Miracle-dz/UniFAR-FTUs huggingface dataset:
Reply to Chagla et al., and Thomas.

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Effects of female gonadal hormones and LPS on depressive-like behavior in rats

Considerable evidence shows an association of depression with the immune system and emphasizes the importance of gender in the etiology of the disease and the response to inflammatory stimuli. We examined the influence of immune-challenged systems on depressive-like behavior in female rats in the context of gonadal hormones. We used a neuroinflammatory model of depression elicited by lipopolysaccharide (LPS) administration on naive and ovariectomized (OVX) female rats, and examined the effects of estradiol (E2) and/or progesterone (P4) replacement therapy on animal behavior, as assessed by the forced swimming test (FST). We found that LPS and OVX increase immobility in the FST, while LPS also decreased body weight in naive female rats. Further, even though P4 application alone showed beneficial effects on the behavioral profile (it reduced immobility and increased climbing), supplementation of both hormones (E2 and P4) together to OVX rats failed to do so. When OVX rats were exposed to LPS-induced immune challenge, neither hormone individually nor their combination had any effect on immobility, however, their joint supplementation increased climbing behavior. In conclusion, our study confirmed that both LPS and OVX induced depressive-like behavior in female rats. Furthermore, our results potentiate P4 supplementation in relieving the depressive-like symptomatology in OVX rats, most likely through fine-tuning of different neurotransmitter systems. In the context of an activated immune system, the application of E2 and/or P4 does not provide any advantageous effects on depressive-like behavior.
Prescription of oral anticoagulants and antiplatelets for stroke prophylaxis in atrial fibrillation: nationwide time series ecological analysis.

AIMS To investigate trends in the prescription of oral anticoagulants (OACs) and antiplatelet agents for atrial fibrillation (AF). METHODS AND RESULTS Prescription data for 450 518 patients with AF from 3352 General Practices in England, was obtained from the GRASP-AF registry, 2009-2018. Annualized temporal trends for OAC and antiplatelet prescription were reported according to eligibility based on stroke risk (CHADS2 or CHA2DS2-VASc scores ≥1 or >2, respectively). From 2009 to 2018, the prevalence of AF increased from 1.6% [95% confidence interval (CI) 1.5-1.7%] to 2.4% (2.3-2.5%), and for those with AF the proportion prescribed OAC increased from 47.6% to 75.0% (P-trend < 0.001; relative risk 1.57, 95% CI 1.55-1.60) and for antiplatelet decreased from 37.4% to 9.2% (P-trend < 0.001). In early-years (2009-2013), eligible patients aged ≥80 years were less likely to be prescribed OAC than patients aged <80 years [odds ratio (OR) 0.55, 95% CI 0.51-0.59 for CHADS2≥1 in 2009] (all P-trends < 0.001). This 'OAC prescription gap' reduced over the study period (OR 0.93, 0.90-0.96 in 2018). Whilst the prescription of direct oral anticoagulant (DOAC) as a proportion of all OAC increased from 0.1% (95% CI 0.0-0.2%) in 2011 to 58.8% (58.4-59.2%) in 2018, it was inversely associated with patient age (P-trend < 0.001) and their risk of stroke. CONCLUSION Between 2009 and 2018, in England, the use of OAC for stroke prophylaxis in AF increased, with DOAC accounting for over half of OAC uptake in 2018. Despite a reduction in the OAC-prescription gap, a new paradox exists relating to DOAC prescription for the elderly and those at higher risk of stroke.
Efficacy of Single-Dose Primaquine With Artemisinin Combination Therapy on Plasmodium falciparum Gametocytes and Transmission: An Individual Patient Meta-Analysis

