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Most phase III trials in drug-resistant tuberculosis have either been underpowered to quantify differences in microbiological endpoints or have taken up to a decade to complete. Composite primary endpoints, dominated by differences in treatment discontinuation and regimen changes, may mask important differences in treatment failure and relapse. Although new regimens for drug-resistant tuberculosis appear very effective, resistance to new drugs is emerging rapidly. There is a need for shorter, safer and more tolerable regimens, including those active against bedaquiline-resistant tuberculosis. Transitioning from multiple regimen A versus regimen B trials to a single large phase III platform trial would accelerate the acquisition of robust estimates of relative efficacy and safety. Further efficiencies could be achieved by adopting modern adaptive platform designs. Collaboration among trialists, affected community representatives, funders and regulators is essential for developing such a phase III platform trial for drug-resistant tuberculosis treatment regimens. La majorite des essais de phase III relatifs a la tuberculose pharmacoreslstante soit n'etaient pas assez puissants pour quantifier les fluctuations au niveau des criteres microbiologiques, soit etaient trop longs, se poursuivant parfois pendant dix ans. Les criteres primaires composites, domines par des differences dans l'interruption du traitement et les changements de schema, pourraient dissimuler d'importantes variations en termes d'echec therapeutique et de rechute. Bien que les nouveaux traitements contre la tuberculose pharmacoresistante semblent tres efficaces, la resistance aux nouveaux medicaments evolue rapidement. Il est donc necessaire d'opter pour des traitements plus courts, plus surs et mieux toleres, y compris ceux actifs contre la tuberculose resistant a la bedaquiline. Delaisser la multitude d'essais opposant un schema de traitement A a un schema de traitement B pour se diriger vers un unique essai plateforme de phase III de grande envergure permettrait d'obtenir plus vite des estimations solides concernant l'innocuite et l'efficacite relative. En outre, adopter des modeles de plateforme modernes et adaptatifs contribuerait a de meilleures performances. Enfin, la collaboration entre investigateurs, representants des communautes concernees, bailleurs de fonds et organismes de reglementation est essentielle a l'elaboration de ce type d'essai plateforme de phase III sur les traitements contre la tuberculose pharmacoresistante. La mayoria de los ensayos en fase III sobre tuberculosis resistente a los farmacos no ha tenido la potencia suficiente para cuantificar diferencias en los criterios de valoracion microbiologicos o ha tardado hasta una decada en completarse. Los criterios de valoracion principales compuestos, dominados por las diferencias en la interrupcion del tratamiento y los cambios de regimen, pueden ocultar diferencias importantes en el fracaso del tratamiento y la recaida. Aunque los nuevos regimenes de tratamiento para la tuberculosis resistente a los farmacos parecen muy eficaces, la resistencia a los nuevos farmacos esta apareciendo rapidamente. Se necesitan regimenes de tratamiento mas cortos, seguros y tolerables, incluidos los activos contra la tuberculosis resistente a la bedaquilina. La transicion de multiples ensayos de regimen A frente a regimen B a un unico gran ensayo de plataforma en fase III aceleraria la obtencion de estimaciones solidas de la eficacia y seguridad relativas. Podrian lograrse mayores eficiencias si se adoptaran disenos de plataforma adaptativos modernos. La colaboracion entre los autores de los ensayos, los representantes de las comunidades afectadas, los financiadores y los reguladores es esencial para desarrollar un ensayo de plataforma en fase III de este tipo para los regimenes de tratamiento de la tuberculosis resistente a los farmacos., Introduction Rifampicin and isoniazid are key drugs in treatment regimens for drug-susceptible tuberculosis. Rifampicin-resistant tuberculosis and multidrug-resistant tuberculosis (tuberculosis which is resistant to both isoniazid and rifampicin) are managed similarly, [...]

