Equipping providers to offer novel MPTs: Developing counseling messages for the Dual Prevention Pill in clinical studies and beyond

IntroductionThe pipeline for multi-purpose prevention technologies includes products that simultaneously prevent HIV, pregnancy and/or other sexually transmitted infections. Among these, the Dual Prevention Pill (DPP) is a daily pill co-formulating oral pre-exposure prophylaxis (PrEP), and combined oral contraception (COC). Clinical cross-over acceptability studies for the DPP require training providers to counsel on a combined product. From February 2021–April 2022, a working group of eight HIV and FP experts with clinical and implementation expertise developed counseling recommendations for the DPP based on existing PrEP/COC guidance.Assessment of policy/guidelines options and implicationsThe working group conducted a mapping of counseling messages from COC and oral PrEP guidance and provider training materials. Six topics were prioritized: uptake, missed pills, side effects, discontinuation and switching, drug interactions and monitoring. Additional evidence and experts were consulted to answer outstanding questions and counseling recommendations for the DPP were developed. Missed pills was the topic with the most complexity, raising questions about whether women could “double up” on missed pills or skip the last week of the pack to recover protection faster. Uptake required aligning the time to reach protective levels for both DPP components and explaining the need to take DPP pills during week 4 of the pack. The potential intensity of DPP side effects, given the combination of oral PrEP with COC, was an important consideration. Discontinuation and switching looked at managing risk of HIV and unintended pregnancy when stopping or switching from the DPP. Guidance on drug interactions contended with differing contraindications for COC and PrEP. Monitoring required balancing clinical requirements with potential user burden.Actionable recommendationsThe working group developed counseling recommendations for the DPP to be tested in clinical acceptability studies. Uptake: Take one pill every day for the DPP until the pack is empty. Days 1–21 contain COC and oral PrEP. Days 22–28 do not contain COC to allow for monthly bleeding, but do contain oral PrEP and pills should be taken to maintain HIV protection. Take the DPP for 7 consecutive days to reach protective levels against pregnancy and HIV. Missed pills: If you miss 1 pill multiple times in a month or 2+ consecutive pills, take the DPP as soon as you remember. Do not take more than 2 pills in a day. If 2+ consecutive pills are missed, only take the last missed pill and discard the other missed pills. Side effects: You may experience side effects when you start using the DPP, including changes to monthly bleeding. Side effects are typically mild and go away without treatment. Discontinuation/switching: If you decide to discontinue use of the DPP, but want to be protected from HIV and/or unintended pregnancy, in most cases, you can begin using PrEP or another contraceptive method right away. Drug interactions: There are no drug-drug interactions from combining oral PrEP and COC in the DPP. Certain medications are not recommended due to their contraindication with oral PrEP or COC. Monitoring: You will need to get an HIV test prior to initiating or restarting the DPP, and every 3 months during DPP use. Your provider may recommend other screening or testing.DiscussionDeveloping recommendations for the DPP as a novel MPT posed unique challenges, with implications for efficacy, cost, and user and provider comprehension and burden. Incorporating counseling recommendations into clinical cross-over acceptability studies allows for real-time feedback from providers and users. Supporting women with information to use the DPP correctly and confidently is critically important for eventual scale and commercialization

SLC2A9 Is a High-Capacity Urate Transporter in Humans

Serum uric acid levels in humans are influenced by diet, cellular breakdown, and renal elimination, and correlate with blood pressure, metabolic syndrome, diabetes, gout, and cardiovascular disease. Recent genome-wide association scans have found common genetic variants of SLC2A9 to be associated with increased serum urate level and gout. The SLC2A9 gene encodes a facilitative glucose transporter, and it has two splice variants that are highly expressed in the proximal nephron, a key site for urate handling in the kidney. We investigated whether SLC2A9 is a functional urate transporter that contributes to the longstanding association between urate and blood pressure in man

Manajemen Program Siaran Lokal Aceh TV Dalam Upaya Penyebarluasan Syariat Islam Dan Pelestarian Budaya Lokal

