Enhancer Pleiotropy, Gene Expression, and the Architecture of Human Enhancer-Gene Interactions.

Enhancers are often studied as noncoding regulatory elements that modulate the precise spatiotemporal expression of genes in a highly tissue-specific manner. This paradigm has been challenged by recent evidence of individual enhancers acting in multiple tissues or developmental contexts. However, the frequency of these enhancers with high degrees of "pleiotropy" out of all putative enhancers is not well understood. Consequently, it is unclear how the variation of enhancer pleiotropy corresponds to the variation in expression breadth of target genes. Here, we use multi-tissue chromatin maps from diverse human tissues to investigate the enhancer-gene interaction architecture while accounting for 1) the distribution of enhancer pleiotropy, 2) the variations of regulatory links from enhancers to target genes, and 3) the expression breadth of target genes. We show that most enhancers are tissue-specific and that highly pleiotropy enhancers account for <1% of all putative regulatory sequences in the human genome. Notably, several genomic features are indicative of increasing enhancer pleiotropy, including longer sequence length, greater number of links to genes, increasing abundance and diversity of encoded transcription factor motifs, and stronger evolutionary conservation. Intriguingly, the number of enhancers per gene remains remarkably consistent for all genes (∼14). However, enhancer pleiotropy does not directly translate to the expression breadth of target genes. We further present a series of Gaussian Mixture Models to represent this organization architecture. Consequently, we demonstrate that a modest trend of more pleiotropic enhancers targeting more broadly expressed genes can generate the observed diversity of expression breadths in the human genome.

Myxosporea (Myxozoa, Cnidaria) Lack DNA Cytosine Methylation.

DNA cytosine methylation is central to many biological processes, including regulation of gene expression, cellular differentiation, and development. This DNA modification is conserved across animals, having been found in representatives of sponges, ctenophores, cnidarians, and bilaterians, and with very few known instances of secondary loss in animals. Myxozoans are a group of microscopic, obligate endoparasitic cnidarians that have lost many genes over the course of their evolution from free-living ancestors. Here, we investigated the evolution of the key enzymes involved in DNA cytosine methylation in 29 cnidarians and found that these enzymes were lost in an ancestor of Myxosporea (the most speciose class of Myxozoa). Additionally, using whole-genome bisulfite sequencing, we confirmed that the genomes of two distant species of myxosporeans, Ceratonova shasta and Henneguya salminicola, completely lack DNA cytosine methylation. Our results add a notable and novel taxonomic group, the Myxosporea, to the very short list of animal taxa lacking DNA cytosine methylation, further illuminating the complex evolutionary history of this epigenetic regulatory mechanism.

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.

Identification of a Human Immunodeficiency Virus Type 1 and Neurosyphilis Cluster in Vermont.

BACKGROUND: Rates of syphilis in the United States have more than doubled over the last several decades, largely among men who have sex with men (MSM). Our study characterizes a cluster of neurosyphilis cases among people with human immunodeficiency virus 1 (HIV-1) in Vermont in 2017-2018. METHODS: Vermont Department of Health disease intervention specialists conduct interviews with newly diagnosed HIV-1 cases and pursue sexual networking analyses. Phylogenetic and network analyses of available Vermont HIV-1 polymerase (pol) sequences identified clusters of infection. Fishers-exact and independent t-tests were used to compare people with HIV-1 within or outside an identified cluster. RESULTS: Between 1 January 2017 and 31 December 2018, 38 residents were diagnosed with HIV-1 infection. The mean age was 35.5 years, 79% were male and 82% were White. Risk factors for HIV-1 included MSM status (79%) and methamphetamine use (21%). Eighteen cases (49%) had HIV-1 viral loads (VLs) >100 000 copies/mL and 47% had CD4 cell counts <200/mm3. Eleven of the 38 (29%) had positive syphilis serology, including four (36%) with neurosyphilis. Sexual networking analysis revealed a ten-person cluster with higher VLs at diagnosis (90% with VLs > 100 000 copies/mL vs 33%, P = 0.015). Phylogenetic analysis of pol sequences showed a cluster of 14 cases with sequences that shared 98%-100% HIV-1 nucleotide identity. CONCLUSIONS: This investigation of newly infected HIV-1 cases in Vermont led to identification of a cluster that appeared more likely to have advanced HIV-1 disease and neurosyphilis, supported by phylogenetic and network analyses.

