Miracle-dz/UniFAR-FTUs huggingface dataset:
Impact of IRS: Four-years of entomological surveillance of the Indian Visceral Leishmaniases elimination programme

Background In 2005, Bangladesh, India and Nepal agreed to eliminate visceral leishmaniasis (VL) as a public health problem. The approach to this was through improved case detection and treatment, and controlling transmission by the sand fly vector Phlebotomus argentipes, with indoor residual spraying (IRS) of insecticide. Initially, India applied DDT with stirrup pumps for IRS, however, this did not reduce transmission. After 2015 onwards, the pyrethroid alpha-cypermethrin was applied with compression pumps, and entomological surveillance was initiated in 2016. Methods Eight sentinel sites were established in the Indian states of Bihar, Jharkhand and West Bengal. IRS coverage was monitored by household survey, quality of insecticide application was measured by HPLC, presence and abundance of the VL vector was monitored by CDC light traps, insecticide resistance was measured with WHO diagnostic assays and case incidence was determined from the VL case register KAMIS. Results Complete treatment of houses with IRS increased across all sites from 57% in 2016 to 70% of houses in 2019, rising to >80% if partial house IRS coverage is included (except West Bengal). The quality of insecticide application has improved compared to previous studies, average doses of insecticide on filters papers ranged from 1.52 times the target dose of 25mg/m2 alpha-cypermethrin in 2019 to 1.67 times in 2018. Resistance to DDT has continued to increase, but the vector was not resistant to carbamates, organophosphates or pyrethroids. The annual and seasonal abundance of P. argentipes declined between 2016 to 2019 with an overall infection rate of 0.03%. This was associated with a decline in VL incidence for the blocks represented by the sentinel sites from 1.16 per 10,000 population in 2016 to 0.51 per 10,000 in 2019. Conclusion Through effective case detection and management reducing the infection reservoirs for P. argentipes in the human population combined with IRS keeping P. argentipes abundance and infectivity low has reduced VL transmission. This combination of effective case management and vector control has now brought India within reach of the VL elimination targets.
Canagliflozin and myocardial oxidative stress: SGLT1 inhibition takes centre stage.

Center for Cardiovascular Research (CCR), Department of Cardiology, Charité – Universitätsmedizin Berlin, Berlin, Germany; DZHK (German Centre for Cardiovascular Research), Partner Site Berlin, Berlin, Germany; Translational Approaches in Heart Failure and Cardiometabolic Disease, Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin, Germany; and Division of Cardiology, Department of Advanced Biomedical Sciences, Federico II University, Naples, Italy
Design and Synthesis of Novel Ibuprofen Derivatives as Selective COX-2 inhibitors and potential anti-inflammatory agents: Evaluation of PGE2, TNF-α, IL-6 and histopathological study.

BACKGROUND The reported binding mode of ibuprofen in the COX-2 binding site indicated that the carboxylic group binds with Arg-120 and Tyr-355 at the entrance of the cyclooxygenase channel and does not extend into the pocket. This accounted for the non-selectivity of ibuprofen. Based on this fact, we assumed that extending the length of the carboxylic acid moiety in ibuprofen and adding more bulky rigid groups as well as bulky groups carrying H-bonding functions might increase the selectivity and reduce the side effects of ibuprofen while maintaining its analgesic and anti-inflammatory activities. OBJECTIVE In this work, four series of ibuprofen derivatives were designed and prepared. The compounds were designed by increasing the length of the carboxylate group along with the incorporation of large hydrophobic groups. METHOD Four series of ibuprofen derivatives were synthesized starting from ibuprofen. Their chemical structure was confirmed by spectral data. All the compounds were tested for their COX inhibitory activity. RESULTS The best COX-2 activity and selectivity were obtained with compounds 5c and 5d, which were subjected to further in vivo testing (carrageenan-induced paw edema, rat serum PGE2, TNF- α and IL-6, hot plate latency test) to investigate their anti-inflammatory and analgesic activities as well as their effects on the gastric mucosa. The anti-inflammatory activity of both compounds was comparable to that of ibuprofen, diclofenac, and indomethacin. Both compounds suppressed the production of PGE2 as well as the rat serum concentrations of both TNF-α and IL-6. This potent anti-inflammatory and analgesic behavior was not accompanied by any effect on the gastric mucosa. Docking simulation studies of the two compounds explained the higher selectivity for the COX-2 enzyme. CONCLUSION Potent and selective ibuprofen derivatives can be successively obtained by extending the length of the carboxylic acid moiety in ibuprofen and adding more bulky rigid groups as well as bulky groups with H-bonding functions.
Automated Assessment of Brain CT After Cardiac Arrest—An Observational Derivation/Validation Cohort Study

