Miracle-dz/UniFAR-FTUs huggingface dataset:
Expression and immobilization of trypsin‐like domain of serine protease from Pseudomonas aeruginosa for improved stability and catalytic activity

Protein engineering and enzyme immobilization strategies have produced numerous biocatalysts for modern industrial applications. In this study, we have also used these two strategies for improving the operational stability and catalytic efficiency of serine protease from Pseudomonas aeruginosa. The enzyme serine protease was truncated to separate its trypsin‐like domain from the PDZ1 and PDZ2 domains. The truncated trypsin‐like domain was expressed in Escherichia coli BL21, and its catalytic activity and thermostability were estimated. Later this trypsin‐like domain was immobilized with 2% Na‐alginate. The immobilized domain showed 10°C increase in optimum temperature compared to its free counterpart. Kinetic studies showed two‐folds increased Vmax of the immobilized domain. Likewise, the Km value of this domain was 11.5 folds lower compared to the free trypsin‐like domain. The catalytic efficiency (Kcat/Km) of the immobilized enzyme also elevated to 311 folds. Additionally, the immobilized trypsin‐like domain remained active in the presence of surfactants (Triton‐X 100, SDS, and Tween‐40) and metal ions (Mg2+, Ca2+, Na+, and Zn2+). It also efficiently removes gelatin layer from X‐ray film and hair from sheepskin. Thus, the immobilized trypsin‐like domain of serine protease, with increased thermostability and catalytic efficiency, is operationally more stable than the soluble truncated trypsin‐like domain.
Interneuron diversity in the rat dentate gyrus: An unbiased in vitro classification

Information processing in cortical circuits, including the hippocampus, relies on the dynamic control of neuronal activity by GABAergic interneurons (INs). INs form a heterogenous population with defined types displaying distinct morphological, molecular, and physiological characteristics. In the major input region of the hippocampus, the dentate gyrus (DG), a number of IN types have been described which provide synaptic inhibition to distinct compartments of excitatory principal cells (PrCs) and other INs. In this study, we perform an unbiased classification of GABAergic INs in the DG by combining in vitro whole‐cell patch‐clamp recordings, intracellular labeling, morphological analysis, and unsupervised cluster analysis to better define IN type diversity in this region. This analysis reveals that DG INs divide into at least 13 distinct morpho‐physiological types which reflect the complexity of the local IN network and serve as a basis for further network analyses.
Does Root Cause Analysis Improve Patient Safety? A Systematic Review at the Department of Veterans Affairs

Background and Objectives: While root cause analysis (RCA) is used to analyze medical errors with a systems approach, evidence demonstrating its effectiveness in reducing patient harm remains sparse. The heterogeneity of the RCA methodology at different health care organizations has posed challenges to studying its value. The Department of Veterans Affairs (VA) has an established and standardized RCA approach, making it an ideal context to study RCA's impact. This review assessed whether implemented interventions recommended by RCAs were effective in mitigating preventable adverse events at the VA. Methods: PubMed, Web of Science, CINAHL and Business Source were searched for studies on RCAs performed at the VA that evaluated effectiveness of interventions and were published between 2010 and 2020. The Appraisal Tool for Cross-sectional Studies (AXIS) was used to assess bias of bias. Results: The majority of studies eliminated during our eligibility process reported on RCAs without attention to their specific impact on patient safety. Ten retrospective studies met inclusion criteria and were part of the final review. Studies were grouped into adverse events related to incorrect surgical/invasive procedures, suicides, falls with injury, and all-cause adverse events. Six studies reported on effectiveness by demonstrating quantitative changes in adverse events over time or by location following a specific intervention. Four studies reported on the effectiveness of implemented interventions using a facility-based rating of “much better” or “better. ” Conclusions: Of the studies included in this review, all reported improvements following interventions implemented after RCAs, but with variability in study definitions and methodology to assess effectiveness. Increased reporting of outcomes following RCAs, with an emphasis on quantitative patient-related outcome measures, is needed to demonstrate the impact and value of the RCA.
Secondary primary malignancies after treatment with chemo-immunotherapy in treatment-naïve patients with CLL: a systematic literature review

