AI is a viable alternative to high throughput screening: a 318-target study

: High throughput screening (HTS) is routinely used to identify bioactive small molecules. This requires physical compounds, which limits coverage of accessible chemical space. Computational approaches combined with vast on-demand chemical libraries can access far greater chemical space, provided that the predictive accuracy is sufficient to identify useful molecules. Through the largest and most diverse virtual HTS campaign reported to date, comprising 318 individual projects, we demonstrate that our AtomNet® convolutional neural network successfully finds novel hits across every major therapeutic area and protein class. We address historical limitations of computational screening by demonstrating success for target proteins without known binders, high-quality X-ray crystal structures, or manual cherry-picking of compounds. We show that the molecules selected by the AtomNet® model are novel drug-like scaffolds rather than minor modifications to known bioactive compounds. Our empirical results suggest that computational methods can substantially replace HTS as the first step of small-molecule drug discovery

Global, regional, and national burden of disorders affecting the nervous system, 1990–2021: a systematic analysis for the Global Burden of Disease Study 2021

BackgroundDisorders affecting the nervous system are diverse and include neurodevelopmental disorders, late-life neurodegeneration, and newly emergent conditions, such as cognitive impairment following COVID-19. Previous publications from the Global Burden of Disease, Injuries, and Risk Factor Study estimated the burden of 15 neurological conditions in 2015 and 2016, but these analyses did not include neurodevelopmental disorders, as defined by the International Classification of Diseases (ICD)-11, or a subset of cases of congenital, neonatal, and infectious conditions that cause neurological damage. Here, we estimate nervous system health loss caused by 37 unique conditions and their associated risk factors globally, regionally, and nationally from 1990 to 2021.MethodsWe estimated mortality, prevalence, years lived with disability (YLDs), years of life lost (YLLs), and disability-adjusted life-years (DALYs), with corresponding 95% uncertainty intervals (UIs), by age and sex in 204 countries and territories, from 1990 to 2021. We included morbidity and deaths due to neurological conditions, for which health loss is directly due to damage to the CNS or peripheral nervous system. We also isolated neurological health loss from conditions for which nervous system morbidity is a consequence, but not the primary feature, including a subset of congenital conditions (ie, chromosomal anomalies and congenital birth defects), neonatal conditions (ie, jaundice, preterm birth, and sepsis), infectious diseases (ie, COVID-19, cystic echinococcosis, malaria, syphilis, and Zika virus disease), and diabetic neuropathy. By conducting a sequela-level analysis of the health outcomes for these conditions, only cases where nervous system damage occurred were included, and YLDs were recalculated to isolate the non-fatal burden directly attributable to nervous system health loss. A comorbidity correction was used to calculate total prevalence of all conditions that affect the nervous system combined.FindingsGlobally, the 37 conditions affecting the nervous system were collectively ranked as the leading group cause of DALYs in 2021 (443 million, 95% UI 378–521), affecting 3·40 billion (3·20–3·62) individuals (43·1%, 40·5–45·9 of the global population); global DALY counts attributed to these conditions increased by 18·2% (8·7–26·7) between 1990 and 2021. Age-standardised rates of deaths per 100 000 people attributed to these conditions decreased from 1990 to 2021 by 33·6% (27·6–38·8), and age-standardised rates of DALYs attributed to these conditions decreased by 27·0% (21·5–32·4). Age-standardised prevalence was almost stable, with a change of 1·5% (0·7–2·4). The ten conditions with the highest age-standardised DALYs in 2021 were stroke, neonatal encephalopathy, migraine, Alzheimer's disease and other dementias, diabetic neuropathy, meningitis, epilepsy, neurological complications due to preterm birth, autism spectrum disorder, and nervous system cancer.InterpretationAs the leading cause of overall disease burden in the world, with increasing global DALY counts, effective prevention, treatment, and rehabilitation strategies for disorders affecting the nervous system are needed

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

Produção de metabólitos primários e secundários em capim-braquiária em adubação nitrogenado

