Effect of Hydrocortisone on Mortality and Organ Support in Patients With Severe COVID-19: The REMAP-CAP COVID-19 Corticosteroid Domain Randomized Clinical Trial.

Importance: Evidence regarding corticosteroid use for severe coronavirus disease 2019 (COVID-19) is limited. Objective: To determine whether hydrocortisone improves outcome for patients with severe COVID-19. Design, Setting, and Participants: An ongoing adaptive platform trial testing multiple interventions within multiple therapeutic domains, for example, antiviral agents, corticosteroids, or immunoglobulin. Between March 9 and June 17, 2020, 614 adult patients with suspected or confirmed COVID-19 were enrolled and randomized within at least 1 domain following admission to an intensive care unit (ICU) for respiratory or cardiovascular organ support at 121 sites in 8 countries. Of these, 403 were randomized to open-label interventions within the corticosteroid domain. The domain was halted after results from another trial were released. Follow-up ended August 12, 2020. Interventions: The corticosteroid domain randomized participants to a fixed 7-day course of intravenous hydrocortisone (50 mg or 100 mg every 6 hours) (n = 143), a shock-dependent course (50 mg every 6 hours when shock was clinically evident) (n = 152), or no hydrocortisone (n = 108). Main Outcomes and Measures: The primary end point was organ support-free days (days alive and free of ICU-based respiratory or cardiovascular support) within 21 days, where patients who died were assigned -1 day. The primary analysis was a bayesian cumulative logistic model that included all patients enrolled with severe COVID-19, adjusting for age, sex, site, region, time, assignment to interventions within other domains, and domain and intervention eligibility. Superiority was defined as the posterior probability of an odds ratio greater than 1 (threshold for trial conclusion of superiority >99%). Results: After excluding 19 participants who withdrew consent, there were 384 patients (mean age, 60 years; 29% female) randomized to the fixed-dose (n = 137), shock-dependent (n = 146), and no (n = 101) hydrocortisone groups; 379 (99%) completed the study and were included in the analysis. The mean age for the 3 groups ranged between 59.5 and 60.4 years; most patients were male (range, 70.6%-71.5%); mean body mass index ranged between 29.7 and 30.9; and patients receiving mechanical ventilation ranged between 50.0% and 63.5%. For the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively, the median organ support-free days were 0 (IQR, -1 to 15), 0 (IQR, -1 to 13), and 0 (-1 to 11) days (composed of 30%, 26%, and 33% mortality rates and 11.5, 9.5, and 6 median organ support-free days among survivors). The median adjusted odds ratio and bayesian probability of superiority were 1.43 (95% credible interval, 0.91-2.27) and 93% for fixed-dose hydrocortisone, respectively, and were 1.22 (95% credible interval, 0.76-1.94) and 80% for shock-dependent hydrocortisone compared with no hydrocortisone. Serious adverse events were reported in 4 (3%), 5 (3%), and 1 (1%) patients in the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively. Conclusions and Relevance: Among patients with severe COVID-19, treatment with a 7-day fixed-dose course of hydrocortisone or shock-dependent dosing of hydrocortisone, compared with no hydrocortisone, resulted in 93% and 80% probabilities of superiority with regard to the odds of improvement in organ support-free days within 21 days. However, the trial was stopped early and no treatment strategy met prespecified criteria for statistical superiority, precluding definitive conclusions. Trial Registration: ClinicalTrials.gov Identifier: NCT02735707

The impact of surgical delay on resectability of colorectal cancer: An international prospective cohort study

AIM: The SARS-CoV-2 pandemic has provided a unique opportunity to explore the impact of surgical delays on cancer resectability. This study aimed to compare resectability for colorectal cancer patients undergoing delayed versus non-delayed surgery. METHODS: This was an international prospective cohort study of consecutive colorectal cancer patients with a decision for curative surgery (January-April 2020). Surgical delay was defined as an operation taking place more than 4 weeks after treatment decision, in a patient who did not receive neoadjuvant therapy. A subgroup analysis explored the effects of delay in elective patients only. The impact of longer delays was explored in a sensitivity analysis. The primary outcome was complete resection, defined as curative resection with an R0 margin. RESULTS: Overall, 5453 patients from 304 hospitals in 47 countries were included, of whom 6.6% (358/5453) did not receive their planned operation. Of the 4304 operated patients without neoadjuvant therapy, 40.5% (1744/4304) were delayed beyond 4 weeks. Delayed patients were more likely to be older, men, more comorbid, have higher body mass index and have rectal cancer and early stage disease. Delayed patients had higher unadjusted rates of complete resection (93.7% vs. 91.9%, P = 0.032) and lower rates of emergency surgery (4.5% vs. 22.5%, P < 0.001). After adjustment, delay was not associated with a lower rate of complete resection (OR 1.18, 95% CI 0.90-1.55, P = 0.224), which was consistent in elective patients only (OR 0.94, 95% CI 0.69-1.27, P = 0.672). Longer delays were not associated with poorer outcomes. CONCLUSION: One in 15 colorectal cancer patients did not receive their planned operation during the first wave of COVID-19. Surgical delay did not appear to compromise resectability, raising the hypothesis that any reduction in long-term survival attributable to delays is likely to be due to micro-metastatic disease