ABSTRACT Objectives In chronic lymphocytic leukemia (CLL), therapy-related cytotoxicity and the resulting immunodeficiency are thought to contribute to the development of secondary primary malignancies (SPM). Here, we analyzed clinical trial data on the occurrence of SPM following chemo-immunotherapy (CIT) regimens in treatment-naïve CLL patients. Methods A systematic literature search was conducted covering multiple databases between 2003 and 2019. Data from relevant clinical trials on the proportion of patients with SPMs were extracted. Then, the number of SPM patients/person-years was calculated by taking into account the trials’ follow-up time. Finally, a random-effects meta-analysis to pool the rates from individual studies was performed. Results We identified 22 studies reporting SPM data available for analysis. Random-effects meta-analysis estimated that the number of SPM patients/1000 person-years was 24 (95%CI: 19–29). Results from trials with cancer-specific data indicated 19 (95%CI: 14–26) solid and 9 (95%CI: 6–12) hematological SPM patients/1000 person-years. These estimations did not change significantly when sub-groups were analyzed by CIT regimens. Conclusion Although pooling data with the intention to analyze adverse event rates is challenging, our study concluded that for CIT regimens, SPM should be considered an important adverse outcome. Different regimens showed similar trends; however, other clinical and demographic factors also have profound impact.
Assessing the effects of stress on feeding behaviors in laboratory mice

Stress often affects eating behaviors, increasing caloric intake in some individuals and decreasing it in others. The determinants of feeding responses to stress are unknown, in part because this issue is rarely studied in rodents. We focused our efforts on the novelty-suppressed feeding (NSF) assay, which uses latency to eat as readout of anxiety-like behavior, but rarely assesses feeding per se. We explored how key variables in experimental paradigms – estrous and diurnal cyclicity, age and duration of social isolation, prandial state, diet palatability, and elevated body weight – influence stress-induced anxiety-like behavior and food intake in male and female C57BL/6J mice. Latency to eat in the novel environment is increased in both sexes across most of the conditions tested, while effects on caloric intake are variable. In the common NSF assay (i.e., lean mice in the light cycle), sex-specific effects of the length of social isolation, and not estrous cyclicity, are the main source of variability. Under conditions that are more physiologically relevant for humans (i.e., overweight mice in the active phase), the novel stress now elicits robust hyperphagia in both sexes . This novel model of stress eating can be used to identify underlying neuroendocrine and neuronal substrates. Moreover, these studies can serve as a framework to integrate cross-disciplinary studies of anxiety and feeding related behaviors in rodents.
Associations between self‐reported periodontal disease and nutrient intakes and nutrient‐based dietary patterns in the UK Biobank

Abstract Aim To examine the cross‐sectional associations between single nutrient intakes and posteriori nutrient‐based dietary patterns and periodontal disease risk in a subset of the UK Biobank cohort. Materials and Methods Dietary data were collected by 24‐h dietary recall on up to five separate occasions over 16 months. A touchscreen questionnaire was used to collect oral health information. Participants were considered at high risk of periodontal disease if they reported having painful gums and/or bleeding gums and/or loose teeth. Principal component analysis identified four nutrient‐based dietary patterns from 20 nutrients. Logistic regression was used to estimate the odds ratio of periodontal disease risk for single nutrients and nutrient‐based dietary patterns. Results A total of 9476 participants (mean age 56.2 years [SD 8.0]) were included in the analysis. Higher intakes of vitamin B6, B12, C, and E, folate, iron, potassium, magnesium, polyunsaturated fatty acids, and total sugar were associated with a lower risk of periodontal disease. Higher intake of saturated fat was associated with an increased risk. A dietary pattern characterized by high micronutrients and fibre intake was associated with low risk of periodontal disease. Conclusion Within this sample of middle‐aged and older adults, a “high micronutrient and fibre” dietary pattern was associated with reduced risk of periodontal disease.
Influence of exclusive breastfeeding on hippocampal structure, satiety responsiveness, and weight status