Supplemental Digital Content is available in the text. OBJECTIVES: Prognostication of outcome is an essential step in defining therapeutic goals after cardiac arrest. Gray-white-matter ratio obtained from brain CT can predict poor outcome. However, manual placement of regions of interest is a potential source of error and interrater variability. Our objective was to assess the performance of poor outcome prediction by automated quantification of changes in brain CTs after cardiac arrest. DESIGN: Observational, derivation/validation cohort study design. Outcome was determined using the Cerebral Performance Category upon hospital discharge. Poor outcome was defined as death or unresponsive wakefulness syndrome/coma. CTs were automatically decomposed using coregistration with a brain atlas. SETTING: ICUs at a large, academic hospital with circulatory arrest center. PATIENTS: We identified 433 cardiac arrest patients from a large previously established database with brain CTs within 10 days after cardiac arrest. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Five hundred sixteen brain CTs were evaluated (derivation cohort n = 309, validation cohort n = 207). Patients with poor outcome had significantly lower radiodensities in gray matter regions. Automated GWR_si (putamen/posterior limb of internal capsule) was performed with an area under the curve of 0.86 (95%-CI: 0.80-0.93) for CTs taken later than 24 hours after cardiac arrest (similar performance in the validation cohort). Poor outcome (Cerebral Performance Category 4–5) was predicted with a specificity of 100% (95% CI, 87–100%, derivation; 88–100%, validation) at a threshold of less than 1.10 and a sensitivity of 49% (95% CI, 36–58%, derivation) and 38% (95% CI, 27–50%, validation) for CTs later than 24 hours after cardiac arrest. Sensitivity and area under the curve were lower for CTs performed within 24 hours after cardiac arrest. CONCLUSIONS: Automated gray-white-matter ratio from brain CT is a promising tool for prediction of poor neurologic outcome after cardiac arrest with high specificity and low-to-moderate sensitivity. Prediction by gray-white-matter ratio at the basal ganglia level performed best. Sensitivity increased considerably for CTs performed later than 24 hours after cardiac arrest.
The effect of hormone therapy on breast density following risk-reducing salpingo-oophorectomy in women with an increased risk for breast and ovarian cancer

Abstract Objective: To compare the effect of tibolone to conjugated estrogens with medroxyprogesterone-acetate (CEE + MPA) on breast density, as a predictor for breast cancer risk, in women with a high risk of breast and ovarian cancer. Methods: Women aged 30-50 (N = 114) who had undergone risk-reducing salpingo-oophorectomy (RRSO) were randomized to tibolone or CEE + MPA. Results: Breast density decreased 46% after RRSO in untreated women, 39% after treatment with tibolone, and 17% after treatment with CEE + MPA; the decrease in breast density after CEE + MPA was significantly different compared with that of untreated women (P = 0.017). Conclusions: A decline in breast density is seen after premenopausal RRSO despite the use of both CEE + MPA or tibolone, although lower breast density is seen after tibolone use.
A hospital-based multidimensional intervention for high risk pediatric patients with asthma

