COVID-19 vaccine uptake, confidence and hesitancy in rural KwaZulu-Natal, South Africa between April 2021 and April 2022: A continuous cross-sectional surveillance study

High COVID-19 vaccine hesitancy in South Africa limits protection against future epidemic waves. We evaluated how vaccine hesitancy and its correlates evolved April 2021-April 2022 in a well-characterized rural KwaZulu-Natal setting. All residents aged >15 in the Africa Health Research Institute's surveillance area were invited to complete a home-based, in-person interview. We described vaccine uptake and hesitancy trends, then evaluated associations with pre-existing personal factors, dynamic environmental context, and cues to action using ordinal logistic regression. Among 10,011 respondents, vaccine uptake rose as age-cohorts became vaccine-eligible before levelling off three months post-eligibility; younger age-groups had slower uptake and plateaued faster. Lifetime receipt of any COVID-19 vaccine rose from 3.0% in April-July 2021 to 32.9% in January-April 2022. Among 7,445 unvaccinated respondents, 47.7% said they would definitely take a free vaccine today in the first quarter of the study time period, falling to 32.0% in the last. By March/April 2022 only 48.0% of respondents were vaccinated or said they would definitely would take a vaccine. Predictors of lower vaccine hesitancy included being male (adjusted odds ratio [aOR]: 0.70, 95% confidence interval [CI]: 0.65-0.76), living with vaccinated household members (aOR:0.65, 95%CI: 0.59-0.71) and knowing someone who had had COVID-19 (aOR: 0.69, 95%CI: 0.59-0.80). Mistrust in government predicted greater hesitancy (aOR: 1.47, 95%CI: 1.42-1.53). Despite several COVID-19 waves, vaccine hesitancy was common in rural South Africa, rising over time and closely tied to mistrust in government. However, interpersonal experiences countered hesitancy and may be entry-points for interventions

PROTAC-mediated degradation of Bruton's tyrosine kinase is inhibited by covalent binding

The impact of covalent binding on PROTAC-Mediated degradation of BTK was investigated through the preparation of both covalent binding and reversible binding PROTACs derived from the covalent BTK inhibitor ibrutinib. It was determined that a covalent binding PROTAC inhibited BTK degradation despite evidence of target engagement, while BTK degradation was observed with a reversible binding PROTAC. These observations were consistently found when PROTACs that were able to recruit either IAP or cereblon E3 ligases were employed. Proteomics analysis determined that the use of a covalently bound PROTAC did not result in the degradation of covalently bound targets, while degradation was observed for some reversibly bound targets. This observation highlights the importance of catalysis for successful PROTAC-Mediated degradation and highlights a potential caveat for the use of covalent target binders in PROTAC design

Closing in on Asymmetric Dark Matter I: Model independent limits for interactions with quarks

It is argued that experimental constraints on theories of asymmetric dark matter (ADM) almost certainly require that the DM be part of a richer hidden sector of interacting states of comparable mass or lighter. A general requisite of models of ADM is that the vast majority of the symmetric component of the DM number density must be removed in order to explain the observed relationship $\Omega_B\sim\Omega_{DM}$ via the DM asymmetry. Demanding the efficient annihilation of the symmetric component leads to a tension with experimental limits if the annihilation is directly to Standard Model (SM) degrees of freedom. A comprehensive effective operator analysis of the model independent constraints on ADM from direct detection experiments and LHC monojet searches is presented. Notably, the limits obtained essentially exclude models of ADM with mass 1GeV$\lesssim m_{DM} \lesssim$ 100GeV annihilating to SM quarks via heavy mediator states. This motivates the study of portal interactions between the dark and SM sectors mediated by light states. Resonances and threshold effects involving the new light states are shown to be important for determining the exclusion limits.Comment: 18+6 pages, 18 figures. v2: version accepted for publicatio

Access to primary healthcare during lockdown measures for COVID-19 in rural South Africa: an interrupted time series analysis.