Plants produce a number of substances and products and primary and secondary metabolites (SM) are amongst them with many benefits but limitation as well. Usually, the fodder are not considered toxic to animals or as a source having higher SM. The Brachiaria decumbens has a considerable nutritional value, but it is considered as a toxic grass for causing photosensitization in animals, if the grass is not harvested for more than 30 days or solely. The absence of detailed information in the literature about SM in Brachiaria, metabolites production and its chemical profile enable us to focus not only on the nutritive value but to get answers in all aspects and especially on toxicity. The study was conducted in the period of december 2013 to december 2014; in greenhouse FZEA-USP. B. decumbens was used with two cutting heights (10 and 20 cm) and nitrogen doses (0, 150, 300 and 450 kg ha-1) in complete randomized block design. The bromatological analysis were carried out on near infrared spectroscopy. Generally, the application of 150 kg ha-1 N was sufficient to promote the nutritional value in B. decumbens but above it the nitrogen use efficiency decline significantly. The highest dry matter yield (99.97 g/pot) was observed in autumn and the lowest was in winter (30.20 g/pot). While, as per nitrogen dose the average highest dry matter yield was at 150 kg ha-1 (79.98 g/pot). The highest crude protein was observed in winter (11.88%) and the lowest in autumn (7.78%). By the cutting heights; the 10 cm proved to have high CP (9.51%). In respect of fibrous contents, the highest acid detergent fiber was noted in summer (36.37%) and lowest in winter (30.88%). While the neutral detergent fiber was being highest in autumn and lowest in spring (79.60%). The highest in vitro dry matter and organic matter digestibilities were noted at 300 kg ha-1 N; being 68.06 and 60.57%; respectively; with the lowest observed in without N treatments (62.63% and 57.97), respectively. For determination of the classes, types and concentration of SM in B. decumbens, phytochemical tests, thin layer and liquid chromatography-mass spectrometry and nuclear magnetic resonance analysis were carried out. Height, nitrogen and seasons significantly (P <0.0001) affected the secondary metabolic profile. A new protodioscin isomer (protoneodioscin (25S-)) was identified for first time in B. decumbens and is supposed to be the probable toxicity reason. Its structure was verified by 1D and 2D NMR techniques (1H, 13C) and 1D (COSY-45, edited HSQC, HMBC, H2BC, HSQC -TOCSY, NOESY and 1 H, 1 H, J). All factors influence the metabolic profile significantly (P <0.0001). The lowest phenols were at 300 kg ha-1 while the lowest flavones were at 0 kg ha-1. Season wise the highest phenols occurred in autumn (19.65 mg/g d.wt.) and highest flavones (28.87 mg/g d.wt.) in spring. Seasons effect the saponin production significantly (P <0.0001) and the results showed significant differences in the protodioscin (17.63±4.3 - 22.57±2.2 mg/g d.wt.) and protoneodioscin (23.3±1.2 - 31.07±2.9 mg/g d.wt.) concentrations. The highest protodioscin isomers concentrations were observed in winter and spring and by N doses the highest were noted in 300 kg ha-1. Simply, all factors significantly played their role in varying concentrations of secondary metabolites.As plantas produzem diversas substâncias e produtos e os metabólitos primários e secundários (MS) estão entre eles, apresentando tanto efeitos benéficos como limitação de utilização. Geralmente, a