Elevated Risk of Bacterial Vaginosis Among Users of the Copper Intrauterine Device: A Prospective Longitudinal Cohort Study.

BACKGROUND: Limited evidence suggests that the nonhormonal contraceptive copper intrauterine device (Cu-IUD) may increase bacterial vaginosis (BV) risk, possibly due to increased volume and duration of menses, a common side effect of Cu-IUD use. Although increases in bleeding typically resolve within 6-12 months following initiation, evaluations of the association between Cu-IUD and BV have not included more than 6 months of follow-up. METHODS: This secondary analysis of a human immunodeficiency virus type 1 prevention trial included 2585 African women ages 18-45 followed for up to 33 months. Women reported contraceptive use each month. BV was evaluated by Nugent score in 6-monthly intervals and, if clinically indicated, by Amsel criteria. Andersen-Gill proportional hazards models were used to (1) evaluate BV risk among Cu-IUD users relative to women using no/another nonhormonal contraceptive and (2) test changes in BV frequency before, while using, and following Cu-IUD discontinuation. RESULTS: BV frequency was highest among Cu-IUD users at 153.6 episodes per 100 person-years (95% confidence interval [CI]: 145.2, 162.4). In adjusted models, Cu-IUD users experienced 1.28-fold (95% CI: 1.12, 1.46) higher BV risk relative to women using no/another nonhormonal contraception. Compared to the 6 months prior to initiation, BV risk was 1.52-fold (95% CI: 1.16, 2.00) higher in the first 6 months of Cu-IUD use and remained elevated over 18 months of use (P < .05). Among women who discontinued Cu-IUD, BV frequency was similar to pre-initiation rates within 1 year. CONCLUSIONS: Cu-IUD users experienced elevated BV risk that persisted throughout use. Women and their providers may wish to consider BV risk when discussing contraceptive options.

Koala methylomes reveal divergent and conserved DNA methylation signatures of X chromosome regulation.

X chromosome inactivation (XCI) mediated by differential DNA methylation between sexes is an iconic example of epigenetic regulation. Although XCI is shared between eutherians and marsupials, the role of DNA methylation in marsupial XCI remains contested. Here, we examine genome-wide signatures of DNA methylation across fives tissues from a male and female koala (Phascolarctos cinereus), and present the first whole-genome, multi-tissue marsupial 'methylome atlas'. Using these novel data, we elucidate divergent versus common features of representative marsupial and eutherian DNA methylation. First, tissue-specific differential DNA methylation in koalas primarily occurs in gene bodies. Second, females show significant global reduction (hypomethylation) of X chromosome DNA methylation compared to males. We show that this pattern is also observed in eutherians. Third, on average, promoter DNA methylation shows little difference between male and female koala X chromosomes, a pattern distinct from that of eutherians. Fourth, the sex-specific DNA methylation landscape upstream of Rsx, the primary lncRNA associated with marsupial XCI, is consistent with the epigenetic regulation of female-specific (and presumably inactive X chromosome-specific) expression. Finally, we use the prominent female X chromosome hypomethylation and classify 98 previously unplaced scaffolds as X-linked, contributing an additional 14.6 Mb (21.5%) to genomic data annotated as the koala X chromosome. Our work demonstrates evolutionarily divergent pathways leading to functionally conserved patterns of XCI in two deep branches of mammals.

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.

Use of a Vaginal Ring Containing Dapivirine for HIV-1 Prevention in Women.