Recent advances in single-cell technologies have led to the discovery of thousands of brain cell types; however, our understanding of the gene regulatory programs in these cell types is far from complete1-4. Here we report a comprehensive atlas of candidate cis-regulatory DNA elements (cCREs) in the adult mouse brain, generated by analysing chromatin accessibility in 2.3 million individual brain cells from 117 anatomical dissections. The atlas includes approximately 1 million cCREs and their chromatin accessibility across 1,482 distinct brain cell populations, adding over 446,000 cCREs to the most recent such annotation in the mouse genome. The mouse brain cCREs are moderately conserved in the human brain. The mouse-specific cCREs-specifically, those identified from a subset of cortical excitatory neurons-are strongly enriched for transposable elements, suggesting a potential role for transposable elements in the emergence of new regulatory programs and neuronal diversity. Finally, we infer the gene regulatory networks in over 260 subclasses of mouse brain cells and develop deep-learning models to predict the activities of gene regulatory elements in different brain cell types from the DNA sequence alone. Our results provide a resource for the analysis of cell-type-specific gene regulation programs in both mouse and human brains.

Cytosine DNA methylation is essential in brain development and is implicated in various neurological disorders. Understanding DNA methylation diversity across the entire brain in a spatial context is fundamental for a complete molecular atlas of brain cell types and their gene regulatory landscapes. Here we used single-nucleus methylome sequencing (snmC-seq3) and multi-omic sequencing (snm3C-seq)1 technologies to generate 301,626 methylomes and 176,003 chromatin conformation-methylome joint profiles from 117 dissected regions throughout the adult mouse brain. Using iterative clustering and integrating with companion whole-brain transcriptome and chromatin accessibility datasets, we constructed a methylation-based cell taxonomy with 4,673 cell groups and 274 cross-modality-annotated subclasses. We identified 2.6 million differentially methylated regions across the genome that represent potential gene regulation elements. Notably, we observed spatial cytosine methylation patterns on both genes and regulatory elements in cell types within and across brain regions. Brain-wide spatial transcriptomics data validated the association of spatial epigenetic diversity with transcription and improved the anatomical mapping of our epigenetic datasets. Furthermore, chromatin conformation diversities occurred in important neuronal genes and were highly associated with DNA methylation and transcription changes. Brain-wide cell-type comparisons enabled the construction of regulatory networks that incorporate transcription factors, regulatory elements and their potential downstream gene targets. Finally, intragenic DNA methylation and chromatin conformation patterns predicted alternative gene isoform expression observed in a whole-brain SMART-seq2 dataset. Our study establishes a brain-wide, single-cell DNA methylome and 3D multi-omic atlas and provides a valuable resource for comprehending the cellular-spatial and regulatory genome diversity of the mouse brain.

Abstract Background Pre-exposure prophylaxis (PrEP) is a highly effective pharmaceutical intervention that prevents HIV infection, but PrEP uptake across the US has been slow among men who have sex with men (MSM), especially among Black/African American (B/AA) and Hispanic /Latino (H/L) MSM. This study investigates the acceptability and essential components of a peer-driven intervention (PDI) for promoting PrEP uptake among MSM, with a specific focus on B/AA and H/L communities. Methods We conducted 28 semi-structured, qualitative interviews with MSM in southern New England to explore the components of a PDI, including attitudes, content, and effective communication methods. A purposive sampling strategy was used to recruit diverse participants who reflect the communities with the highest burden of HIV infection. Results Of 28 study participants, the median age was 28 years (interquartile range [IQR]: 25, 35). The sample comprised B/AA (39%, n = 11) and H/L (50%, n = 14) individuals. Notably, nearly half of the participants (46%) were current PrEP users. We found that many participants were in favor of using a PDI approach for promoting PrEP. Additionally, several participants showed interest in becoming peer educators themselves. They emphasized the need for strong communication skills to effectively teach others about PrEP. Moreover, participants noted that peer education should cover key topics like how PrEP works, how effective it is, and any possible side effects. Conclusions Our study shows that effective PDIs, facilitated by well-trained peers knowledgeable about PrEP, could enhance PrEP uptake among MSM, addressing health disparities and potentially reducing HIV transmission in B/AA and H/L communities.

