"Something Like That": Awareness and Acceptability of HIV PrEP and PEP Among Kenyan Adolescents.

BACKGROUND: Adolescents account for 15% of new HIV cases in Kenya. HIV pre-exposure prophylaxis (PrEP) and post-exposure prophylaxis (PEP) are highly effective prevention tools, but uptake is low among adolescents, particularly in resource-limited settings. We assessed awareness and acceptability of PrEP and PEP among Kenyan adolescents. METHOD: Focus group discussions were conducted with 120 adolescent boys and girls ages 15 to 19 in Kisumu. Data were analyzed using the Framework Approach. RESULTS: Adolescent participants often had not heard of or could not differentiate between PrEP and PEP. They also confused these HIV prevention tools with emergency contraceptives. Taking a daily pill to prevent HIV was perceived as analogous to taking a pill to treat HIV. Boys were aware of and willing to consider using PrEP and PEP due to their dislike for using condoms. Adolescents identified insufficient information, cost, and uncomfortableness speaking with healthcare workers about their HIV prevention needs due to sexuality stigma as barriers to using PrEP and PEP. CONCLUSION: Low awareness and poor understanding of PrEP and PEP among adolescents reveal the need for increased education and sensitization about these HIV prevention options. Expanding access to sexual and reproductive health services that are tailored to the needs of adolescents and staffed with non-judgmental providers could help reduce sexuality stigma as a barrier to accessing care. New HIV prevention approaches such as long-acting injectables or implants, on-demand regimens, and multipurpose prevention technologies may encourage increased uptake of PrEP and PEP by adolescents.

The endometrial transcriptome transition preceding receptivity to embryo implantation in mice.

BACKGROUND: Receptivity of the uterus is essential for embryo implantation and progression of mammalian pregnancy. Acquisition of receptivity involves major molecular and cellular changes in the endometrial lining of the uterus from a non-receptive state at ovulation, to a receptive state several days later. The precise molecular mechanisms underlying this transition and their upstream regulators remain to be fully characterized. Here, we aimed to generate a comprehensive profile of the endometrial transcriptome in the peri-ovulatory and peri-implantation states, to define the genes and gene pathways that are different between these states, and to identify new candidate upstream regulators of this transition, in the mouse. RESULTS: High throughput RNA-sequencing was utilized to identify genes and pathways expressed in the endometrium of female C57Bl/6 mice at estrus and on day 3.5 post-coitum (pc) after mating with BALB/c males (n = 3-4 biological replicates). Compared to the endometrium at estrus, 388 genes were considered differentially expressed in the endometrium on day 3.5 post-coitum. The transcriptional changes indicated substantial modulation of uterine immune and vascular systems during the pre-implantation phase, with the functional terms Angiogenesis, Chemotaxis, and Lymphangiogenesis predominating. Ingenuity Pathway Analysis software predicted the activation of several upstream regulators previously shown to be involved in the transition to receptivity including various cytokines, ovarian steroid hormones, prostaglandin E2, and vascular endothelial growth factor A. Our analysis also revealed four candidate upstream regulators that have not previously been implicated in the acquisition of uterine receptivity, with growth differentiation factor 2, lysine acetyltransferase 6 A, and N-6 adenine-specific DNA methyltransferase 1 predicted to be activated, and peptidylprolyl isomerase F predicted to be inhibited. CONCLUSIONS: This study confirms that the transcriptome of a receptive uterus is vastly different to the non-receptive uterus and identifies several genes, regulatory pathways, and upstream drivers not previously associated with implantation. The findings will inform further research to investigate the molecular mechanisms of uterine receptivity.

Information fraction estimation: Strategies for a phase 3 non-inferiority maximum duration design with time to event outcome.

