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BackgroundCOVID-19 is a pandemic respiratory and vascular disease caused by SARS-CoV-2 virus. There is a growing number of sensory deficits associated with COVID-19 and molecular mechanisms underlying these deficits are incompletely understood.MethodsWe report a series of ten COVID-19 patients with audiovestibular symptoms such as hearing loss, vestibular dysfunction and tinnitus. To investigate the causal relationship between SARS-CoV-2 and audiovestibular dysfunction, we examine human inner ear tissue, human inner ear in vitro cellular models, and mouse inner ear tissue.ResultsWe demonstrate that adult human inner ear tissue co-expresses the angiotensin-converting enzyme 2 (ACE2) receptor for SARS-CoV-2 virus, and the transmembrane protease serine 2 (TMPRSS2) and FURIN cofactors required for virus entry. Furthermore, hair cells and Schwann cells in explanted human vestibular tissue can be infected by SARS-CoV-2, as demonstrated by confocal microscopy. We establish three human induced pluripotent stem cell (hiPSC)-derived in vitro models of the inner ear for infection: two-dimensional otic prosensory cells (OPCs) and Schwann cell precursors (SCPs), and three-dimensional inner ear organoids. Both OPCs and SCPs express ACE2, TMPRSS2, and FURIN, with lower ACE2 and FURIN expression in SCPs. OPCs are permissive to SARS-CoV-2 infection; lower infection rates exist in isogenic SCPs. The inner ear organoids show that hair cells express ACE2 and are targets for SARS-CoV-2.ConclusionsOur results provide mechanistic explanations of audiovestibular dysfunction in COVID-19 patients and introduce hiPSC-derived systems for studying infectious human otologic disease.Jeong et al. report a series of COVID-19 patients with hearing- and balance-related symptoms. The authors show that human and mouse inner ear tissues, as well as human inner ear cells and organoids derived from induced pluripotent stem cells, express SARS-CoV-2 entry factors, and that these in vitro models of the human inner ear are susceptible to SARS-CoV-2 infection

Tragic explosion of a Virgin Galactic spaceship, a rocket plane during a test flight over the Mojave Desert in California

Background Postoperative chemoradiation and perioperative chemotherapy using epirubicin/cisplatin/5-fluorouracil (ECF) represent two standards of care for resectable gastric cancer. In the TOPGEAR (Trial Of Preoperative therapy for Gastric and Esophagogastric junction AdenocaRcinoma) trial, we hypothesized that adding preoperative chemoradiation to perioperative ECF will improve survival; however, the safety and feasibility of preoperative chemoradiation have yet to be determined. Methods TOPGEAR is an international phase III trial in which patients with adenocarcinoma of the stomach were randomized to perioperative ECF alone or with preoperative chemoradiation. The ECF-alone group received three preoperative cycles of ECF, while the chemoradiation group received two cycles of preoperative ECF followed by chemoradiation. Both groups received three postoperative cycles of ECF. A planned interim analysis of the first 120 patients was conducted, and was reviewed by the Independent Data Safety Monitoring Committee to assess treatment compliance, toxicity/safety, and response rates. Results The proportion of patients who received all cycles of preoperative chemotherapy was 93% (ECF group) and 98% (chemoradiation group), while 65 and 53%, respectively, received all cycles of postoperative chemotherapy. Overall, 92% of patients allocated to preoperative chemoradiation received this treatment. The proportion of patients proceeding to surgery was 90% (ECF group) and 85% (chemoradiation group). Grade 3 or higher surgical complications occurred in 22% of patients in both groups. Furthermore, grade 3 or higher gastrointestinal toxicity occurred in 32% (ECF group) and 30% (chemoradiation group) of patients, while hematologic toxicity occurred in 50 and 52% of patients. Conclusions These results demonstrate that preoperative chemoradiation can be safely delivered to the vast majority of patients without a significant increase in treatment toxicity or surgical morbidity.