Abstract We present the evolution of the electronic structure of CrSBr from its antiferromagnetic ground state to the paramagnetic phase above T N = 132 K, in both experiment and theory. Low-temperature angle-resolved photoemission spectroscopy (ARPES) results are obtained using a novel method to overcome sample charging issues, revealing quasi-2D valence bands in the ground state. The results are very well reproduced by our $${\rm{QSG}}\hat{{\rm{W}}}$$ QSG W ̂ calculations, which further identify certain bands at the X points to be exchange-split pairs of states with mainly Br and S character. By tracing band positions as a function of temperature, we show the splitting disappears above T N . The energy splitting is interpreted as an effective exchange splitting in individual layers in which the Cr moments all align, within the so-called A-type antiferromagnetic arrangement. Our results lay firm foundations for the interpretation of the many other intriguing physical and optical properties of CrSBr.

Abstract Background This paper outlines a pilot of a new memory aide for breastfeeding conducted in the Northeast of England and North Cumbria between April and August 2023. The United Kingdom has some of the lowest rates of breastfeeding, particularly in the Northeast of England, and as such more needs to be done to support mothers to breastfeed for as long as they would like to. Good support from health professionals can be effective in influencing decisions to breastfeed as well as helping to ensure initiation and continuation of breastfeeding but there is evidence to suggest that professionals and students do not always feel adequately trained and it is here, where memory aides may have value. Methods Key breastfeeding practitioners and educators were brought together to select one of two memory aides for principles of attachment for effective breastfeeding. The selected memory aide, LATCHS, was piloted with 57 participants with a key role in promotion and support of breastfeeding in the Northeast of England and North Cumbria. Results Participants conveyed mixed views about the proposed memory aide with more experienced staff reporting more favourable opinions than student midwives and early years practitioners. Experienced staff felt the new memory aide would complement an early memory aide, CHINS, which focused on principles of positioning. Discussion Findings of the pilot indicate there is a role for a mnemonic to help practitioners understand, recall, and retain theory around attachment for effective breastfeeding and that memory aides can play an important role in complementing existing approaches to education and practice. The participants felt the proposed memory aide had some limitations and suggested important ways for it to be improved, particularly in adding an E to reflect the expecting wording. This produced the final memory aide: LATCHES. Conclusion Using data from the pilot, the memory aide was refined, and the final version LATCHES agreed for wider dissemination. Future research is needed to understand the value of LATCHES on the wider breastfeeding workforce and whether any future improvements can be made to enhance its utility.

Abstract Introduction Following NOVA (part 1) and the approval of the subcutaneous (SC) route of administration of natalizumab by the European Medicines Agency, an extension phase of the NOVA phase IIIb study (part 2) was initiated to collect patient preference data for SC versus intravenous (IV) dosing in patients receiving every-6-week (Q6W) dosing of natalizumab. This study was performed to evaluate patient preference for SC versus IV natalizumab administration and explore the efficacy, safety, and pharmacology characteristics of both routes of administration. Methods In part 2, participants received natalizumab (Tysabri®) 300 mg via IV infusion Q6W for 36 weeks and then were randomized to 48 weeks of crossover treatment (24 weeks SC Q6W and 24 weeks IV Q6W, or vice versa). The primary endpoint was the proportion of participants who indicated a preference for natalizumab SC administration on the Patient Preference Questionnaire. Results A total of 153 participants were randomized in NOVA part 2. Of 123 with patient preference data, 108 (87.8%) preferred the SC route of administration for natalizumab over the IV route; 102 (82.9%) specified “requires less time in the clinic” as the reason for the SC preference. Conclusion In NOVA (part 2), most participants on Q6W dosing of natalizumab preferred SC administration versus IV administration. ClinicalTrials.gov NCT03689972. Infographic