There is considerable debate surrounding the choice of methods to estimate information fraction for futility monitoring in a randomized non-inferiority maximum duration trial. This question was motivated by a pediatric oncology study that aimed to establish non-inferiority for two primary outcomes. While non-inferiority was determined for one outcome, the futility monitoring of the other outcome failed to stop the trial early, despite accumulating evidence of inferiority. For a one-sided trial design for which the intervention is inferior to the standard therapy, futility monitoring should provide the opportunity to terminate the trial early. Our research focuses on the Total Control Only (TCO) method, which is defined as a ratio of observed events to total events exclusively within the standard treatment regimen. We investigate its properties in stopping a trial early in favor of inferiority. Simulation results comparing the TCO method with alternative methods, one based on the assumption of an inferior treatment effect (TH0), and the other based on a specified hypothesis of a non-inferior treatment effect (THA), were provided under various pediatric oncology trial design settings. The TCO method is the only method that provides unbiased information fraction estimates regardless of the hypothesis assumptions and exhibits a good power and a comparable type I error rate at each interim analysis compared to other methods. Although none of the methods is uniformly superior on all criteria, the TCO method possesses favorable characteristics, making it a compelling choice for estimating the information fraction when the aim is to reduce cancer treatment-related adverse outcomes.

HIV drug resistance in persons initiating or reinitiating first-line antiretroviral therapy in Paraguay: Results of a National Patient Survey.

Human immunodeficiency virus (HIV) drug resistance increases mortality and morbidity and antiretroviral therapy (ART) costs. We describe Paraguay's first nationally representative survey on pretreatment drug resistance (PDR) conducted among persons who initiated or reinitiated ART in 2019. ​​​​We conducted a cross-sectional survey of antiretroviral (ARV) drug resistance in Paraguay in 2019. Participants were sampled at four comprehensive care clinics where 90% of patients with HIV in Paraguay initiate ART. Patients included were adults ≥18 years old who initiated first-line ART or reinitiated the same first-line ART regimen after ≥3 months of discontinuation. Of 208 patients, 93.8% had no prior ART exposure, 3.8% reinitiated the same regimen, 2.4% had unknown prior ART exposure; and 31.3% had a CD4 count <200 cells/µl. Mutations associated with resistance were present in 15.4% of patients. Mutations associated with resistance to nonnucleoside reverse transcriptase inhibitors (NNRTI) were present in 13.0% of patients, nucleoside reverse transcriptase inhibitors in 4.3%, and integrase inhibitors in 3.4%. Mutations associated with resistance to tenofovir were present in 1.0% of patients and emtricitabine/lamivudine in 1.4%. ​​Nearly one in six patients had PDR in Paraguay's first nationally representative sample. High NNRTI PDR prevalence underscores the need to accelerate the transition to dolutegravir-based first-line ART. The low PDR prevalence of tenofovir and emtricitabine is reassuring as these ARVs are part of the World Health Organization (WHO)-recommended oral pre-exposure prophylaxis regimen. The high proportion of individuals initiating ART at a late disease stage highlights the need to improve treatment linkage strategies and implement WHO rapid ART initiation recommendations.

Community-Based HIV Testing for Urban Youth in Western Kenya.

Youth aged 15-24 years comprise 48% of new HIV infections and 15% of persons living with HIV in Kisumu County, Kenya. We assessed factors associated with HIV infection among youth participating in the Community Health Initiative (CHI) implemented in an urban informal settlement in 2018. Predictors of HIV infection were assessed by multivariable logistic regression. CHI engaged 4,441 youth through community health campaigns and home-based HIV testing. HIV prevalence was 3.5% overall and 7.1% among young women aged 20-24. There were 24 youth newly identified as HIV-positive out of 157 total HIV-positive youth. HIV-positive status was positively associated with being female (aOR = 2.46; 95% CI 1.57, 3.84) and aged 20-24 (aOR = 2.40; 95% CI 1.52, 3.79), and inversely associated with secondary school education or higher (aOR = 0.27; 95% CI 0.16, 0.44). Our findings highlight the need for HIV prevention programs specially tailored for youth to further reduce new HIV infections in this priority population.

