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Viral infections can alter host transcriptomes by manipulating host splicing machinery. Despite intensive transcriptomic studies on SARS-CoV-2, a systematic analysis of alternative splicing (AS) in severe COVID-19 patients remains largely elusive. Here we integrated proteomic and transcriptomic sequencing data to study AS changes in COVID-19 patients. We discovered that RNA splicing is among the major down-regulated proteomic signatures in COVID-19 patients. The transcriptome analysis showed that SARS-CoV-2 infection induces widespread dysregulation of transcript usage and expression, affecting blood coagulation, neutrophil activation, and cytokine production. Notably, CD74 and LRRFIP1 had increased skipping of an exon in COVID-19 patients that disrupts a functional domain, which correlated with reduced antiviral immunity. Furthermore, the dysregulation of transcripts was strongly correlated with clinical severity of COVID-19, and splice-variants may contribute to unexpected therapeutic activity. In summary, our data highlight that a better understanding of the AS landscape may aid in COVID-19 diagnosis and therapy.

The mechanisms by which microRNAs (miRNAs) affect cell fate decisions remain poorly understood. Herein, we report that miR-200a can suppress the differentiation of mouse embryonic stem (ES) cells into endoderm and mesoderm. Interestingly, miR-200a directly targets growth factor receptor-bound protein 2 (Grb2), which is a key adaptor in the Erk signaling pathway. Furthermore, high levels of miR-200a dramatically decrease Grb2 levels and suppress the appearance of mesoderm and endoderm lineages in embryoid body formation, as well as suppressing the activation of Erk. Finally, Grb2 supplementation significantly rescues the miR-200a-induced layer-formation bias and the Erk suppression. Collectively, our results demonstrate that miR-200a plays critical roles in ES cell lineage commitment by directly regulating Grb2 expression and Erk signaling.

In mammalian germ cells, meiotic commitment requires the expression of Stimulated by retinoic acid gene 8 (Stra8), which is transcriptionally activated by retinoic acid (RA). However, little is known about the epigenetic mechanism by which RA induces Stra8 expression. Utilizing a chromatin immunoprecipitation assay (ChIP), we showed that RA increases histone acetylation at the Stra8 promoter in murine embryonic stem cells (ESCs), a model for germ cell differentiation. Furthermore, we explored whether two coregulators with histone acetyltransferase (HAT) activity, Creb-binding protein (CBP) and p300, are involved in the activation of Stra8. The lentiviral shRNA knockdown of endogenous CBP led to Stra8 repression, while the overexpression of CBP enhanced Stra8 expression at both the mRNA and protein levels. ChIP analysis confirmed that CBP is the crucial coactivator for RA-mediated Stra8 transcription and that it enhances the level of histone acetylation and recruits RNA polymerase II to establish transcriptionally active chromatin. Furthermore, shRNA of p300 enhanced Stra8 expression, and the overexpression of p300 reduced Stra8 expression, independently of its HAT activity. ChIP showed that the knockdown of p300 significantly increased the level of CBP at the Stra8 promoter. These findings demonstrate that CBP and p300 play distinct roles in RA-mediated Stra8 gene transcription.

ObjectiveTo compare preferences, uptake, and cofactors for unassisted home-based oral self-testing (HB-HIVST) versus clinic-based rapid diagnostic blood tests (CB-RDT) for maternal HIV retesting.DesignProspective cohort.MethodsBetween November 2017 and June 2019, HIV-negative pregnant Kenyan women receiving antenatal care were enrolled and given a choice to retest with HB-HIVST or CB-RDT. Women were asked to retest between 36 weeks gestation and 1-week post-delivery if the last HIV test was ResultsOverall, 994 women enrolled and 33% (n = 330) selected HB-HIVST. HB-HIVST was selected because it was private (n = 224, 68%), convenient (n = 211, 63%), and offered flexibility in the timing of retesting (n = 207, 63%), whereas CB-RDT was selected due to the trust of providers to administer the test (n = 510, 77%) and convenience of clinic testing (n = 423, 64%). Among 905 women who reported retesting at follow-up, 135 (15%) used HB-HIVST. Most (n = 595, 94%) who selected CB-RDT retested with this strategy, compared to 39% (n = 120) who selected HB-HIVST retesting with HB-HIVST. HB-HIVST retesting was more common among women with higher household income and those who may have been unable to test during pregnancy (both retested postpartum and delivered ConclusionsWhile most women preferred CB-RDT for maternal retesting, HB-HIVST was acceptable and feasible and could be used to expand HIV retesting options.

