Miracle-dz/UniFAR-FTUs huggingface dataset:
Dectin-1/IL-15 Pathway Affords Protection against Extrapulmonary Aspergillus fumigatus Infection by Regulating Natural Killer Cell Survival

Aspergillus fumigatus is a ubiquitous, yet potentially pathogenic, mold. The immune system employs innate receptors, such as dectin-1, to recognize fungal pathogens, but the immunological networks that afford protection are poorly explored. Here, we investigated the role of dectin-1 in anti-A. fumigatus response in an experimental model of acute invasive aspergillosis. Mice lacking dectin-1 presented enhanced signs of inflammation, with increased production of inflammatory cytokines and neutrophil infiltration, quickly succumbing to the infection. Curiously, resistance did not require T/B lymphocytes or IL-17. Instead, the main effector function of dectin-1 was the preservation of the NK cell population in the kidneys by the provision of the cytokine IL-15. While the depletion of NK cells impaired host defense in wild-type mice, IL-15 administration restored antifungal responses in dectin-1-deficient mice. Our results uncover a new effector mechanism for dectin-1 in anti-Aspergillus defense, adding an alternative approach to understand the pathophysiology of this infection.
Mapping the signaling network of BIN2 kinase using TurboID-mediated biotin labeling and phosphoproteomics

Abstract Elucidating enzyme–substrate relationships in posttranslational modification (PTM) networks is crucial for understanding signal transduction pathways but is technically difficult because enzyme–substrate interactions tend to be transient. Here, we demonstrate that TurboID-based proximity labeling (TbPL) effectively and specifically captures the substrates of kinases and phosphatases. TbPL-mass spectrometry (TbPL-MS) identified over 400 proximal proteins of Arabidopsis thaliana BRASSINOSTEROID-INSENSITIVE2 (BIN2), a member of the GLYCOGEN SYNTHASE KINASE 3 (GSK3) family that integrates signaling pathways controlling diverse developmental and acclimation processes. A large portion of the BIN2-proximal proteins showed BIN2-dependent phosphorylation in vivo or in vitro, suggesting that these are BIN2 substrates. Protein–protein interaction network analysis showed that the BIN2-proximal proteins include interactors of BIN2 substrates, revealing a high level of interactions among the BIN2-proximal proteins. Our proteomic analysis establishes the BIN2 signaling network and uncovers BIN2 functions in regulating key cellular processes such as transcription, RNA processing, translation initiation, vesicle trafficking, and cytoskeleton organization. We further discovered significant overlap between the GSK3 phosphorylome and the O-GlcNAcylome, suggesting an evolutionarily ancient relationship between GSK3 and the nutrient-sensing O-glycosylation pathway. Our work presents a powerful method for mapping PTM networks, a large dataset of GSK3 kinase substrates, and important insights into the signaling network that controls key cellular functions underlying plant growth and acclimation.
Preoperative Chemotherapy for Operable Colon Cancer: Mature Results of an International Randomized Controlled Trial

PURPOSE Neoadjuvant chemotherapy (NAC) has potential advantages over standard postoperative chemotherapy for locally advanced colon cancer but requires formal evaluation. METHODS Patients with radiologically staged T3-4, N0-2, M0 colon cancer were randomly allocated (2:1) to 6 weeks oxaliplatin-fluoropyrimidine preoperatively plus 18 postoperatively (NAC group) or 24 weeks postoperatively (control group). Patients with RAS-wildtype tumors could also be randomly assigned 1:1 to receive panitumumab or not during NAC. The primary end point was residual disease or recurrence within 2 years. Secondary outcomes included surgical morbidity, histopathologic stage, regression grade, completeness of resection, and cause-specific mortality. Log-rank analyses were by intention-to-treat. RESULTS Of 699 patients allocated to NAC, 674 (96%) started and 606 (87%) completed NAC. In total, 686 of 699 (98.1%) NAC patients and 351 of 354 (99.2%) control patients underwent surgery. Thirty patients (4.3%) allocated to NAC developed obstructive symptoms requiring expedited surgery, but there were fewer serious postoperative complications with NAC than with control. NAC produced marked T and N downstaging and histologic tumor regression (all P < .001). Resection was more often histopathologically complete: 94% (648/686) versus 89% (311/351), P < . 001. Fewer NAC than control patients had residual or recurrent disease within 2 years (16.9% [118/699] v 21.5% [76/354]; rate ratio, 0.72 [95% CI, 0.54 to 0.98]; P = .037). Tumor regression correlated strongly with freedom from recurrence. Panitumumab did not enhance the benefit from NAC. Little benefit from NAC was seen in mismatch repair–deficient tumors. CONCLUSION Six weeks of preoperative oxaliplatin-fluoropyrimidine chemotherapy for operable colon cancer can be delivered safely, without increasing perioperative morbidity. This chemotherapy regimen, when given preoperatively, produces marked histopathologic down-staging, fewer incomplete resections, and better 2-year disease control. Histologic regression after NAC is a strong predictor of lower postoperative recurrence risk so has potential use as a guide for postoperative therapy. Six weeks of NAC should be considered as a treatment option for locally advanced colon cancer.
Implementing a Fall Prevention Initiative in Nurse-Facilitated Annual Wellness Visits

