National HIV and HCV Screening Rates for Hospitalized People who Use Drugs Are Suboptimal and Heterogeneous Across 11 US Hospitals.

Background: To end the HIV and hepatitis C virus (HCV) epidemics, people who use drugs (PWUD) need more opportunities for testing. While inpatient hospitalizations are an essential opportunity to test people who use drugs (PWUD) for HIV and HCV, there is limited research on rates of inpatient testing for HIV and HCV among PWUD. Methods: Eleven hospital sites were included in the study. Each site created a cohort of inpatient encounters associated with injection drug use. From these cohorts, we collected data on HCV and HIV testing rates and HIV testing consent policies from 65 276 PWUD hospitalizations. Results: Hospitals had average screening rates of 40% for HIV and 32% for HCV, with widespread heterogeneity in screening rates across facilities. State consent laws and opt-out testing policies were not associated with statistically significant differences in HIV screening rates. On average, hospitals that reflexed HCV viral load testing on HCV antibody testing did not have statistically significant differences in HCV viral load testing rates. We found suboptimal testing rates during inpatient encounters for PWUD. As treatment (HIV) and cure (HCV) are necessary to end these epidemics, we need to prioritize understanding and overcoming barriers to testing.

DNA methylation differences between the female and male X chromosomes in human brain.

The mechanisms of X chromosome inactivation suggest fundamental epigenetic differences between the female and male X chromosomes. However, DNA methylation studies often exclude the X chromosomes. In addition, many previous studies relied on techniques that examine non-randomly selected subsets of positions such as array-based methods, rather than assessing the whole X chromosome. Consequently, our understanding of X chromosome DNA methylation lags behind that of autosomes. Here we addressed this gap of knowledge by studying X chromosome DNA methylation using 89 whole genome bisulfite sequencing (WGBS) maps from neurons and oligodendrocytes. Using this unbiased and comprehensive data, we show that DNA methylation of the female X chromosomes is globally reduced (hypomethylated) across the entire chromosome compared to the male X chromosomes and autosomes. On the other hand, the majority of X-linked promoters were more highly methylated (hypermethylated) in females compared to males, consistent with the role of DNA methylation in X chromosome inactivation and dosage compensation. Remarkably, hypermethylation of female X promoters was limited to a group of previously lowly methylated promoters. The other group of highly methylated promoters were both hyper- and hypo-methylated in females with no obvious association with gene expression. Therefore, X chromosome inactivation by DNA methylation was exclusive to a subset of promoters with distinctive epigenetic feature. Apart from this group of promoters, differentially methylated regions in the female and male X chromosomes were dominated by female hypomethylation. Our study furthers the understanding of X-chromosome dosage regulation by DNA methylation on the chromosomal level as well as on individual gene level.

COVID-19 infection and a repeated false positivity effect in HIV testing: A case report.

Several reports in the literature have described the association between SARS-CoV-2 infection and false positive HIV testing results. We present a case of a cisgender male who has sex with men with a false positive HIV test after fully recovering from COVID-19 14 days prior. Initial 4th generation HIV 1 and 2 antibody/antigen testing was positive twice, but confirmatory antibody testing was negative. HIV viral load was persistently undetectable. Most of the previously published case reports describe concurrent testing and positivity for HIV and COVID-19. Our report stands out due to the implication of a potentially prolonged association that could persist for several weeks.

A randomized trial of safety, acceptability and adherence of three rectal microbicide placebo formulations among young sexual and gender minorities who engage in receptive anal intercourse (MTN-035).