Abstract Longer exclusive breastfeeding duration has been associated with differences in neural development, better satiety responsiveness, and decreased risk for childhood obesity. Given hippocampus sensitivity to diet and potential role in the integration of satiety signals, hippocampus may play a role in these relationships. We conducted a secondary analysis of 149, 7–11‐year‐olds (73 males) who participated in one of five studies that assessed neural responses to food cues. Hippocampal grey matter volume was extracted from structural scans using CAT12, weight status was assessed using age‐ and sex‐adjusted body mass index (%BMIp85), and parents reported exclusive breastfeeding duration and satiety responsiveness (Children's Eating Behaviour Questionnaire). Separate path models for left and right hippocampus tested: (1) the direct effect of exclusive breastfeeding on satiety responsiveness and its indirect effect through hippocampal grey matter volume; (2) the direct effect of hippocampal grey matter volume on %BMIp85 and its indirect effect through satiety responsiveness. %BMIp85 was adjusted for maternal education, yearly income, and premature birth while hippocampal grey matter volume was adjusted for total intercranial volume, age, and study from which data were extracted. Longer exclusive breastfeeding duration was associated with greater bilateral hippocampal grey matter volumes. In addition, better satiety responsiveness and greater left hippocampal grey matter volume were both associated with lower %BMIp85. However, hippocampal grey matter volumes were not associated with satiety responsiveness. Although no relationship was found between breastfeeding and child weight status, these results highlight the potential impact of exclusive breastfeeding duration on the hippocampal structure.
Cut-off score of the modified Ashworth scale corresponding to walking ability and functional mobility in individuals with chronic stroke

Abstract Purpose To determine the optimal cut-off score for the Modified Ashworth Scale (MAS) corresponding to unfavorable outcomes for mobility and walking ability. Methods The level of plantar flexor muscle spasticity and the 10-meter walking test (10mWT), timed up and go (TUG), and five time sit-to-stand (FTSTS) outcomes were evaluated in individuals after stroke. The correlation between MAS and the tests was investigated, and the optimal cut-off score, sensitivity, and specificity were evaluated through receiver operating characteristic (ROC) curve. Results Twenty-one participants with chronic stroke and plantar flexors spasticity (11 men; 10 women; mean age = 57.6 ± 12.5 years) participated in the study. Significant correlations between MAS and 10mWT (r= −0.45; p < 0.05), MAS and TUG (r = 0.48; p < 0.05) were found. The optimal cut-off scores were MAS > 2 for unfavorable 10mWT (sensitivity = 100%; specificity = 54.5%; ROC = 0.782) and MAS ≤ 2 for favorable TUG outcomes (sensitivity = 55.5%; specificity = 91.6%; ROC = 0.782). Conclusions This study revealed that moderate level of plantar flexors spasticity results in the highest sensitivity to predict poor gait speed performance and the highest specificity to predict good mobility performance in individuals after stroke. These findings will help clinicians in their evidence-based decision making on the role of spasticity for mobility and walking ability. Implications for rehabilitation Moderate level of spasticity (MAS <2) is the optimal cut-off score for 10mWT and TUG tests. Reducing the level of spasticity of plantar flexors below this cut-off point might be associated with an increased walking speed in this population. MAS <2 might not limit walking and mobility in individuals after stroke. Calf muscles spasticity might not compromise five time sit-to-stand (FTSTS) performances and might be related to a smaller influence on the sit to stand task.
Predictors of Glucocorticoid Use for Acute Optic Neuritis in the United States, 2005-2019