Abstract Background Since the World Health Organization recommended single low-dose (0.25 mg/kg) primaquine (PQ) in combination with artemisinin-based combination therapies (ACTs) in areas of low transmission or artemisinin-resistant Plasmodium falciparum, several single-site studies have been conducted to assess efficacy. Methods An individual patient meta-analysis to assess gametocytocidal and transmission-blocking efficacy of PQ in combination with different ACTs was conducted. Random effects logistic regression was used to quantify PQ effect on (1) gametocyte carriage in the first 2 weeks post treatment; and (2) the probability of infecting at least 1 mosquito or of a mosquito becoming infected. Results In 2574 participants from 14 studies, PQ reduced PCR-determined gametocyte carriage on days 7 and 14, most apparently in patients presenting with gametocytemia on day 0 (odds ratio [OR], 0.22; 95% confidence interval [CI], .17–.28 and OR, 0.12; 95% CI, .08–.16, respectively). Rate of decline in gametocyte carriage was faster when PQ was combined with artemether-lumefantrine (AL) compared to dihydroartemisinin-piperaquine (DP) (P = .010 for day 7). Addition of 0.25 mg/kg PQ was associated with near complete prevention of transmission to mosquitoes. Conclusions Transmission blocking is achieved with 0.25 mg/kg PQ. Gametocyte persistence and infectivity are lower when PQ is combined with AL compared to DP.
Evaluation of a decision support system for precision feeding of gestating sows

Abstract Precision feeding (PF) with the daily mixing of 2 diets with different lysine content (high (H) or low (L)) was previously reported for growing pigs to reduce protein intake and N excretion compared with a conventional feeding (CF) based on a single diet (C). Using a simulation approach based on farm data, the objective of the present paper was to describe and evaluate a decision support system for the PF of gestating sows allowing the daily distribution of a tailored ration to each sow. Two datasets, 1 of 2,511 gestations (farm A) and 1 of 2,528 gestations (farm B), reporting sows’ characteristics at insemination and objectives at farrowing were used as inputs for a Python model. This model, mainly based on InraPorc, calculates the nutrient requirements of each sow over gestation and simulates the impact of PF in comparison to CF. Simulated diets L, H, and C contained 3.0, 6.5, and 4.8 g/kg of standardized ileal digestible lysine (SID Lys) and 2.0, 3.3, and 2.5 g/kg of standardized total tract digestible phosphorus (STTD-P), respectively. The influence of farm, parity, gestation week, and their interactions, on calculated SID Lys and STTD-P requirements was analyzed applying a mixed model. The calculated SID Lys and STTD-P requirements increased markedly in the last third of gestation (P < 0.01) and were higher for primiparous than for multiparous sows, unless after week 14 for STTD-P requirement. The calculated SID AA and mineral requirements were lower for farm B than farm A (respectively, 2.94 vs. 3.08 g/kg for SID Lys and 1.30 vs. 1.35 g/kg for STTD-P, P < 0.01). On average, feed L represented 86% and 92% of the feed projected to be delivered by the PF strategy in farms A and B, respectively. Compared to CF, average calculated dietary SID Lys content was lowered by 27% and 32% with PF, for farms A and B, respectively, while average calculated dietary phosphorus content was lowered by 13% and 16%. The simulated proportions of sows in excess and deficient in SID Lys were reduced with PF. Compared to CF, the PF strategy allowed for a 3.6% reduction in simulated feed cost per sow during gestation, and reduced nitrogen and phosphorus intake (by 11.0% and 13.8%, respectively) and excretion (by 16.7% and 15.4%, respectively). To conclude, these simulations indicate that PF of gestating sow appears to be relevant to meet the amino acid requirement while reducing feed cost, and supplies and excretion of nitrogen and phosphorus.
Inflammasome activation by Pseudomonas aeruginosa's ExlA pore‐forming toxin is detrimental for the host

During acute Pseudomonas aeruginosa infection, the inflammatory response is essential for bacterial clearance. Neutrophil recruitment can be initiated following the assembly of an inflammasome within sentinel macrophages, leading to activation of caspase‐1, which in turn triggers macrophage pyroptosis and IL‐1β/IL‐18 maturation. Inflammasome formation can be induced by a number of bacterial determinants, including Type III secretion systems (T3SSs) or pore‐forming toxins, or, alternatively, by lipopolysaccharide (LPS) via caspase‐11 activation. Surprisingly, previous studies indicated that a T3SS‐induced inflammasome increased pathogenicity in mouse models of P. aeruginosa infection. Here, we investigated the immune reaction of mice infected with a T3SS‐negative P. aeruginosa strain (IHMA879472). Virulence of this strain relies on ExlA, a secreted pore‐forming toxin. IHMA879472 promoted massive neutrophil infiltration in infected lungs, owing to efficient priming of toll‐like receptors, and thus enhanced the expression of inflammatory proteins including pro‐IL‐1β and TNF‐α. However, mature‐IL‐1β and IL‐18 were undetectable in wild‐type mice, suggesting that ExlA failed to effectively activate caspase‐1. Nevertheless, caspase‐1/11 deficiency improved survival following infection with IHMA879472, as previously described for T3SS+ bacteria. We conclude that the detrimental effect associated with the ExlA‐induced inflammasome is probably not due to hyperinflammation, rather it stems from another inflammasome‐dependent process.
Clinical factors associated with trunk control after stroke: A prospective study