Efforts to develop a range of HIV prevention products that can serve as behaviorally congruent viable alternatives to consistent condom use and oral pre-exposure prophylaxis (PrEP) remain crucial. MTN-035 was a randomized crossover trial seeking to evaluate the safety, acceptability, and adherence to three placebo modalities (insert, suppository, enema) prior to receptive anal intercourse (RAI). If participants had no RAI in a week, they were asked to use their assigned product without sex. We hypothesized that the modalities would be acceptable and safe for use prior to RAI, and that participants would report high adherence given their behavioral congruence with cleansing practices (e.g., douches and/or enemas) and their existing use to deliver medications (e.g., suppositories; fast-dissolving inserts) via the rectum. Participants (N = 217) were sexual and gender minorities enrolled in five different countries (Malawi, Peru, South Africa, Thailand, and the United States of America). Mean age was 24.9 years (range 18-35 years). 204 adverse events were reported by 98 participants (45.2%); 37 (18.1%) were deemed related to the study products. The proportion of participants reporting "high acceptability" was 72% (95%CI: 65% - 78%) for inserts, 66% (95%CI: 59% - 73%) for suppositories, and 73% (95%CI: 66% - 79%) for enemas. The proportion of participants reporting fully adherent per protocol (i.e., at least one use per week) was 75% (95%CI: 69% - 81%) for inserts, 74% (95%CI: 68% - 80%) for suppositories, and 83% (95%CI: 77% - 88%) for enemas. Participants fully adherent per RAI-act was similar among the three products: insert (n = 99; 58.9%), suppository (n = 101; 58.0%) and enema (n = 107; 58.8%). The efficacy and effectiveness of emerging HIV prevention drug depends on safe and acceptable delivery modalities that are easy to use consistently. Our findings demonstrate the safety and acceptability of, and adherence to, enemas, inserts, and suppositories as potential modalities through which to deliver a rectal microbicide.

Measurement of change in angle kappa and its correlation with ocular biometric parameters pre- and post-phacoemulsification.

Purpose: Angle kappa has been considered to play a role in causing glare and haloes despite accurate centration during implantation of multifocal intraocular lenses following phacoemulsification. There is a lack of substantial data regarding whether angle kappa is a constant entity or changes following ocular surgical procedures. To answer this question, in this prospective observational study, we measured change in angle kappa following phacoemulsification, and studied the ocular biometric parameters correlating with this change. Methods: Angle kappa was measured objectively using synoptophore. Ocular Biometric parameters (Anterior Chamber Depth, Corneal White-to-White measurement, Lens Thickness, and Axial Length) using LenStar LS 900 Haag Streit Anterior Segment imaging system. outcome measures were a quantitative change in angle kappa from the preoperative value by one degree or more and observation of correlation between change in angle kappa and ocular biometric parameters. The Wilcoxin Signed Rank Test was used to determine the difference between pre-operative and post-operative measurements for angle kappa. A p-value of less than 0.05 was considered statistically significant. Pearson's correlation coefficient was employed to find the relationship between preoperative ocular biometric parameters and a change in angle kappa. A linear regression model was used to derive an equation considering corneal white-to-white measurement as the predictor and change in angle kappa as the outcome measure. Results: A significant change in angle kappa was recorded, and a significant correlation was found with corneal white to white measurements. This change could be predicted preoperatively, for a known corneal white to white measurement using the standard equation y=mx+c. Conclusion: This study explains the possible cause of dissatisfaction among seemingly ideal patients who undergo multifocal IOL implantation and the potential for better decision-making during patient selection for multifocal IOL implantation.

The Impact of Standardized Infectious Diseases Consultation on Postsplenectomy Care and Outcomes.

Background: Patients who receive splenectomy are at risk for overwhelming postsplenectomy infection (OPSI). Guidelines recommend that adult asplenic patients receive a complement of vaccinations, education on the risks of OPSI, and on-demand antibiotics. However, prior literature suggests that a majority of patients who have had a splenectomy receive incomplete asplenic patient care and thus remain at increased risk. This study assessed the impact of standardized involvement of infectious diseases (ID) providers on asplenic patient care outcomes in patients undergoing splenectomy. Methods: A quasi-experimental study design compared a prospective cohort of patients undergoing splenectomy from August 2017 to June 2021 who received standardized ID involvement in care of the asplenic patient with a historic control cohort of patients undergoing splenectomy at the same institution from January 2010 through July 2017 who did not. There were 11 components of asplenic patient care defined as primary outcomes. Secondary outcomes included the occurrence of OPSI, death, and death from OPSI. Results: Fifty patients were included in the prospective intervention cohort and 128 in the historic control cohort. There were significant improvements in 9 of the 11 primary outcomes in the intervention arm as compared with the historic controls. Survival analysis showed no statistically significant difference in the incidence of OPSI-free survival between the groups (P = .056), though there was a trend toward improvement in the prospective intervention arm. Conclusions: Standardized involvement of an ID provider in the care of patients undergoing splenectomy improves asplenic patient care outcomes. Routine involvement of ID in this setting may be warranted.

