A study on the water chemistry and plankton in blackwater lakelets of the south-western Cape

Includes bibliographies.Blackwater lakelets in the south-western Cape are amongst the most darkly coloured humic waters in the world. In addition the aquatic invertebrate fauna of this region represents a relict and highly endemic group of the South Temperate Gondwanian fauna. The major environmental and biological variables were investigated over a period of fifteen months in six south-western Cape vleis (Suurdam, Gillidam, Sirkelsvlei, Grootrondevlei, Grootwitvlei and Rondevlei), which range in colour from a very dark brown to only slightly stained and vary in pH from 3.7 to 10.1. Using absorbance and fluorescence measurements and the Folin-Ciocallteu reagent, relative measures of the quantity and quality of humic compounds were obtained. Suurdam, Gillidam and Sirkelsvlei contained waters of greatest humic content (Suurdam mean A₂₉₀ = 6.561), with a common mid-winter to spring minimum; levels were lower in Grootrondevlei and Grootwitvlei (Grootrondevlei mean A₂₉₀ = 0.996), with a common mid-winter to spring maximum; and lowest in Rondevlei (mean A₂₉₀ = 0.284), with a slight peak in winter. Maxima were related to increased inflow of water with winter rain. Humic compounds in Suurdam, Gillidam and Grootrondevlei were of relatively high molecular weight and phenolic content, indicating an allochthonous origin. In Sirkelsvlei humic compounds were of lower molecular weight and phenolic content, possibly as a result of precipitation of the higher molecular weight fraction due to the high total salinity. Grootwitvlei and Rondevlei had lower molecular weight fractions probably as a result of autochthonous humic production, precipitation with calcium and greater rates of humic degradation; a higher molecular weight allochthonous fraction was present in winter in these two vleis. Buffering at low pH and the complexation of both iron and soluble reactive phosphorous were evident in Suurdam and Gillidam. Catchment geology, atmospheric precipitation, evaporation and the input of vertebrate excreta explain the inorganic chemical environments of the vleis. Acid, well-leached soils and calcareous sands resulted in mean pH values of 3.8 and 4.2 in Suurdam and Gillidam and 8.0 and 8.6 in Grootwitvlei and Rondevlei. The cation composition of the vleis on well-leached acid soils was primarily determined by the atmospheric precipitation of marine salt; evaporation and calcareous sands increased the salinity or relative calcium concentrations in some vleis. Animal excreta in Grootwitvlei and Rondevlei also alter the cation composition slightly, and increase the load of major nutrients. Nitrogen and phosphorous are largely of biological origin. Nutrient levels in the vleis are variously affected by marginal macrophytes, the sediments, primary production and the levels of humics. Chlorophyll a levels indicated low phytoplankton biomass in Suurdam, Gillidam and Grootrondevlei (Suurdam, mean chlorophyll a = 0.9ug1-¹ ) and no distinct seasonality; intermediate levels in Sirkelsvlei (mean chlorophyll a = 11.6ug1-¹ ) and high levels in Grootwitvlei and Rondevlei (Rondevlei, mean chlorophyll a = 60.4ug1-¹ ) displayed a common mid- to late-summer peak. Summer stratification was present only in Suurdam and Gillidam. Maximum phytoplankton biomass of the different vleis related to pH, the quantity and quality of the humic substances, and the nutrient loading. Chlorophyll b: chlorophyll a ratios and chlorophyll c: chlorophyll a ratios indicated a dominance of b- and c-containing species in Suurdam, Gillidam and Grootrondevlei and a dominance of species containing only chlorophyll a in Grootwitvlei and Rondevlei. Multi-dimensional scaling showed four distinct zooplankton community groupings. In Suurdam, the community was dominated by Microcyclops crassipes and was characterised by low zooplankton abundance (mean no.m-³ = 1783), a low species richness, an absence of limnetic cladocerans, and high species diversity (H') and evenness (J') indices. The community appeared to be limited by the low pH and the pH-dependent humic toxicity of the water. The communities in Gillidam, Grootrondevlei and Grootwitvlei were dominated by Metadiaptomus purcelli; otherwise that of Gillidam showed similar characteristics to that of Suurdam and was probably limited by the same factors. Both communities contained individuals of small mean size, more likely a result of limitation by the chemical environment rather than of predation pressure. A number of large-bodied limnetic cladoceran species and Lovenula simplex were present in Grootrondevlei, but absent from Grootwitvlei, possibly as a result of a visual predation pressure. In Sirkelsvlei the community was dominated by Metadiaptomus capensis and Lovenula simplex was present in lower numbers. Species richness, species diversity (H') and evenness (J') were low, with few limnetic cladoceran species present. High total salinity probably determines the community composition and seasonal variation. The eutrophic Rondevlei contains a community dominated by cosmopolitan and common Pan-Ethiopian species, in contrast to the endemic south temperate Gondwanian species of the other vleis. The community was dominated by Thermocyclops oblongatus, Brachionus calyciflorus and Brachionus rubens, and was characterized by greater species richness, and high species diversity (H') and evenness (J'). Total zooplankton abundances were much greater than in the other vleis (mean no.m-³ = 618944). Size-selective predation and the quantity and quality of the phytoplankton probably determine community composition. It is concluded that zooplankton diversity and abundance are influenced, both directly and indirectly, by the concentration and character of the humic substances and the pH, particularly at high concentration and low pH