This special issue of the South African Journal of Science arises out of a selection of key contributions made in Pretoria at the Science Forum South Africa held in December 2020. The Science Forum is a platform developed by the Department of Science and Innovation (DSI) for the purpose of convening the country's leading scientists, scholars and intellectuals around the questions of economic, social, cultural and technological development. Driving the initiative is the desire to bring the knowledge-producing community into a simultaneously open yet rigorous intellectual space. It is about critically exploring the best of what is known in the sciences, through and with the advantage of multidisciplinary perspectives, to understand how the issues which trouble the world chiefly those of social inequality and planetary sustainability - can be approached through insightful enquiry, and how solutions may be proposed which offer pathways to new futures which are just, equitable and sustainable. While the issues of social justice and equity have framed all seven previous iterations of the Science Forum, the 2020 occasion foregrounded the work of the humanities and the social sciences in South Africa, formalised through a partnership between DSI and a consortium of institutions of the social sciences and humanities led by the Human Sciences Research Council (HSRC). Prompting this focus were two important issues. The first was the 50th anniversary of the HSRC and the 90th anniversary of its predecessor, the National Bureau for Educational and Social Research. The anniversary, conceptualised and given form by a consortium of leading figures and institutions in the science and humanities fields inside and outside of the country - including the heads of the Academy of Science of South Africa (ASSAf), Universities South Africa, and the International Science Council, and the heads of several Humanities Faculties throughout the country (the Consortium) - was marked by a yearlong series of public events, colloquia and exhibitions. The shared understanding of the Consortium was that the occasion of the HSRC's anniversary provided South Africa with an important opportunity to interrogate the role of the social sciences and the humanities in working with the multiple developmental challenges of South Africa and the world. Also recognised was that the occasion offered opportunities to understand a range of important questions about the state of scholarship and research in South Africa, and the relationship of the social sciences and the humanities with what are oftentimes called the 'hard sciences'. This includes the contention, in the context of the decolonisation movement around the world, that the dominant scientific project, shaped by the Global North, was in crisis and was not - in particular - able to deal with the compounding challenges of global inequality and climate change; that scientific discourse had become over-determined by technology, the hubris of the Fourth Industrial Revolution and its accompanying artificial intelligence conceit; and, not least of all, the concern that precisely at the moment in which the social sciences and humanities should be playing a key role in generating understandings of the critical changes affecting the world - with critical reference here to the COVID-19 pandemic, still looming large in December 2020 - they were largely absent and unresponsive. The crisis of COVID-19 was the second reason for foregrounding the social sciences and humanities at the 2020 Science Forum. Indeed, the pandemic was not simply a scientific and biomedical question, but had deep implications for how people lived as both individuals and communities, how they managed their livelihoods and how they could begin the process of cultivating social imaginations of compassion, care and solidarity in the face of worldwide retreats into self-serving nationalisms, and ethnically and racially defined self-preservational forms of isolationism. The importance of addressing COVID-19 as an interdisciplinary issue with substantial social science input has been stressed in another recent special issue of this Journal (https://sajs.co.za/issue/view/1024), and in part this latest special issue takes that work forward. Following the events of the onset of COVID-19 - which are yet to fully unfold - the acute conditions of inequality that the pandemic exacerbated in societies across the world demanded that the social sciences and the humanities were taken more seriously. There was, it was understood, much to be done to better understand the production of inequality, and how inequality continued to arise in new ways and with new effects. This is the critical role of the social sciences and of the humanities. This special issue, it is important to clarify, keeps in mind both the prompts which informed the shaping of the Science Forum. It is, however, the state of the social sciences and the humanities which figures most prominently here. While the special issue brings the questions of the place of the 'hard sciences' into play, it is the concern with the responsibilities of the social sciences and the humanities which this special issue explores most fully. This concern arises out of the need to understand, historically, the point and place at which the social sciences and humanities find themselves. The occasion of the HSRC's anniversary is, as a consequence, more than simply fortuitous. It is timely. It is timely because it is in the substance and character of a key state institution of the social sciences such as the HSRC that the country might come to understand what role its social scientists and humanities scholars might play in the development of the country.

Limited research exists about the unique experiences and possible marginalization of children with sexual minority parents. From a larger longitudinal project of diverse adoptive families, we examined cross-sectional data using mixed methods from interviews with 49 adopted children ( M age  = 8 years; 47 % female) in 27 two-father and 22 two-mother families. Using thematic analysis, we coded themes of awareness of difference, microaggressions, and resilience (i.e., coping and positive family conceptualizations). Children experienced “feeling different” and microaggressions from peers, but generally at a low to medium intensity and with neutral (not negative) emotion. More instances of resilience and positive family conceptualizations were reported than microaggressions or feelings of difference, suggesting that children develop positive perceptions of their family and navigate experiences of difference with resilience. Filling important gaps in the literature, we discuss implications of our results for practice and policy.