BACKGROUND: Antiretroviral medications that are used as prophylaxis can prevent acquisition of human immunodeficiency virus type 1 (HIV-1) infection. However, in clinical trials among African women, the incidence of HIV-1 infection was not reduced, probably because of low adherence. Longer-acting methods of drug delivery, such as vaginal rings, may simplify use of antiretroviral medications and provide HIV-1 protection. METHODS: We conducted a phase 3, randomized, double-blind, placebo-controlled trial of a monthly vaginal ring containing dapivirine, a non-nucleoside HIV-1 reverse-transcriptase inhibitor, involving women between the ages of 18 and 45 years in Malawi, South Africa, Uganda, and Zimbabwe. RESULTS: Among the 2629 women who were enrolled, 168 HIV-1 infections occurred: 71 in the dapivirine group and 97 in the placebo group (incidence, 3.3 and 4.5 per 100 person-years, respectively). The incidence of HIV-1 infection in the dapivirine group was lower by 27% (95% confidence interval [CI], 1 to 46; P=0.046) than that in the placebo group. In an analysis that excluded data from two sites that had reduced rates of retention and adherence, the incidence of HIV-1 infection in the dapivirine group was lower by 37% (95% CI, 12 to 56; P=0.007) than that in the placebo group. In a post hoc analysis, higher rates of HIV-1 protection were observed among women over the age of 21 years (56%; 95% CI, 31 to 71; P<0.001) but not among those 21 years of age or younger (-27%; 95% CI, -133 to 31; P=0.45), a difference that was correlated with reduced adherence. The rates of adverse medical events and antiretroviral resistance among women who acquired HIV-1 infection were similar in the two groups. CONCLUSIONS: A monthly vaginal ring containing dapivirine reduced the risk of HIV-1 infection among African women, with increased efficacy in subgroups with evidence of increased adherence. (Funded by the National Institutes of Health; ClinicalTrials.gov number, NCT01617096 .).

The impact of simulation-based medical education on resident management of emergencies in pediatric anesthesiology.

BACKGROUND: Resident education in pediatric anesthesiology is challenging. Traditional curricula for anesthesiology residency programs have included a combination of didactic lectures and mentored clinical service, which can be variable. Limited pediatric medical knowledge, technical inexperience, and heightened resident anxiety further challenge patient care. We developed a pediatric anesthesia simulation-based curriculum to address crises related to hypoxemia and dysrhythmia management in the operating room as an adjunct to traditional didactic and clinical experiences. AIMS: The primary objective of this trial was to evaluate the impact of a simulation curriculum designed for anesthesiology residents on their performance during the management of crises in the pediatric operating room. A secondary objective was to compare the retention of learned knowledge by assessment at the eight-week time point during the rotation. METHODS: In this prospective, observational trial 30 residents were randomized to receive simulation-based education on four perioperative crises (Laryngospasm, Bronchospasm, Supraventricular Tachycardia (SVT), and Bradycardia) during the first week (Group A) or fifth week (Group B) of an eight-week rotation. Assessment sessions that included two scenarios (Laryngospasm, SVT) were performed in the first week, fifth week, and the eighth week of their rotation for all residents. The residents were assessed in real time and by video review using a 7-point checklist generated by a modified Delphi technique of senior pediatric anesthesiology faculty. RESULTS: Residents in Group A showed improvement between the first week and fifth week assessment as well as between first week and eighth week assessments without decrement between the fifth week and eighth week assessments for both the laryngospasm and SVT scenarios. Residents in Group B showed improvement between the first week and eighth week assessments for both scenarios and between the fifth week and eighth week assessment for the SVT scenario. CONCLUSION: This adjunctive simulation-based curriculum enhanced the learner's management of laryngospasm and SVT management and is a reasonable addition to didactic and clinical curricula for anesthesiology residents.

Pediatric anesthesiology fellow education: is a simulation-based boot camp feasible and valuable?

BACKGROUND: Pediatric anesthesiologists must manage crises in neonates and children with timely responses and limited margin for error. Teaching the range of relevant skills during a 12-month fellowship is challenging. An experiential simulation-based curriculum can augment acquisition of knowledge and skills. OBJECTIVES: To develop a simulation-based boot camp (BC) for novice pediatric anesthesiology fellows and assess learner perceptions of BC activities. We hypothesize that BC is feasible, not too basic, and well received by fellows. METHODS: Skills stations, team-based in situ simulations, and group discussions of complex cases were designed. Stations were evaluated by anonymous survey; fellows rated usefulness in improving knowledge, self-confidence, technical skill, and clinical performance using a Likert scale (1 strongly disagree to 5 strongly agree). They were also asked if stations were too basic or too short. Median and interquartile range (IQR) data were calculated and noted as median (IQR). RESULTS: Fellows reported the difficult airway station and simulated scenarios improved knowledge, self-confidence, technical skill, and clinical performance. They disagreed that stations were too basic or too short with exception of the difficult airway session, which was too short [4 (4-3)]. Fellows believed the central line station improved knowledge [4 (4-3)], technical skills [4 (4-4)], self-confidence [4 (4-3)], and clinical performance [4 (4-3)]; scores trended toward neutral likely because the station was perceived as too basic [3.5 (4-3)]. An interactive session on epinephrine and intraosseous lines was valued. Complicated case discussion was of educational value [4 (5-4)], the varied opinions of faculty were helpful [4 (5-4)], and the session was neither too basic [2 (2-2)] nor too short [2 (2-2)]. CONCLUSION: A simulation-based BC for pediatric anesthesiology fellows was feasible, perceived to improve confidence, knowledge, technical skills, and clinical performance, and was not too basic.