Racial representation in clinical trials for dermatological new molecular entities.

Under-representation of ethnic minorities in clinical research has major implications for equality of access to current treatments in the field of dermatology. To determine whether there has been equitable representation of black individuals in the clinical trials for dermatological new molecular entities (NMEs) approved by the US Food and Drug Administration (FDA) since 2015, we analysed data from the FDA Drug Trials Snapshots programme from January 2015 to the present. During this period, there was significant under-representation of black participants in clinical trials for NMEs treating acne vulgaris, plaque psoriasis, actinic keratosis and squamous cell carcinoma. These findings highlight the need to prioritize representation of ethnic minorities in clinical trials to enhance clinical practice in the field of dermatology and to improve the care and health of minorities.

Outcome of patients with relapsed or progressive Ewing sarcoma enrolled on cooperative group phase 2 clinical trials: A report from the Children's Oncology Group.

SevenChildren's Oncology Group phase 2 trials for patients with relapsed/progressive solid tumors were analyzed to estimate the event-free survival (EFS) for relapsed/progressive Ewing sarcoma. One hundred twenty-eight Ewing sarcoma patients were enrolled and 124 events occurred. The 6-month EFS was 12.7%, demonstrating the poor outcome of these patients. Only docetaxel achieved its protocol-specified radiographic response rate for activity; however, the EFS for docetaxel was similar to other agents, indicating that a higher radiographic response rate may not translate into superior disease control. This EFS benchmark could be utilized as an additional endpoint in trials for recurrent Ewing sarcoma.

"We Don't Fear HIV. We Just Fear Walking around Pregnant.": A Qualitative Analysis of Adolescent Sexuality and Pregnancy Stigma in Informal Settlements in Kisumu, Kenya.

In Kenya, adolescent pregnancy rates are high, contraception utilization is low, and adolescent sexuality is stigmatized. We describe how perceptions of sexuality and pregnancy stigma influence decision-making among adolescents in the informal settlements of Kisumu. We used purposive sampling to recruit 120 adolescent boys and girls aged 15-19 for focus group discussions. A semistructured interview guide was used to elicit social norms and community attitudes about sexual and reproductive health. We analyzed the data using the Framework Approach. The social stigma of adolescent sexuality and the related fear of pregnancy as an unambiguous marker of sexual activity emerged as main themes. This stigma led adolescents to fear social retribution but did not lead to more frequent contraception use due to additional stigma. The intensity of this fear was most acutely expressed by girls, leading some to seek unsafe, sometimes fatal, abortions, and to contemplate suicide. Fear of pregnancy outweighed fear of contracting HIV that was viewed as both treatable and less stigmatized. Our findings illustrate how fear of pregnancy among these adolescents is driven primarily by fears that their community will discover that they are sexually active. Interventions are urgently needed to address adolescent sexual stigma and to prevent negative outcomes.

The role of drug resistance in poor viral suppression in rural South Africa: findings from a population-based study.

BACKGROUND: Understanding factors driving virological failure, including the contribution of HIV drug resistance mutations (DRM), is critical to ensuring HIV treatment remains effective. We examine the contribution of drug resistance mutations for low viral suppression in HIV-positive participants in a population-based sero-prevalence survey in rural South Africa. METHODS: We conducted HIV drug resistance genotyping and ART analyte testing on dried blood spots (DBS) from HIV-positive adults participating in a 2014 survey in North West Province. Among those with virologic failure (> 5000 copies/mL), we describe frequency of DRM to protease inhibitors (PI), nucleoside reverse transcriptase inhibitors (NRTI), and non-nucleoside reverse transcriptase inhibitors (NNRTI), report association of resistance with antiretroviral therapy (ART) status, and assess resistance to first and second line therapy. Analyses are weighted to account for sampling design. RESULTS: Overall 170 DBS samples were assayed for viral load and ART analytes; 78.4% of men and 50.0% of women had evidence of virologic failure and were assessed for drug resistance, with successful sequencing of 76/107 samples. We found ≥1 DRM in 22% of participants; 47% were from samples with detectable analyte (efavirenz, nevirapine or lopinavir). Of those with DRM and detectable analyte, 60% showed high-level resistance and reduced predicted virologic response to ≥1 NRTI/NNRTI typically used in first and second-line regimens. CONCLUSIONS: DRM and predicted reduced susceptibility to first and second-line regimens were common among adults with ART exposure in a rural South African population-based sample. Results underscore the importance of ongoing virologic monitoring, regimen optimization and adherence counseling to optimize durable virologic suppression.

