Disrupted biographies and gendered identities: A qualitative study exploring sexuality and blood cancer.

PURPOSE: This study examines how blood cancer impacts patients' sexuality and sense of gendered identity. METHODS: An interpretive epistemological framework necessitated a qualitative study design. Participants (6 male and 6 female), recruited from a hospital Haematology department in a large Northern English City, took part in semi-structured in-depth interviews to gather rich data about their subjective experiences. RESULTS: A key theme from the qualitative data was a sense of disruption in relation to several aspects of their gendered identities and sexual life. Participants explained disruption to their sexual function and sexual sense of self. They narrated concerns about future imagined relationships. The emotional burden of sexuality related concerns was strongly articulated. A gendered perspective enabled the similarities and differences between men and women to be explored. CONCLUSION: This study, drawing on rich qualitative data, documents the sexuality concerns of blood cancer patients; for some such concerns arise many years post treatment. The findings highlight the need for gender appropriate care around sexuality which should continue to be accessible well after diagnosis and treatment phases have ceased.

Identification and characterization of protein interactions with the major Niemann-Pick type C disease protein in yeast reveals pathways of therapeutic potential.

Niemann-Pick type C (NP-C) disease is a rare lysosomal storage disease caused by mutations in NPC1 (95% cases) or NPC2 (5% cases). These proteins function together in cholesterol egress from the lysosome, whereby upon mutation, cholesterol and other lipids accumulate causing major pathologies. However, it is not fully understood how cholesterol is transported from NPC1 residing at the lysosomal membrane to the endoplasmic reticulum (ER) and plasma membrane. The yeast ortholog of NPC1, Niemann-Pick type C-related protein-1 (Ncr1), functions similarly to NPC1; when transfected into a mammalian cell lacking NPC1, Ncr1 rescues the diagnostic hallmarks of cholesterol and sphingolipid accumulation. Here, we aimed to identify and characterize protein-protein interactions (PPIs) with the yeast Ncr1 protein. A genome-wide split-ubiquitin membrane yeast two-hybrid (MYTH) protein interaction screen identified 11 ER membrane-localized, full-length proteins interacting with Ncr1 at the lysosomal/vacuolar membrane. These highlight the importance of ER-vacuole membrane interface and include PPIs with the Cyb5/Cbr1 electron transfer system, the ceramide synthase complex, and the Sec61/Sbh1 protein translocation complex. These PPIs were not detected in a sterol auxotrophy condition and thus depend on normal sterol metabolism. To provide biological context for the Ncr1-Cyb5 PPI, a yeast strain lacking this PPI (via gene deletions) exhibited altered levels of sterols and sphingolipids including increased levels of glucosylceramide that mimic NP-C disease. Overall, the results herein provide new physical and genetic interaction models to further use the yeast model of NP-C disease to better understand human NP-C disease.

Contraceptive and pregnancy concerns in the UK during the first COVID-19 lockdown: A rapid study.

OBJECTIVES: COVID-19 resulted in significant disruption to sexual and reproductive health (SRH) services globally and the impact of this remains under explored. This study aimed to explore the impact of COVID-19 on SRH during the initial weeks of the first UK lockdown. DESIGN: This rapid study employed a cross-sectional anonymous survey design. Between 9th April and 4th May 2020, participants completed an online questionnaire around the impacts of COVID-19 on SRH. The survey was completed by 194 participants. The findings in this paper, report on data from closed and free text questions from 32% (n = 62) of the total sample who said they were able to get pregnant. RESULTS: Participants raised concerns around reduced access to, or a denial of, SRH services as well as reduced choice when such services were available. Participants felt their right to access SRH care was impinged and there were anxieties around the impact of COVID-19 on maternal and foetal health. CONCLUSIONS: The study contributes to a better understanding of the concerns, during the first 8 weeks of the UK lockdown, of those who could get pregnant. Policy makers and planners must ensure that SRH policy, that recognises the importance of bodily autonomy and rights, is central to pandemic planning and responses both in the UK and globally. Such policies should ensure the immediate implementation of protocols that protect SRH service delivery, alongside informing service users of both their right to access such care and how to do so. Further work is necessary with members from minority communities who are mostly absent from this study to explore if, and how, COVID-19 may have exacerbated already existing disparities.

Potential COVID-19 therapeutics from a rare disease: weaponizing lipid dysregulation to combat viral infectivity.

The coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus (SARS-CoV)-2 has resulted in the death of more than 328,000 persons worldwide in the first 5 months of 2020. Herculean efforts to rapidly design and produce vaccines and other antiviral interventions are ongoing. However, newly evolving viral mutations, the prospect of only temporary immunity, and a long path to regulatory approval pose significant challenges and call for a common, readily available, and inexpensive treatment. Strategic drug repurposing combined with rapid testing of established molecular targets could provide a pause in disease progression. SARS-CoV-2 shares extensive structural and functional conservation with SARS-CoV-1, including engagement of the same host cell receptor (angiotensin-converting enzyme 2) localized in cholesterol-rich microdomains. These lipid-enveloped viruses encounter the endosomal/lysosomal host compartment in a critical step of infection and maturation. Niemann-Pick type C (NP-C) disease is a rare monogenic neurodegenerative disease caused by deficient efflux of lipids from the late endosome/lysosome (LE/L). The NP-C disease-causing gene (NPC1) has been strongly associated with viral infection, both as a filovirus receptor (e.g., Ebola) and through LE/L lipid trafficking. This suggests that NPC1 inhibitors or NP-C disease mimetics could serve as anti-SARS-CoV-2 agents. Fortunately, there are such clinically approved molecules that elicit antiviral activity in preclinical studies, without causing NP-C disease. Inhibition of NPC1 may impair viral SARS-CoV-2 infectivity via several lipid-dependent mechanisms, which disturb the microenvironment optimum for viral infectivity. We suggest that known mechanistic information on NPC1 could be utilized to identify existing and future drugs to treat COVID-19.