Brain abscess with pyogenic ventriculitis.

The authors present the case of a 57-year-old male with a large polymicrobial brain abscess complicated by eruption into the intraventricular space. He was treated with parenteral ampicillin, cefepime, and metronidazole and adjuvant intraventricular vancomycin/gentamicin as well as surgical debridement. The authors discuss the diagnosis, treatment, and prognosis of brain abscesses, with a focus on prior cases with pyogenic ventriculitis and those treated with intraventricular antimicrobials.

Patterns of Adherence to a Dapivirine Vaginal Ring for HIV-1 Prevention Among South African Women in a Phase III Randomized Controlled Trial.

BACKGROUND: Persistent use of HIV prevention methods can be a challenge, particularly for some younger women. The long-acting, discreet, woman-centric dapivirine vaginal ring offers promise as a prevention method with less user burden, which could support continued use. We assessed dapivirine vaginal ring use to understand adherence patterns and identify characteristics influencing patterns. SETTING: Participants enrolled in South Africa in the MTN-020/ASPIRE randomized placebo-controlled trial. METHODS: We used group-based trajectory modeling to identify clusters of participants with similar longitudinal patterns of adherence in the last year of participation and potential predictors of group membership. Women with at least 1 year of follow-up were included (n = 626). RESULTS: Five adherence patterns were identified: (1) consistently high, 34%, (2) consistently moderate, 34%, (3) consistently low, 16%, (4) decreasing, 9%, and (5) increasing, 7%. Women younger than 22 years [adjusted odds ratio (AOR) 1.8, 95% confidence interval (CI): 1.0 to 3.0], using an intrauterine device (AOR 3.3, 95% CI: 1.4 to 7.8) or oral contraceptives (AOR 3.9, 95% CI: 1.7 to 8.9), experiencing menses (AOR 1.8, 95% CI: 1.1 to 3.0), and who reported inconsistent condom use (AOR 1.8, 95% CI: 1.0 to 3.3) were more likely to be classified as consistently low compared to consistently high (referent). CONCLUSIONS: Most South African women successfully persisted with a moderate or high level of use. Encouraging ring replacement with completion of menses may help to decrease concerns about hygiene and improve persistence. Associations between contraception and persistent low adherence suggest efforts may be needed to ensure contraceptive method choice does not interfere with ring use.

Acceptability of an extended duration vaginal ring for HIV prevention and interest in a multi-purpose ring.

Given challenges with adherence to existing HIV prevention products, the development of an extended duration vaginal ring could improve adherence while reducing patient and provider burden. Additionally, women have other interlinked sexual health concerns such as unintended pregnancy. We evaluated acceptability of a 90-day ring to prevent HIV and hypothetical preferences for a dual (HIV and contraceptive) indication. This was a secondary analysis of a Phase 1, two-arm, multi-site, placebo-controlled randomized trial evaluating safety and pharmacokinetics of a 90-day vaginal ring containing tenofovir for HIV prevention (N = 49). We used a mixed methods approach to assess quantitative data on acceptability (n = 49) and used qualitative data from a random subset to explain the quantitative findings (N = 25). The 3-month extended duration tenofovir ring was highly acceptable. Participants perceived the ring to be easy to use, comfortable and reported liking it more over time. About half felt the ring during sex but most of those participants said it bothered them only a little. Concerns about hygiene increased over the study period but were often outweighed by the benefits of an extended duration ring. Interest in a multi-purpose ring was high (77%) and even higher among those who were sexually active and had male partners. The 3-month extended duration tenofovir ring for HIV prevention was highly acceptable among women and interest in an MPT was high.

Does the Ring Work? Perceptions and Understanding of the Efficacy of a Dapivirine Vaginal Ring for HIV Prevention Amongst Women in a Placebo-Controlled Trial.