Background: Falls are the leading cause of injury-related death and disability in community-dwelling older adults. Local Problem: Evidence-based fall prevention activities in primary care, including nurse-facilitated wellness visits, have been limited. Barriers including patient engagement and adherence exist. Method: A quality improvement project integrating components of the Centers for Disease Control and Prevention's Stopping Elder Accidents, Deaths & Injury (STEADI) was introduced by registered nurses during older adult annual wellness visits. Intervention: Nurses assessed risk and implemented patient-centered fall prevention plans including follow-up. Results: A total of 522 patients were screened, with 21% (n = 111) having increased fall risk. Of these, 78% (n = 87) engaged in home safety, gait, strength, and balance assessments and the majority (n = 83; 95%) participated in fall prevention plans of care. At 2-week follow-up, patients' self-reported adherence was 74% for gait/strength/balance and 67% for home safety. Conclusion: An expanded primary care team model shows promise for promoting fall prevention behaviors.
Assessing the impact of open-label designs in patient-reported outcomes: investigation in oncology clinical trials

Abstract Background Knowledge of treatment assignment may affect patient-reported outcomes (PROs), which is of concern in oncology, where open-label trials are common. This study measured the magnitude of open-label bias by comparing PROs for similar patient groups in oncology trials with different degrees of concealment. Methods Individual patient data from ipilimumab arms of 2 melanoma and docetaxel arms of 2 non-small cell lung cancer (NSCLC) trials were adjusted for differences using propensity score weighting. Patients were aware of treatment assignment in CA184-022 and CheckMate 057 (open-label) but not in MDX010-20 and VITAL (blinded). Overall survival (OS) and mean changes from baseline to week 12 in the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (melanoma) and Lung Cancer Symptom Scale (NSCLC) scores were compared between open-label and blinded groups. Results After adjustment, baseline characteristics were balanced between blinded (melanoma, n = 125; NSCLC, n = 424) and open-label (melanoma, n = 69; NSCLC, n = 205) groups. Study discontinuation and PRO completion rates at week 12 and OS were similar. There was no clear direction in differences in change scores between groups. In the melanoma trials, role functioning (mean = -5.2, 95% confidence interval [CI] = −15.4 to 5.0), global health status (mean = -1.3, 95% CI = -8.7 to 6.1), and pain (mean = 6.2 , 95% CI = −1.8 to 14.2) favored the blinded, whereas emotional functioning (mean = 2.2, 95% CI = -5.8 to 10.2) and diarrhea (mean = -8.3, 95% CI = −17.3 to 0.7) favored the open-label group. In the NSCLC trials, changes in dyspnea (mean = 5.4, 95% CI = -0.7 to 11.5) favored the blinded and changes in appetite (mean = -1.2, 95% CI = -8.1 to 5.7) favored the open-label group. None were clinically or statistically significant. Conclusions This study adds to the growing evidence demonstrating that concerns regarding open-label bias should not prohibit the interpretation of large and meaningful treatment effects on PROs.
Sentiment analysis of the Twitter response to Netflix's Our Planet documentary

