Clinician perceptions of research priorities for the management of noncritically ill patients admitted to hospital with SARS-CoV-2 infection.

The changing phenotype of coronarvirus disease 2019 (COVID-19) may quickly render guideline-recommended interventions obsolete. We developed a 40-question clinician survey in consultation with the Australasian COVID-19 Trial site investigators. The survey was designed to assess clinician perceptions of the current treatment strategies and future research priorities in the management of non-critically ill patients admitted to hospital with SARS-CoV-2 infection. There were 84 complete responses from predominantly Australian and New Zealand clinicians. The perceived prevalence of patients with incidental COVID-19, nosocomial infection, underlying illness exacerbated by COVID-19, and/or immunocompromised status suggests new populations to target. The results highlighted clinician interest in antiviral therapies for future research in both immunocompetent and immunocompromised cohorts. These survey results underscore the need for ongoing surveillance of COVID-19 disease phenotypes and clinician and patient priorities for future research.

TMPRSS2 inhibitors for the treatment of COVID-19 in adults: a systematic review and meta-analysis of randomized clinical trials of nafamostat and camostat mesylate.

BACKGROUND: Synthetic serine protease inhibitors block the cellular enzyme transmembrane protease serine 2, thus preventing SARS-CoV-2 cell entry. There are two relevant drugs in this class, namely, nafamostat (intravenous formulation) and camostat (oral formulation). OBJECTIVE: To determine whether transmembrane protease serine 2 inhibition with nafamostat or camostat is associated with a reduced risk of 30-day all-cause mortality in adults with COVID-19. DATA SOURCES: Scientific databases and clinical trial registry platforms. STUDY ELIGIBILITY CRITERIA, INTERVENTIONS, AND PARTICIPANTS: Preprints or published randomized clinical trials (RCTs) of nafamostat or camostat vs. usual care or placebo in adults requiring treatment for COVID-19. METHODS OF DATA SYNTHESIS AND RISK-OF-BIAS ASSESSMENT: The primary outcome of the meta-analysis was 30-day all-cause mortality. Secondary outcomes included time to recovery, adverse events, and serious adverse events. Risk of bias (RoB) was assessed using the revised Cochrane RoB 2 tool for individually randomized trials. Meta-analysis was conducted in the R package meta (v7.0-0) using inverse variance and random effects. Protocol registration number was INPLASY202320120. RESULTS: Twelve RCTs were included. Overall, the number of available patients was small (nafamostat = 387; camostat = 1061), the number of enrolled patients meeting the primary outcome was low (nafamostat = 12; camostat = 13), and heterogeneity was high. In hospitalized adults, we did not identify differences in 30-day all-cause mortality (risk ratio [95% CI]: 0.58 [0.19, 1.80], p 0.34; I2 = 0%; n = 6) and time to recovery (mean difference [95% CI]: 0.08 days [-0.74, 0.89], p 0.86; n = 2) between nafamostat vs. usual care; and for 30-day all-cause mortality (risk ratio [95% CI]: 0.99 [0.31, 3.18], p 0.99; n = 2) between camostat vs. placebo. CONCLUSION: The RCT evidence is inconclusive to determine whether there is a mortality reduction and safety with either nafamostat or camostat for the treatment of adults with COVID-19. There were high RoB, small sample size, and high heterogeneity between RCTs.

Anticoagulation Strategies in Non-Critically Ill Patients with Covid-19.