As demonstrated by the Phase III clinical trial, MTN-020/ASPIRE, the monthly dapivirine vaginal ring is well tolerated and reduces the risk of HIV-1 as a woman-initiated prevention option. This analysis uses data from the follow-on MTN-032/Assessment of ASPIRE and HOPE Adherence (AHA) qualitative study to understand how perceptions (or misperceptions) of ring efficacy may have influenced behavior during ASPIRE, and affected intention to use the ring in future ring projects, specifically HOPE, the planned open-label extension study. Single in-depth interviews (n = 98) and 12 focus group discussions (n = 89) were conducted with women at seven sites in Malawi, South Africa, Uganda and Zimbabwe. Eligibility included participation in the ASPIRE active arm, and ring use for ≥ 3 months or at least 1 month if seroconversion occurred. Interviews were audio-recorded, transcribed into English, coded in Dedoose and thematically analyzed. Demographic and behavioral questionnaire data were summarized in Stata. Most AHA participants perceived the ring to be effective, and described simply trusting it or having confidence in it because they, or other participants in risky situations, remained HIV-uninfected. Participants described ring efficacy after receiving ASPIRE results as a binary assessment: the ring worked or not. Many did not remember exact efficacy percentages because of lack of comprehension or memory but recalled key details about age differences. The majority expressed interest in future ring use. There is a need to investigate improved ways of explaining placebo-controlled trials and efficacy to women in Sub-Saharan Africa. Now that ring efficacy, is known, these benefits must be well communicated, and understood by end-users and key stakeholders. Engagement with end-users to construct effective messages and to develop tools to measure understanding of partial efficacy will be essential.

Acceptability of a Dapivirine/Placebo Gel Administered Rectally to HIV-1 Seronegative Adults (MTN-026).

This study describes the acceptability of a rectal microbicide gel formulation using dapivirine (DPV) among men and women from two countries (United States and Thailand) participating in the Microbicide Trials Network-026 trial. We evaluated participants' acceptability of a rectal DPV/placebo gel as part of a Phase I trial (N = 26; 18 male, 8 female). Participants reported favorable acceptability of the study gel, with most participants reporting that they liked the gel the same (n = 14; 53.8%) or more (n = 11; 42.4%) than when they started the trial. Over half of participants noted that they would prefer the gel over condoms (n = 13; 50%) or that they liked condoms and the gel equally (n = 8; 30.8%). Side effects across products included leakage (n = 8; 30.8%), diarrhea (n = 4; 15.4%), or soiling (n = 1; 3.8%). The high acceptability of a rectal gel underscores its promise as a short-acting biomedical prevention, warranting future research for HIV prevention.Trial Registration: NCT03239483.

RESUMEN: Este estudio describe la aceptabilidad de un microbicida rectal (RM) con dapivirina (DPV) formulado como un gel por hombres y mujeres de dos países (Estados Unidos y Tailandia) que participaron como parte del Microbicide Trials Network (MTN)-026. Evaluamos la aceptabilidad de un gel rectal de DPV y un placebo como parte de un estudio de Fase I (N = 26; 18 hombres, 8 mujeres). Los participants informaron una aceptabilidad favorable sobre el gel del estudio; la mayoría de los participantes informaron que les gustó el gel igual (n = 14; 53.8%) o más (n = 11; 42.4%) que cuando comenzaron el estudio. Más de la mitad de los participantes señalaron que preferirían el gel sobre los condones (n = 13; 50%) o que les gustaban los condones y el gel por igual (n = 8; 30,8%). Los efectos de los productos incluyeron fugas (n = 8; 30,8%), diarrea (n = 4; 15,4%) o ensuciamiento (n = 1; 3,8%). La alta aceptabilidad de un gel rectal enfatiza su promesa para la prevención biomédica de acción corta y justifica futuras investigaciones para la prevención del VIH.

A Randomized, Double Blind, Placebo-Controlled, Phase 1 Safety, and Pharmacokinetic Study of Dapivirine Gel (0.05%) Administered Rectally to HIV-1 Seronegative Adults (MTN-026).