The role of nature documentaries in shaping public attitudes and behavior toward conservation and wildlife issues is unclear. We analyzed the emotional content of over 2 million tweets related to Our Planet, a major nature documentary released on Netflix, with dictionary and rule‐based automatic sentiment analysis. We also compared the sentiment associated with species mentioned in Our Planet and a set of control species with similar features but not mentioned in the documentary. Tweets were largely negative in sentiment at the time of release of the series. This effect was primarily linked to the highly skewed distributions of retweets and, in particular, to a single negatively valenced and massively retweeted tweet (>150,000 retweets). Species mentioned in Our Planet were associated with more negative sentiment than the control species, and this effect coincided with a short period following the airing of the series. Our results are consistent with a general negativity bias in cultural transmission and document the difficulty of evoking positive sentiment, on social media and elsewhere, in response to environmental problems.
Quantifying changes in the T cell receptor repertoire during thymic development

One of the feats of adaptive immunity is its ability to recognize foreign pathogens while sparing the self. During maturation in the thymus, T cells are selected through the binding properties of their antigen-specific T-cell receptor (TCR), through the elimination of both weakly (positive selection) and strongly (negative selection) self-reactive receptors. However, the impact of thymic selection on the TCR repertoire is poorly understood. Here, we use transgenic Nur77-mice expressing a T-cell activation reporter to study the repertoires of thymic T cells at various stages of their development, including cells that do not pass selection. We combine high-throughput repertoire sequencing with statistical inference techniques to characterize the selection of the TCR in these distinct subsets. We find small but significant differences in the TCR repertoire parameters between the maturation stages, which recapitulate known differentiation pathways leading to the CD4+ and CD8+ subtypes. These differences can be simulated by simple models of selection acting linearly on the sequence features. We find no evidence of specific sequences or sequence motifs or features that are suppressed by negative selection. These results favour a collective or statistical model for T-cell self non-self discrimination, where negative selection biases the repertoire away from self recognition, rather than ensuring lack of self-reactivity at the single-cell level.
Utilizing quantitative dried blood spot analysis to objectively assess adherence to cardiovascular pharmacotherapy among patients at Kenyatta National Hospital, Nairobi, Kenya

The burden of cardiovascular disease (CVD) is rising in Kenya and non-adherence to cardiovascular pharmacotherapy is a growing global public health issue that leads to treatment failure, an increased risk of cardiac events and poor clinical outcomes. This study assessed adherence to selected cardiovascular therapy medications among CVD patients attending outpatient clinics at Kenyatta National Hospital, Kenya by determining drug concentration(s) in patient dried blood spot (DBS) samples. Patients who had been taking one or more of the five commonly prescribed CVD medications (amlodipine, atenolol, atorvastatin, losartan, and valsartan) for at least six months were enrolled. Each patient completed a short questionnaire about their medication history and then provided a finger-prick blood spot sample from which drug concentrations were determined by liquid chromatography-high resolution mass spectrometry analysis. Two hundred and thirty-nine patients (62.3% female) participated in the study. The median number of medications used by patients was 2 (IQR 75%-25% is 3–1). Less than half (117; 49.0%) of patients were adherent to their prescribed CVD pharmacotherapy. Binary regression analysis revealed a significant correlation between non-adherence and the number of medications in the treatment regimen (Odds Ratio (OR) 1.583; 95%CI: 0.949–2.639; P-value = 0.039) and that gender was not an independent predictor of medication adherence (OR 1.233; 95%CI: 0.730–2.083; P-value = 0.216). Valuable information about adherence to each medication in the patient’s treatment regimen was obtained using quantitative DBS analysis showing that adherence to CVD medications was not uniform. DBS sampling, due its minimally invasive nature, convenience and ease of transport is a useful alternative matrix to monitor adherence to pharmacotherapies objectively, when combined with hyphenated mass spectrometry analytical techniques. This information can provide physicians with an evidence-based novel approach towards personalization and optimization of CVD pharmacotherapy and implementing interventions in the Kenyan population, thereby improving clinical outcomes.
Distinguishing central from obstructive hypopneas on a clinical polysomnogram.

