Differential Role of “Signal 3” Inflammatory Cytokines in Regulating CD8 T Cell Expansion and Differentiation in vivo

Following an infection, naïve CD8 T cells are stimulated by dendritic cells (DC) displaying pathogen-derived peptides on MHC class I molecules (signal 1) and costimulatory molecules (signal 2). Additionally, pathogen-induced inflammatory cytokines also act directly on the responding CD8 T cells to regulate their expansion and differentiation. In particular, both type I interferons (IFNs) and IL-12 have been described as critical survival signals (signal 3) for optimal CD8 T cell accumulation during the expansion phase. Furthermore, expansion in numbers of antigen-specific CD8 T cells is coupled with their acquisition of effector functions to combat the infection. However, it still remains unclear whether these same cytokines also regulate the effector/memory differentiation program of the CD8 T cell response in vivo. Here, we demonstrate that defective signaling by either type I IFNs or IL-12 to the responding CD8 T cells impairs maximal expansion in response to DC immunization + CpG ODN, but neither of these cytokines is essential to regulate the effector/memory differentiation program. In addition, lack of direct IL-12 signaling to CD8 T cells accelerates the development of central memory phenotype in both primary and secondary antigen-specific memory CD8 T cells

TextANIMAR: Text-based 3D Animal Fine-Grained Retrieval

3D object retrieval is an important yet challenging task, which has drawn more and more attention in recent years. While existing approaches have made strides in addressing this issue, they are often limited to restricted settings such as image and sketch queries, which are often unfriendly interactions for common users. In order to overcome these limitations, this paper presents a novel SHREC challenge track focusing on text-based fine-grained retrieval of 3D animal models. Unlike previous SHREC challenge tracks, the proposed task is considerably more challenging, requiring participants to develop innovative approaches to tackle the problem of text-based retrieval. Despite the increased difficulty, we believe that this task has the potential to drive useful applications in practice and facilitate more intuitive interactions with 3D objects. Five groups participated in our competition, submitting a total of 114 runs. While the results obtained in our competition are satisfactory, we note that the challenges presented by this task are far from being fully solved. As such, we provide insights into potential areas for future research and improvements. We believe that we can help push the boundaries of 3D object retrieval and facilitate more user-friendly interactions via vision-language technologies.Comment: arXiv admin note: text overlap with arXiv:2304.0573

Awareness and preparedness of healthcare workers against the first wave of the COVID-19 pandemic: A cross-sectional survey across 57 countries.

BACKGROUND: Since the COVID-19 pandemic began, there have been concerns related to the preparedness of healthcare workers (HCWs). This study aimed to describe the level of awareness and preparedness of hospital HCWs at the time of the first wave. METHODS: This multinational, multicenter, cross-sectional survey was conducted among hospital HCWs from February to May 2020. We used a hierarchical logistic regression multivariate analysis to adjust the influence of variables based on awareness and preparedness. We then used association rule mining to identify relationships between HCW confidence in handling suspected COVID-19 patients and prior COVID-19 case-management training. RESULTS: We surveyed 24,653 HCWs from 371 hospitals across 57 countries and received 17,302 responses from 70.2% HCWs overall. The median COVID-19 preparedness score was 11.0 (interquartile range [IQR] = 6.0-14.0) and the median awareness score was 29.6 (IQR = 26.6-32.6). HCWs at COVID-19 designated facilities with previous outbreak experience, or HCWs who were trained for dealing with the SARS-CoV-2 outbreak, had significantly higher levels of preparedness and awareness (p<0.001). Association rule mining suggests that nurses and doctors who had a 'great-extent-of-confidence' in handling suspected COVID-19 patients had participated in COVID-19 training courses. Male participants (mean difference = 0.34; 95% CI = 0.22, 0.46; p<0.001) and nurses (mean difference = 0.67; 95% CI = 0.53, 0.81; p<0.001) had higher preparedness scores compared to women participants and doctors. INTERPRETATION: There was an unsurprising high level of awareness and preparedness among HCWs who participated in COVID-19 training courses. However, disparity existed along the lines of gender and type of HCW. It is unknown whether the difference in COVID-19 preparedness that we detected early in the pandemic may have translated into disproportionate SARS-CoV-2 burden of disease by gender or HCW type

Safety and efficacy of fluoxetine on functional outcome after acute stroke (AFFINITY): a randomised, double-blind, placebo-controlled trial