Temporal discrimination threshold: VBM evidence for an endophenotype in adult onset primary torsion dystonia.

Familial adult-onset primary torsion dystonia is an autosomal dominant disorder with markedly reduced penetrance. Most adult-onset primary torsion dystonia patients are sporadic cases. Disordered sensory processing is found in adult-onset primary torsion dystonia patients; if also present in their unaffected relatives this abnormality may indicate non-manifesting gene carriage. Temporal discrimination thresholds (TDTs) are abnormal in adult-onset primary torsion dystonia, but their utility as a possible endophenotype has not been examined. We examined 35 adult-onset primary torsion dystonia patients (17 familial, 18 sporadic), 42 unaffected first-degree relatives of both familial and sporadic adult-onset primary torsion dystonia patients, 32 unaffected second-degree relatives of familial adult-onset primary torsion dystonia (AOPTD) patients and 43 control subjects. TDT was measured using visual and tactile stimuli. In 33 unaffected relatives, voxel-based morphometry was used to compare putaminal volumes between relatives with abnormal and normal TDTs. The mean TDT in 26 control subjects under 50 years of age was 22.85 ms (SD 8.00; 95% CI: 19.62-26.09 ms). The mean TDT in 17 control subjects over 50 years was 30.87 ms (SD 5.48; 95% CI: 28.05-33.69 ms). The upper limit of normal, defined as control mean + 2.5 SD, was 42.86 ms in the under 50 years group and 44.58 ms in the over 50 years group. Thirty out of thirty-five (86%) AOPTD patients had abnormal TDTs with similar frequencies of abnormalities in sporadic and familial patients. Twenty-two out of forty-two (52%) unaffected first-degree relatives had abnormal TDTs with similar frequencies in relatives of sporadic and familial AOPTD patients. Abnormal TDTs were found in 16/32 (50%) of second-degree relatives. Voxel-based morphometry analysis comparing 13 unaffected relatives with abnormal TDTs and 20 with normal TDTs demonstrated a bilateral increase in putaminal grey matter in unaffected relatives with abnormal TDTs. The prevalence of abnormal TDTs in sporadic and familial AOPTD patients and their first-degree relatives follows the rules for a useful endophenotype. A structural correlate of abnormal TDTs in unaffected first-degree relatives was demonstrated using voxel-based morphometry. Voxel-based morphometry findings indicate that putaminal enlargement in AOPTD is a primary phenomenon. TDTs may be an effective tool in AOPTD research with particular relevance to genetic studies of the disorder

Quantifying the drivers of larval density patterns in two tropical mosquito species to maximize control efficiency

Understanding the contribution of environmental variation and density feedback are essential for designing effective vector control. Monitoring datasets describing relative larval densities over 7 years of the two dominant mosquito species, Aedes vigilax (Skuse) and Culex annulirostris (Skuse), found in the greater Darwin area, Northern Territory, Australia, were analysed using generalised linear modelling and linear mixed-effects modelling to discover the environmental determinants of spatio-temporal patterns in relative abundance. The most important spatial drivers of Ae. vigilax and Cx. annulirostris larval densities were elevation above sea level and water presence. Ae. vigilax density was negatively correlated with elevation, whereas there was a positive relationship between Cx. annulirostris density and elevation. This result demonstrates how larval habitats used by the salt-water influenced breeder Ae. vigilax and the obligate fresh-water breeder Cx. annulirostris are separated in a tidally influenced swamp. The models examining temporal drivers of larval density also identified this discrimination between freshwater and saltwater habitats. Ae. vigilax larval densities exhibited positive relationships with maximum tide heights and high tide frequencies, whereas the Cx. annulirostris larval densities were positively related to elevation above sea level and rainfall. The most important temporal driver of the larval densities in both species was adult numbers from the previous month, providing a clear dynamical link between the two main life phases in mosquito development. This study demonstrates the importance of considering both spatial and temporal drivers, and intrinsic population dynamics, when planning vector control strategies, to reduce larval density, adult population density, and disease transmission effectively