Information fraction estimation based on the number of events within the standard treatment regimen.

For a Phase III randomized trial that compares survival outcomes between an experimental treatment versus a standard therapy, interim monitoring analysis is used to potentially terminate the study early based on efficacy. To preserve the nominal Type I error rate, alpha spending methods and information fractions are used to compute appropriate rejection boundaries in studies with planned interim analyses. For a one-sided trial design applied to a scenario in which the experimental therapy is superior to the standard therapy, interim monitoring should provide the opportunity to stop the trial prior to full follow-up and conclude that the experimental therapy is superior. This paper proposes a method called total control only (TCO) for estimating the information fraction based on the number of events within the standard treatment regimen. Based on theoretical derivations and simulation studies, for a maximum duration superiority design, the TCO method is not influenced by departure from the designed hazard ratio, is sensitive to detecting treatment differences, and preserves the Type I error rate compared to information fraction estimation methods that are based on total observed events. The TCO method is simple to apply, provides unbiased estimates of the information fraction, and does not rely on statistical assumptions that are impossible to verify at the design stage. For these reasons, the TCO method is a good approach when designing a maximum duration superiority trial with planned interim monitoring analyses.

Promoting 'Equitable Access' to PrEP in Australia: Taking Account of Stakeholder Perspectives.

As evidence of the safety and effectiveness of HIV pre-exposure prophylaxis (PrEP) has grown, so has attention to the views of prospective users and providers. However, far less attention has been paid to understanding the perspectives of other stakeholders in the rollout of PrEP access programs. We conducted 21 semi-structured qualitative interviews in 2017 with key stakeholders working across the policy, advocacy, research and/or clinical dimensions of the Australian HIV response, before federal support for a subsidised access scheme was achieved. Our analysis explored three areas of shared concern: who is a suitable candidate for PrEP; why are disparities in PrEP access important; and how can disparities be addressed? In examining how this diverse group of professionals grappled with the challenges of promoting 'equitable access' to PrEP in an increasingly resource rationed health system, we can see how the principles believed to underpin the Australian response to HIV were both reaffirmed and challenged through this period of significant change.

HIV pre-exposure prophylaxis and the 'problems' of reduced condom use and sexually transmitted infections in Australia: a critical analysis from an evidence-making intervention perspective.

HIV pre-exposure prophylaxis (PrEP) has been embraced in Australia, making PrEP available with public funding to people at risk of HIV. Here, we consider the associated 'problems' of reduced condom use and sexually transmissible infections (STIs), as seen by HIV professionals. Twenty-one interviews were conducted during May-August 2017. All agreed that PrEP was a valuable addition to HIV prevention, but their views about reduced condom use and STIs were variable. Using poststructural policy analysis, three main stances were identified: (1) Concerned/alarmed. PrEP was seen as causing reduced condom use, STIs and antibiotic resistance, posing threats to the general population; (2) Neutral/normalising. Stakeholders emphasised that condom use was declining and STIs increasing independently of PrEP, and that PrEP was simply a new tool to be accommodated; (3) Optimistic/critical. PrEP was seen as diminishing fear of HIV and engaging users in more frequent testing and treatment that could lead to declining STI rates. What linked all three stances was the selective performance of evidence, deploying a mixture of personal experience, clinical observations, behavioural data and epidemiology. Anticipating possible futures through evidence-making suggested practical, political and moral consequences for what PrEP could become. We encourage others to consider these consequences with care.