Dapivirine (DPV), formulated as vaginal ring, demonstrated HIV risk reduction. MTN-026 explored DPV, formulated as rectal gel, for safety, pharmacokinetics (PK), and acceptability. HIV-uninfected men and women aged 18-45 years were enrolled at United States and Thailand sites and randomized 2:1 to receive DPV 0.05% or placebo gel via rectal applicator. A single-dose phase was followed by seven observed daily doses. Plasma and fluid and tissue from both rectum and cervix were collected at baseline and after the final dose over 72 h for PK, ex-vivo HIV-1 biopsy challenge, histology, and flow cytometry. Twenty-eight participants were randomized; 2 terminated early; 9 were female and 19 male; 12 were white, 11 Asian, 4 black, and 1 other race/ethnicity. Mean age was 28.5 and 34.2 years in the DPV and placebo arms, respectively. Thirty adverse events occurred (all Grade 1 or 2, except one unrelated Grade 3) without study arm differences. DPV rectal tissue concentrations [median (interquartile range)] 0.5-1 and 2 h after a single dose were 256 ng/g [below the lower limit of quantification (BLQ)-666] and BLQ (BLQ-600), respectively, then BLQ (BLQ-BLQ) from 24 to 72 h; concentrations following multiple doses were similar. The largest median DPV plasma concentrations were 0.33 ng/mL (0.15-0.48) after one dose and 0.40 (0.33-0.49) after seven doses. The DPV rectal gel was acceptable and without safety concerns. While DPV plasma concentrations were similar to the vaginal ring, rectal tissue concentrations were well below vaginal ring tissue concentrations, suggesting need for reformulation. Clinical trial number: NCT03239483.

Investigating Noise Exposure to Newborn Infants From Respiratory Support: Methodological Considerations.

Background and objective Excessive noise in the neonatal intensive care unit (NICU) may lead to serious long-term effects on hearing and sensory development in newborns. As such, the maximum allowed noise level is 45 A-weighted decibels (dBA). Studies regarding noise exposure to ventilated preterm infants show inconsistent results; however, these studies also vary considerably in their methodology in terms of noise ascertainment. We hypothesized that the study methodology can significantly influence data quality when measuring noise levels. In this study, we aimed to investigate whether the variations in ventilator noise levels in NICUs could be a result of methodological differences in study designs. Methods A ventilator circuit was set up using nasal continuous positive airway pressure (nCPAP) and high-frequency (HF) modes with nasal prongs. Noise levels were measured using a commercially calibrated noise meter. Three different scenarios were tested: (1) measurements were taken at different angles (0° to 180°), with 180° facing the end of the nasal prongs, without a mannequin, with the membrane/orifice of the noise meter placed 2 mm laterally from the prongs; (2) noise levels were measured at 180° at distances of 0-20 mm from the nasal prongs; (3) measurements were taken in the oral cavity of a life-size intubation mannequin of a newborn baby. Results Overall, the noise levels produced at different settings varied significantly, ranging from 45.7 dB to 82.2 dB. The average environmental background noise was 44.4 dB. Noise levels typically increased as the angle increased, with the highest noise level recorded at 180° for both HF and nCPAP modes, at 58.4 dB and 58.2 dB, respectively. Noise levels recorded at HF were slightly higher than nCPAP values. Furthermore, with regard to distance, the highest mean value, 82.2 dB, was recorded with the noise meter approximately 3 mm from the nasal prongs, and the lowest mean value, 47.6 dB, was recorded at ~20 mm. During trials with the mannequin, the lowest value, 50.1 dB, was recorded at the entrance of the mouth with slightly higher values being recorded within the oral cavity. Conclusion The results indicate that small changes in experimental settings, such as positioning and distance from the nasal prongs, can greatly influence noise levels, particularly above the recommended levels for neonates. These differences may be attributed to wind-generated noise. In summary, some study results are potentially influenced more by the study design than the device type or ventilator setting. We recommend further research and detailed reporting in the NICU to gain deeper insights into the topic.

Invasive Aspergillus flavus sinusitis in an immunocompetent patient using intranasal cocaine.

Invasive fungal sinusitis is a rare and potentially fatal infection that tends to occur in immunocompromised hosts. Presented is the case of a 33-year-old immunocompetent male with several months of recurrent facial and nasal pain refractory to several antibacterial courses before a diagnosis of invasive Aspergillus sinusitis was made. The patient's symptoms and infection were successfully treated with a combination of surgical debridement and voriconazole. The authors review the epidemiology, risk factors, diagnosis, and treatment of invasive fungal sinusitis due to Aspergillus.

Acceptability of a Dapivirine Gel Administered Rectally to HIV-1 Seronegative Adults (MTN-033 Study).