Abstract Objective To determine the effects of a multi-dimensional intervention (consisting of education, recommendations for medical management, and short-term case management) provided by pulmonology nurse practitioners(NP) on inpatient and post-discharge outcomes for patients admitted with asthma exacerbations to a Pediatric Intensive Care Unit(PICU). Methods A retrospective cohort study was completed on subjects with an asthma exacerbation admitted to the PICU from 1 January 2015 to 31 December 2018. Records were reviewed for 12-months post-discharge. We compared inpatient and post-discharge outcomes for those who did vs. did not receive NP consultation. The primary outcome evaluated was optimization of discharge medications. Rates of follow up, repeat ED visits and hospitalizations were also reviewed. Results Two hundred and twenty two subjects met inclusion and exclusion criteria; of those, 101 (45.5%) patients received NP consultation and 121 (54.5%) had PICU management only. Patients with NP consultation were more likely to have controllers initiated (34.6% vs. 15%) or adjusted (55.5% vs. 33.3%) per asthma guidelines (p < 0.001). The consult group were more likely to have an asthma follow-up appointment made prior to discharge (99% vs. 45%, p < 0.001), and were more likely to attend the appointment (51% vs. 21%, p < 0.001). There were no significant differences between groups for ED visits or readmission for asthma 12-months post-discharge. Conclusions Patients with NP consultation were more likely to have controllers started or adjusted per guidelines and were more likely to attend specialty follow-up appointments post-discharge. No impact was seen on ED visits or readmissions. Implementation of such a program may aid in optimizing asthma management and continuity of care post hospitalization.
Evolution towards Virulence in a Burkholderia Two-Component System

Infections caused by members of the Burkholderia cepacia complex (BCC) are a serious concern for patients with cystic fibrosis (CF) as these bacteria are often resistant to many antibiotics. During long-term infection of CF patients with BCC, mutations in genes encoding the FixLJ system often become prevalent, suggesting that these changes may benefit the bacteria during infection. ABSTRACT Bacteria in the Burkholderia cepacia complex (BCC) are significant pathogens for people with cystic fibrosis (CF) and are often extensively antibiotic resistant. Here, we assess the impacts of clinically observed mutations in fixL, which encodes the sensor histidine kinase FixL. FixL along with FixJ compose a two-component system that regulates multiple phenotypes. Mutations in fixL across two species, B. dolosa and B. multivorans, have shown evidence of positive selection during chronic lung infection in CF. Herein, we find that BCC carrying the conserved, ancestral fixL sequence have lower survival in macrophages and in murine pneumonia models than mutants carrying evolved fixL sequences associated with clinical decline in CF patients. In vitro phosphotransfer experiments found that one evolved FixL protein, W439S, has a reduced ability to autophosphorylate and phosphorylate FixJ, while LacZ reporter experiments demonstrate that B. dolosa carrying evolved fixL alleles has reduced fix pathway activity. Interestingly, B. dolosa carrying evolved fixL alleles was less fit in a soil assay than those strains carrying the ancestral allele, demonstrating that increased survival of these variants in macrophages and the murine lung comes at a potential expense in their environmental reservoir. Thus, modulation of the two-component system encoded by fixLJ by point mutations is one mechanism that allows BCC to adapt to the host infection environment. IMPORTANCE Infections caused by members of the Burkholderia cepacia complex (BCC) are a serious concern for patients with cystic fibrosis (CF) as these bacteria are often resistant to many antibiotics. During long-term infection of CF patients with BCC, mutations in genes encoding the FixLJ system often become prevalent, suggesting that these changes may benefit the bacteria during infection. The system encoded by fixLJ is involved in sensing oxygen and regulating many genes in response and is required for full virulence of the bacteria in a murine pneumonia model. Evolved fixL mutations seen later in infection improve bacterial persistence within macrophages and enhance infection within mice. However, these adaptations are short sighted because they reduce bacterial fitness within their natural habitat, soil.
Ubx-Collier signaling cascade maintains blood progenitors in the posterior lobes of the Drosophila larval lymph gland

Drosophila larval hematopoiesis occurs in a specialized multi-lobed organ called the lymph gland. Extensive characterization of the organ has provided mechanistic insights into events related to developmental hematopoiesis. Spanning from the thoracic to the abdominal segment of the larvae, this organ comprises a pair of primary, secondary, and tertiary lobes. Much of our understanding arises from the studies on the primary lobe, while the secondary and tertiary lobes have remained mostly unexplored. Previous studies have inferred that these lobes are composed of progenitors that differentiate during pupation; however, the mechanistic basis of this extended progenitor state remains unclear. This study shows that posterior lobe progenitors are maintained by a local signaling center defined by Ubx and Collier in the tertiary lobe. This Ubx zone in the tertiary lobe shares several markers with the niche of the primary lobe. Ubx domain regulates the homeostasis of the posterior lobe progenitors in normal development and an immune-challenged scenario. Our study establishes the lymph gland as a model to tease out how the progenitors interface with the dual niches within an organ during development and disorders.
Quantitative evaluation of footwear evidence: Initial workflow for an end‐to‐end system