Abstract Background Randomised trials are essential to reliably assess medical interventions. Nevertheless, interpretation of such studies, particularly when considering absolute effects, is enhanced by understanding how the trial population may differ from the populations it aims to represent. Methods We compared baseline characteristics and mortality of RECOVERY participants recruited in England (n = 38,510) with a reference population hospitalised with COVID-19 in England (n = 346,271) from March 2020 to November 2021. We used linked hospitalisation and mortality data for both cohorts to extract demographics, comorbidity/frailty scores, and crude and age- and sex-adjusted 28-day all-cause mortality. Results Demographics of RECOVERY participants were broadly similar to the reference population, but RECOVERY participants were younger (mean age [standard deviation]: RECOVERY 62.6 [15.3] vs reference 65.7 [18.5] years) and less frequently female (37% vs 45%). Comorbidity and frailty scores were lower in RECOVERY, but differences were attenuated after age stratification. Age- and sex-adjusted 28-day mortality declined over time but was similar between cohorts across the study period (RECOVERY 23.7% [95% confidence interval: 23.3–24.1%]; vs reference 24.8% [24.6–25.0%]), except during the first pandemic wave in the UK (March–May 2020) when adjusted mortality was lower in RECOVERY. Conclusions Adjusted 28-day mortality in RECOVERY was similar to a nationwide reference population of patients admitted with COVID-19 in England during the same period but varied substantially over time in both cohorts. Therefore, the absolute effect estimates from RECOVERY were broadly applicable to the target population at the time but should be interpreted in the light of current mortality estimates. Trial registration ISRCTN50189673- Feb. 04, 2020, NCT04381936- May 11, 2020.

Abstract Van der Waals heterostructures have opened new opportunities to develop atomically thin (opto)electronic devices with a wide range of functionalities. The recent focus on manipulating the interlayer twist angle has led to the observation of out-of-plane room temperature ferroelectricity in twisted rhombohedral bilayers of transition metal dichalcogenides. Here we explore the switching behaviour of sliding ferroelectricity using scanning probe microscopy domain mapping and tunnelling transport measurements. We observe well-pronounced ambipolar switching behaviour in ferroelectric tunnelling junctions with composite ferroelectric/non-polar insulator barriers and support our experimental results with complementary theoretical modelling. Furthermore, we show that the switching behaviour is strongly influenced by the underlying domain structure, allowing the fabrication of diverse ferroelectric tunnelling junction devices with various functionalities. We show that to observe the polarisation reversal, at least one partial dislocation must be present in the device area. This behaviour is drastically different from that of conventional ferroelectric materials, and its understanding is an important milestone for the future development of optoelectronic devices based on sliding ferroelectricity.

Abstract Purpose The rising burden of mosquito-borne diseases in Europe extends beyond urban areas, encompassing rural and semi-urban regions near managed and natural wetlands evidenced by recent outbreaks of Usutu and West Nile viruses. While wetland management policies focus on biodiversity and ecosystem services, few studies explore the impact on mosquito vectors. Methods Our research addresses this gap, examining juvenile mosquito and aquatic predator communities in 67 ditch sites within a South England coastal marsh subjected to different wetland management tiers. Using joint distribution models, we analyse how mosquito communities respond to abiotic and biotic factors influenced by wetland management. Results Of the 12 mosquito species identified, Culiseta annulata (Usutu virus vector) and Culex pipiens (Usutu and West Nile virus vector) constitute 47% of 6825 larval mosquitoes. Abundant predators include Coleoptera (water beetles) adults, Corixidae (water boatmen) and Zygoptera (Damselfy) larvae. Models reveal that tier 3 management sites (higher winter water levels, lower agricultural intensity) associated with shade and less floating vegetation are preferred by specific mosquito species. All mosquito species except Anopheles maculipennis s.l., are negatively impacted by potential predators. Culiseta annulata shows positive associations with shaded and turbid water, contrary to preferences of Corixidae predators. Conclusions Tier 3 areas managed for biodiversity, characterised by higher seasonal water levels and reduced livestock grazing intensity, provide favourable habitats for key mosquito species that are known vectors of arboviruses, such as Usutu and West Nile. Our findings emphasise the impact of biodiversity-focused wetland management, altering mosquito breeding site vegetation to enhance vector suitability. Further exploration of these trade-offs is crucial for comprehending the broader implications of wetland management.