BACKGROUND: Optimal thromboprophylaxis for hospitalized patients with coronavirus disease 2019 (Covid-19) is uncertain. METHODS: In an open-label, adaptive platform trial, we randomly assigned hospitalized adults with Covid-19 to low-dose low-molecular-weight heparin thromboprophylaxis or intermediate-dose or low-dose plus aspirin. In response to external evidence, the aspirin intervention was discontinued and a therapeutic-dose arm added. The primary end point was death or the requirement for new organ support by day 28, analyzed with a Bayesian logistic model. Enrolment was closed as a result of operational constraints. RESULTS: Between February 2021 and March 2022, 1574 patients were randomly assigned. Among 1526 participants included in the analysis (India, n=1273; Australia and New Zealand, n=138; and Nepal, n=115), the primary outcome occurred in 35 (5.9%) of 596 in low-dose, 25 (4.2%) of 601 in intermediate-dose, 20 (7.2%) of 279 in low-dose plus aspirin, and 7 (14%) of 50 in therapeutic-dose anticoagulation. Compared with low-dose thromboprophylaxis, the median adjusted odds ratio for the primary outcome for intermediate-dose was 0.74 (95% credible interval [CrI], 0.43 to 1.27; posterior probability of effectiveness [adjusted odds ratio<1; Pr], 86%), for low-dose plus aspirin 0.88 (95% CrI, 0.47 to 1.64; Pr, 65%), and for therapeutic-dose anticoagulation 2.22 (95% CrI, 0.77 to 6.20; Pr, 7%). Overall thrombotic and bleeding rates were 0.8% and 0.4%, respectively. There were 10 serious adverse reactions related to anticoagulation strategy, of which nine were grade 1 or 2 across study interventions and one grade 4 episode of retroperitoneal hematoma in a patient receiving intermediate-dose anticoagulation. CONCLUSIONS: In hospitalized non­critically ill adults with Covid-19, compared with low-dose, there was an 86% posterior probability that intermediate-dose, 65% posterior probability that low-dose plus aspirin, and a 7% posterior probability that therapeutic-dose anticoagulation reduced the odds of death or requirement for organ support. No treatment strategy met prespecified stopping criteria before trial closure, precluding definitive conclusions. (Funded by Australian National Health and Medical Research Council or Medical Research Future Fund Investigator and Practitioner Grants and others; ClinicalTrials.gov number, NCT04483960.)

A Randomized Trial of Nafamostat for Covid-19.

BACKGROUND: Nafamostat mesylate is a potent in vitro antiviral agent that inhibits the host transmembrane protease serine 2 enzyme used by severe acute respiratory syndrome coronavirus 2 for cell entry. METHODS: This open-label, pragmatic, randomized clinical trial in Australia, New Zealand, and Nepal included noncritically ill hospitalized patients with coronavirus disease 2019 (Covid-19). Participants were randomly assigned to usual care or usual care plus nafamostat. The primary end point was death (any cause) or receipt of new invasive or noninvasive ventilation or vasopressor support within 28 days after randomization. Analysis was with a Bayesian logistic model in which an adjusted odds ratio <1.0 indicates improved outcomes with nafamostat. Enrollment was closed due to falling numbers of eligible patients. RESULTS: We screened 647 patients in 21 hospitals (15 in Australia, 4 in New Zealand, and 2 in Nepal) and enrolled 160 participants from May 2021 to August 2022. In the intention-to-treat population, the primary end point occurred in 8 (11%) of 73 patients with usual care and 4 (5%) of 82 with nafamostat. The median adjusted odds ratio for the primary end point for nafamostat was 0.40 (95% credible interval, 0.12 to 1.34) with a posterior probability of effectiveness (adjusted odds ratio <1.0) of 93%. For usual care compared with nafamostat, hyperkalemia occurred in 1 (1%) of 67 and 7 (9%) of 78 participants, respectively, and clinically relevant bleeding occurred in 1 (1%) of 73 and 7 (8%) of 82 participants. CONCLUSIONS: Among hospitalized patients with Covid-19, there was a 93% posterior probability that nafamostat reduced the odds of death or organ support. Prespecified stopping criteria were not met, precluding definitive conclusions. Hyperkalemia and bleeding were more common with nafamostat. (Funded by ASCOT and others; ClinicalTrials.gov number, NCT04483960.)

ASCOT ADAPT study of COVID-19 therapeutics in hospitalised patients: an international multicentre adaptive platform trial.