In the United States, footwear examiners make decisions about the sources of crime scene shoe impressions using subjective criteria. This has raised questions about the accuracy, repeatability, reproducibility, and scientific validity of footwear examinations. Currently, most footwear examiners follow a workflow that compares a questioned and test impression with regard to outsole design, size, wear, and randomly acquired characteristics (RACs). We augment this workflow with computer algorithms and statistical analysis so as to improve in the following areas: (1) quantifying the degree of correspondence between the questioned and test impressions with respect to design, size, wear, and RACs, (2) reducing the potential for cognitive bias, and (3) providing an empirical basis for examiner conclusions by developing a reference database of case‐relevant pairs of impressions containing known mated and known nonmated impressions. Our end‐to‐end workflow facilitates all three of these points and is directly relatable to current practice. We demonstrate the workflow, which includes obtaining and interpreting outsole pattern scores, RAC comparison scores, and final scores, on two scenarios—a pristine example (involving very high quality Everspry EverOS scanner impressions) and a mock crime scene example that more closely resembles real casework. These examples not only demonstrate the workflow but also help identify the algorithmic, computational, and statistical challenges involved in improving the system for eventual deployment in casework.
Low Back Pain

Low back pain is a common problem that is the leading cause of disability and is associated with high costs. Evaluation focuses on identification of risk factors indicating a serious underlying condition and increased risk for persistent disabling symptoms in order to guide selective use of diagnostic testing (including imaging) and treatments. Nonpharmacologic therapies, including exercise and psychosocial management, are preferred for most patients with low back pain and may be supplemented with adjunctive drug therapies. Surgery and interventional procedures are options in a minority of patients who do not respond to standard treatments.
Efficacy and safety of dronedarone across age and sex subgroups: a post hoc analysis of the ATHENA study among patients with non-permanent atrial fibrillation/flutter

Abstract Aims Age and sex may impact the efficacy of antiarrhythmic drugs on cardiovascular outcomes and arrhythmia recurrences in patients with atrial fibrillation (AF). We report on a post hoc analysis of the ATHENA study (NCT00174785), which examined cardiovascular outcomes in patients with non-permanent AF treated with dronedarone vs. placebo. Methods and results Efficacy and safety of dronedarone were assessed in patients according to age and sex. Baseline characteristics were comparable across subgroups, except for cardiovascular comorbidities, which were more frequent with increasing age. Dronedarone significantly reduced the risk of cardiovascular hospitalization or death due to any cause among patients 65–74 [n = 1830; hazard ratio (HR) 0.71, 95% confidence interval (CI) 0.60–0.83; P < 0.0001] and ≥75 (n = 1925; HR 0.75, 95% CI 0.65–0.88; P = 0.0002) years old and among males (n = 2459; HR 0.74, 95% CI 0.64–0.84; P < 0.00001) and females (n = 2169; HR 0.77, 95% CI 0.67–0.89; P = 0.0002); outcomes were similar for time to AF/AFL recurrence. Among patients aged <65 years (n = 873), cardiovascular hospitalization or death due to any cause with dronedarone vs. placebo was associated with an HR of 0.89 (95% CI 0.71–1.11; P = 0.3). The incidence of all treatment-emergent adverse events (TEAEs) and TEAEs leading to treatment discontinuation was comparable among males and females, and increased with increasing age. Conclusions These results support the use of dronedarone for the improvement of clinical outcomes among patients aged ≥65 years and regardless of sex.
Ochratoxin a levels in fermented specialty coffees from Caparaó, Brazil: Is it a cause of concern for coffee drinkers?