Background Trials of fluoxetine for recovery after stroke report conflicting results. The Assessment oF FluoxetINe In sTroke recoverY (AFFINITY) trial aimed to show if daily oral fluoxetine for 6 months after stroke improves functional outcome in an ethnically diverse population. Methods AFFINITY was a randomised, parallel-group, double-blind, placebo-controlled trial done in 43 hospital stroke units in Australia (n=29), New Zealand (four), and Vietnam (ten). Eligible patients were adults (aged ≥18 years) with a clinical diagnosis of acute stroke in the previous 2–15 days, brain imaging consistent with ischaemic or haemorrhagic stroke, and a persisting neurological deficit that produced a modified Rankin Scale (mRS) score of 1 or more. Patients were randomly assigned 1:1 via a web-based system using a minimisation algorithm to once daily, oral fluoxetine 20 mg capsules or matching placebo for 6 months. Patients, carers, investigators, and outcome assessors were masked to the treatment allocation. The primary outcome was functional status, measured by the mRS, at 6 months. The primary analysis was an ordinal logistic regression of the mRS at 6 months, adjusted for minimisation variables. Primary and safety analyses were done according to the patient's treatment allocation. The trial is registered with the Australian New Zealand Clinical Trials Registry, ACTRN12611000774921. Findings Between Jan 11, 2013, and June 30, 2019, 1280 patients were recruited in Australia (n=532), New Zealand (n=42), and Vietnam (n=706), of whom 642 were randomly assigned to fluoxetine and 638 were randomly assigned to placebo. Mean duration of trial treatment was 167 days (SD 48·1). At 6 months, mRS data were available in 624 (97%) patients in the fluoxetine group and 632 (99%) in the placebo group. The distribution of mRS categories was similar in the fluoxetine and placebo groups (adjusted common odds ratio 0·94, 95% CI 0·76–1·15; p=0·53). Compared with patients in the placebo group, patients in the fluoxetine group had more falls (20 [3%] vs seven [1%]; p=0·018), bone fractures (19 [3%] vs six [1%]; p=0·014), and epileptic seizures (ten [2%] vs two [<1%]; p=0·038) at 6 months. Interpretation Oral fluoxetine 20 mg daily for 6 months after acute stroke did not improve functional outcome and increased the risk of falls, bone fractures, and epileptic seizures. These results do not support the use of fluoxetine to improve functional outcome after stroke

Global, regional, and national burden of disorders affecting the nervous system, 1990–2021: a systematic analysis for the Global Burden of Disease Study 2021

BackgroundDisorders affecting the nervous system are diverse and include neurodevelopmental disorders, late-life neurodegeneration, and newly emergent conditions, such as cognitive impairment following COVID-19. Previous publications from the Global Burden of Disease, Injuries, and Risk Factor Study estimated the burden of 15 neurological conditions in 2015 and 2016, but these analyses did not include neurodevelopmental disorders, as defined by the International Classification of Diseases (ICD)-11, or a subset of cases of congenital, neonatal, and infectious conditions that cause neurological damage. Here, we estimate nervous system health loss caused by 37 unique conditions and their associated risk factors globally, regionally, and nationally from 1990 to 2021.MethodsWe estimated mortality, prevalence, years lived with disability (YLDs), years of life lost (YLLs), and disability-adjusted life-years (DALYs), with corresponding 95% uncertainty intervals (UIs), by age and sex in 204 countries and territories, from 1990 to 2021. We included morbidity and deaths due to neurological conditions, for which health loss is directly due to damage to the CNS or peripheral nervous system. We also isolated neurological health loss from conditions for which nervous system morbidity is a consequence, but not the primary feature, including a subset of congenital conditions (ie, chromosomal anomalies and congenital birth defects), neonatal conditions (ie, jaundice, preterm birth, and sepsis), infectious diseases (ie, COVID-19, cystic echinococcosis, malaria, syphilis, and Zika virus disease), and diabetic neuropathy. By conducting a sequela-level analysis of the health outcomes for these conditions, only cases where nervous system damage occurred were included, and YLDs were recalculated to isolate the non-fatal burden directly attributable to nervous system health loss. A comorbidity correction was used to calculate total prevalence of all conditions that affect the nervous system combined.FindingsGlobally, the 37 conditions affecting the nervous system were collectively ranked as the leading group cause of DALYs in 2021 (443 million, 95% UI 378–521), affecting 3·40 billion (3·20–3·62) individuals (43·1%, 40·5–45·9 of the global population); global DALY counts attributed to these conditions increased by 18·2% (8·7–26·7) between 1990 and 2021. Age-standardised rates of deaths per 100 000 people attributed to these conditions decreased from 1990 to 2021 by 33·6% (27·6–38·8), and age-standardised rates of DALYs attributed to these conditions decreased by 27·0% (21·5–32·4). Age-standardised prevalence was almost stable, with a change of 1·5% (0·7–2·4). The ten conditions with the highest age-standardised DALYs in 2021 were stroke, neonatal encephalopathy, migraine, Alzheimer's disease and other dementias, diabetic neuropathy, meningitis, epilepsy, neurological complications due to preterm birth, autism spectrum disorder, and nervous system cancer.InterpretationAs the leading cause of overall disease burden in the world, with increasing global DALY counts, effective prevention, treatment, and rehabilitation strategies for disorders affecting the nervous system are needed