ABSTRACT Purpose Acute optic neuritis (ON) is variably treated with glucocorticoids. We aimed to describe factors associated with glucocorticoid use. Methods In this retrospective, longitudinal cohort study of insured patients in the United States (2005–2019), adults 18–50 years old with one inpatient or ≥2 outpatient diagnoses of ON within 90 days were included. Glucocorticoid use was classified as none, any dose, and high-dose (>100 mg prednisone equivalent ≥1 days). The primary outcome was glucocorticoid receipt within 90 days of the first ON diagnosis. Multivariable logistic regression models assessed the relationship between glucocorticoid use and sociodemographics, comorbidities, clinician specialty, visit number, and year. Results Of 3026 people with ON, 65.8% were women (n = 1991), median age (interquartile range) was 38 years (31,44), and 68.6% were white (n = 2075). Glucocorticoids were received by 46% (n = 1385); 54.6% (n = 760/1385) of whom received high-dose. The odds of receiving glucocorticoids were higher among patients with multiple sclerosis (OR 1.61 [95%CI 1.28–2.04]; P < .001), MRI (OR 1.75 [95%CI 1.09–2.80]; P = .02), 3 (OR 1.80 [95%CI 1.46–2.22]; P < .001) or more (OR 4.08 [95%CI 3.37–4.95]; P < .001) outpatient ON visits, and in certain regions. Compared to ophthalmologists, patients diagnosed by neurologists (OR 1.36 [95%CI: 1.10–1.69], p = .005), emergency medicine (OR 3.97 [95%CI: 2.66–5.94]; P < .001) or inpatient clinicians (OR 2.94 [95%CI: 2.22–3.90]; P < .001) had higher odds of receiving glucocorticoids. Use increased 1.1% annually (P < .001). Conclusions Demyelinating disease, care intensity, setting, region, and clinician type were associated with glucocorticoid use for ON. To optimize care, future studies should explore reasons for ON care variation, and patient/clinician preferences.
MiR-122-5p promotes peritoneal fibrosis in a rat model of peritoneal dialysis by targeting Smad5 to activate Wnt/β-catenin pathway

Abstract Peritoneal fibrosis (PF) is the main reason leading to declining efficiency and ultrafiltration failure of peritoneum, which restricts the application of peritoneal dialysis (PD). We aimed to investigate the effects and mechanisms of miR-122-5p on the PF. Sprague-Dawley (SD) rats were infused with glucose-based standard PD fluid to establish PF model. HE staining was performed to evaluate the extent of PF. Real-time fluorescence quantitative polymerase chain reaction (RT-qPCR) and fluorescence in situ hybridization (FISH) were performed to measure the expression level of miR-122-5p. Western blot was used to test the expression of transforming growth factor (TGF)-β1, platelet-derived growth factor (PDGF)-A, Fibronectin 1 (FN1), extracellular matrix protein 1 (ECM1), Smad5, α-smooth muscle actin (SMA), collagen type 1(COL-1), Vimentin, E-Cadherin, Wnt1, β-catenin, p-β-catenin, c-Myc, c-Jun, and Cyclin D1. Immunohistochemistry (IHC) staining was used to detect type I collagen alpha 1 (Col1α1), α-SMA, and E-Cadherin expression. We found PF was glucose concentration-dependently enhanced in peritoneum of PD rat. The PD rats showed increased miR-122-5p and decreased Smad5 expression. MiR-122-5p silencing improved PF and epithelial–mesenchymal transition (EMT) process in PD rats. MiR-122-5p silencing attenuated the activity of the Wnt/β-catenin signaling pathway. Importantly, dual-luciferase reporter assay showed Smad5 was a target gene of miR-122-5p. Smad5 overexpression significantly reversed the increases of PF and EMT progression induced by miR-122-5p overexpression. Moreover, miR-122-5p mimic activated Wnt/β-catenin activity, which was blocked by Smad5 overexpression. Overall, present results demonstrated that miR-122-5p overexpression showed a deterioration effect on PD-related PF by targeting Smad5 to activate Wnt/β-catenin pathway.
Comparison of chlorthalidone and spironolactone as additional diuretic therapy in patients with acute heart failure and preserved ejection fraction.