forrageiras não são consideradas tóxicas aos animais ou como fonte de MS. As espécies de braquiárias são caracterizadas pelo alto valor nutricional, entretando a Brachiaria decumbens é a espécie mais tóxica para causar a fotossensibilização. A ausência de informações detalhadas na literatura a respeito de MS, sua produção e perfil químico nos faz focar não somente no aumento da produção de matéria fresca e no valor nutritivo da planta mas, em obter respostas em todos os aspectos e na redução de sua toxicidade. O estudo foi conduzido no período de dezembro 2013 ate dezembro 2014, em casa de vegetação localizada na FZEA-USP. Utilizou-se duas alturas de corte (10 e 20 cm) e quatro doses de nitrogênio (0, 150, 300 e 450 kgoha-1) em delineamento de blocos casualizados (4x2). Altura, doses de N e estação afetaram significativamente o perfil de MS. Houve aumento na produção de saponina nas estações da primavera e outono devido ao estresse. A análise bromatológica foi feita por espectroscopia de infravermelho próximo. Geralmente, a aplicação de 150 kgoha-1 de N foi suficiente para promover o valor nutricional na B. decumbens, entretanto acima desse valor a eficiência de uso de Nitrogênio decai significativamente. A maior produção de matéria seca (MS) (99,97 g/vaso) foi observada no outono e a menor foi no inverno (30,20 g/vaso). Embora, de acordo com a dose de nitrogênio, o maior rendimento médio de matéria seca foi de 150 kgoha-1 (79,98 g/vaso). Observou-se que o maior teor de proteína bruta (CP) foi no inverno (11,88%) e o menor foi no outono (7,78%). Pelas alturas de corte, os 10 cm provaram ter alta CP (9,51%). A respeito do conteúdo fibroso, o maior teor de fibra detergente ácida foi observado no verão (36,37%) e o teor mais baixo no inverno (30,88%). Por outro lado, o teor da fibra em detergente neutro foi maior no outono e o menor teor na primavera (79,60%). As maiores digestibilidades in vitro da matéria seca e matéria orgânica foram observadas em 300 kgoha-1 de N, sendo 68,06% e 60,57% com o menor valor observado em tratamentos sem N (62,63% e 57,97%), respectivamente. Para determinação das classes, tipos e concentração de MS em B. decumbens, foram realizados testes por fitoquímico, cromatografia de camada fina, cromatografia líquida acoplada à espectrometria de massa e ressonância magnética nuclear. Foi identificado um novo isômero de protodioscina (protoneodioscina (25S-) pra primeria vez na B. decumbens que é supostamente a provável razão da toxicidade. Sua estrutura foi verificada pelo 1D e 2D (1H combinação de 1D (1H, 13C) e a técnica 1D RMN (COSY-45, editado HSQC, HMBC, H2BC, HSQC-TOCSY, NOESY e 1H, 1H, J) como O-α-L -rhamnopyranosyl- (1 4) -O-β-D- glucopiranosil- (1 6) -O-β-D-6-O-acetylglucopyranosyl-] (1 2) - p-D-glucopiranosil-28 medicagen. Todos os fatores influenciaram o perfil metabólico significativamente (P <0,0001). Para flavonas, a menor produção foi observada em outono (19,65 mg/g peso seco (p.s)) e a maior na primavera (28.87 mg/g p.s). As concentrações de saponina foram afetadas significativamente (P<0,0001) pelas estações e os resultados mostraram diferenças na protodioscina (17,63±4,3 - 22,57±2,2 p.s) e protoneodioscina (23,3±1,2 - 31,07±2,9 p.s). Os maiores teores da concentração dos isômeros de protodioscina foram observados no inverno e na primavera e em relação ao N aplicado, o maior teor foi de 300 kgoha-1. Simplesmente, todos os fatores influenciaram significativamente a variação das concentrações dos metabólitos secundários

