro proof-of-concept investigation of the construction of thermo-responsive polymer valves designed for targeted activation within a physiologically realizable temperature range as a first step towards potential development of a noninvasively-actuatable implantable device to facilitate dynamic tracheal occlusion (dTO) therapy.MethodsSix thermo-responsive polymer valves, with a critical solution temperature slightly higher than normal physiological body temperature of 37°C, were fabricated using a copolymer of n-isopropylacrylamide (NIPAM) and dimethylacrylamide (DMAA). Three of the valves underwent ethylene oxide (EtO) sterilization while the other three served as controls for EtO-processing compatibility testing. Thermal response actuation of the valves and their steady-state flow performances were evaluated using water and caprine amniotic fluid.ResultsAll six valves consisting of 0.3-mole fraction of DMAA were tested for thermal actuation of caprine amniotic fluid flow at temperatures ranging from 30-44°C. They all exhibited initiation of valve actuation opening at ~40°C with full completion at ~44°C. The overall average coefficient of variation (CV) for the day-to-day flow performance of the valves tested was less than 12%. Based on a Student t-test, there was no significant difference in the operational characteristics for the EtO processed versus the non-EtO processed valves tested.ConclusionsWe successfully fabricated and demonstrated physiological realizable temperature range operation of thermo-responsive polymer valves in-vitro and their suitability for standard EtO sterilization processing, a prerequisite for future in-vivo surgical implantation testing.

IntroductionCommunity health workers (CHWs) are lay workers who have the potential to enhance services to prevent mother-to-child HIV transmission (PMTCT) and improve the health of women living with HIV infection. We conducted a cluster-randomized trial of an intervention to integrate CHWs with 'Option B+' PMTCT services in Shinyanga Region, Tanzania.MethodsThe intervention was implemented for 11 months and included four integrated components: 1) formal linkage of CHWs to health facilities; 2) CHW-led antiretroviral therapy (ART) adherence counseling; 3) loss to follow-up tracing by CHWs; and 4) distribution of Action Birth Cards (ABCs), a birth planning tool. We cluster-randomized 32 facilities offering PMTCT services, within strata of size, to the intervention (n = 15) or comparison (standard of care, n = 17) groups. Intervention effectiveness was determined with a difference-in-differences strategy based on clinical and pharmacy data from HIV-infected postpartum women at baseline (births in 2014) and endline (births April-Oct 2015). The primary outcome was retention in care between 60 and 120 days postpartum. Secondary outcomes included ART initiation, timing of ART initiation (as measured by week of gestation), and ART adherence 90 days postpartum, measured using the medication possession ratio (MPR≥95%).ResultsIntervention and comparison facilities were similar at baseline. Data were collected from 1,152 and 678 mother-infant pairs at baseline and endline, respectively. There were no significant differences in retention in care, ART initiation, or timing of ART initiation between the intervention and control groups. Adherence (MPR≥95%) at 90 days postpartum was 11.3 percentage points higher in the intervention group in ITT analyses (95% CI: -0.7, 23.3, p = 0.06), though this effect was attenuated after adjusting for baseline imbalance (9.5 percentage points, 95% CI: -2.9, 22.0, p = 0.13). Among only sites that had the greatest fidelity to the intervention, however, we found a stronger effect on adherence (13.6 percentage points, 95% CI: 2.5, 24.6).ConclusionsDespite being feasible and acceptable, the CHW-based intervention did not have strong effects on most PMTCT indicators. CHW involvement in PMTCT programs may improve ART adherence among HIV-infected postpartum women, however, and success appears heavily dependent on program implementation.Trial registrationRegistry for International Development Impact Evaluations (RIDIE, ID 552553838b402) and ClinicalTrials.gov (NCT03058484).