OBJECTIVES: We evaluated whether implementation of lockdown orders in South Africa affected ambulatory clinic visitation in rural Kwa-Zulu Natal (KZN). DESIGN: Observational cohort SETTING: Data were analysed from 11 primary healthcare clinics in northern KZN. PARTICIPANTS: A total of 46 523 individuals made 89 476 clinic visits during the observation period. EXPOSURE OF INTEREST: We conducted an interrupted time series analysis to estimate changes in clinic visitation with a focus on transitions from the prelockdown to the level 5, 4 and 3 lockdown periods. OUTCOME MEASURES: Daily clinic visitation at ambulatory clinics. In stratified analyses, we assessed visitation for the following subcategories: child health, perinatal care and family planning, HIV services, non-communicable diseases and by age and sex strata. RESULTS: We found no change in total clinic visits/clinic/day at the time of implementation of the level 5 lockdown (change from 90.3 to 84.6 mean visits/clinic/day, 95% CI -16.5 to 3.1), or at the transitions to less stringent level 4 and 3 lockdown levels. We did detect a >50% reduction in child healthcare visits at the start of the level 5 lockdown from 11.9 to 4.7 visits/day (-7.1 visits/clinic/day, 95% CI -8.9 to 5.3), both for children aged <1 year and 1-5 years, with a gradual return to prelockdown within 3 months after the first lockdown measure. In contrast, we found no drop in clinic visitation in adults at the start of the level 5 lockdown, or related to HIV care (from 37.5 to 45.6, 8.0 visits/clinic/day, 95% CI 2.1 to 13.8). CONCLUSIONS: In rural KZN, we identified a significant, although temporary, reduction in child healthcare visitation but general resilience of adult ambulatory care provision during the first 4 months of the lockdown. Future work should explore the impacts of the circulating epidemic on primary care provision and long-term impacts of reduced child visitation on outcomes in the region

Cosmological phase transitions in warped space: gravitational waves and collider signatures

We study the electroweak phase transition within a 5D warped model including a scalar potential with an exponential behavior, and strong back-reaction over the metric, in the infrared. By means of a novel treatment of the superpotential formalism, we explore parameter regions that were previously inaccessible. We nd that for large enough values of the t'Hooft parameter (e.g. N = 25) the holographic phase transition occurs, and it can force the Higgs to undergo a rst order electroweak phase transition, suitable for electroweak baryogenesis. The model exhibits gravitational waves and colliders signatures. It typically predicts a stochastic gravitational wave background observable both at the Laser Interferometer Space Antenna and at the Einstein Telescope. Moreover the radion tends to be heavy enough such that it evades current constraints, but may show up in future LHC runs.The work of EM is supported by the Spanish MINEICO under Grant FPA2015-64041-C2-1-P and FIS2017-85053-C2-1-P, by the Junta de Andaluc a under Grant FQM-225, by the Basque Government under Grant IT979-16, and by the Spanish Consolider Ingenio 2010 Programme CPAN (CSD2007-00042). The research of EM is also supported by the Ram on y Cajal Program of the Spanish MINEICO, and by the Universidad del Pa s Vasco UPV/EHU, Bilbao, Spain, as a Visiting Professor. GN is supported by the Swiss National Science Foundation (SNF) under grant 200020-168988. The work of MQ is partly supported by Spanish MINEICO under Grant CICYT-FEDER-FPA2014- 55613-P and FPA2017-88915-P, by the Severo Ochoa Excellence Program of MINEICO under Grant SEV-2016-0588, and by CNPq PVE fellowship project 405559/2013-5

Endomyocardial Fibrosis: Still a Mystery after 60 Years

The pathologist Jack N. P. Davies identified endomyocardial fibrosis in Uganda in 1947. Since that time, reports of this restrictive cardiomyopathy have come from other parts of tropical Africa, South Asia, and South America. In Kampala, the disease accounts for 20% of heart disease patients referred for echocardiography. We conducted a systematic review of research on the epidemiology and etiology of endomyocardial fibrosis. We relied primarily on articles in the MEDLINE database with either “endomyocardial fibrosis” or “endomyocardial sclerosis” in the title. The volume of publications on endomyocardial fibrosis has declined since the 1980s. Despite several hypotheses regarding cause, no account of the etiology of this disease has yet fully explained its unique geographical distribution

