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The presence of bradycardic arrhythmias during volitional apnea at altitude may be caused by chemoreflex activation/sensitization. We investigated whether bradyarrhythmic episodes became prevalent in apnea following short-term hypoxia exposure. Electrocardiograms (ECG; lead II) were collected from 22 low-altitude residents (F = 12; age=25 ± 5 years) at 671 m. Participants were exposed to normobaric hypoxia (SpO 2 ~79 ± 3%) over a 5-h period. ECG rhythms were assessed during both free-breathing and maximal volitional end-expiratory and end-inspiratory apnea at baseline during normoxia and hypoxia exposure (20 min [AHX]; 5 h [HX5]). Free-breathing HR became elevated at AHX (78 ± 10 bpm; p < 0.0001) and HX5 (80 ± 12 bpm; p < 0.0001) compared to normoxia (68 ± 10 bpm), whereas apnea caused significant bradycardia at AHX (nadir end-expiratory -17 ± 14 bpm; p < 0.001) and HX5 (nadir end-expiratory -19 ± 15 bpm; p < 0.001), but not during normoxia (nadir end-expiratory -4 ± 13 bpm), with no difference in bradycardia responses between apneas at AHX and HX5. Conduction abnormalities were noted in five participants during normoxia (Premature Ventricular Contraction, Sinus Pause, Junctional Rhythm, Atrial Foci), which remained unchanged during apnea at AHX and HX5 (Premature Ventricular Contraction, Premature Atrial Contraction, Sinus Pause). End-inspiratory apneas were overall longer across conditions (normoxia p < 0.05; AHX p < 0.01; HX5 p < 0.001), with comparable HR responses to end-expiratory and fewer occurrences of arrhythmia. While short-term hypoxia is sufficient to elicit bradycardia during apnea, the occurrence of arrhythmias in response to apnea was not affected. These findings indicate that previously observed bradyarrhythmic events in untrained individuals at altitude only become prevalent following chronic hypoxia specificlly., (© 2021 The Authors. Physiological Reports published by Wiley Periodicals LLC on behalf of The Physiological Society and the American Physiological Society.)

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.

COVID-19 patients (n = 34) suffering from ARDS were treated with tocilizumab (TCZ). Outcome was classified in two groups: "Death" and "Recovery". Predictive factors of mortality were studied. Mean age was 75.3, mean oxygen (O 2 ) requirements 10.4 l/min. At baseline, all patients had multiple biological abnormalities (lymphopenia, increased CRP, ferritin, fibrinogen, D-dimer and liver enzymes). 24 patients (70.5%) recovered after TCZ therapy and 10 died (29.5%). Deceased subjects differed from patients in whom treatment was effective with regard to more pronounced lymphopenia (0.6 vs 1.0 G/l; p = 0.037), lower platelet number (156 vs 314 G/l; p = 0.0001), lower fibrinogen serum level (0.6 vs 1.0 G/l; p = 0.03), higher aspartate-amino-transferase (108 vs 57 UI/l; p = 0.05) and greater O 2 requirements (11 vs 8 l/min; p = 0.003)., Competing Interests: Declaration of Competing Interest The authors declare that they have no conflict interests., (Copyright © 2020 Institut Pasteur. Published by Elsevier Masson SAS. All rights reserved.)

As climate change continues to exert increasing pressure upon the livelihoods and agricultural sector of many developing and developed nations, a need exists to understand and prioritise at the sub national scale which areas and communities are most vulnerable. The purpose of this study is to develop a robust, rigorous and replicable methodology that is flexible to data limitations and spatially prioritizes the vulnerability of agriculture and rural livelihoods to climate change. We have applied the methodology in Vietnam, Uganda and Nicaragua, three contrasting developing countries that are particularly threatened by climate change. We conceptualize vulnerability to climate change following the widely adopted combination of sensitivity, exposure and adaptive capacity. We used Ecocrop and Maxent ecological models under a high emission climate scenario to assess the sensitivity of the main food security and cash crops to climate change. Using a participatory approach, we identified exposure to natural hazards and the main indicators of adaptive capacity, which were modelled and analysed using geographic information systems. We finally combined the components of vulnerability using equal-weighting to produce a crop specific vulnerability index and a final accumulative score. We have mapped the hotspots of climate change vulnerability and identified the underlying driving indicators. For example, in Vietnam we found the Mekong delta to be one of the vulnerable regions due to a decline in the climatic suitability of rice and maize, combined with high exposure to flooding, sea level rise and drought. However, the region is marked by a relatively high adaptive capacity due to developed infrastructure and comparatively high levels of education. The approach and information derived from the study informs public climate change policies and actions, as vulnerability assessments are the bases of any National Adaptation Plans (NAP), National Determined Contributions (NDC) and for accessing climate finance., Competing Interests: The authors have declared that no competing interests exist.