ABSTRACT Introduction Poor trunk control after stroke can impact recovery of global functional abilities. Therefore, the aim of this study was to evaluate whether clinical and functional data from stroke participants can be used to predict trunk control at 90 days. Methods This is a prospective study of 37 participants with stroke. The variables evaluated at hospital discharge were stroke severity (National Institute of Health Stroke Scale - NIHSS); functional capacity (modified Rankin scale - mRS); handgrip; and cognitive function. At 90 days, the variables evaluated were autonomy (Functional Independence Measure – FIM, Barthel Index); gait mobility (Tinetti mobility test -TMT); quality of life (European Quality of Life Scale - EuroQol-5D) and trunk control (trunk impairment scale - TIS). The participants were considered to have satisfactory (TIS³14) or non-satisfactory trunk control (TIS≤13), and the differences between them were assessed by chi-square test (categorical variables) and Mann-Whitney/unpaired t-test (continuous variables). A ROC curve was used to show cut-off value of clinical variables to predict trunk control. Results The unsatisfactory trunk control group presented ahigher NIHSS at discharge (p=0.01), higher mRS at discharge (p=0.00), lower Barthel Index at 90 days (p=0.03), lower FIM at 90 days (p=0.01) and lower TMT at 90 days (p=0.00) than the satisfactory trunk control group. The best cut-off points for the NIHSS and mRS scores at discharge for predicting unsatisfactory trunk control are ≥6 and ≥3, respectively. Conclusion Greater NIHSS and mRS scores at hospital discharge increase the chance of unsatisfactory trunk control at 90 days after stroke.
Grain and dietary fiber intake and bladder cancer risk: a pooled analysis of prospective cohort studies

ABSTRACT Background Higher intakes of whole grains and dietary fiber have been associated with lower risk of insulin resistance, hyperinsulinemia, and inflammation, which are known predisposing factors for cancer. Objectives Because the evidence of association with bladder cancer (BC) is limited, we aimed to assess associations with BC risk for intakes of whole grains, refined grains, and dietary fiber. Methods We pooled individual data from 574,726 participants in 13 cohort studies, 3214 of whom developed incident BC. HRs, with corresponding 95% CIs, were estimated using Cox regression models stratified on cohort. Dose–response relations were examined using fractional polynomial regression models. Results We found that higher intake of total whole grain was associated with lower risk of BC (comparing highest with lowest intake tertile: HR: 0.87; 95% CI: 0.77, 0.98; HR per 1-SD increment: 0.95; 95% CI: 0.91, 0.99; P for trend: 0.023). No association was observed for intake of total refined grain. Intake of total dietary fiber was also inversely associated with BC risk (comparing highest with lowest intake tertile: HR: 0.86; 95% CI: 0.76, 0.98; HR per 1-SD increment: 0.91; 95% CI: 0.82, 0.98; P for trend: 0.021). In addition, dose–response analyses gave estimated HRs of 0.97 (95% CI: 0.95, 0.99) for intake of total whole grain and 0.96 (95% CI: 0.94, 0.98) for intake of total dietary fiber per 5-g daily increment. When considered jointly, highest intake of whole grains with the highest intake of dietary fiber showed 28% reduced risk (95% CI: 0.54, 0.93; P for trend: 0.031) of BC compared with the lowest intakes, suggesting potential synergism. Conclusions Higher intakes of total whole grain and total dietary fiber are associated with reduced risk of BC individually and jointly. Further studies are needed to clarify the underlying mechanisms for these findings.
Molecular Characterization of Zinc- and Iron- Containing Alcohol Dehydrogenases from Anaerobic Hyperthermophiles

