TET proteins regulate the lineage specification and TCR-mediated expansion of iNKT cells

TET proteins oxidize 5-methylcytosine in DNA to 5-hydroxymethylcytosine and other oxidation products. We found that simultaneous deletion of Tet2 and Tet3 in mouse CD4+CD8+ double-positive thymocytes resulted in dysregulated development and proliferation of invariant natural killer T cells (iNKT cells). Tet2-Tet3 double-knockout (DKO) iNKT cells displayed pronounced skewing toward the NKT17 lineage, with increased DNA methylation and impaired expression of genes encoding the key lineage-specifying factors T-bet and ThPOK. Transfer of purified Tet2-Tet3 DKO iNKT cells into immunocompetent recipient mice resulted in an uncontrolled expansion that was dependent on the nonclassical major histocompatibility complex (MHC) protein CD1d, which presents lipid antigens to iNKT cells. Our data indicate that TET proteins regulate iNKT cell fate by ensuring their proper development and maturation and by suppressing aberrant proliferation mediated by the T cell antigen receptor (TCR)

Mapping genetic variations to three- dimensional protein structures to enhance variant interpretation: a proposed framework

The translation of personal genomics to precision medicine depends on the accurate interpretation of the multitude of genetic variants observed for each individual. However, even when genetic variants are predicted to modify a protein, their functional implications may be unclear. Many diseases are caused by genetic variants affecting important protein features, such as enzyme active sites or interaction interfaces. The scientific community has catalogued millions of genetic variants in genomic databases and thousands of protein structures in the Protein Data Bank. Mapping mutations onto three-dimensional (3D) structures enables atomic-level analyses of protein positions that may be important for the stability or formation of interactions; these may explain the effect of mutations and in some cases even open a path for targeted drug development. To accelerate progress in the integration of these data types, we held a two-day Gene Variation to 3D (GVto3D) workshop to report on the latest advances and to discuss unmet needs. The overarching goal of the workshop was to address the question: what can be done together as a community to advance the integration of genetic variants and 3D protein structures that could not be done by a single investigator or laboratory? Here we describe the workshop outcomes, review the state of the field, and propose the development of a framework with which to promote progress in this arena. The framework will include a set of standard formats, common ontologies, a common application programming interface to enable interoperation of the resources, and a Tool Registry to make it easy to find and apply the tools to specific analysis problems. Interoperability will enable integration of diverse data sources and tools and collaborative development of variant effect prediction methods

Prevalence, associated factors and outcomes of pressure injuries in adult intensive care unit patients: the DecubICUs study

Funder: European Society of Intensive Care Medicine; doi: http://dx.doi.org/10.13039/501100013347Funder: Flemish Society for Critical Care NursesAbstract: Purpose: Intensive care unit (ICU) patients are particularly susceptible to developing pressure injuries. Epidemiologic data is however unavailable. We aimed to provide an international picture of the extent of pressure injuries and factors associated with ICU-acquired pressure injuries in adult ICU patients. Methods: International 1-day point-prevalence study; follow-up for outcome assessment until hospital discharge (maximum 12 weeks). Factors associated with ICU-acquired pressure injury and hospital mortality were assessed by generalised linear mixed-effects regression analysis. Results: Data from 13,254 patients in 1117 ICUs (90 countries) revealed 6747 pressure injuries; 3997 (59.2%) were ICU-acquired. Overall prevalence was 26.6% (95% confidence interval [CI] 25.9–27.3). ICU-acquired prevalence was 16.2% (95% CI 15.6–16.8). Sacrum (37%) and heels (19.5%) were most affected. Factors independently associated with ICU-acquired pressure injuries were older age, male sex, being underweight, emergency surgery, higher Simplified Acute Physiology Score II, Braden score 3 days, comorbidities (chronic obstructive pulmonary disease, immunodeficiency), organ support (renal replacement, mechanical ventilation on ICU admission), and being in a low or lower-middle income-economy. Gradually increasing associations with mortality were identified for increasing severity of pressure injury: stage I (odds ratio [OR] 1.5; 95% CI 1.2–1.8), stage II (OR 1.6; 95% CI 1.4–1.9), and stage III or worse (OR 2.8; 95% CI 2.3–3.3). Conclusion: Pressure injuries are common in adult ICU patients. ICU-acquired pressure injuries are associated with mainly intrinsic factors and mortality. Optimal care standards, increased awareness, appropriate resource allocation, and further research into optimal prevention are pivotal to tackle this important patient safety threat

Correction to: Prevalence, associated factors and outcomes of pressure injuries in adult intensive care unit patients: the DecubICUs study