Good housing: camels and their interaction with the environment

Camel farming is undergoing a profound transformation. To date, camels can be reared in many different ways, ranging from traditional nomadic breeding to more technological housing systems, with milking parlours and intensive farming systems similar to those used in dairy cows. The different types of housing systems used for camel farming will be described in this chapter. Improper housing systems and facilities can cause severe welfare issues in camels. The chapter emphasizes how a poor environment may affect camel welfare and provides suggestions for designing facilities in compliance with the welfare principle named “good housing”. In particular, good housing is ensured when camels are reared in an environment and building meeting the welfare criteria of “comfort around resting”, “ease of movement”, and “thermal comfort”. Providing camels with adequate space allowance, clean beddings, shelters and shaded areas, and building facilities following the camels’ behavioural needs for movement and sociability are key points for ensuring farming systems respecting the principle of good housing. Overcrowding, lack of movement, and insufficient social interactions are among the main welfare issues associated with improper housing systems. In addition, concerning the “thermal comfort” criterium, more studies are needed to provide more precise guidance on the temperature and humidity ranges to keep camels within their thermal comfort zone

Bacteriological and Physicochemical Analysis of Groundwater of Kasur

Earth is a blue planet because of the rudimentary cause of life, that is water. All the biochemical reactions which are pre-requisite for nourishing life of animals and plants, use water as a basic element. Being a universal solvent, it dissolves almost all minerals present in the soil. It is one of the basic and necessary compounds responsible for the survival of life. The main purpose of research was to determine the quality of groundwater in Kasur near the tanneries. The study is focused on the bacteriological and physicochemical (pH, Temperature, DO, BOD, CO2, TOSM, TDS, TM and heavy metals) parameters. We selected four sites as Din Garh, Qatal Garhi, Mangal Mandi and Kot Haleem Khan for investigation. Coliforms were present in high concentration that produce viruses and bacterial diseases such as typhoid fever, hepatitis, gastrocnemii, dysentery and ear infections. World Health Organization (WHO) has justified that the drinkable water must have zero level of coliform and E.coli. Regarding the Total Suspended Matter (TSM), the values ranged from 0.3-0.5g/l in DIN GHARH, 0.2-0.5g/l in QATAL GHARHI, 0.2-0.5g/l in MANGAL MANDI and 0.2-0.6g/l in KOT HALEEM KHAN. The study concludes that the water pollution due to tanneries in Kasur have changed the bacteriological and physicochemical properties of ground water to a considerable level which is not drinkable. It also conclude that groundwater was contaminated with high concentrations of BOD, TOSM, TDS, TM and Heavy metals due to discharge of industrial effluents.  Full Tex

Modifier Genes in Microcephaly: A Report on WDR62, CEP63, RAD50 and PCNT Variants Exacerbating Disease Caused by Biallelic Mutations of ASPM and CENPJ

Congenital microcephaly is the clinical presentation of significantly reduced head circumference at birth. It manifests as both non-syndromic-microcephaly primary hereditary (MCPH)-and syndromic forms and shows considerable inter- and intrafamilial variability. It has been hypothesized that additional genetic variants may be responsible for this variability, but data are sparse. We have conducted deep phenotyping and genotyping of five Pakistani multiplex families with either MCPH (n = 3) or Seckel syndrome (n = 2). In addition to homozygous causal variants in ASPM or CENPJ, we discovered additional heterozygous modifier variants in WDR62, CEP63, RAD50 and PCNT-genes already known to be associated with neurological disorders. MCPH patients carrying an additional heterozygous modifier variant showed more severe phenotypic features. Likewise, the phenotype of Seckel syndrome caused by a novel CENPJ variant was aggravated to microcephalic osteodysplastic primordial dwarfism type II (MOPDII) in conjunction with an additional PCNT variant. We show that the CENPJ missense variant impairs splicing and decreases protein expression. We also observed centrosome amplification errors in patient cells, which were twofold higher in MOPDII as compared to Seckel cells. Taken together, these observations advocate for consideration of additional variants in related genes for their role in modifying the expressivity of the phenotype and need to be considered in genetic counseling and risk assessment

Impact of the COVID-19 pandemic on paediatric patients with cancer in low-income, middle-income and high-income countries: protocol for a multicentre, international, observational cohort study

Introduction Childhood cancers are a leading cause of non-communicable disease deaths for children around the world. The COVID-19 pandemic may have impacted on global children’s cancer services, which can have consequences for childhood cancer outcomes. The Global Health Research Group on Children’s Non-Communicable Diseases is currently undertaking the first international cohort study to determine the variation in paediatric cancer management during the COVID-19 pandemic, and the short-term to medium-term impacts on childhood cancer outcomes.Methods and analysis This is a multicentre, international cohort study that will use routinely collected hospital data in a deidentified and anonymised form. Patients will be recruited consecutively into the study, with a 12-month follow-up period. Patients will be included if they are below the age of 18 years and undergoing anticancer treatment for the following cancers: acute lymphoblastic leukaemia, Burkitt lymphoma, Hodgkin lymphoma, Wilms tumour, sarcoma, retinoblastoma, gliomas, medulloblastomas and neuroblastomas. Patients must be newly presented or must be undergoing active anticancer treatment from 12 March 2020 to 12 December 2020. The primary objective of the study was to determine all-cause mortality rates of 30 days, 90 days and 12 months. This study will examine the factors that influenced these outcomes. χ2 analysis will be used to compare mortality between low-income and middle-income countries and high-income countries. Multilevel, multivariable logistic regression analysis will be undertaken to identify patient-level and hospital-level factors affecting outcomes with adjustment for confounding factors.Ethics and dissemination At the host centre, this study was deemed to be exempt from ethical committee approval due to the use of anonymised registry data. At other centres, participating collaborators have gained local approvals in accordance with their institutional ethical regulations. Collaborators will be encouraged to present the results locally, nationally and internationally. The results will be submitted for publication in a peer-reviewed journal