Hyperthermophiles grow optimally at 80 C and above, and many of them have the ability to utilize various carbohydrates as carbon source and produce ethanol as an end product. Alcohol dehydrogenase (ADH) is a key enzyme responsible for alcohol production, catalyzing interconversions between alcohols and corresponding ketones or aldehydes. ADHs from hyperthermophiles are of great interests due to their thermostability, high activity and enantioselectivity. The gene encoding ADH from hyperthermophilic archaeon Thermococcus guaymasensis was cloned, sequenced and over-expressed. DNA fragments of the genes encoding the ADHs were amplified directly from the corresponding genomic DNA by combining the use of conventional and inverse PCRs. The entire gene was detected to be 1092 bp and the deduced amino acid sequence had a total of 364 amino acids with a calculated molecular mass of 39463 Dalton. The enzyme belonged to the family of zinc-containing ADHs with catalytic zinc only. It was verified that the enzyme had binding motifs of catalytic zinc only (GHEX2GX5GX2V, residues 62-76) and coenzyme NADP (GXGX2G, residues 183-188). The tertiary structural modeling showed two typical domains, one catalytic domain close to aminoterminal (N-terminal) end and one coenzyme-binding domain close to carboxy-terminal (C-terminal) end. Since its codon usage pattern seemed to be different from that of Escherichia coli, the enzyme was over-expressed in the E. coli codon plus strain using pET-30a vector. The recombinant enzyme was detected to be soluble and active (1073 U/mg), which was virtually the same to the native enzyme (1049 U/mg). The recombinant ADH possessed almost identical properties with the native enzyme. The optimal pHs for ethanol oxidation and acetaldehyde reduction were 10.5 and 7.5 respectively, while the activity for alcohol oxidation was much higher than that of aldehyde reduction. The enzyme activity was inhibited in the presence of 100 μM Zn in the assay mixture and it has a half-life of 6 hours after exposure to air. Thermotoga hypogea is an extremely thermophilic anaerobic bacterium capable of growing at 90 C. The gene encoding an alcohol dehydrogenase from T. hypogea was cloned, sequenced and over-expressed. The gene sequence (1164 bp) was obtained
The Impact of Sheltering in Place During the COVID-19 Pandemic on Older Adults’ Social and Mental Well-Being

Abstract Objectives We examined whether social isolation due to the COVID-19 shelter-in-place orders was associated with greater loneliness and depression for older adults, and, if so, whether declines in social engagement or relationship strength moderated that relationship. Methods Between April 21 and May 21, 2020, 93 older adults in the United States who had completed measures characterizing their personal social networks, subjective loneliness, and depression 6–9 months prior to the pandemic completed the same measures via phone interview, as well as questions about the impact of the pandemic on their social relationships. Results Older adults reported higher depression and greater loneliness following the onset of the pandemic. Loneliness positively predicted depression. Perceived relationship strength, but not social engagement, moderated this relationship such that loneliness only predicted depression for individuals who became closer to their networks during the pandemic. For those who felt less close, depression was higher irrespective of loneliness. Discussion The COVID-19 pandemic negatively affected older adults’ mental health and social well-being in the short term. Potential long-term impacts are considered.
Witnessing Intimate Partner Violence Across Contexts: Mental Health, Delinquency, and Dating Violence Outcomes Among Mexican Heritage Youth

Immigrant Mexican American (MA) youth are at greater risk for violence exposure due to risk factors associated with migration–postmigration processes and as they settle into urban U.S. communities marked by crime and poverty. Less is known about the contexts of this exposure. Specifically, what are the ecological contexts in which youth witness intimate partner violence (IPV), how do these experiences differ by immigration generational status, and what is the impact on youth’s externalizing and internalizing behaviors? MA adolescents (N = 279; 15–17 years, M = 16.17, SD = 0.81) from the Southwest United States participated in an online survey. Over half of adolescents had witnessed at least one incidence of IPV in the prior 2 weeks, usually involving their peers. Adolescents who had spent more time in the United States were more likely to witness violence and rated it as more severe than more recently immigrated youth. A cross-sectional path model revealed that witnessing IPV was associated with internalizing and externalizing problems. However, the associations between witnessing IPV and dating violence perpetration and victimization were mediated through acceptance of dating violence norms. Each successive generation may be more likely to witness violence across a range of ecological contexts. Witnessing violence may be central to a host of negative outcomes, including deviancy, poor mental health, and dating violence. However, preventive interventions can help youth to challenge violence norms within intimate partnerships as well as to cope with violence in their homes, peer groups, and communities.
The potential for overdiagnosis and underdiagnosis because of blood pressure variability: a comparison of the 2017 ACC/AHA, 2018 ESC/ESH and 2019 NICE hypertension guidelines

