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Ever since its discovery, apoptosis has been inextricably linked with cancer. This Timeline article seeks to provide insights into the key discoveries in the field and therapeutic applications based on apoptotic strategies. In multicellular organisms, the total number of cells is a balance between the cell-generating effects of mitosis and cell death that is induced through apoptosis. A disruption of this delicate balance can lead to the development of cancer. This Timeline article focuses on how the field of apoptosis biology has developed in the context of its contribution to our understanding of cell death, or lack of it, in the development of malignant disease. It traces the course of research from key discoveries in fundamental biology to potential therapeutic applications.

Coronavirus Disease 2019 (COVID-19), caused by the novel Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), has affected over 30 million globally to date. Although high rates of venous thromboembolism and evidence of COVID-19-induced endothelial dysfunction have been reported, the precise aetiology of the increased thrombotic risk associated with COVID-19 infection remains to be fully elucidated. Therefore, we assessed clinical platelet parameters and circulating platelet activity in patients with severe and nonsevere COVID-19. An assessment of clinical blood parameters in patients with severe COVID-19 disease (requiring intensive care), patients with nonsevere disease (not requiring intensive care), general medical in-patients without COVID-19, and healthy donors was undertaken. Platelet function and activity were also assessed by secretion and specific marker analysis. We demonstrated that routine clinical blood parameters including increased mean platelet volume (MPV) and decreased platelet:neutrophil ratio are associated with disease severity in COVID-19 upon hospitalisation and intensive care unit (ICU) admission. Strikingly, agonist-induced ADP release was 30- to 90-fold higher in COVID-19 patients compared with hospitalised controls and circulating levels of platelet factor 4 (PF4), soluble P-selectin (sP-selectin), and thrombopoietin (TPO) were also significantly elevated in COVID-19. This study shows that distinct differences exist in routine full blood count and other clinical laboratory parameters between patients with severe and nonsevere COVID-19. Moreover, we have determined all COVID-19 patients possess hyperactive circulating platelets. These data suggest abnormal platelet reactivity may contribute to hypercoagulability in COVID-19 and confirms the role that platelets/clotting has in determining the severity of the disease and the complexity of the recovery path.

Radio and optical spectroscopic observations of a brown dwarf reveal auroral emissions powered by magnetospheric currents, showing that aurorae may be a signature of magnetospheres much larger than those observed in our Solar System. Planet-like aurorae on a dwarf star Radio and optical spectroscopic observations of a dwarf star reveal auroral emissions powered by magnetospheric currents, the first confirmed detection of a planet-like aurora from a body outside our Solar System. The Sun-like coronal activity thought to dominate in main sequence stars is powered by processes that occur in their lower atmospheres, whereas on this dwarf star — at the boundary between stars and brown dwarfs — the aurorae are powered by processes originating much further out in the magnetosphere and coupled to the lower atmosphere. Aurorae are detected from all the magnetized planets in our Solar System, including Earth 1 . They are powered by magnetospheric current systems that lead to the precipitation of energetic electrons into the high-latitude regions of the upper atmosphere. In the case of the gas-giant planets, these aurorae include highly polarized radio emission at kilohertz and megahertz frequencies produced by the precipitating electrons 2 , as well as continuum and line emission in the infrared, optical, ultraviolet and X-ray parts of the spectrum, associated with the collisional excitation and heating of the hydrogen-dominated atmosphere 3 . Here we report simultaneous radio and optical spectroscopic observations of an object at the end of the stellar main sequence, located right at the boundary between stars and brown dwarfs, from which we have detected radio and optical auroral emissions both powered by magnetospheric currents. Whereas the magnetic activity of stars like our Sun is powered by processes that occur in their lower atmospheres, these aurorae are powered by processes originating much further out in the magnetosphere of the dwarf star that couple energy into the lower atmosphere. The dissipated power is at least four orders of magnitude larger than what is produced in the Jovian magnetosphere, revealing aurorae to be a potentially ubiquitous signature of large-scale magnetospheres that can scale to luminosities far greater than those observed in our Solar System. These magnetospheric current systems may also play a part in powering some of the weather phenomena reported on brown dwarfs.