Impact of the COVID-19 pandemic on patients with paediatric cancer in low-income, middle-income and high-income countries: a multicentre, international, observational cohort study

OBJECTIVES: Paediatric cancer is a leading cause of death for children. Children in low-income and middle-income countries (LMICs) were four times more likely to die than children in high-income countries (HICs). This study aimed to test the hypothesis that the COVID-19 pandemic had affected the delivery of healthcare services worldwide, and exacerbated the disparity in paediatric cancer outcomes between LMICs and HICs. DESIGN: A multicentre, international, collaborative cohort study. SETTING: 91 hospitals and cancer centres in 39 countries providing cancer treatment to paediatric patients between March and December 2020. PARTICIPANTS: Patients were included if they were under the age of 18 years, and newly diagnosed with or undergoing active cancer treatment for Acute lymphoblastic leukaemia, non-Hodgkin's lymphoma, Hodgkin lymphoma, Wilms' tumour, sarcoma, retinoblastoma, gliomas, medulloblastomas or neuroblastomas, in keeping with the WHO Global Initiative for Childhood Cancer. MAIN OUTCOME MEASURE: All-cause mortality at 30 days and 90 days. RESULTS: 1660 patients were recruited. 219 children had changes to their treatment due to the pandemic. Patients in LMICs were primarily affected (n=182/219, 83.1%). Relative to patients with paediatric cancer in HICs, patients with paediatric cancer in LMICs had 12.1 (95% CI 2.93 to 50.3) and 7.9 (95% CI 3.2 to 19.7) times the odds of death at 30 days and 90 days, respectively, after presentation during the COVID-19 pandemic (p<0.001). After adjusting for confounders, patients with paediatric cancer in LMICs had 15.6 (95% CI 3.7 to 65.8) times the odds of death at 30 days (p<0.001). CONCLUSIONS: The COVID-19 pandemic has affected paediatric oncology service provision. It has disproportionately affected patients in LMICs, highlighting and compounding existing disparities in healthcare systems globally that need addressing urgently. However, many patients with paediatric cancer continued to receive their normal standard of care. This speaks to the adaptability and resilience of healthcare systems and healthcare workers globally

Career intentions of medical students in the UK: a national, cross-sectional study (AIMS study)

Objective To determine current UK medical students’ career intentions after graduation and on completing the Foundation Programme (FP), and to ascertain the motivations behind these intentions.Design Cross-sectional, mixed-methods survey of UK medical students, using a non-random sampling method.Setting All 44 UK medical schools recognised by the General Medical Council.Participants All UK medical students were eligible to participate. The study sample consisted of 10 486 participants, approximately 25.50% of the medical student population.Outcome measures Career intentions of medical students postgraduation and post-FP, motivations behind these career intentions, characterising the medical student population and correlating demographic factors and propensity to leave the National Health Service (NHS).Results The majority of participating students (8806/10 486, 83.98%) planned to complete both years of the FP after graduation, with under half of these students (4294/8806, 48.76%) intending to pursue specialty training thereafter. A subanalysis of career intentions after the FP by year of study revealed a significant decrease in students’ intentions to enter specialty training as they advanced through medical school. Approximately a third of surveyed students (3392/10 486, 32.35%) intended to emigrate to practise medicine, with 42.57% (n=1444) of those students not planning to return. In total, 2.89% of students intended to leave medicine altogether (n=303). Remuneration, work-life balance and working conditions were identified as important factors in decision-making regarding emigration and leaving the profession. Subgroup analyses based on gender, type of schooling, fee type and educational background were performed. Only 17.26% of surveyed students were satisfied or very satisfied with the overall prospect of working in the NHS.Conclusions The Ascertaining the career Intentions of UK Medical Students study highlights UK students’ views and career intentions, revealing a concerning proportion of those surveyed considering alternative careers or emigration. Addressing factors such as remuneration, work-life balance and working conditions may increase retention of doctors and improve workforce planning efforts