BackgroundHIV testing services (HTS) are the first steps in reaching the UNAIDS 95-95-95 goals to achieve and maintain low HIV incidence. Evaluating the effectiveness of different demand creation interventions to increase uptake of efficient and effective HTS is useful to prioritize limited programmatic resources. This review was undertaken to inform World Health Organization (WHO) 2019 HIV testing guidelines and assessed the research question, "Which demand creation strategies are effective for enhancing uptake of HTS?" focused on populations globally.Methods and findingsThe following electronic databases were searched through September 28, 2021: PubMed, PsycInfo, Cochrane CENTRAL, CINAHL Complete, Web of Science Core Collection, EMBASE, and Global Health Database; we searched IAS and AIDS conferences. We systematically searched for randomized controlled trials (RCTs) that compared any demand creation intervention (incentives, mobilization, counseling, tailoring, and digital interventions) to either a control or other demand creation intervention and reported HTS uptake. We pooled trials to evaluate categories of demand creation interventions using random-effects models for meta-analysis and assessed study quality with Cochrane's risk of bias 1 tool. This study was funded by the WHO and registered in Prospero with ID CRD42022296947. We screened 10,583 records and 507 conference abstracts, reviewed 952 full texts, and included 124 RCTs for data extraction. The majority of studies were from the African (N = 53) and Americas (N = 54) regions. We found that mobilization (relative risk [RR]: 2.01, 95% confidence interval [CI]: [1.30, 3.09], p < 0.05; risk difference [RD]: 0.29, 95% CI [0.16, 0.43], p < 0.05, N = 4 RCTs), couple-oriented counseling (RR: 1.98, 95% CI [1.02, 3.86], p < 0.05; RD: 0.12, 95% CI [0.03, 0.21], p < 0.05, N = 4 RCTs), peer-led interventions (RR: 1.57, 95% CI [1.15, 2.15], p < 0.05; RD: 0.18, 95% CI [0.06, 0.31], p < 0.05, N = 10 RCTs), motivation-oriented counseling (RR: 1.53, 95% CI [1.07, 2.20], p < 0.05; RD: 0.17, 95% CI [0.00, 0.34], p < 0.05, N = 4 RCTs), short message service (SMS) (RR: 1.53, 95% CI [1.09, 2.16], p < 0.05; RD: 0.11, 95% CI [0.03, 0.19], p < 0.05, N = 5 RCTs), and conditional fixed value incentives (RR: 1.52, 95% CI [1.21, 1.91], p < 0.05; RD: 0.15, 95% CI [0.07, 0.22], p < 0.05, N = 11 RCTs) all significantly and importantly (≥50% relative increase) increased HTS uptake and had medium risk of bias. Lottery-based incentives and audio-based interventions less importantly (25% to 49% increase) but not significantly increased HTS uptake (medium risk of bias). Personal invitation letters and personalized message content significantly but not importantly (ConclusionsMobilization, couple- and motivation-oriented counseling, peer-led interventions, conditional fixed value incentives, and SMS are high-impact demand creation interventions and should be prioritized for programmatic consideration. Reduced duration counseling and video-based interventions are an efficient and effective alternative to address staffing shortages. Investment in demand creation activities should prioritize those with undiagnosed HIV or ongoing HIV exposure. Selection of demand creation interventions must consider risks and benefits, context-specific factors, feasibility and sustainability, country ownership, and universal health coverage across disease areas.