BACKGROUND: SARS-CoV-2 infection is associated with a significant risk of hospitalisation, death, and prolonged impact on quality of life. Evaluation of new treatment options and optimising therapeutic management of people hospitalised with SARS-CoV-2 infection remains essential, but rapid changes in pandemic conditions and potential therapies have limited the utility of traditional approaches to randomised controlled trials. METHODS: ASCOT ADAPT is an international, investigator-initiated, adaptive platform, randomised controlled trial of therapeutics for non-critically ill patients hospitalised with COVID-19. The study design is open label and pragmatic. Potential participants are hospitalised adults with PCR confirmed, symptomatic, SARS-CoV-2 infection, within 14 days of symptom onset. Domains include antiviral, antibody and anticoagulant interventions, with a composite primary outcome of 28-day mortality or progression to intensive-care level respiratory or haemodynamic support. Initial interventions include intravenous nafamostat and variable dose anticoagulation. A range of secondary endpoints, and substudies for specific domains and interventions are outlined. DISCUSSION: This paper presents the trial protocol and management structure, including international governance, remote site monitoring and biobanking activities and provides commentary on ethical and pragmatic considerations in establishing the ASCOT ADAPT trial under pandemic conditions. TRIAL REGISTRATION: Australian and New Zealand Clinical Trials Registry (ACTRN12620000445976) and ClinicalTrials.gov (NCT04483960).

Higher habitual dietary flavonoid intake associates with lower central blood pressure and arterial stiffness in healthy older adults.

Flavonoids have shown anti-hypertensive and anti-atherosclerotic properties: the impact of habitual flavonoid intake on vascular function, central haemodynamics and arterial stiffness may be important. We investigated the relationship between habitual flavonoid consumption and measures of central blood pressure and arterial stiffness. We performed cross-sectional analysis of 381 non-smoking healthy older adults (mean age 66·0 (sd 4·1) years; BMI, 26·4 (sd 4·41) kg/m2; 41 % male) recruited as part of the Australian Research Council Longevity Intervention study. Flavonoid intake (i.e. flavonols, flavones, flavanones, anthocyanins, isoflavones, flavan-3-ol monomers, proanthocyanidins, theaflavins/thearubigins and total consumption) was estimated from FFQ using the US Department of Agriculture food composition databases. Measures of central haemodynamics and arterial stiffness included systolic blood pressure (cSBP), diastolic blood pressure (cDBP), mean arterial pressure (cMAP) and augmentation index (cAIx). After adjusting for demographic and lifestyle confounders, each sd/d higher intake of anthocyanins ((sd 44·3) mg/d) was associated with significantly lower cDBP (-1·56 mmHg, 95 % CI -2·65, -0·48) and cMAP (-1·62 mmHg, 95 % CI -2·82, -0·41). Similarly, each sd/d higher intake of flavanones ((sd 19·5) mg/d) was associated with ~1 % lower cAIx (-0·93 %, 95 % CI -1·77, -0·09). These associations remained significant after additional adjustment for (1) a dietary quality score and (2) other major nutrients that may affect blood pressure or arterial stiffness (i.e. Na, K, Ca, Mg, n-3, total protein and fibre). This study suggests a possible benefit of dietary anthocyanin and flavanone intake on central haemodynamics and arterial stiffness; these findings require corroboration in further research.

The Neurocognitive Effects of Bacopa monnieri and Cognitive Training on Markers of Brain Microstructure in Healthy Older Adults.

Bacopa monnieri (BM) is a herbal supplement that increases signaling molecules implicated in synaptogenesis. Combined with cognitive stimulation, it may be a viable supplement to enhance long-term potentiation (LTP) and improve cognitive health in older adults. This randomized, double-blind, placebo-controlled trial asked 28 healthy adults aged over 55 years to complete cognitive training (CT) 3 hours weekly for 12 weeks. Fifteen consumed a standardized extract of BM and 13 consumed a placebo daily. Cognitive tasks, life-satisfaction, memory complaints and mood were assessed, and bloods analyzed for serum brain-derived neurotrophic factor (BDNF) before and after 12-weeks of the intervention. Diffusion tensor imaging (DTI) and neurite orientation dispersion and density imaging (NODDI) in gray (GM) and white matter (WM) were also analyzed. Results demonstrated slower reaction time in an image discrimination task in the BM group and faster reaction time in a spatial working memory task (SWM-O RT) in the placebo group. Mean accuracy was higher in the BM group for these tasks, suggesting a change in the speed accuracy trade-off. Exploratory neuroimaging analysis showed increased WM mean diffusivity (MD) and GM dispersion of neurites (orientation dispersion index, ODI) and decreased WM fractional anisotropy (FA) and GM neurite density (ND) in the BM group. No other outcomes reached statistical significance. An increase in ODI with a decrease in MD and ND in the BM group may indicate an increase in network complexity (through higher dendritic branching) accompanied by dendritic pruning to enhance network efficiency. These neuroimaging outcomes conflict with the behavioral results, which showed poorer reaction time in the BM group. Given the exploratory outcomes and inconsistent findings between the behavioral and neuroimaging data, a larger study is needed to confirm the synaptogenic mechanisms of BM.