Abstract BackgroundLittle is known about how best to reach people with social marketing messages promoting use of clinical HIV and sexually transmitted infection (STI) services. ObjectiveWe evaluated a multiplatform, digital social marketing campaign intended to increase use of HIV/STI testing, treatment, and prevention services among gay, bisexual, and other men who have sex with men (MSM) at an LGBTQ+ (lesbian, gay, bisexual, transgender, queer, and/or questioning) community health center. MethodsWe evaluated engagement with a social marketing campaign launched by Open Door Health, the only LGBTQ+ community health center in Rhode Island, during the first 8 months of implementation (April to November 2021). Three types of advertisements encouraging use of HIV/STI services were developed and implemented on Google Search, Google Display, Grindr, and Facebook. Platforms tracked the number of times that an advertisement was displayed to a user (impressions), that a user clicked through to a landing page that facilitated scheduling (clicks), and that a user requested a call to schedule an appointment from the landing page (conversions). We calculated the click-through rate (clicks per impression), conversion rate (conversions per click), and the dollar amount spent per 1000 impressions and per click and conversion. ResultsOverall, Google Search yielded the highest click-through rate (7.1%) and conversion rate (7.0%) compared to Google Display, Grindr, and Facebook (click-through rates=0.4%‐3.3%; conversion rates=0%‐0.03%). Although the spend per 1000 impressions and per click was higher for Google Search compared to other platforms, the spend per conversion—which measures the number of people intending to attend the clinic for services—was substantially lower for Google Search (US $48.19 vs US $3120.42-US $3436.03). ConclusionsCampaigns using the Google Search platform may yield the greatest return on investment for engaging MSM in HIV/STI services at community health clinics. Future studies are needed to measure clinical outcomes among those who present to the clinic for services after viewing campaign advertisements and to compare the return on investment with use of social marketing campaigns relative to other approaches.

The objectives of this study are to provide a systematic review of a novel alloplastic hard-tissue grafting material, carbonate apatite granules (CO3Ap-granules), to provide a clinical case presentation of CO3Ap-granules in periodontal surgery. The following three electronic databases were searched independently by two of the authors (MN) and (CR): National Library of Medicine [MEDLINE (PubMed) and ClinicalTrials.gov], EMBASE (OVID) and the Cochrane Central Register of Controlled Trials (CENTRAL). After searching electronic databases, select journals in periodontics and implantology were also manually searched. Of the 43 studies identified from the systematic review, the following classifications were determined: (1) in vitro studies – 5 studies, (2) animal studies – 28 studies, (3) clinical studies – 7 studies, (4) reviews – 3 studies. Results from selected animal studies and all human studies were summarized. These results demonstrate that the novel alloplast CO3Ap-granules has the potential ability to stimulate new bone formation while CO3Ap-granules simultaneously resorb over time. Replacement of CO3Ap-granules with new bone formation has been shown to be comparable to autogenous bone grafting with one study showing superior results to a bovine-derived xenograft.

Missense and truncating variants in the X-chromosome-linked CLCN4 gene, resulting in reduced or complete loss-of-function (LOF) of the encoded chloride/proton exchanger ClC-4, were recently demonstrated to cause a neurocognitive phenotype in both males and females. Through international clinical matchmaking and interrogation of public variant databases we assembled a database of 90 rare CLCN4 missense variants in 90 families: 41 unique and 18 recurrent variants in 49 families. For 43 families, including 22 males and 33 females, we collated detailed clinical and segregation data. To confirm causality of variants and to obtain insight into disease mechanisms, we investigated the effect on electrophysiological properties of 59 of the variants in Xenopus oocytes using extended voltage and pH ranges. Detailed analyses revealed new pathophysiological mechanisms: 25% (15/59) of variants demonstrated LOF, characterized by a shift of the voltage-dependent activation to more positive voltages, and nine variants resulted in a toxic gain-of-function, associated with a disrupted gate allowing inward transport at negative voltages. Functional results were not always in line with in silico pathogenicity scores, highlighting the complexity of pathogenicity assessment for accurate genetic counselling. The complex neurocognitive and psychiatric manifestations of this condition, and hitherto under-recognized impacts on growth, gastrointestinal function, and motor control are discussed. Including published cases, we summarize features in 122 individuals from 67 families with CLCN4-related neurodevelopmental condition and suggest future research directions with the aim of improving the integrated care for individuals with this diagnosis.