Hepatitis B Vaccination and Infection Prevalence Among Men Who Have Sex With Men Who Travel Internationally.

Among men who have sex with men traveling internationally, self-reported hepatitis B virus (HBV) vaccination prevalence was 77% and less prevalent among older men and those with HBV infection. The HBV infection prevalence was 25% and was associated with older age and HIV infection. Testing for chronic infection, universal vaccination, and treatment for populations with multiple risks is needed.

Whose Responsibility Is It? Beliefs About Preventing HIV Transmission Among Men Who Have Sex With Men.

HIV-negative and HIV-positive men believed that they both are responsible for preventing HIV. Responsibility beliefs, however, did not always correspond with discussing HIV status or refraining from serodiscordant condomless anal sex. Discrepancies between individuals' HIV prevention responsibility beliefs and their sexual risk behaviors merit further examination, particularly in the preexposure prophylaxis era.

Characterization of HIV Recent Infection Among High-Risk Men at Public STI Clinics in Mumbai.

We examined associations with HIV recent infection and estimated transmitted drug resistance (TDR) prevalence among 3345 men at sexually transmitted infection clinics in Mumbai (2002-2005). HIV seroincidence was 7.92% by the BED-CEIA and was higher at a clinic located near brothels (12.39%) than at a hospital-based clinic (3.94%). HIV recent infection was associated with a lifetime history of female sex worker (FSW) partners, HSV-2, genital warts, and gonorrhea. TDR prevalence among recent infection cases was 5.7%. HIV testing services near sex venues may enhance case detection among high-risk men who represent a bridging population between FSWs and the men's other sexual partners.

HIV sero disclosure among men who have sex with men and transgender women on HIV pre-exposure prophylaxis.

HIV pre-exposure prophyalxis (PrEP) might lead individuals to view serodisclosure as unnecessary. We examined the prevalence of non-disclosure and lack of knowledge of partner status in a global cohort of men who have sex with men (MSM) and transgender women (TW) enrolled in the iPrEx Open Label Extension (OLE). We calculated prevalence ratios by fitting a logistic model and estimating predicted probabilities using marginal standardization. Prevalence of non-disclosure and lack of knowledge of partner status were highest in Thailand (73% and 74%, respectively) and lowest in the USA (23% and 37%, respectively). In adjusted analyses, PrEP use was not significantly associated with non-disclosure or lack of knowledge of partner status (p-values>0.05). We found that relationship characteristics were significantly associated with both outcomes. Non-disclosure was higher among casual (adjusted prevalence ratio [aPR] 1.54, [95% confidence interval 1.24-1.84]) and transactional sex partners (aPR 2.03, [1.44-2.62]), and among partners whom participants have known only minutes or hours before their first sexual encounter (aPR 1.62, [1.33-1.92]). Similarly, participants were less likely to know the HIV status of casual partners (aPR 1.50, [1.30-1.71]), transactional sex partners (aPR 1.62, [1.30-1.95]), and those they have known for only days or weeks (aPR 1.13, [0.99-1.27]) or minutes or hours (aPR 1.27, [1.11-1.42]). Our findings underscore the role of dyadic factors in influencing serodisclosure. Comprehensive risk reduction counseling provided in conjunction with PrEP that address relationship characteristics are needed to help patients navigate discussions around HIV status.

Candida catenulata Candidaemia and Possible Endocarditis in a Cirrhotic Patient Successfully De-escalated to Oral Fluconazole.