Quantifying the drivers of larval density patterns in two tropical mosquito species to maximize control efficiency

Understanding the contribution of environmental variation and density feedback are essential for designing effective vector control. Monitoring datasets describing relative larval densities over 7 years of the two dominant mosquito species, Aedes vigilax (Skuse) and Culex annulirostris (Skuse), found in the greater Darwin area, Northern Territory, Australia, were analysed using generalised linear modelling and linear mixed-effects modelling to discover the environmental determinants of spatio-temporal patterns in relative abundance. The most important spatial drivers of Ae. vigilax and Cx. annulirostris larval densities were elevation above sea level and water presence. Ae. vigilax density was negatively correlated with elevation, whereas there was a positive relationship between Cx. annulirostris density and elevation. This result demonstrates how larval habitats used by the salt-water influenced breeder Ae. vigilax and the obligate fresh-water breeder Cx. annulirostris are separated in a tidally influenced swamp. The models examining temporal drivers of larval density also identified this discrimination between freshwater and saltwater habitats. Ae. vigilax larval densities exhibited positive relationships with maximum tide heights and high tide frequencies, whereas the Cx. annulirostris larval densities were positively related to elevation above sea level and rainfall. The most important temporal driver of the larval densities in both species was adult numbers from the previous month, providing a clear dynamical link between the two main life phases in mosquito development. This study demonstrates the importance of considering both spatial and temporal drivers, and intrinsic population dynamics, when planning vector control strategies, to reduce larval density, adult population density, and disease transmission effectively.Date:2009-0

Experimental comparison of aerial larvicides and habitat modification for controlling disease carrying Aedes vigilax mosquitoes

Microbial and insect-growth-regulator larvicides dominate current vector control programmes because they reduce larval abundance and are relatively environmentally benign. However, their short persistence makes them expensive,and environmental manipulation of larval habitat might be an alternative control measure. Aedes vigilax is a major vector species in northern Australia. A field experiment was implemented in Darwin, Australia, to test the hypotheses that (1) aerial microbial larvicide application effectively decreases Ae. vigilax larval presence, and therefore adult emergence, and (2) environmental manipulation is an effective alternative control measure. Generalised linear and mixed-effects modelling and information theoretic comparisons were used to test these hypotheses. RESULTS: It is shown that the current aerial larvicide application campaign is effective at suppressing the emergence of Ae. vigilax, whereas vegetation removal is not as effective in this context. In addition, the results indicate that current larval sampling procedures are inadequate for quantifying larval abundance or adult emergence. CONCLUSIONS: This field-based comparison has shown that the existing larviciding campaign is more effective than a simple environmental management strategy for mosquito control. It has also identified an important knowledge gap in the use of larval sampling to evaluate the effectiveness of vector control strategies. c 2011 Society of Chemical Industr

Validation of composite proxy measures of cognitive reserve: What can longitudinal cohorts tell us about the association between modifiable dementia risk factors and the ageing

Background: Cognitive reserve (CR) enables individuals to maintain cognitive function despite the presence of brain pathology or atrophy [1]. CR is typically measured via proxy variables that reflect exposure to lifetime experiences, such as education [2]. Composite measures of multiple proxies combine contributions from several experiences and display consistent positive relationships with cognitive function [3]. However, the optimal set of proxies for inclusion in composite measures remains to be determined [2]. Here, we aimed to identify a combination of proxies that best reflects the ability to maintain cognitive function despite cortical thinning. Method: As part of a larger analysis, 277 healthy adult participants provided data for this study (mean age = 69.18, SD age = 6.66, 141 females). Global cognition was defined as average of z‐scores from the Animal Naming task, Colour Trails Test 1 and 2, Immediate and Delayed Recall. Mean cortical thickness was calculated using FreeSurfer using a previously reported method [4]. CR proxies were: educational attainment, occupational complexity, premorbid intelligence, social engagement, cognitively stimulating activity, leisure activity, and physical activity. For each composite, a three‐step hierarchical‐multiple regression was performed to predict global cognition. Independent variables in Step 1 were age, gender, cortical thickness, CR composite was added in Step 2, and an interaction term (cortical thickness*composite) was further added in Step 3. Positive associations between CR composites and global cognition – independent of age, gender and cortical thickness – were ranked on significant R‐squared change values from Step 1 to Step 2. Moderation effects were identified by significant R‐squared change values from Step 2 to Step 3. Result: Most CR composites had positive associations with global cognition, independent of age, gender, and cortical thickness (see Figure 1). A CR composite measuring cognitively stimulating activity, leisure activity, and physical activity had the biggest negative moderation effect (R2 change = 0.013, p = 0.0276) on the cortical thickness‐global cognition relationship. Conclusion: A composite measure of cognitively stimulating‐, leisure‐, and physical‐activity, displays construct validity as a measure of CR in addition to a wide range of composites which display positive, independent, associations with cognitive function