The Relationship between Gut Microbiome and Cognition in Older Australians.

Ageing is associated with changes in biological processes, including reductions in cognitive functions and gut microbiome diversity. However, not much is known about the relationship between cognition and the microbiome with increasing age. Therefore, we examined the relationship between the gut microbiome and cognition in 69 healthy participants aged 60-75 years. The gut microbiome was analysed with the 16S rRNA sequencing method. The cognitive assessment included the Cognitive Drug Research computerised assessment battery, which produced five cognitive factors corresponding to 'Quality of Episodic Secondary Memory', 'Quality of Working Memory', 'Continuity of Attention, 'Speed of Memory' and 'Power of Concentration'. Multiple linear regression showed that the bacterial family Carnobacteriaceae explained 9% of the variance in predicting Quality of Episodic Secondary Memory. Alcaligenaceae and Clostridiaceae explained 15% of the variance in predicting Quality of Working Memory; Bacteroidaceae, Barnesiellaceae, Rikenellaceae and Gemellaceae explained 11% of the variance in Power of Concentration. The present study provides specific evidence of a relationship between specific families of bacteria and different domains of cognition.

Neurotrophins as a reliable biomarker for brain function, structure and cognition: A systematic review and meta-analysis.

Neurotrophins are signalling molecules involved in the formation and maintenance of synapses in the brain. They can cross the blood-brain barrier and be detected in peripheral blood, suggesting they may be a potential biomarker for brain health and function. In this review, the available literature was systematically searched for studies comparing peripheral neurotrophins levels with MRI and cognitive measures in healthy adults. Twenty-four studies were identified, six of which included a neuroimaging outcome. Fifteen studies measuring cognition were eligible for meta-analysis. The majority of studies measured levels of brain-derived neurotrophic factor (BDNF), with few assessing other neurotrophins. Results revealed BDNF is related to some neuroimaging outcomes, with some studies suggesting older age may be an important factor. A higher proportion of studies who had older samples observed significant effects between cognition and neurotrophin levels. When cognitive studies were pooled together in a meta-analysis, there was a weak non-significant effect between BDNF and cognitive outcomes. There was also a high level of heterogeneity between cognitive studies. Results indicated that gender was a notable source of the heterogeneity, but additional studies employing relevant covariates are necessary to better characterise the inter-relationship between circulating neurotrophins and cognition.

Increased Posterior Cingulate Functional Connectivity Following 6-Month High-Dose B-Vitamin Multivitamin Supplementation: A Randomized, Double-Blind, Placebo-Controlled Trial.

B vitamins are essential for optimal brain and body function, and are particularly important for cortical metabolic processes that have downstream effects on mitigating oxidative stress. Oxidative stress has been linked to poor psychological outcomes including psychological distress, which has wide-reaching implications for the community and the workplace. Given work-related stress has been associated with poor mental health outcomes, high-dose B vitamin supplementation may be effective in improving brain function and psychological outcomes via attenuation of oxidative stress. This randomized, double-blind, placebo-controlled study investigated psychological outcomes following 6-month supplementation of a high-B-vitamin multivitamin in a large sample of healthy adults (n = 108, aged 30-70 years), as well as changes in default mode network functional connectivity in a subset of the original sample (n = 28). Improvements in occupational stress, general health, perceived stress, depressive symptoms, and mood profiles were identified for both active and placebo groups over time (p < 0.05 corrected). Seed-based functional connectivity analysis centered on the posterior cingulate cortex (PCC) showed that connectivity between the PCC and the caudate increased for the active treatment group, but decreased for the placebo group (p < 0.05 corrected). These findings reveal a substantial intervention effect for both active and placebo treatments, which could in part be associated with a placebo effect in subjective measures. There was, however, a significant treatment effect in the objective measure of functional connectivity, suggesting that reduced psychological stress and high-B-vitamin multivitamin supplementation may lead to an increase in DMN and caudate functional connectivity, which might reflect a strengthening of neurocircuitry within areas associated with reward and emotion at rest. Future studies should consider a placebo run-in methodology to reduce the placebo effect on the subjective measures of stress.