We triangulated quantitative and qualitative assessments to evaluate participants' acceptability of 0.05% dapivirine rectal microbicide (RM) gel administered via two separate modalities (a rectal applicator and an artificial phallus for use as a coital simulation device) as part of a Phase I trial (N = 14) among men who have sex with men (MSM) randomized using a 1:1 ratio. Overall, participants reported favorable acceptability of the gel (n = 11; 78.6%), the same or more at the end of the study compared to when they started the study. Additionally, when discussing their preferred administration modality, they noted that both methods had positive qualities but also potential areas of improvement. Our findings underscore the need to create multiple delivery methods for a future microbicide gel (i.e., with and without the need for an applicator) and highlight the importance of offering MSM choices in how biomedical HIV prevention strategies are delivered.

Using Emoji Stickers to Understand End-User Opinions of the Dapivirine Vaginal Ring for HIV Prevention.

Globally, HIV affects women disproportionally to men, particularly in sub-Saharan Africa. While the monthly dapivirine vaginal ring (VR) is a promising female-initiated HIV prevention method, it is important to understand how well the ring is liked. With former participants of HOPE, an open-label extension trial of the ring, we used emoji stickers and a worksheet to explore female end-user's acceptability of and opinions about the VR. We aimed to understand these participants' opinions about the VR, and how they had changed over time, particularly in the context of known efficacy of the dapivirine VR. Most participants easily understood the exercise and how to use the emoji stickers, with a few exceptions. For those who had trouble understanding how to use the emoji, interviewer support and encouragement helped them to understand and continue with the exercise. Emoji interpretation varied widely with participants using the same emoji to express divergent opinions. Using the emoji stickers, participants expressed mostly positive opinions of the vaginal ring for HIV prevention, with some lingering concerns about the product's partial effectiveness. This paper contributes to the literature supporting the assertion that the dapivirine VR for HIV prevention is acceptable to women, and that acceptability increases with time and proper education. This analysis also provides evidence that emoji visual tools can enhance understanding of acceptability of an intervention when used in qualitative research.

Correlates of Adherence to the Dapivirine Vaginal Ring for HIV-1 Prevention.

Understanding characteristics associated with adherence to pre-exposure prophylaxis (PrEP) methods for HIV-1 prevention may assist with optimizing implementation efforts. The dapivirine vaginal ring is a novel topical PrEP delivery method. Using data from a randomized, double-blind, placebo-controlled, phase III trial of the dapivirine vaginal ring conducted in four African countries, generalized estimating equation models were used to evaluate correlates of ring adherence. Two levels of quarterly dapivirine blood plasma, and dapivirine released from returned rings defined measures of adherence for recent and cumulative use, respectively. Time on study, calendar time, primary partner knowledge that the participant was taking part in the study, and use of long-acting contraceptive methods were associated with ring adherence whereas younger age, ring worries, condom use, episodes of menstrual bleeding and vaginal washing were associated with non-adherence. These findings may be useful for recruitment into future clinical studies and dapivirine ring implementation efforts.

On the origin and evolution of SARS-CoV-2.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is responsible for the ongoing global outbreak of a coronavirus disease (herein referred to as COVID-19). Other viruses in the same phylogenetic group have been responsible for previous regional outbreaks, including SARS and MERS. SARS-CoV-2 has a zoonotic origin, similar to the causative viruses of these previous outbreaks. The repetitive introduction of animal viruses into human populations resulting in disease outbreaks suggests that similar future epidemics are inevitable. Therefore, understanding the molecular origin and ongoing evolution of SARS-CoV-2 will provide critical insights for preparing for and preventing future outbreaks. A key feature of SARS-CoV-2 is its propensity for genetic recombination across host species boundaries. Consequently, the genome of SARS-CoV-2 harbors signatures of multiple recombination events, likely encompassing multiple species and broad geographic regions. Other regions of the SARS-CoV-2 genome show the impact of purifying selection. The spike (S) protein of SARS-CoV-2, which enables the virus to enter host cells, exhibits signatures of both purifying selection and ancestral recombination events, leading to an effective S protein capable of infecting human and many other mammalian cells. The global spread and explosive growth of the SARS-CoV-2 population (within human hosts) has contributed additional mutational variability into this genome, increasing opportunities for future recombination.