AIMS Patients with acute heart failure (AHF) require intensification in the diuretic strategy. However, the optimal diuretic strategy remains unclear. In this work, we aimed to evaluate the effect of chlorthalidone compared with spironolactone on diuretic efficacy and safety profile in a cohort of patients with AHF and preserved ejection fraction (AHF-pEF). METHODS AND RESULTS It was a prospective observational study in a single centre in Spain, included 44 consecutive patients admitted between June 2020 and March 2021, with AHF-pEF in which an additional diuretic was prescribed. The primary endpoint was changes in urinary sodium at 24 and 72 h, and the secondary were urine output, and other security endpoints. Mixed linear regression models were used to analyse the endpoints. Estimates were reported as least squares mean with their respective 95% confidence intervals. The median age of the study population was 85 years (82.5-88.5), and 30 (68.2%) were women. After multivariate analysis, the linear mixed regression analysis confirmed a greater natriuretic response of chlorthalidone over spironolactone, especially at 24 h (P = 0.009). Multivariate analysis also showed a greater cumulative diuretic response in those treated with chlorthalidone (P = 0.001). We did not find significant differences in glomerular filtration rate, serum sodium, and serum potassium at 72 h, neither significant differences were found in 24 and 72 h in systolic blood pressure. CONCLUSION In patients with AHF and left ventricular ejection fraction ≥50% receiving intravenous loop diuretics, chlorthalidone administration was associated with a greater short-term natriuresis.
Weight of Evidence Approach for Skin Sensitization Potency Categorization of Fragrance Ingredients

Background Reliable human potency data are necessary for conducting quantitative risk assessments, as well as development and validation of new nonanimal methods for skin sensitization assessments. Previously, human skin sensitization potency of fragrance materials was derived primarily from human data or the local lymph node assay. Objectives This study aimed to define skin sensitization potency of fragrance materials via weight of evidence approach, incorporating all available human, animal, in vitro, in chemico, and in silico data. Methods All available data on 106 fragrance materials were considered to assign each material into 1 of the 6 defined potency categories (extreme, strong, moderate, weak, very weak, and nonsensitizer). Results None of the 106 materials were considered an extreme sensitizer, whereas a total of 6, 23, 41, and 26 materials were categorized as strong, moderate, weak, and very weak sensitizers, respectively. Ten materials lacked evidence for the induction of skin sensitization. Conclusions Skin sensitization potency categorization of the 106 fragrance materials based on the described weight of evidence approach can serve as a useful resource in evaluation of nonanimal methods, as well as in risk assessment.
Need for cognitive closure is associated with different intra-network functional connectivity patterns: A resting state EEG study

ABSTRACT Need for Cognitive Closure (NCC) is a construct referring to the desire for predictability, unambiguity and firm answers to issues. Neuroscientific literature about NCC processes has mainly focused on task-related brain activity. According to the Triple Network model (TN), the main aim of the current study was to investigate resting state (RS) electroencephalographic (EEG) intra-network dynamics associated with NCC. Fifty-two young adults (39 females) were enrolled and underwent EEG recordings during RS. Functional connectivity analysis was computed through exact Low-Resolution Electromagnetic Tomography (eLORETA) software. Our results showed that higher levels of NCC were associated with both i) decreased alpha EEG connectivity within the Central Executive Network (CEN), and ii) increased delta connectivity within the Default Mode Network (DMN). No significant correlations were observed between NCC and functional connectivity in the Salience Network (SN). Our data would seem to suggest that high levels of NCC are characterized by a specific communication pattern within the CEN and the DMN during RS. These neurophysiological patterns might reflect several typical NCC-related cognitive characteristics (e.g., lower flexibility and preference for habitual and rigid response schemas).
The impact of GeneMatcher on international data sharing and collaboration

GeneMatcher (genematcher.org) is a tool designed to connect individuals with an interest in the same gene. Now used around the world to create collaborations and generate the evidence needed to support novel disease gene identification, GeneMatcher is a founding member of the Matchmaker Exchange (MME; matchmakerexchange.org) and strongest possible advocate for global data sharing including those in resource‐limited environments. As of October 1, 2021, there are 12,531 submitters from 94 countries who have submitted 58,134 submissions with 13,498 unique genes in the database. Among these genes, 8970 (64%) have matched at least once and the total number of matches is 378,806, growing by about 10,000 per month. GeneMatcher submitters increase by 80–120 each month and submissions grow by >800 per month, while unique genes and gene matches continue to grow steadily at rate of about 80 per month. The number of genes without a match peaked at 4371 in February of 2019 and despite the increase in the number of new submissions, the number of unique genes without a match continues to slowly decline, currently standing at 4,016. All submissions in GeneMatcher are available for matching across the MME.