Repair of Acute Respiratory Distress Syndrome in COVID-19 by Stromal Cells (REALIST-COVID Trial):A Multicentre, Randomised, Controlled Trial

RationaleMesenchymal stromal cells (MSCs) may modulate inflammation, promoting repair in COVID-19-related Acute Respiratory Distress Syndrome (ARDS).ObjectivesWe investigated safety and efficacy of ORBCEL-C (CD362-enriched, umbilical cord-derived MSCs) in COVID-related ARDS.MethodsThis multicentre, randomised, double-blind, allocation concealed, placebo-controlled trial (NCT03042143) randomised patients with moderate-to-severe COVID-related ARDS to receive ORBCEL-C (400million cells) or placebo (Plasma-Lyte148).MeasurementsThe primary safety and efficacy outcomes were incidence of serious adverse events and oxygenation index at day 7 respectively. Secondary outcomes included respiratory compliance, driving pressure, PaO2/FiO2 ratio and SOFA score. Clinical outcomes relating to duration of ventilation, length of intensive care unit and hospital stays, and mortality were collected. Long-term follow up included diagnosis of interstitial lung disease at 1 year, and significant medical events and mortality at 2 years. Transcriptomic analysis was performed on whole blood at day 0, 4 and 7.Main results60 participants were recruited (final analysis n=30 ORBCEL-C, n=29 placebo: 1 in placebo group withdrew consent). 6 serious adverse events occurred in the ORBCEL-C and 3 in the placebo group, RR 2.9(0.6-13.2)p=0.25. Day 7 mean[SD] oxygenation index did not differ (ORBCEL-C 98.357.2], placebo 96.667.3). There were no differences in secondary surrogate outcomes, nor mortality at day 28, day 90, 1 or 2 years. There was no difference in prevalence of interstitial lung disease at 1year nor significant medical events up to 2 years. ORBCEL-C modulated the peripheral blood transcriptome.ConclusionORBCEL-C MSCs were safe in moderate-to-severe COVID-related ARDS, but did not improve surrogates of pulmonary organ dysfunction. Clinical trial registration available at www.Clinicaltrialsgov, ID: NCT03042143. This article is open access and distributed under the terms of the Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/)

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

Bi-allelic Loss-of-Function CACNA1B Mutations in Progressive Epilepsy-Dyskinesia.

The occurrence of non-epileptic hyperkinetic movements in the context of developmental epileptic encephalopathies is an increasingly recognized phenomenon. Identification of causative mutations provides an important insight into common pathogenic mechanisms that cause both seizures and abnormal motor control. We report bi-allelic loss-of-function CACNA1B variants in six children from three unrelated families whose affected members present with a complex and progressive neurological syndrome. All affected individuals presented with epileptic encephalopathy, severe neurodevelopmental delay (often with regression), and a hyperkinetic movement disorder. Additional neurological features included postnatal microcephaly and hypotonia. Five children died in childhood or adolescence (mean age of death: 9 years), mainly as a result of secondary respiratory complications. CACNA1B encodes the pore-forming subunit of the pre-synaptic neuronal voltage-gated calcium channel Cav2.2/N-type, crucial for SNARE-mediated neurotransmission, particularly in the early postnatal period. Bi-allelic loss-of-function variants in CACNA1B are predicted to cause disruption of Ca2+ influx, leading to impaired synaptic neurotransmission. The resultant effect on neuronal function is likely to be important in the development of involuntary movements and epilepsy. Overall, our findings provide further evidence for the key role of Cav2.2 in normal human neurodevelopment.MAK is funded by an NIHR Research Professorship and receives funding from the Wellcome Trust, Great Ormond Street Children's Hospital Charity, and Rosetrees Trust. E.M. received funding from the Rosetrees Trust (CD-A53) and Great Ormond Street Hospital Children's Charity. K.G. received funding from Temple Street Foundation. A.M. is funded by Great Ormond Street Hospital, the National Institute for Health Research (NIHR), and Biomedical Research Centre. F.L.R. and D.G. are funded by Cambridge Biomedical Research Centre. K.C. and A.S.J. are funded by NIHR Bioresource for Rare Diseases. The DDD Study presents independent research commissioned by the Health Innovation Challenge Fund (grant number HICF-1009-003), a parallel funding partnership between the Wellcome Trust and the Department of Health, and the Wellcome Trust Sanger Institute (grant number WT098051). We acknowledge support from the UK Department of Health via the NIHR comprehensive Biomedical Research Centre award to Guy's and St. Thomas' National Health Service (NHS) Foundation Trust in partnership with King's College London. This research was also supported by the NIHR Great Ormond Street Hospital Biomedical Research Centre. J.H.C. is in receipt of an NIHR Senior Investigator Award. The research team acknowledges the support of the NIHR through the Comprehensive Clinical Research Network. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR, Department of Health, or Wellcome Trust. E.R.M. acknowledges support from NIHR Cambridge Biomedical Research Centre, an NIHR Senior Investigator Award, and the University of Cambridge has received salary support in respect of E.R.M. from the NHS in the East of England through the Clinical Academic Reserve. I.E.S. is supported by the National Health and Medical Research Council of Australia (Program Grant and Practitioner Fellowship)

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

Thigh-length compression stockings and DVT after stroke

Controversy exists as to whether neoadjuvant chemotherapy improves survival in patients with invasive bladder cancer, despite randomised controlled trials of more than 3000 patients. We undertook a systematic review and meta-analysis to assess the effect of such treatment on survival in patients with this disease