Among sleep-related disordered breathing events, hypopneas are the most frequent. Like obstructive and central apneas, hypopneas may be obstructive or central (reduced drive) in origin. Nevertheless, unlike apneas, categorizing hypopneas as either "obstructive" or "central" is often difficult or ambiguous. It has been suggested that hypopneas could be categorized as obstructive when associated with snoring, inspiratory flow limitation or paradoxical thoraco-abdominal excursions. This approach, however, has not been extensively tested and misclassification of hypopneas is unavoidable. Yet, much rides on the accurate distinction of these events to guide therapy with medical devices or pharmacological therapy in each patient. Additionally, accurate hypopnea classification is critical for design of clinical trials because therapeutic responses differ depending on the subtype of hypopnea. Correctly classifying hypopneas can also allay concerns in obtaining coverage for therapies that specifically target either central or obstructive sleep disordered breathing events. The present paper expands on the current criteria for differentiating obstructive from central hypopneas and provides illustrative tracings which can help classify these events.
Assessing primary health care readiness for large-scale electronic health record system implementation: Project team perspective

Introduction: The introduction of information technology was one of the key priorities for policymakers in healthcare organisations over the last two decades, due to the potential benefits of this technology to improve healthcare services and quality. However, about 50% of those projects failed to achieve their intended aims. This was as a result of several factors and included the level of readiness to the new IT projects. Aim: The aim of the study was to assess the readiness of Saudi primary health care centres (PHCCs) readiness for the implementation of an electronic health record system (EHRS) from the project team perspective. Methods: Explanatory mixed methods design was used with both qualitative and quantitative methods. Thirty-one members of project team at the ministry of health (MOH) participated in the online-based questionnaire, while 13 participants from the same population took part in the semi-structure interviews. Eight different readiness scales were quantitatively examined. These scales include resources, Knowledge, process, management structure and administrative support, end user, technology and values and goals. Result: Although, very high level of readiness has been recorded at the process, management structure and administrative support levels, readiness was average at the end user, technology and values and goals levels. Moreover, the study findings revealed that primary health care centres readiness for an electronic health record system must be considered in the early stages of implementation (pre-implementation phase), particularly readiness at a technical level, such as preparedness of the infrastructure. A positive significant correlation has been recorded between all readiness scales with centralization of management system and financial resources. Conclusion: Overall, the level of primary health care centres readiness recorded to be high, which indicates that primary health care centres are ready for implementation of the electronic health record system, and in this context, management structure, organizational process, financial recourses and administrative support play significant roles to increase the project success rate.
Relationship of ulna styloid fracture to the distal radio-ulnar joint stability. A clinical, functional, and radiographic outcome study

Background Ulna styloid fracture occurs approximately about 55% of all distal end of radius fractures. However, the clinical and functional outcome of these fractures remains indefinite. Results Only 56 patients with distal radius fractures had concomitant ulna styloid fractures. The mean age was 32 years (range: 18–69; SD: ± 12.7). The majority were men. The mean time from injury was 18.7 months (range: 6–84; SD: ± 13.3). The most common was Frykman 2, followed by 6, type 8, and type 4. All were closed fractures; 60.7% were base, and 39.3% were tip fractures. 50% were treated with casting, 48.3% plating, and 1.8% external fixation. The mean period of casting was 7.67 weeks (range: 4–16; SD ± 3.1). The ulna styloid was united in 35.7%. There is no significant difference in the range of movement between those with ulna styloid union and non-union. The Ballottement test and Piano key sign was statistically insignificant between both groups. All the displacements were dorsal except in 1 case. The mean displacement of ulna styloid is 1.88mm (SD±1.08, Range: 0.20–4.60mm). The mean VAS score at rest and work is not statistically significant. The mean grip strength and functional score (DASH) are similar in both groups. Conclusion Ulna styloid fractures do not contribute to the DRUJ instability and the status of the union of the ulna styloid and the site of the ulna styloid fracture (tip or base) did not have a bearing on the range of movement and functional status of the affected wrist. Temporary DRUJ immobilization might allow TFCC recovery.
Effects of telework on anxiety and depression across the United States during the covid-19 crisis