ABSTRACT Although postharvest coffee fruit fermentation can improve coffee flavour and quality, the mycotoxin ochratoxin A (OTA) can also be a result of microbiological activity, albeit in the later drying step of coffee processing. To evaluate the possible occurrence of OTA contamination in postharvest fruit fermentation, fourteen coffees that entailed two different postharvest fruit fermentation times were evaluated. These coffees originated in the surroundings of the village of Pedra Menina in the qualified Denomination of Origin and coffee producer region of Caparaó on the border between Minas Gerais and Espírito Santo states in Brazil. All coffees were classified according to the Specialty Coffee Association (SCA) protocol and 12 achieved specialty level. OTA was determined in all 14 coffees using immunoaffinity for sample clean-up and high-performance liquid chromatography with fluorescence detection for quantification. One sample presented an OTA concentration of 0.75 µg kg−1 and two samples showed OTA concentrations of 0.87 µg kg−1. The other samples had concentrations of OTA below the limit of quantification obtained in this work (0.64 µg kg−1). Thus, all samples showed OTA concentrations far below the most stringent maximum residue limit (MRL) of 5 µg kg−1 established for roasted coffees by European legislation. These low levels were similar to most of the previous results for Brazilian coffees listed and tabled in this work. This comparison showed that OTA contamination due to this kind of postharvest process – fruit fermentation – should not be a concern for producers and consumers of these fermented coffees. GRAPHICAL ABSTRACT
A meta-analysis of the effect and safety of platinum-based neoadjuvant chemotherapy in treatment of resectable triple-negative breast cancer

Supplemental Digital Content is available in the text. Triple-negative breast cancer (TNBC) is the most aggressive and fatal subtype of breast cancer. The effectiveness of platinum-based neoadjuvant chemotherapy in treatment of cancer has many divergent opinions. A search was conducted in the PubMed, EBSCO, Web of Science and Cochrane Library databases for relevant studies published before August 2020. The primary endpoint was pathological complete response (pCR) while the secondary endpoints were objective response rate (ORR), overall survival (OS) and progression-free survival (PFS). Nine randomized controlled trials comprised of 1873 patients were included in this meta-analysis. Platinum-based neoadjuvant chemotherapy showed significant improvements in pCR (RR = 1.51, 95% CI, 1.25–1.82, P < 0.001), ORR (RR = 1.20, 95% CI, 1.07–1.34, P = 0.001), OS (HR=0.56; 95% CI, 0.15–0.96, P < 0.001) and PFS (HR = 0.48, 95% CI, 0.22–0.73, P < 0.001) compared to nonplatinum neoadjuvant chemotherapy. Moreover, addition of platinum compounds did not significantly increase the side effects of any grade. However, there was an increase in blood toxicity of grade 3 patients which meant that it was mainly confined to the bone marrow/blood system. Platinum-based neoadjuvant chemotherapy can safely improve short-term and long-term outcomes in resectable TNBC patients.
Genotypic Distribution and Antimicrobial Susceptibilities of Carbapenemase-Producing Enterobacteriaceae Isolated From Rectal and Clinical Samples in Korean University Hospitals Between 2016 and 2019

Background The emergence of carbapenemase-producing Enterobacteriaceae (CPE) represents a major clinical problem. Recently, the occurrence of CPE has increased globally, but epidemiological patterns vary across region. We report the trends in the genotypic distribution and antimicrobial susceptibility of CPE isolated from rectal and clinical samples during a four-year period. Methods Between January 2016 and December 2019, 1,254 nonduplicated CPE isolates were obtained from four university hospitals in Korea. Carbapenemase genotypes were determined by multiplex real-time PCR. Antimicrobial susceptibility was profiled using the Vitek 2 system (bioMérieux, Hazelwood, MO, USA) or MicroScan Walkaway-96 system (Siemens West Sacramento, CA, USA). The proportions of carbapenemase genotypes and nonsusceptibility were analyzed using Pearson’s chi-square test. Results Among the 1,254 CPE isolates, 486 (38.8%), 371 (29.6%), 357 (28.5%), 8 (0.6%), 8 (0.6%), and 24 (1.9%) were Klebsiella pneumoniae carbapenemase (KPC), oxacillinase (OXA)-48-like, New Delhi metallo-β-lactamase (NDM), imipenemase (IMP), Verona integron-encoded metallo-β-lactamase (VIM), and multiple producers, respectively. The predominant species was K. pneumoniae (72.6%), followed by Escherichia coli (6.5%). More than 90% of the isolates harboring KPC, NDM, and OXA-48-like were nonsusceptible to cephalosporins, aztreonam, and carbapenems. Conclusions The impact of CPE is primarily due to KPC-, NDM-, and OXA-48-like-producing K. pneumoniae isolates. Isolates carrying these carbapenemase are mostly multidrug-resistant. Control strategies based on these genotypic distributions and antimicrobial susceptibilities of CPE isolates are required.