Effects of sustained cognitive activity on white matter microstructure and cognitive outcomes in healthy middle-aged adults: A systematic review.

Adults who remain cognitively active may be protected from age-associated changes in white matter (WM) and cognitive decline. To determine if cognitive activity is a precursor for WM plasticity, the available literature was systematically searched for Region of Interest (ROI) and whole-brain studies assessing the efficacy of cognitive training (CT) on WM microstructure using Diffusion Tensor Imaging (DTI) in healthy adults (> 40 years). Seven studies were identified and included in this review. Results suggest there are beneficial effects to WM microstructure after CT in frontal and medial brain regions, with some studies showing improved performance in cognitive outcomes. Benefits of CT were shown to be protective against age-related WM microstructure decline by either maintaining or improving WM after training. These results have implications for determining the capacity for training-dependent WM plasticity in older adults and whether CT can be utilised to prevent age-associated cognitive decline. Additional studies with standardised training and imaging protocols are needed to confirm these outcomes.

The Effect of a High-Dose Vitamin B Multivitamin Supplement on the Relationship between Brain Metabolism and Blood Biomarkers of Oxidative Stress: A Randomized Control Trial.

A diet rich in B-group vitamins is essential for optimal body and brain function, and insufficient amounts of such vitamins have been associated with higher levels of neural inflammation and oxidative stress, as marked by increased blood plasma homocysteine. Neural biomarkers of oxidative stress quantified through proton magnetic spectroscopy (1H-MRS) are not well understood, and the relationship between such neural and blood biomarkers is seldom studied. The current study addresses this gap by investigating the direct effect of 6-month high-dose B-group vitamin supplementation on neural and blood biomarkers of metabolism. Using a randomized, double-blind, placebo-controlled design, 32 healthy adults (20 female, 12 male) aged 30⁻65 years underwent blood tests (vitamin B6, vitamin B12, folate, and homocysteine levels) and 1H-MRS of the posterior cingulate cortex (PCC) and dorsolateral prefrontal cortex (DLPFC) before and after supplementation. Results confirmed the supplement was effective in increasing vitamin B6 and vitamin B12 levels and reducing homocysteine, whereas there was no change in folate levels. There were significant relationships between vitamin B6 and N-acetylaspartate (NAA), choline, and creatine, as well as between vitamin B12 and creatine (ps < 0.05), whereas NAA in the PCC increased, albeit not significantly (p > 0.05). Together these data provide preliminary evidence for the efficacy of high-dose B-group supplementation in reducing oxidative stress and inflammation through increasing oxidative metabolism. It may also promote myelination, cellular metabolism, and energy storage.

Trait and state anxiety is marked by increased working memory-related parietal BOLD signal.

Anxiety is associated with compromised cognitive control functions, such as working memory. State and trait anxiety within the non-clinical population can be utilised to investigate potential neural markers for anxiety, which may help to elucidate potential prevention and intervention methods. Thirty-two healthy adults (20 female, 12 male), aged between 30 and 65 years, performed a 2-back task whilst fMRI BOLD signal was acquired using a 3T scanner. Mean BOLD signal was obtained in cognitive control network regions of interest of: left and right dorsolateral prefrontal cortex (DLPFC) and posterior parietal lobe (PPL), and medial prefrontal cortex (MPFC). State and trait anxiety levels were recorded. Higher overall anxiety was moderately associated with more left and right PPL BOLD signal; there was a weak relationship between anxiety and left DLPFC BOLD signal. MPFC BOLD signal and trait anxiety were moderately associated with overall 2-back task performance. These findings suggest that non-clinical anxiety affects the recruitment of cortical resources during working memory, but that anxiety does not impair performance during a 2-back task.