"This Is Me, This Is What I Am, I Am a Man": The Masculinities of Men Who Pay for Sex with Women.

This paper draws on theories of masculinity to explore men's motivations for beginning and continuing to pay for sex with women. Based on in-depth interviews with 35 male clients of female sex workers in the UK during 2007/2008, our findings suggest that a desire to pay for sex is often entrenched in notions of hegemonic masculinity such as sex as a drive, or need for a variety of experiences and partners and is rationalized as an economic exchange. Yet, the men interviewed also expressed a need for intimacy, female friendship and conversation in a controlled environment, which challenged dominant masculine ideals. For participants, there was often an overlap between various motivational factors, and accounts were complicated by the anxieties and disappointments the men expressed about their non-commercial relationships and the intimacy and emotion frequently attached to encounters with sex workers. The pathologization of men who engage with paid sexual services fails to account for participants' complex, diverse motivations, which should be understood in the context of other relationships and gender relations rather than as a distinct type of interaction. We find that the theory of hegemonic masculinity provides a useful but partial account of the range of behaviors and characteristics expressed in paid-for sex, which participants use to negotiate the expectations, ambivalences and disappointments of everyday life and relationships.

The complexity of a monogenic neurodegenerative disease: More than two decades of therapeutic driven research into Niemann-Pick type C disease.

Niemann-Pick type C (NP-C) disease is a rare and fatal neurodegenerative disease typified by aberrations in intracellular lipid transport. Cholesterol and other lipids accumulate in the late endosome/lysosome of all diseased cells thereby causing neuronal and visceral atrophy. A cure for NP-C remains elusive despite the extensive molecular advances emanating from the identification of the primary genetic defect in 1997. Penetration of the blood-brain barrier and efficacy in the viscera are prerequisites for effective therapy, however the rarity of NP-C disease is the major impediment to progress. Disease diagnosis is challenging and establishment of appropriate test populations for clinical trials difficult. Fortunately, disease models that span the diversity of microbial and metazoan life have been utilized to advance the quest for a therapy. The complexity of lipid storage in this disorder and in the model systems, has led to multiple theories on the primary disease mechanism and consequently numerous and varied proposed interventions. Here, we conduct an evaluation of these studies.

Normalization of Hepatic Homeostasis in the Npc1nmf164 Mouse Model of Niemann-Pick Type C Disease Treated with the Histone Deacetylase Inhibitor Vorinostat.

Niemann-Pick type C (NP-C) disease is a fatal genetic lipidosis for which there is no Food and Drug Administration (FDA)-approved therapy. Vorinostat, an FDA-approved inhibitor of histone deacetylases, ameliorates lysosomal lipid accumulation in cultured NP-C patient fibroblasts. To assess the therapeutic potential of histone deacetylase inhibition, we pursued these in vitro observations in two murine models of NP-C disease. Npc1nmf164 mice, which express a missense mutation in the Npc1 gene, were treated intraperitoneally, from weaning, with the maximum tolerated dose of vorinostat (150 mg/kg, 5 days/week). Disease progression was measured via gene expression, liver function and pathology, serum and tissue lipid levels, body weight, and life span. Transcriptome analyses of treated livers indicated multiple changes consistent with reversal of liver dysfunction that typifies NP-C disease. Significant improvements in liver pathology and function were achieved by this treatment regimen; however, NPC1 protein maturation and levels, disease progression, weight loss, and animal morbidity were not detectably altered. Vorinostat concentrations were >200 µm in the plasma compartment of treated animals but were almost 100-fold lower in brain tissue. Apolipoprotein B metabolism and the expression of key components of lipid homeostasis in primary hepatocytes from null (Npc1-/-) and missense (Npc1nmf164 ) mutant mice were altered by vorinostat treatment, consistent with a response by these cells independent of the status of the Npc1 locus. These results suggest that HDAC inhibitors have utility to treat visceral NP-C disease. However, it is clear that improved blood-brain barrier penetration will be required to alleviate the neurological symptoms of human NP-C disease.

Preventing repeat teen pregnancy: postpartum depot medroxyprogesterone acetate, oral contraceptive pills, or the patch?

STUDY OBJECTIVE: To prospectively evaluate the repeat teen pregnancy rates, within one year of delivery, among adolescents who choose the contraceptive patch (Ortho Evra) versus oral contraceptive pills (OCP) versus Depot Medroxyprogesterone Acetate (Depo Provera, DMPA) for postpartum contraception. DESIGN: Observational, prospective cohort study. Comparison groups are postpartum teens, who self-select the contraceptive patch (n = 55) versus DMPA (n = 142) versus OCPs (n = 55) immediately postpartum. SETTING: Medical University of South Carolina, a tertiary medical center. PARTICIPANTS: Postpartum teens, 11-19 years old; 72% were African American, and 96% qualified for Medicaid insurance. INTERVENTIONS: A structured telephone interview was performed every 3 months. MAIN OUTCOME MEASURES: The primary outcome measure was a repeat pregnancy within 12 months of the index delivery. Secondary outcome variables were contraceptive continuation rates, reasons for discontinuation, side effects and condom usage. RESULTS: At 1-year follow-up, repeat pregnancy rates were 14.2%, 29.7%, and 31.8% among DMPA, OCP, and patch users respectively (P = 0.02). DMPA users were significantly more likely to be using any form of hormonal contraception 1 year postpartum than patch or OCP users. Condom use was similarly low among all cohorts. CONCLUSION: Adolescents who choose DMPA for postpartum contraception are significantly less likely to become pregnant within 1 year of delivery, as compared to teens who choose OCPs or the patch.