Managing broadcasting management is not easy. Managing the broadcasting business is a difficult and challenging. This research aims to analyze the activity of management and organizational performance ACEH TV television media in an effort to disseminate the Islamic Sharia and Preservation of Local Culture in Aceh. This research is descriptive qualitative. Informants of this research is managing director, program director, executive producer, cameraman / reporter, as well as additional informants Regional Chairman of the Indonesian Broadcasting Commission (KPID) Aceh, Aceh Province Department of Islamic Law, and local media observers. The location of this research is in Banda Aceh, Aceh province. Sampling was done purposively. Data collected through observation, interviews, and documentation. Data were analyzed by analysis of an interactive model of Miles and Huberman. The results showed that the ACEH TV as the medium of television that is broadcasting management ACEH have done according to a local television broadcasting standard. Agenda setting function of mass media performed in the ACEH TV dissemination of Islamic Shariah in Aceh and local culture to influence the people of Aceh to implement Islamic Sharia and also maintain the culture and local wisdom Aceh. It can be seen from all the programs that are aired ACEH TV is a program of local cultural nuances of Islamic law. There are still some shortcomings in running broadcasting broadcasting technology such as lack of equipment that is increasingly sophisticated. The results of image editing is very simple, and some programs presenter still looks stiff when in front of the camera

Localization of type 1 diabetes susceptibility to the MHC class I genes HLA-B and HLA-A

The major histocompatibility complex (MHC) on chromosome 6 is associated with susceptibility to more common diseases than any other region of the human genome, including almost all disorders classified as autoimmune. In type 1 diabetes the major genetic susceptibility determinants have been mapped to the MHC class II genes HLA-DQB1 and HLA-DRB1 (refs 1-3), but these genes cannot completely explain the association between type 1 diabetes and the MHC region. Owing to the region's extreme gene density, the multiplicity of disease-associated alleles, strong associations between alleles, limited genotyping capability, and inadequate statistical approaches and sample sizes, which, and how many, loci within the MHC determine susceptibility remains unclear. Here, in several large type 1 diabetes data sets, we analyse a combined total of 1,729 polymorphisms, and apply statistical methods - recursive partitioning and regression - to pinpoint disease susceptibility to the MHC class I genes HLA-B and HLA-A (risk ratios >1.5; Pcombined = 2.01 × 10-19 and 2.35 × 10-13, respectively) in addition to the established associations of the MHC class II genes. Other loci with smaller and/or rarer effects might also be involved, but to find these, future searches must take into account both the HLA class II and class I genes and use even larger samples. Taken together with previous studies, we conclude that MHC-class-I-mediated events, principally involving HLA-B*39, contribute to the aetiology of type 1 diabetes. ©2007 Nature Publishing Group

Polymorphisms in the WNK1 gene are associated with blood pressure variation and urinary potassium excretion.

WNK1--a serine/threonine kinase involved in electrolyte homeostasis and blood pressure (BP) control--is an excellent candidate gene for essential hypertension (EH). We and others have previously reported association between WNK1 and BP variation. Using tag SNPs (tSNPs) that capture 100% of common WNK1 variation in HapMap, we aimed to replicate our findings with BP and to test for association with phenotypes relating to WNK1 function in the British Genetics of Hypertension (BRIGHT) study case-control resource (1700 hypertensive cases and 1700 normotensive controls). We found multiple variants to be associated with systolic blood pressure, SBP (7/28 tSNPs min-p = 0.0005), diastolic blood pressure, DBP (7/28 tSNPs min-p = 0.002) and 24 hour urinary potassium excretion (10/28 tSNPs min-p = 0.0004). Associations with SBP and urine potassium remained significant after correction for multiple testing (p = 0.02 and p = 0.01 respectively). The major allele (A) of rs765250, located in intron 1, demonstrated the strongest evidence for association with SBP, effect size 3.14 mmHg (95%CI:1.23-4.9), DBP 1.9 mmHg (95%CI:0.7-3.2) and hypertension, odds ratio (OR: 1.3 [95%CI: 1.0-1.7]).We genotyped this variant in six independent populations (n = 14,451) and replicated the association between rs765250 and SBP in a meta-analysis (p = 7 x 10(-3), combined with BRIGHT data-set p = 2 x 10(-4), n = 17,851). The associations of WNK1 with DBP and EH were not confirmed. Haplotype analysis revealed striking associations with hypertension and BP variation (global permutation p10 mmHg reduction) and risk for hypertension (OR<0.60). Our data indicates that multiple rare and common WNK1 variants contribute to BP variation and hypertension, and provide compelling evidence to initiate further genetic and functional studies to explore the role of WNK1 in BP regulation and EH

New genetic loci link adipose and insulin biology to body fat distribution.

Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms

Identification of Genomic Regions Associated with Phenotypic Variation between Dog Breeds using Selection Mapping

Peer reviewe

Clinical Characteristics, Racial Inequities, and Outcomes in Patients with Breast Cancer and COVID-19: A COVID-19 and Cancer Consortium (CCC19) Cohort Study

BACKGROUND: Limited information is available for patients with breast cancer (BC) and coronavirus disease 2019 (COVID-19), especially among underrepresented racial/ethnic populations. METHODS: This is a COVID-19 and Cancer Consortium (CCC19) registry-based retrospective cohort study of females with active or history of BC and laboratory-confirmed severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection diagnosed between March 2020 and June 2021 in the US. Primary outcome was COVID-19 severity measured on a five-level ordinal scale, including none of the following complications, hospitalization, intensive care unit admission, mechanical ventilation, and all-cause mortality. Multivariable ordinal logistic regression model identified characteristics associated with COVID-19 severity. RESULTS: 1383 female patient records with BC and COVID-19 were included in the analysis, the median age was 61 years, and median follow-up was 90 days. Multivariable analysis revealed higher odds of COVID-19 severity for older age (aOR per decade, 1.48 [95% CI, 1.32-1.67]); Black patients (aOR 1.74; 95 CI 1.24-2.45), Asian Americans and Pacific Islander patients (aOR 3.40; 95 CI 1.70-6.79) and Other (aOR 2.97; 95 CI 1.71-5.17) racial/ethnic groups; worse ECOG performance status (ECOG PS ≥2: aOR, 7.78 [95% CI, 4.83-12.5]); pre-existing cardiovascular (aOR, 2.26 [95% CI, 1.63-3.15])/pulmonary comorbidities (aOR, 1.65 [95% CI, 1.20-2.29]); diabetes mellitus (aOR, 2.25 [95% CI, 1.66-3.04]); and active and progressing cancer (aOR, 12.5 [95% CI, 6.89-22.6]). Hispanic ethnicity, timing, and type of anti-cancer therapy modalities were not significantly associated with worse COVID-19 outcomes. The total all-cause mortality and hospitalization rate for the entire cohort was 9% and 37%, respectively however, it varied according to the BC disease status. CONCLUSIONS: Using one of the largest registries on cancer and COVID-19, we identified patient and BC-related factors associated with worse COVID-19 outcomes. After adjusting for baseline characteristics, underrepresented racial/ethnic patients experienced worse outcomes compared to non-Hispanic White patients. FUNDING: This study was partly supported by National Cancer Institute grant number P30 CA068485 to Tianyi Sun, Sanjay Mishra, Benjamin French, Jeremy L Warner; P30-CA046592 to Christopher R Friese; P30 CA023100 for Rana R McKay; P30-CA054174 for Pankil K Shah and Dimpy P Shah; KL2 TR002646 for Pankil Shah and the American Cancer Society and Hope Foundation for Cancer Research (MRSG-16-152-01-CCE) and P30-CA054174 for Dimpy P Shah. REDCap is developed and supported by Vanderbilt Institute for Clinical and Translational Research grant support (UL1 TR000445 from NCATS/NIH). The funding sources had no role in the writing of the manuscript or the decision to submit it for publication. CLINICAL TRIAL NUMBER: CCC19 registry is registered on ClinicalTrials.gov, NCT04354701

Low-Frequency and Rare-Coding Variation Contributes to Multiple Sclerosis Risk

Multiple sclerosis is a complex neurological disease, with 3c20% of risk heritability attributable to common genetic variants, including >230 identified by genome-wide association studies. Multiple strands of evidence suggest that much of the remaining heritability is also due to additive effects of common variants rather than epistasis between these variants or mutations exclusive to individual families. Here, we show in 68,379 cases and controls that up to 5% of this heritability is explained by low-frequency variation in gene coding sequence. We identify four novel genes driving MS risk independently of common-variant signals, highlighting key pathogenic roles for regulatory T cell homeostasis and regulation, IFN\u3b3 biology, and NF\u3baB signaling. As low-frequency variants do not show substantial linkage disequilibrium with other variants, and as coding variants are more interpretable and experimentally tractable than non-coding variation, our discoveries constitute a rich resource for dissecting the pathobiology of MS. In a large multi-cohort study, unexplained heritability for multiple sclerosis is detected in low-frequency coding variants that are missed by GWAS analyses, further underscoring the role of immune genes in MS pathology