Supplemental Digital Content is available in the text Objective: To estimate the extent that BP measurement variability may drive over- and underdiagnosis of ‘hypertension’ when measurements are made according to current guidelines. Methods: Using data from the National Health and Nutrition Examination Survey and empirical estimates of within-person variability, we simulated annual SBP measurement sets for 1 000 000 patients over 5 years. For each measurement set, we used an average of multiple readings, as recommended by guidelines. Results: The mean true SBP for the simulated population was 118.8 mmHg with a standard deviation of 17.5 mmHg. The proportion overdiagnosed with ‘hypertension’ after five sets of office or nonoffice measurements using the 2017 American College of Cardiology guideline was 3–5% for people with a true SBP less than 120 mmHg, and 65–72% for people with a true SBP 120–130 mmHg. These proportions were less than 1% and 14–33% using the 2018 European Society of Hypertension and 2019 National Institute for Health and Care Excellence guidelines (true SBP <120 and 120–130 mmHg, respectively). The proportion underdiagnosed with ‘hypertension’ was less than 3% for people with true SBP at least 140 mmHg after one set of office or nonoffice measurements using the 2017 American College of Cardiology guideline, and less than 18% using the other two guidelines. Conclusion: More people are at risk of overdiagnosis under the 2017 American College of Cardiology guideline than the other two guidelines, even if nonoffice measurements are used. Making clinical decisions about cardiovascular prediction based primarily on absolute risk, minimizes the impact of blood pressure variability on overdiagnosis.
Hereditary alpha tryptasemia is a valid genetic biomarker for severe mediator-related symptoms in mastocytosis.

Mastocytosis is a hematopoietic neoplasm characterized by expansion of KIT D816V-mutated clonal mast cells in various organs and severe or even life-threatening anaphylactic reactions. Recently, hereditary α-tryptasemia (HαT) has been described as a common genetic trait with increased copy numbers of the α-tryptase encoding gene, TPSAB1, and associated with an increased basal serum tryptase level and a risk of mast cell activation. The purpose of our study was to elucidate the clinical relevance of HαT in patients with mastocytosis. TPSAB1 germline copy number variants were assessed by digital PCR in 180 mastocytosis patients, 180 sex-matched control subjects, 720 patients with other myeloid neoplasms, and 61 additional mastocytosis patients of an independent validation cohort. α-tryptase encoding TPSAB1 copy number gains, compatible with HαT, were identified in 17.2% of mastocytosis patients and 4.4% of the control population (p<0.001). Patients with HαT exhibited higher tryptase levels than patients without HαT (median tryptase in HαT+ cases: 49.6 ng/mL vs. HαT- cases: 34.5 ng/mL, p=0.004) independent of the mast cell burden. Hymenoptera venom hypersensitivity reactions and severe cardiovascular mediator-related symptoms/anaphylaxis were by far more frequently observed in mastocytosis patients with HαT than in those without HαT. Results were confirmed in an independent validation cohort. The high prevalence of HαT in mastocytosis hints at a potential pathogenic role of germline α-tryptase encoding TPSAB1 copy number gains in disease evolution. Together, our data suggest that HαT is a novel emerging robust biomarker in mastocytosis that is useful for determining the individual patient´s risk of developing severe anaphylaxis.
A Review of Remdesivir for COVID-19: Data to Date

Severe acute respiratory coronavirus-2 (SARS-CoV-2) is responsible for one of the greatest public health challenges of our lifetime, the coronavirus disease 2019 (COVID-19) pandemic. Because of the complicated postinfection sequelae and grave consequences, the search for effective therapies has become a worldwide priority. The antiviral agent remdesivir has become a viable option and is now available in the United States for hospitalized patients through an emergency use authorization. This article describes remdesivir’s historical background, pharmacology, key trials, adverse events, and issues regarding accessibility.