WHAT IS KNOWN AND OBJECTIVE: Candida catenulata is a fungus commonly found in Australian cheeses. C. catenulata has been identified as the causative pathogen for one report of onychomycosis and one report of candidaemia. CASE DESCRIPTION: A 37-year-old male underwent surgery for an incarcerated umbilical hernia repair and bowel obstruction and presented with severe abdominal pain and ascitic fluid draining from the surgical site. C. catenulata was isolated in blood cultures. The patient was treated with antifungal therapy for approximately 6 weeks. WHAT IS NEW AND CONCLUSION: To our knowledge, this is the first case describing successful treatment of possible fungal endocarditis caused by C. catenulata.

Phylogeography of red muntjacs reveals three distinct mitochondrial lineages.

BACKGROUND: The members of the genus Muntiacus are of particular interest to evolutionary biologists due to their extreme chromosomal rearrangements and the ongoing discussions about the number of living species. Red muntjacs have the largest distribution of all muntjacs and were formerly considered as one species. Karyotype differences led to the provisional split between the Southern Red Muntjac (Muntiacus muntjak) and the Northern Red Muntjac (M. vaginalis), but uncertainties remain as, so far, no phylogenetic study has been conducted. Here, we analysed whole mitochondrial genomes of 59 archival and 16 contemporaneous samples to resolve uncertainties about their taxonomy and used red muntjacs as model for understanding the evolutionary history of other species in Southeast Asia. RESULTS: We found three distinct matrilineal groups of red muntjacs: Sri Lankan red muntjacs (including the Western Ghats) diverged first from other muntjacs about 1.5 Mya; later northern red muntjacs (including North India and Indochina) and southern red muntjacs (Sundaland) split around 1.12 Mya. The diversification of red muntjacs into these three main lineages was likely promoted by two Pleistocene barriers: one through the Indian subcontinent and one separating the Indochinese and Sundaic red muntjacs. Interestingly, we found a high level of gene flow within the populations of northern and southern red muntjacs, indicating gene flow between populations in Indochina and dispersal of red muntjacs over the exposed Sunda Shelf during the Last Glacial Maximum. CONCLUSIONS: Our results provide new insights into the evolution of species in South and Southeast Asia as we found clear genetic differentiation in a widespread and generalist species, corresponding to two known biogeographical barriers: The Isthmus of Kra and the central Indian dry zone. In addition, our molecular data support either the delineation of three monotypic species or three subspecies, but more importantly these data highlight the conservation importance of the Sri Lankan/South Indian red muntjac.

International Sexual Partnerships May Be Shaped by Sexual Histories and Socioeconomic Status.

Exchange sex and higher education were associated with an increased likelihood of international sexual partnerships (ISPs). Exchange sex and older age were associated with an increased likelihood of condomless sex in ISPs. Educational and socioeconomic factors may create unbalanced power dynamics that influence exchange sex and condomless sex in ISPs.

A systematic review on the relations between pasta consumption and cardio-metabolic risk factors.

AIMS: The traditional Italian dish pasta is a major food source of starch with low glycemic index (GI) and an important low-GI component of the Mediterranean diet. This systematic review aimed at assessing comprehensively and in-depth the potential benefit of pasta on cardio-metabolic disease risk factors. DATA SYNTHESIS: Following a standard protocol, we conducted a systematic literature search of PubMed, CINAHL, and Cochrane Central Register of Controlled Trials for prospective cohort studies and randomized controlled dietary intervention trials that examined pasta and pasta-related fiber and grain intake in relation to cardio-metabolic risk factors of interest. Studies comparing postprandial glucose response to pasta with that to bread or potato were quantitatively summarized using meta-analysis of standardized mean difference. Evidence from studies with pasta as part of low-GI dietary intervention and studies investigating different types of pasta were qualitatively summarized. CONCLUSIONS: Pasta meals have significantly lower postprandial glucose response than bread or potato meals, but evidence was lacking in terms of how the intake of pasta can influence cardio-metabolic disease risk. More long-term randomized controlled trials are needed where investigators directly contrast the cardio-metabolic effects of pasta and bread or potato. Long-term prospective cohort studies with required data available should also be analyzed regarding the effect of pasta intake on disease endpoints.