The original version of this article unfortunately contained a mistake

Prevalence, associated factors and outcomes of pressure injuries in adult intensive care unit patients: the DecubICUs study

Funder: European Society of Intensive Care Medicine; doi: http://dx.doi.org/10.13039/501100013347Funder: Flemish Society for Critical Care NursesAbstract: Purpose: Intensive care unit (ICU) patients are particularly susceptible to developing pressure injuries. Epidemiologic data is however unavailable. We aimed to provide an international picture of the extent of pressure injuries and factors associated with ICU-acquired pressure injuries in adult ICU patients. Methods: International 1-day point-prevalence study; follow-up for outcome assessment until hospital discharge (maximum 12 weeks). Factors associated with ICU-acquired pressure injury and hospital mortality were assessed by generalised linear mixed-effects regression analysis. Results: Data from 13,254 patients in 1117 ICUs (90 countries) revealed 6747 pressure injuries; 3997 (59.2%) were ICU-acquired. Overall prevalence was 26.6% (95% confidence interval [CI] 25.9–27.3). ICU-acquired prevalence was 16.2% (95% CI 15.6–16.8). Sacrum (37%) and heels (19.5%) were most affected. Factors independently associated with ICU-acquired pressure injuries were older age, male sex, being underweight, emergency surgery, higher Simplified Acute Physiology Score II, Braden score 3 days, comorbidities (chronic obstructive pulmonary disease, immunodeficiency), organ support (renal replacement, mechanical ventilation on ICU admission), and being in a low or lower-middle income-economy. Gradually increasing associations with mortality were identified for increasing severity of pressure injury: stage I (odds ratio [OR] 1.5; 95% CI 1.2–1.8), stage II (OR 1.6; 95% CI 1.4–1.9), and stage III or worse (OR 2.8; 95% CI 2.3–3.3). Conclusion: Pressure injuries are common in adult ICU patients. ICU-acquired pressure injuries are associated with mainly intrinsic factors and mortality. Optimal care standards, increased awareness, appropriate resource allocation, and further research into optimal prevention are pivotal to tackle this important patient safety threat

Self-sustainability of phosphorus cycle in rubber (Hevea brasiliensis) plantations: Annual recycling through litter and removal through latex

Low phosphorus availability is one of the main soil factors limiting forest productivity in tropical and subtropical regions. Rubber (Hevea brasiliensis) trees are predominantly cultivated in warm humid tropics and the self-sustainability of rubber plantation with respect to phosphorus nutrition was studied in a PB 217 plantation planted in 1984 and received phosphorus at various levels (0, 10, 20, 30 and 40 kg ha-1yr-1) from 1998 onwards. All the treatments received nitrogen and potassium uniformly at the rate of 30 kg ha-1yr-1. Before the commencement of the experiment all the trees were uniformly manured with nitrogen, phosphorus and potassium. Yield of latex, recycling of P through litter and removal through latex were quantified during 2003-04. Recycling and removal of other nutrients were also quantified. Yield of latex was not influenced by the levels of P applied. Content of P in litter and latex and quantity of litter added were also not influenced by the levels of P. Recycling and removal of other major and micronutrients were also comparable in all the treatments. Annual recycling of P through litter was marginally greater than removal through latex whereas, recycling of other nutrients was substantially higher than their export through latex. The data indicate the self-sustainability of P cycle in a mature rubber plantation adequately supplied with phosphorus during the actively growing phase

An efficacy and safety report based on randomized controlled single-blinded multi-centre clinical trial of ZingiVir-H, a novel herbo-mineral formulation designed as an add-on therapy in adult patients with mild to moderate COVID-19.