Effective antiretroviral therapy (ART) has improved the life expectancy of people with HIV (PWH). However, this population is now experiencing accelerated age-related comorbidities, contributed to by chronic immune activation and inflammation, with dysbiosis of the gut microbiome also implicated. We conducted a systematic literature search of PubMed, Embase, Scopus, Cochrane reviews and international conference abstracts for articles that examined for the following non-communicable diseases (NCDs); cardiovascular disease, cancer, frailty, metabolic, bone, renal and neurocognitive disease, in PWH aged >18 years. Studies were included that measured gut microbiome diversity and composition, microbial translocation markers or microbial metabolite markers. In all, 567 articles were identified and screened of which 87 full-text articles were assessed for eligibility and 56 were included in the final review. The data suggest a high burden NCD, in particular cardiovascular and metabolic disease in PWH. Alterations in bacterial diversity and structure varied by NCD type, but a general trend in reduced diversity was seen together with alterations in bacterial abundances between different NCD. Lipopolysaccharide was the most commonly investigated marker of microbial translocation across NCD followed by soluble CD14. Short-chain fatty acids, tryptophan and choline metabolites were associated with cardiovascular outcomes and also associated with chronic liver disease (CLD). This systematic review is the first to summarise the evidence for the association between gut microbiome dysbiosis and NCDs in PWH. Understanding this interaction will provide insights into the pathogenesis of many NCD and help develop novel diagnostic and therapeutic strategies for PWH.

Background Transgender women in Malaysia face social and healthcare marginalisation. Research about their oral health and oral health care utilisation is sparse. Despite growing clinical evidence highlighting the risk of transmission of sexually transmitted infections (STIs) through oral sexual practices, research in this area remains less explored. This study aimed to understand the experiences of transgender women in Malaysia by exploring oral health care needs and the barriers and enablers of oral health care utilisation as well as safe sexual practices relating to oral transmission of STIs. Methods Participants were recruited through a snow-balling method of sampling with the help of community workers. Semi-structured in-depth interviews (IDIs) with transgender women in northern Malaysia and Focus group discussion (FGD) with a mixed group of transgender women and health care professionals were conducted to gain insights into the needs of the community. Data obtained from IDIs and FGD were coded, transcribed, and thematically analysed to derive codes and themes through the interpretative lens of the Information, Motivation and Behavioural skills (IMB) theory. Results Participants of the IDIs were transgender women ( n  = 20, median age 39.8 (9.75 IQR) years). Aesthetic dental needs were prioritised, yet poor utilisation of dental services was reported, with many opting for self-medication or care from a non-qualified dental practitioner. Routine engagement in oral sex practices, primarily receptive fellatio with or without ejaculation with multiple cis-gender male partners, was reported. Low awareness of oral STIs, along with a perceived low risk of transmission of STIs through oral sex, was reported, with most (18, 90%) not using condoms for clients/partners or inconsistently using them during oral sexual practices. The themes identified from IDIs and FGD included: ‘Place in the society’ ‘ Attitudes and beliefs linked with dental care’ , ‘Access to dental care’ , ‘Lack of trans-specific health care’ and ‘ Use of condoms for oral sex’ . Conclusion The study’s findings report poor dental service utilisation among transgender women despite aesthetics being prioritised. Gaps in knowledge regarding the oral transmission of STIs were also noted. These insights underscore the need for trans-specific health campaigns designed to address these concerns and enhance awareness through an integrated approach to improve access to inclusive oral health care and sexual health care for this vulnerable population.