Objectives: The purpose of this study was to establish if people with chronic low back pain (CLBP) demonstrate impairments in the ability to localize sensory information delivered to the back more than pain-free controls and determine whether any sensory abnormalities are related to pain-related variables., Methods: Vision was occluded and participants were stimulated using light touch or pinprick over a number of body areas in random order. To assess for mislocalizations participants were asked to nominate the location of each stimulus in reference to a marked body chart. To assess referred sensations participants who were asked whether they experienced any sensations elsewhere during stimulation. If referred sensations were reported, testing was repeated with visualization of the stimulated area., Results: Although a small number of CLBP patients demonstrated referral of sensations, this was not statistically different from what was observed in a pain-free control group (P=0.381). In contrast, mislocalizations were very common in the patient sample and statistically more common than we found in controls (P=0.034). No statistically significant associations were detected between sensory function and the measured pain-related variables (all P>0.05)., Discussion: These data add to a growing body of evidence suggesting that disturbed self-perception is a feature of CLBP. It is plausible that altered self-perception is maladaptive and contributes to the maintenance of the problem and may represent a target of treatment for CLBP.

Sandhoff disease is an autosomal recessive neurodegenerative disease characterized by a GM2 ganglioside intralysosomal accumulation. It is due to mutations in the beta-hexosaminidases beta-chain gene, resulting in a beta-hexosaminidases A (alphabeta) and B (betabeta) deficiency. Mono and bicistronic lentiviral vectors containing the HEXA or/and HEXB cDNAs were constructed and tested on human Sandhoff fibroblasts. The bicistronic SIV.ASB vector enabled a massive restoration of beta-hexosaminidases activity on synthetic substrates and a 20% correction on the GM2 natural substrate. Metabolic labeling experiments showed a large reduction of ganglioside accumulation in SIV.ASB transduced cells, demonstrating a correct recombinant enzyme targeting to the lysosomes. Moreover, enzymes secreted by transduced Sandhoff fibroblasts were endocytosed in deficient cells via the mannose 6-phosphate pathway, allowing GM2 metabolism restoration in cross-corrected cells. Therefore, our bicistronic lentivector supplying both alpha- and beta-subunits of beta-hexosaminidases may provide a potential therapeutic tool for the treatment of Sandhoff disease.

An original method of image analysis has been developed, using 'mathematical morphology', in order to detect brain tumors at magnetic resonance imaging of the head following injection of gadolinium-DPTA. The main steps of the analysis are as follows: 1) Spatial reduction by automatic determination of a region of interest, 2) elimination of noise by morphologic filtering (increasing alternate closing-opening sequence), 3) localization of tumor by searching for r-h maxima, and 4) extraction of tumor contours using three-dimensional structuring elements. The preliminary results of this automatic and robust method encourage further studies of the potential of tissue analysis as an aid to tumor diagnosis.

Monoclonal antibodies (MAbs) 19-9 and 73-3 specific for human colon adenocarcinoma were labelled with a high number of gadolinium atoms. Twenty five DTPA were chelated per MAb, with only slight loss of immunoreactivity. The NMR contrast agent Gd-25 DTPA-MAb 19-9 or 73-3 ([Gd] 17 mumole/kg, [MAb] 60 microM) was injected into nude mice bearing human colon adenocarcinoma (SW948). Tumours were removed 24 hr after injection and T1 was measured in vitro. T1 relaxation time varied according to MAb specificity against tumour targets; T1 decreased 20% for MAb 19-9 and MAb 73-3 with SW948 tumour. Imaging was performed with this model. Very good contrast was obtained 24 hr after Gd-25 DTPA-MAb injection.