ObjectiveCoronaviruses, hence named because of the crown-like spikes on the viral envelope, are members of Coronaviridae family and Order Nidovirales. SARS-CoV-2 is the seventh human pathogenic coronavirus identified after HCoV-229E, HCoV-OC43, SARS-CoV (SARS-CoV-1), HCoV-NL63, CoV-HKU1, and MERS-CoV. SARS-Cov-2 is highly similar to SARS-CoV. COVID-19 is the corresponding acute disease caused by SARS-CoV-2 that was initially reported in Wuhan, China towards the end of 2019 and spread to millions of humans globally. Unfortunately, limited studies were available on the efficacy of antiviral drugs to treat COVID-19 at the time of this study. ZingiVir-H is an Ayurvedic formulation for use in early therapy of viral disease. This clinical trial was planned to investigate (1) the efficacy and safety of ZingiVir-H and (2) the efficacy of ZingiVir-H as an add-on therapy to the standard of care in hospitalized adults diagnosed with COVID-19.MethodsA total of 123 eligible subjects as per inclusion criteria were randomized within the study. Three subjects later declined to participate in the study and four subjects didn't meet inclusion criteria, which brought the final evaluable subject count to 116 for the efficacy and safety endpoint analysis. Thus, a total of 116 patients were equally randomised into two groups, namely, ZingiVir-H and Placebo for this clinical trial. The study patients were assigned to receive either ZingiVir-H or Placebo along with the standard of care as per the National Indian COVID-19 treatment protocol. The time interval until a negative RT-PCR obtained, was evaluated during treatment with ZingiVir-H or Placebo for ten days. Liver and kidney function tests were regularly assessed to ensure the safety profile of ZingiVir-H.ResultsThe study found that patients who were administered ZingiVir-H had a median recovery time of 5 days (95% confidence interval (CI) 5-5) when compared to 6 days (95% CI 5-6) in those who received Placebo. Besides, in Ordinal Scale analysis of all the patients treated with ZingiVir-H demonstrated significant redistribution to a better clinical status from ordinal scale 5 to 6 and 7 within five to seven days when compared to that of placebo treatment. The time required for clinical improvement and the number of days needed for hospitalization was significantly less in the ZingiVir-H treated group when compared to placebo. The absence of liver and kidney function changes affirmed the safety profile of ZingiVir-H. No serious adverse events were reported in ZingiVir-H treated patients.ConclusionWe found that ZingiVir-H is effective and safe in managing COVID-19 infections and delaying the disease progression from mild to moderate and moderate to severe. To the best of our knowledge, this is the first clinical trial report on the efficacy/safety of a herbo-mineral Ayurvedic drug against COVID-19 as of yet.Trial registrationClinical Trial Registry of India CTRI/2020/04/024883. Registered on 28/04/2020

An efficacy and safety report based on randomized controlled single-blinded multi-centre clinical trial of ZingiVir-H, a novel herbo-mineral formulation designed as an add-on therapy in adult patients with mild to moderate COVID-19

Objective Coronaviruses, hence named because of the crown-like spikes on the viral envelope, are members of Coronaviridae family and Order Nidovirales. SARS-CoV-2 is the seventh human pathogenic coronavirus identified after HCoV-229E, HCoV-OC43, SARS-CoV (SARS-CoV-1), HCoV-NL63, CoV-HKU1, and MERS-CoV. SARS-Cov-2 is highly similar to SARS-CoV. COVID-19 is the corresponding acute disease caused by SARS-CoV-2 that was initially reported in Wuhan, China towards the end of 2019 and spread to millions of humans globally. Unfortunately, limited studies were available on the efficacy of antiviral drugs to treat COVID-19 at the time of this study. ZingiVir-H is an Ayurvedic formulation for use in early therapy of viral disease. This clinical trial was planned to investigate (1) the efficacy and safety of ZingiVir-H and (2) the efficacy of ZingiVir-H as an add-on therapy to the standard of care in hospitalized adults diagnosed with COVID-19. Methods A total of 123 eligible subjects as per inclusion criteria were randomized within the study. Three subjects later declined to participate in the study and four subjects didn’t meet inclusion criteria, which brought the final evaluable subject count to 116 for the efficacy and safety endpoint analysis. Thus, a total of 116 patients were equally randomised into two groups, namely, ZingiVir-H and Placebo for this clinical trial. The study patients were assigned to receive either ZingiVir-H or Placebo along with the standard of care as per the National Indian COVID-19 treatment protocol. The time interval until a negative RT-PCR obtained, was evaluated during treatment with ZingiVir-H or Placebo for ten days. Liver and kidney function tests were regularly assessed to ensure the safety profile of ZingiVir-H. Results The study found that patients who were administered ZingiVir-H had a median recovery time of 5 days (95% confidence interval (CI) 5–5) when compared to 6 days (95% CI 5–6) in those who received Placebo. Besides, in Ordinal Scale analysis of all the patients treated with ZingiVir-H demonstrated significant redistribution to a better clinical status from ordinal scale 5 to 6 and 7 within five to seven days when compared to that of placebo treatment. The time required for clinical improvement and the number of days needed for hospitalization was significantly less in the ZingiVir-H treated group when compared to placebo. The absence of liver and kidney function changes affirmed the safety profile of ZingiVir-H. No serious adverse events were reported in ZingiVir-H treated patients. Conclusion We found that ZingiVir-H is effective and safe in managing COVID-19 infections and delaying the disease progression from mild to moderate and moderate to severe. To the best of our knowledge, this is the first clinical trial report on the efficacy/safety of a herbo-mineral Ayurvedic drug against COVID-19 as of yet. Trial registration Clinical Trial Registry of India CTRI/2020/04/024883. Registered on 28/04/2020