RNAi-Mediated c-Rel Silencing Leads to Apoptosis of B Cell Tumor Cells and Suppresses Antigenic Immune Response In Vivo

c-Rel is a member of the Rel/NF-κB transcription factor family and is predominantly expressed in lymphoid and myeloid cells, playing a critical role in lymphocyte proliferation and survival. Persistent activation of the c-Rel signal transduction pathway is associated with allergies, inflammation, autoimmune diseases, and a variety of human malignancies. To explore the potential of targeting c-Rel as a therapeutic agent for these disorders, we designed a small interfering RNA (siRNA) to silence c-Rel expression in vitro and in vivo. C-Rel-siRNA expression via a retroviral vector in a B cell tumor cell line leads to growth arrest and apoptosis of the tumor cells. Silencing c-Rel in primary B cells in vitro compromises their proliferative and survival response to CD40 activation signals, similar to the impaired response of c-Rel knockout B cells. Most important, in vivo silencing of c-Rel results in significant impairment in T cell-mediated immune responses to antigenic stimulation. Our study thus validates the efficacy of c-Rel-siRNA, and suggests the development of siRNA-based therapy, as well as small molecular inhibitors for the treatment of B cell tumors as well as autoimmune diseases

Whole-genome sequencing reveals host factors underlying critical COVID-19

Critical COVID-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care1 or hospitalization2–4 after infection with SARS-CoV-2. The GenOMICC (Genetics of Mortality in Critical Care) study enables the comparison of genomes from individuals who are critically ill with those of population controls to find underlying disease mechanisms. Here we use whole-genome sequencing in 7,491 critically ill individuals compared with 48,400 controls to discover and replicate 23 independent variants that significantly predispose to critical COVID-19. We identify 16 new independent associations, including variants within genes that are involved in interferon signalling (IL10RB and PLSCR1), leucocyte differentiation (BCL11A) and blood-type antigen secretor status (FUT2). Using transcriptome-wide association and colocalization to infer the effect of gene expression on disease severity, we find evidence that implicates multiple genes—including reduced expression of a membrane flippase (ATP11A), and increased expression of a mucin (MUC1)—in critical disease. Mendelian randomization provides evidence in support of causal roles for myeloid cell adhesion molecules (SELE, ICAM5 and CD209) and the coagulation factor F8, all of which are potentially druggable targets. Our results are broadly consistent with a multi-component model of COVID-19 pathophysiology, in which at least two distinct mechanisms can predispose to life-threatening disease: failure to control viral replication; or an enhanced tendency towards pulmonary inflammation and intravascular coagulation. We show that comparison between cases of critical illness and population controls is highly efficient for the detection of therapeutically relevant mechanisms of disease

Whole-genome sequencing reveals host factors underlying critical COVID-19

Critical COVID-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care1 or hospitalization2,3,4 after infection with SARS-CoV-2. The GenOMICC (Genetics of Mortality in Critical Care) study enables the comparison of genomes from individuals who are critically ill with those of population controls to find underlying disease mechanisms. Here we use whole-genome sequencing in 7,491 critically ill individuals compared with 48,400 controls to discover and replicate 23 independent variants that significantly predispose to critical COVID-19. We identify 16 new independent associations, including variants within genes that are involved in interferon signalling (IL10RB and PLSCR1), leucocyte differentiation (BCL11A) and blood-type antigen secretor status (FUT2). Using transcriptome-wide association and colocalization to infer the effect of gene expression on disease severity, we find evidence that implicates multiple genes—including reduced expression of a membrane flippase (ATP11A), and increased expression of a mucin (MUC1)—in critical disease. Mendelian randomization provides evidence in support of causal roles for myeloid cell adhesion molecules (SELE, ICAM5 and CD209) and the coagulation factor F8, all of which are potentially druggable targets. Our results are broadly consistent with a multi-component model of COVID-19 pathophysiology, in which at least two distinct mechanisms can predispose to life-threatening disease: failure to control viral replication; or an enhanced tendency towards pulmonary inflammation and intravascular coagulation. We show that comparison between cases of critical illness and population controls is highly efficient for the detection of therapeutically relevant mechanisms of disease

A two-faced selectivity solution to target SMARCA2 for cancer therapy

Two new studies exploring PROTAC-mediated degradation of SMARCA2 for cancer therapy solve an apparently intractable selectivity challenge with SMARCA4 by utilising the requirement for a productive ternary complex between the protein, PROTAC and ligase complex