Cognitive training and Bacopa monnieri: Evidence for a combined intervention to alleviate age associated cognitive decline.

As the elderly population grows the impact of age associated cognitive decline as well as neurodegenerative diseases such as Alzheimer's disease and dementia will increase. Ageing is associated with consistent impairments in cognitive processes (e.g., processing speed, memory, executive function and learning) important for work, well-being, life satisfaction and overall participation in society. Recently, there has been increased effort to conduct research examining methods to improve cognitive function in older citizens. Cognitive training has been shown to improve performance in some cognitive domains; including memory, processing speed, executive function and attention in older adults. These cognitive changes are thought to be related to improvements in brain connectivity and neural circuitry. Bacopa monnieri has also been shown to improve specific domains of cognition, sensitive to age associated cognitive decline (particularly processing speed and memory). These Bacopa monnieri dependent improvements may be due to the increase in specific neuro-molecular mechanisms implicated in the enhancement of neural connections in the brain (i.e. synaptogenesis). In particular, a number of animal studies have shown Bacopa monnieri consumption upregulates calcium dependent kinases in the synapse and post-synaptic cell, crucial for strengthening and growing connections between neurons. These effects have been shown to occur in areas important for cognitive processes, such as the hippocampus. As Bacopa monnieri has shown neuro-molecular mechanisms that encourage synaptogenesis, while cognitive training enhances brain connectivity, Bacopa monnieri supplementation could theoretically enhance and strengthen synaptic changes acquired through cognitive training. Therefore, the current paper hypothesises that the combination of these two interventions could improve cognitive outcomes, over and above the effects of administrating these interventions independently, as an effective treatment to ameliorate age associated cognitive decline.

Reducing occupational stress with a B-vitamin focussed intervention: a randomized clinical trial: study protocol.

BACKGROUND: Workplace stress in Australia and other western countries has been steadily increasing over the past decade. It can be observed not only in terms of increased compensation claims but also costs due to absenteeism, loss of productivity at work and reduced psychological and physiological health and well-being. Given the cost and pervasive effects of stress in the modern workforce, time efficient and cost-effective interventions capable of reducing occupational stress (or strain) and burnout are urgently required for the improved well-being of stressed employees. One intervention gaining scientific traction is supplementation with nutritional interventions, particularly the B group vitamins. METHODS: This study was developed to examine the effects of B group vitamins on workplace stress and mood variables with a sample of full-time employed older adults who subjectively report feeling stressed. The study is a randomized, double-blind, placebo-controlled, parallel-groups clinical trial where 200 (N = 100/group) participants will be randomized to receive Blackmores® Executive B Stress Formula or placebo daily for a period of 6 months. Participants will be tested at baseline and 6 months post-randomization on workplace stress, cognitive, personality and mood measures, cardiovascular (brachial and aortic systolic and diastolic blood pressures as well as arterial stiffness), biochemical (assays to measure inflammation and safety) as well as genetic assessments (to assess stress processing) and neuroimaging measures (to investigate in vivo mechanisms of action of B vitamins). In addition to this pre- and post- supplementation testing, participants will also complete a battery of self-report questionnaires online to assess their stress and mood once a month for the duration of the study. The primary aim of the study is to investigate the effects of B vitamin supplementation on work related stress. The secondary aims are to explore the mechanisms underpinning any changes in mood or workplace stress due to the B vitamin intervention by examining relationships between cognitive, biological, neuroimaging and cardiovascular variables over 6 months. A subset of 40 participants (N = 20/group) will undergo neuroimaging at baseline and at 6 months using functional magnetic resonance imaging (fMRI) and magnetic resonance spectroscopy (MRS) in order to further explore in vivo mechanisms of action of B vitamins. TRIAL REGISTRATION: Australia and New Zealand Clinical Trials Register (ANZCTR):ACTRN12613000294752.