Globally, 2.5 million neonates die and 2 million more are stillborn each year; the vast majority occur where access to life-saving care is limited. High quality, feasible interventions are needed to reach, educate and empower pregnant women and new mothers to improve care-seeking behaviors. Mobile WACh (Mobile solutions for Women's and Children's health) NEO is a human-computer hybrid mobile health (mHealth) system that allows for two-way short message service (SMS) communication between women and healthcare workers during the peripartum period. We performed a secondary prospective cohort analysis of data from the Mobile WACh NEO pilot study to determine maternal characteristics associated with neonatal death and stillbirth and examine participant messaging associated with these events. Pregnant women were enrolled at two Kenyan public health clinics between 28-36 weeks gestation. They received personalized, educational, action-oriented SMS messages during pregnancy and through 14 weeks postpartum. Participants could message the study at any time and study nurses responded. Standardized questionnaires assessed participant characteristics at baseline and 14 weeks postpartum. Outcomes were ascertained at study visits or by SMS report. Among 798 pregnant women enrolled, median age was 24 years [IQR 21, 29], 37% were primiparous and 92% used SMS as a primary mode of communication. Seventeen neonatal deaths and 13 stillbirths occurred. Older maternal age was associated with increased risk of stillbirth [aRR 1.12 (CI 1.02-1.24), p

BackgroundPregnant and postpartum women living with HIV (WLWH) need support for HIV and maternal child health (MCH) care, which could be provided using short message service (SMS).Methods and findingsWe compared 2-way (interactive) and 1-way SMS messaging to no SMS in a 3-arm randomized trial in 6 MCH clinics in Kenya. Messages were developed using the Health Belief Model and Social Cognitive Theory; HIV messages were integrated into an existing MCH SMS platform. Intervention participants received visit reminders and prespecified weekly SMS on antiretroviral therapy (ART) adherence and MCH, tailored to their characteristics and timing. Two-way participants could message nurses as needed. Clinic attendance, viral load (VL), and infant HIV results were abstracted from program records. Primary outcomes were viral nonsuppression (VL ≥1,000 c/ml), on-time clinic attendance, loss to follow-up from clinical care, and infant HIV-free survival. Among 824 pregnant women randomized between November 2015 and May 2017, median age was 27 years, gestational age was 24.3 weeks, and time since initiation of ART was 1.0 year. During follow-up to 2 years postpartum, 9.8% of 3,150 VL assessments and 19.6% of women were ever nonsuppressed, with no significant difference in 1-way versus control (11.2% versus 9.6%, adjusted risk ratio (aRR) 1.02 [95% confidence interval (CI) 0.67 to 1.54], p = 0.94) or 2-way versus control (8.5% versus 9.6%, aRR 0.80 [95% CI 0.52 to 1.23], p = 0.31). Median ART adherence and incident ART resistance did not significantly differ by arm. Overall, 88.9% (95% CI 76.5 to 95.7) of visits were on time, with no significant differences between arms (88.2% in control versus 88.6% in 1-way and 88.8% in 2-way). Incidence of infant HIV or death was 3.01/100 person-years (py), with no significant difference between arms; risk of infant HIV infection was 0.94%. Time to postpartum contraception was significantly shorter in the 2-way arm than control. Study limitations include limited ability to detect improvement due to high viral suppression and visit attendance and imperfect synchronization of SMS reminders to clinic visits.ConclusionsIntegrated HIV/MCH messaging did not improve HIV outcomes but was associated with improved initiation of postpartum contraception. In programs where most women are virally suppressed, targeted SMS informed by VL data may improve effectiveness. Rigorous evaluation remains important to optimize mobile health (mHealth) interventions.Trial registrationClinicalTrials.gov number NCT02400671.