The long-term effects of SARS-CoV-2 infection and optimal follow-up approach are not well-recognised. Here we describe the implementation of a post-COVID clinic in an Irish tertiary centre after the first wave of the pandemic. This study describes the characteristics of our patient cohort and the operations and outcomes of the clinic, exploring some of the risk factors for developing post-COVID syndrome and the appropriateness of the triage system employed. All SARS-CoV-2 positive patients from March 10th to June 14th 2020 were telephone-triaged as red, amber or green based on ongoing symptoms with clinic appointments scheduled accordingly. All clinic visits were face-to-face with the infectious diseases medical team and a proforma for each patient was completed. Data were collected retrospectively by reviewing the proformas and the electronic medical record (EMR). 311 patients attended the clinic. Median time from illness to clinic appointment was 95 days (IQR 77-105.5). 204 patients (66%) were female, 192 (62%) were hospital staff, and the median age was 43 years (IQR 31-53). 138 patients (44%) had required hospital admission. At their first clinic visit 219 patients (70%) had ongoing symptoms. A further appointment was made for 62 patients (20%). 34 patients (11%) were discussed at an MDT meeting, and 55 (18%) were referred onward to a specialist service. 85% of those triaged green, 73% of those triaged amber, and 39% of those triaged red did not receive further follow up after one clinic visit. Patients were more likely to require follow up with reported dyspnoea (OR 5.6; 95% CI 2.8-11.3; p <0.001), cough (OR 3.0; 95% CI 1.1-8.4, p = 0.04), and palpitations (OR 3.6; 95% CI 1.0-12.3; p = 0.04). Female sex was associated with increased odds of a higher triage category (OR 1.8; 95% CI 1.08 to 3.20; p = 0.02), as was requiring admission to hospital (OR 4.0; 95% CI 2.34 to 6.90; p < 0.001). The long-term effects of COVID-19 are significant with 70% of our cohort experiencing persistent symptoms. Persistent dyspnoea, cough and palpitations were associated with increased need for follow up. This study also suggests that a traffic light telephone-triage service followed by a face-to-face medical-led clinic could be an effective way of identifying patients who require further management.

Direct-acting antiviral (DAA) therapy has changed the landscape of hepatitis C virus (HCV) management and has changed the focus to the possibility of HCV elimination in the near future. Glecaprevir, an NS3/4A protease inhibitor, and pibrentasvir, an HCV NS5A inhibitor, have addressed many of the existing shortcomings in the DAA therapy spectrum. This combination has proven to be a highly efficacious pan-genotypic DAA with a high barrier to resistance as a once-daily, all-oral medication. This review explores the design and development of glecaprevir and pibrentasvir, its place in current HCV management in the midst of a myriad of DAA therapy options, and also remaining challenges.

Healthcare workers (HCWs) in Ireland bore a particularly high burden of SARS-CoV-2 infections, representing over 30% of infections during initial waves. We describe the prevalence, incidence and persistence of SARS-CoV-2 anti-nucleocapsid (anti-NC) IgG positivity in a cohort of HCWs working in a Dublin inner-city tertiary hospital, over 48 weeks. The SORTeD (Seroprevalence, Seroconversion Rates and Transmission Dynamics of SARS-CoV-2 among Healthcare Workers) study was a longitudinal cohort study of HCWs working in an inner-city hospital in Dublin between July 2020 and September 2021. Participants had either a prior history of PCR-confirmed SARS-CoV-2 (Group 1) or no prior history of SARS-CoV-2 (Group 2). Serum samples were obtained at weeks 0, 12 and 48, and tested for SARS-CoV-2 nucleocapsid (NC) antibody using a qualitative immunoassay (Abbott Alinity®). Seroprevalence rates are presented using descriptive statistics, with univariate and multivariate analysis examining associations between participant characteristics, IgG status and refractive index in Group 1. Data is presented as n (%) or median (interquartile range (IQR)) where appropriate. Of the 395 HCWs who were recruited, 304 (77.0%) were female, median age was 33 (28-45) years, and 343 (86.8%) had patient-facing roles. In Group 1, time from infection to sampling was 173 (144.0-202.0) days. Seroprevalence of IgG in Group 1 at 0, 12 and 48 weeks was 47.4%, 19.0% and 7.3%, respectively; while seroprevalence in Group 2 was 5.4%, 4.3% and 2.6%, respectively. A lower refractive index was seen in higher sampling intervals (r = -0.5, 95% CI -0.576 to -0.427; p < 0.001). Fourteen incident infections were reported by the cohort during the study, and 3 documented reinfections. Our study shows low seroprevalence in prior confirmed cases among our HCW population, possibly explained by reduced sensitivity of this assay with increasing time from SARS-CoV-2 exposure and timing of testing. Confirmatory testing with a quantitative assay would help understand the true seroprevalence of SARS-CoV-2 IgG in this cohort.