IntroductionDue to the increase in participation and risk of anterior cruciate ligament (ACL) injuries and concussion in women’s Australian Football, an injury prevention programme (Prep-to-Play) was codesigned with consumers (eg, coaches, players) and stakeholders (eg, the Australian Football League). The impact of supported and unsupported interventions on the use of Prep-to-Play (primary aim) and injury rates (secondary aim) will be evaluated in women and girls playing community Australian Football.Methods and analysisThis stepped-wedge, cluster randomised controlled trial will include ≥140 teams from U16, U18 or senior women’s competitions. All 10 geographically separated clusters (each containing ≥14 teams) will start in the control (unsupported) phase and be randomised to one of five dates (or ‘wedges’) during the 2021 or 2022 season to sequentially transition to the intervention (supported Prep-to-Play), until all teams receive the intervention. Prep-to-Play includes four elements: a neuromuscular training warm-up, contact-focussed football skills (eg, tackling), strength exercises and education (eg, technique cues). When transitioning to supported interventions, study physiotherapists will deliver a workshop to coaches and player leaders on how to use Prep-to-Play, attend team training at least two times and provide ongoing support. In the unsupported phase, team will continue usual routines and may freely access available Prep-to-Play resources online (eg, posters and videos about the four elements), but without additional face-to-face support. Outcomes will be evaluated throughout the 2021 and 2022 seasons (~14 weeks per season). Primary outcome: use of Prep-to-Play will be reported via a team designate (weekly) and an independent observer (five visits over the two seasons) and defined as the team completing 75% of the programme, two-thirds (67%) of the time. Secondary outcomes: injuries will be reported by the team sports trainer and/or players. Injury definition: any injury occurring during a football match or training that results in: (1) being unable to return to the field of play for that match or (2) missing ≥ one match. Outcomes in the supported and unsupported phases will be compared using a generalised linear mixed model adjusting for clustering and time. Due to the type III hybrid implementation-effectiveness design, the study is powered to detect a improvement in use of Prep-to-Play and a reduction in ACL injuries.Ethics and disseminationLa Trobe University Ethics Committee (HREC 20488) approved. Coaches provided informed consent to receive the supported intervention and players provided consent to be contacted if they sustained a head or knee injury. Results will be disseminated through partner organisations, peer-reviewed publications and scientific conferences.Trial registration number NCT04856241.

Valproate (VPA) has been used in the treatment of bipolar disorder since the 1990s. However, the therapeutic targets of VPA have remained elusive. Here we employ a preclinical model to identify the therapeutic targets of VPA. We find compounds that inhibit histone deacetylase proteins (HDACs) are effective in normalizing manic-like behavior, and that class I HDACs (e.g., HDAC1 and HDAC2) are most important in this response. Using an RNAi approach, we find that HDAC2, but not HDAC1, inhibition in the ventral tegmental area (VTA) is sufficient to normalize behavior. Furthermore, HDAC2 overexpression in the VTA prevents the actions of VPA. We used RNA sequencing in both mice and human induced pluripotent stem cells (iPSCs) derived from bipolar patients to further identify important molecular targets. Together, these studies identify HDAC2 and downstream targets for the development of novel therapeutics for bipolar mania.

SARS-CoV-2 mutations that cause resistance to monoclonal antibody (mAb) therapy have been reported. However, it remains unclear whether in vivo emergence of SARS-CoV-2 resistance mutations alters viral replication dynamics or therapeutic efficacy in the immune-competent population. As part of the ACTIV-2/A5401 randomized clinical trial (NCT04518410), non-hospitalized participants with symptomatic SARS-CoV-2 infection were given bamlanivimab (700 mg or 7,000 mg) or placebo treatment. Here¸ we report that treatment-emergent resistance mutations [detected through targeted Spike (S) gene next-generation sequencing] were significantly more likely to be detected after bamlanivimab 700 mg treatment compared with the placebo group (7% of 111 vs 0% of 112 participants, P  = 0.003). No treatment-emergent resistance mutations among the 48 participants who received 7,000 mg bamlanivimab were recorded. Participants in which emerging mAb resistant virus mutations were identified showed significantly higher pretreatment nasopharyngeal and anterior nasal viral loads. Daily respiratory tract viral sampling through study day 14 showed the dynamic nature of in vivo SARS-CoV-2 infection and indicated a rapid and sustained viral rebound after the emergence of resistance mutations. Participants with emerging bamlanivimab resistance often accumulated additional polymorphisms found in current variants of concern/interest that are associated with immune escape. These results highlight the potential for rapid emergence of resistance during mAb monotherapy treatment that results in prolonged high-level respiratory tract viral loads. Assessment of viral resistance should be prioritized during the development and clinical implementation of antiviral treatments for COVID-19. This Article reports the emergence of SARS-CoV-2 escape mutations during bamlanivimab therapy in the setting of a phase II clinical trial.