This study serves to provide evidence on how the increase in people working from home due to government induced social distancing measures is contributing to the frequency of individuals suffering from depression or anxiety. Using a compilation of datasets from the NHIS, Household Pulse Survey, and the Oxford Covid-19 Response Tracker, we find a general trend of increased rates of depression and anxiety in those who moved to a remote working format. However, while all regions have an increased frequency in anxiety for those who switched to telework, those in the Northeast and West (that also have implemented strict lockdown measures related to social distancing) have slightly higher rates of anxiety compared to those in the South and Midwest.
The B domain of protein A retains residual structures in 6 M guanidinium chloride as revealed by hydrogen/deuterium‐exchange NMR spectroscopy

The characterization of residual structures persistent in unfolded proteins is an important issue in studies of protein folding, because the residual structures present, if any, may form a folding initiation site and guide the subsequent folding reactions. Here, we studied the residual structures of the isolated B domain (BDPA) of staphylococcal protein A in 6 M guanidinium chloride. BDPA is a small three‐helix‐bundle protein, and until recently its folding/unfolding reaction has been treated as a simple two‐state process between the native and the fully unfolded states. We employed a dimethylsulfoxide (DMSO)‐quenched hydrogen/deuterium (H/D)‐exchange 2D NMR techniques with the use of spin desalting columns, which allowed us to investigate the H/D‐exchange behavior of individually identified peptide amide (NH) protons. We obtained H/D‐exchange protection factors of the 21 NH protons that form an α‐helical hydrogen bond in the native structure, and the majority of these NH protons were significantly protected with a protection factor of 2.0–5.2 in 6 M guanidinium chloride, strongly suggesting that these weakly protected NH protons form much stronger hydrogen bonds under native folding conditions. The results can be used to deduce the structure of an early folding intermediate, when such an intermediate is shown by other methods. Among three native helical regions, the third helix in the C‐terminal side was highly protected and stabilized by side‐chain salt bridges, probably acting as the folding initiation site of BDPA. The present results are discussed in relation to previous experimental and computational findings on the folding mechanisms of BDPA.
Pediatric Critical Care–Associated Parental Traumatic Stress: Beyond the First Year*

OBJECTIVES: Perform a longitudinal analysis of parental traumatic stress up to 30 months after PICU discharge. DESIGN: Prospective observational cohort study. SETTING: Two tertiary care children’s hospitals with mixed medical/surgical/cardiac PICUs. SUBJECTS: Parents of patients unexpectedly admitted to the PICU. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Two hundred sixty-five parents of 188 children were enrolled. Of the 195 parents who completed the 3–9-month assessments, 29 (14.8%) met posttraumatic stress disorder (PTSD) qualification on the PTSD Symptom Scale Interview for Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition. Multivariable analysis showed parents who met acute stress disorder (ASD) qualification (odds ratio [OR] 8.01; 95% CI 2.64–24.3), parents of children with Pediatric Overall Performance Category score of severe or coma at discharge (OR 5.21; 95% CI 1.65–16.4), parents who had concerns for their child’s permanent injury (OR 1.82; 95% CI 1.36–2.43), and parents who reported increased knowledge of child illness during admission (OR 1.82; 95% CI 1.13–2.93) had increased odds of developing parental PTSD. Of the 175 parents (66%) who completed the 18–30-month assessments, 22 (12.5%) met PTSD qualification. Multivariable analysis showed parents who met ASD qualification (OR 4.19; 95% CI 1.12–15.7), parents who had a history of a family member or themselves being admitted to ICU (OR 6.51; 95% CI 1.43–29.6), and parents who had concerns of child’s susceptibility to death post discharge (OR 1.58; 95% CI 1.19–2.09) had increased odds of developing parental PTSD. At 18–30 months post discharge, parents who met the PTSD qualification were more likely to report a decrease in household income following discharge (OR 9.23; 95% CI 1.71–49.9). CONCLUSIONS: Parental PTSD remains a significant morbidity of PICU admission for a subgroup of parents greater than 18 months post admission. Identifiable risk factors will inform the development of targeted interventions.