Retinitis pigmentosa (RP) is a degenerative disease leading to photoreceptor cell loss. Mouse models of RP, such as the rd10 mouse (B6.CXBl-Pde6brd10/J), have enhanced our understanding of the disease, allowing for development of potential therapeutics. In 2011, our group first demonstrated that the synthetic progesterone analogue 'Norgestrel' is neuroprotective in two mouse models of retinal degeneration, including the rd10 mouse. We have since elucidated several mechanisms by which Norgestrel protects stressed photoreceptors, such as upregulating growth factors. This study consequently aimed to further characterize Norgestrel's neuroprotective effects. Specifically, we sought to investigate the role that microglia might play; for microglial-derived inflammation has been shown to potentiate neurodegeneration. Dams of post-natal day (P) 10 rd10 pups were given a Norgestrel-supplemented diet (80mg/kg). Upon weaning, pups remained on Norgestrel. Tissue was harvested from P15-P50 rd10 mice on control or Norgestrel-supplemented diet. Norgestrel-diet administration provided significant retinal protection out to P40 in rd10 mice. Alterations in microglial activity coincided with significant protection, implicating microglial changes in Norgestrel-induced neuroprotection. Utilizing primary cultures of retinal microglia and 661W photoreceptor-like cells, we show that rd10 microglia drive neuronal cell death. We reveal a novel role of Norgestrel, acting directly on microglia to reduce pro-inflammatory activation and prevent neuronal cell death. Norgestrel effectively suppresses cytokine, chemokine and danger-associated molecular pattern molecule (DAMP) expression in the rd10 retina. Remarkably, Norgestrel upregulates fractalkine-CX3CR1 signaling 1 000-fold at the RNA level, in the rd10 mouse. Fractalkine-CX3CR1 signaling has been shown to protect neurons by regulating retinal microglial activation and migration. Ultimately, these results present Norgestrel as a promising treatment for RP, with dual actions as a neuroprotective and anti-inflammatory agent in the retina.

BackgroundWe aimed to study whether improvement in renal function by serelaxin in patients who were hospitalized for acute heart failure (HF) might explain any potential effect on clinical outcomes.MethodsWe included 6318 patients from the RELAXin in AHF-2 (RELAX-AHF2) study. Improvement in renal function was defined as a decrease in serum creatinine of ≥ 0.3 mg/dL and ≥ 25%, or increase in estimated glomerular filtration rate of ≥ 25% between baseline and day 2. Worsening renal function (WRF) was defined as the reverse. We performed causal mediation analyses regarding 180-day all-cause mortality (ACM), cardiovascular death (CVD), and hospitalization for HF/renal failure.ResultsImprovement in renal function was more frequently observed with serelaxin when compared with placebo [OR 1.88 (95% CI 1.64–2.15, p < 0.0001)], but was not associated with subsequent clinical outcomes. WRF occurred less frequent with serelaxin [OR 0.70 (95% CI 0.60–0.83, p < 0.0001)] and was associated with increased risk of ACM, worsening HF and the composite of CVD and HF or renal failure hospitalization. Improvement in renal function did not mediate the treatment effect of serelaxin [CVD HR 1.01 (0.99–1.04), ACM HR 1.01 (0.99–1.03), HF/renal failure hospitalization HR 0.99 (0.97–1.00)].ConclusionsDespite the significant improvement in renal function by serelaxin in patients with acute HF, the potential beneficial treatment effect was not mediated by improvement in renal function. These data suggest that improvement in renal function might not be a suitable surrogate marker for potential treatment efficacy in future studies with novel relaxin agents in acute HF.Central illustration. Conceptual model explaining mediation analysis; treatment efficacy of heart failure therapies mediated by renal function.