Fifty plus in Ireland 2011: First results from The Irish Longitudinal Study on Ageing (TILDA)

The Irish Longitudinal Study on Ageing (TILDA) is a large-scale, nationally representative study of people aged 50 and over in Ireland. It is the most ambitious study of ageing ever carried out in Ireland and represents a step-change in terms of data, knowledge and understanding of ageing with which to inform policy and novel research. TILDA is designed to maximise comparability with other well-established international longitudinal studies. More than 8,000 people aged 50 and over accepted the invitation to participate in the first wave of TILDA, and the majority of these also agreed to undertake a comprehensive health assessment. Contents Executive Summary 1. Introduction - Rose Anne Kenny and Alan Barrett 2. Socio-Demographic Characteristics Of Older People In Ireland - Yumiko Kamiya and Nick Sofroniou 3. Older People As Members Of Their Families And Communities - Yumiko Kamiya and Virpi Timonen 4. Social Engagement Of Older People - Virpi Timonen, Yumiko Kamiya and Siobhan Maty 5. Physical And Behavioural Health Of Older Irish Adults - Hilary Cronin, Claire O?Regan and Rose Anne Kenny 6. Mental Health And Cognitive Function - Claire O?Regan, Hilary Cronin and Rose Anne Kenny 7. Health And Social Care Utilisation - Charles Normand, Yumiko Kamiya, Virpi Timonen and Brendan Whelan 8. Retirement And Labour Market Participation - Irene Mosca and Alan Barrett 9. Income and Asset Levels of Older People - Vincent O? Sullivan and Richard Layte 10. Quality Of Life And Beliefs About Ageing - Hannah McGee, Karen Morgan, Anne Hickey, Helen Burke and George Savva 11. Methodology - George Savv

Fifty plus in Ireland 2011: first results from the Irish longitudinal study on ageing (TILDA).

The health behaviours recorded by TILDA discussed here include smoking, alcohol consumption, physical activity, and participation in preventive health screenings. For example: • Page 85 Section 5.4.2 Alcohol • Page 120: Table 5.A23: Problematic alcohol use and diagnosed substance abuse by age and sex • Page 121: Table 5.A24: Problematic alcohol use and diagnosed substance abuse by age and education • Page 122: Table 5.A25: Problematic alcohol use and diagnosed substance abuse by age and wealt

Human Rhinovirus Species C Infection in Young Children With Acute Wheeze is Associated With Increased Acute Respiratory Hospital Admissions

Rationale: Human rhinovirus species C (HRV-C) is the most common cause of acute wheezing exacerbations in young children presenting to hospital, but its impact on subsequent respiratory illnesses has not been defined. Objectives: To determine whether acute wheezing exacerbations due to HRV-C are associated with increased hospital attendances due to acute respiratory illnesses (ARIs). Methods: Clinical information and nasal samples were collected prospectively from 197 children less than 5 years of age, presenting to hospital with an acute wheezing episode. Information on hospital attendances with an ARI before and after recruitment was subsequently obtained. Measurements and Main Results: HRV was the most common virus identified at recruitment (n = 135 [68.5%]). From the 120 (88.9%) samples that underwent typing, HRV-C was the most common HRV species identified, present in 81 (67.5%) samples. Children with an HRV-related wheezing illness had an increased risk of readmission with an ARI (relative risk, 3.44; 95% confidence interval, 1.17–10.17; P = 0.03) compared with those infected with any other virus. HRV-C, compared with any other virus, was associated with an increased risk of a respiratory hospital admission before (49.4% vs. 27.3%, respectively; P = 0.004) and within 12 months (34.6% vs. 17.0%; P = 0.01) of recruitment. Risk for subsequent ARI admissions was further increased in atopic subjects (relative risk, 6.82; 95% confidence interval, 2.16–21.55; P = 0.001). Admission risks were not increased for other HRV species. Conclusions: HRV-C–related wheezing illnesses were associated with an increased risk of prior and subsequent hospital respiratory admissions. These associations are consistent with HRV-C causing recurrent severe wheezing illnesses in children who are more susceptible to ARIs