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.

Phase 1 randomized trials to assess safety, pharmacokinetics, and vaginal bleeding associated with use of extended duration dapivirine and levonorgestrel vaginal rings.

BACKGROUND: Vaginal rings formulated to deliver two drugs simultaneously have potential as user-controlled, long-acting methods for dual prevention of HIV and pregnancy. METHODS: Two phase 1 randomized trials (MTN-030/IPM 041 and MTN-044/IPM 053/CCN019) respectively enrolled 24 and 25 healthy, HIV-negative participants to evaluate safety, pharmacokinetics, and vaginal bleeding associated with use of a vaginal ring containing 200mg dapivirine (DPV) and 320mg levonorgestrel (LNG) designed for 90-day use. MTN-030/IPM 041 compared the DPV/LNG ring to a DPV-only ring (200mg) over 14 days of use. MTN-044/IPM 053/CCN019 compared continuous or cyclic use of the DPV/LNG ring over 90 days of use. Safety was assessed by recording adverse events (AEs). DPV and LNG concentrations were quantified in plasma, cervicovaginal fluid, and cervical tissue. Vaginal bleeding was self-reported. RESULTS: There were no differences in the proportion of participants with grade ≥2 genitourinary AEs or grade ≥3 AEs with DPV/LNG ring vs. DPV ring use (p = .22), or with DPV/LNG ring continuous vs. cyclic use (p = .67). Higher plasma DPV concentrations were observed in users of DPV/LNG compared to DPV-only rings (Cmax p = 0.049; AUC p = 0.091). Plasma DPV and LNG concentrations were comparable with continuous and cyclic use (Cmax p = 0.74; AUC p = 0.25). With cyclic use, median nadir plasma DPV concentration was approximately 300 pg/mL two days after removal and median t1/2 for cervicovaginal fluid DPV concentration was 5.76 hours (n = 3). Overall bleeding experiences did not differ between continuous and cyclic users (p = 0.12). CONCLUSIONS: The extended duration DPV/ LNG rings were well tolerated and the observed DPV concentrations in plasma and cervicovaginal fluid when used continuously exceeded concentrations observed in previous DPV ring efficacy studies. LNG concentrations in plasma were comparable with other efficacious LNG-based contraceptives. Genital DPV concentrations had a short half-life and were thus not well sustained following ring removal.

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.

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.

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.

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.

Is the pleth variability index a surrogate for pulse pressure variation in a pediatric population undergoing spine fusion?

OBJECTIVE: To compare simultaneous measurements of pulse pressure variation (PPV) and pleth variability index (PVI) in patients undergoing spinal fusion. AIMS: To determine if PVI can be used as a surrogate for PPV and also the influence of the prone position on these measurements. BACKGROUND: Spine fusion is an involved surgical procedure requiring attention to fluid administration. Dynamic indices for assessing fluid responsiveness like PPV have proven useful to guide fluid administration. Plethysmographic waveform variation like PVI is an appealing surrogate for measurements like PPV that require invasive arterial pressure measurement. Spine fusion patients are unique and the potential of either PPV or PVI to guide fluid therapy has not been studied. METHODS: Patients undergoing spine fusion for scoliosis were studied. In addition to the usual monitors including direct arterial pressure measurement, a multi-wavelength pulse co-oximeter was applied to measure PVI. Paired measurements of PPV and PVI were obtained and limits of agreement determined using the method of Bland and Altman. PPV and PVI in prone and supine positions were compared by paired t-test. RESULTS: The bias between PVI and PPV measurements was -0.56% with 95% limits of agreement of +21.67% to -20.55%. There was no significant difference between the prone and supine measurements at the P = 0.05 level (Table 1). CONCLUSIONS: Our data indicate that PVI is not a surrogate for PPV. PVI measurements were not influenced by changing from the supine to prone position and therefore may prove useful for patients undergoing spine surgery.