Miracle-dz/UniFAR-FTUs huggingface dataset:
Brigatinib: Novel ALK Inhibitor for Non–Small-Cell Lung Cancer

Objective: We review here the pharmacology, pharmacokinetics, efficacy, safety, dosage and administration, potential drug-drug interactions and place in therapy of brigatinib for abnormal anaplastic lymphoma kinase (ALK) specific non–small-cell lung cancer (NSCLC). Data Sources: A literature search using PubMed was conducted using the terms brigatinib and ALK positive NSCLC from January 2013 to November 2018. Study Selection and Data Extraction: All English-language articles evaluating brigatinib were analyzed for this review. Data Synthesis: Brigatinib was granted approval for the treatment of patients with metastatic ALK+ NSCLC who have progressed on or are intolerant to crizotinib. It is administered at a dose of 90 mg orally once daily for the first 7 days then, if tolerated, increased to a dose of 180 mg orally once daily. Common adverse effects include nausea, fatigue, diarrhea, increased creatine phosphokinase levels, headache, dyspnea, and hypertension. Serious treatment-emergent adverse effects were pulmonary related. Relevance to Patient Care and Clinical Practice: This article discusses the clinical trials that led to the accelerated approval of brigatinib for its ability to overcome crizotinib-resistant mutations and for its increased central nervous system penetration properties. Conclusion: Brigatinib was granted accelerated approval for the treatment of patients with metastatic ALK+ NSCLC who have progressed on or are intolerant to crizotinib. In a subset of NSCLC patients, brigatinib increases survival for approximately 1 year; however, side effects were detected.
Mechanisms of Communication in the Mammalian Circadian Timing System

24-h rhythms in physiology and behaviour are organized by a body-wide network of endogenous circadian clocks. In mammals, a central pacemaker in the hypothalamic suprachiasmatic nucleus (SCN) integrates external light information to adapt cellular clocks in all tissues and organs to the external light-dark cycle. Together, central and peripheral clocks co-regulate physiological rhythms and functions. In this review, we outline the current knowledge about the routes of communication between the environment, the main pacemakers and the downstream clocks in the body, focusing on what we currently know and what we still need to understand about the communication mechanisms by which centrally and peripherally controlled timing signals coordinate physiological functions and behaviour. We highlight recent findings that shed new light on the internal organization and function of the SCN and neuroendocrine mechanisms mediating clock-to-clock coupling. These findings have implications for our understanding of circadian network entrainment and for potential manipulations of the circadian clock system in therapeutic settings.
Getting to the Heart of Alzheimer Disease

In a somewhat narrow diagnostic lens, Alzheimer disease (AD) has been considered a brain-specific disease characterized by the presence of A&bgr; (&bgr;-amyloid) plaques and tau neural fibrillary tangles and neural inflammation; these pathologies lead to neuronal death and consequently clinical symptoms, such as memory loss, confusion, and impaired cognitive function. However, for decades, researchers have noticed a link between various cardiovascular abnormalities and AD—such as heart failure, coronary artery disease, atrial fibrillation, and vasculopathy. A considerable volume of work has pointed at this head to heart connection, focusing mainly on associations between cerebral hypoperfusion and neuronal degradation. However, new evidence of a possible systemic or metastatic profile to AD calls for further analysis of this connection. A&bgr; aggregations—biochemically and structurally akin to those found in the typical AD pathology—are now known to be present in the hearts of individuals with idiopathic dilated cardiomyopathy, as well as the hearts of patients with AD. These findings suggest a potential systemic profile of proteinopathies and a new hypothesis for the link between peripheral and central symptoms of heart failure and AD. Herein, we provide an overview of the cardiovascular links to Alzheimer disease.
Biomarkers and clinical outcomes in COPD: a systematic review and meta-analysis

Background Conventional measures to evaluate COPD may fail to capture systemic problems, particularly musculoskeletal weakness and cardiovascular disease. Identifying these manifestations and assessing their association with clinical outcomes (ie, mortality, exacerbation and COPD hospital admission) is of increasing clinical importance. Objective To assess associations between 6 min walk distance (6MWD), heart rate, fibrinogen, C reactive protein (CRP), white cell count (WCC), interleukins 6 and 8 (IL-6 and IL-8), tumour necrosis factor-alpha, quadriceps maximum voluntary contraction, sniff nasal inspiratory pressure, short physical performance battery, pulse wave velocity, carotid intima-media thickness and augmentation index and clinical outcomes in patients with stable COPD. Methods We systematically searched electronic databases (August 2018) and identified 61 studies, which were synthesised, including meta-analyses to estimate pooled HRs, following Meta-analysis of Observational Studies in Epidemiology (MOOSE) and Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Results Shorter 6MWD and elevated heart rate, fibrinogen, CRP and WCC were associated with higher risk of mortality. Pooled HRs were 0.80 (95% CI 0.73 to 0.89) per 50 m longer 6MWD, 1.10 (95% CI 1.02 to 1.18) per 10 bpm higher heart rate, 3.13 (95% CI 2.14 to 4.57) per twofold increase in fibrinogen, 1.17 (95% CI 1.06 to 1.28) per twofold increase in CRP and 2.07 (95% CI 1.29 to 3.31) per twofold increase in WCC. Shorter 6MWD and elevated fibrinogen and CRP were associated with exacerbation, and shorter 6MWD, higher heart rate, CRP and IL-6 were associated with hospitalisation. Few studies examined associations with musculoskeletal measures. Conclusion Findings suggest 6MWD, heart rate, CRP, fibrinogen and WCC are associated with clinical outcomes in patients with stable COPD. Use of musculoskeletal measures to assess outcomes in patients with COPD requires further investigation. Trial registration number CRD42016052075.
How does aging influence object-location and name-location binding during a visual short-term memory task?

Abstract Objective: Age-related impairments in human visual short-term memory (VSTM) may reflect a reduced ability to retain bound object representations, viz., object form, name, spatial, and temporal location (so called ‘memory sources’). Our objective is to examine how healthy aging affects VSTM in a battery of memory recognition tasks in which sequentially presented objects, locations, and names (as auditory stimuli) were learned, with one component cued at test. Methods: Thirty-six young healthy adults (18–30 years) and 36 normally aging older adults (>60 years with no underlying health and vision issues) completed five VSTM tasks: 1. Object recognition for two or four objects; 2. Spatial location recognition for two or four objects; 3. Bound object-location recognition for two or four objects; 4. Object recognition with location priming for two or four objects; 5. Bound name (auditory)-location (cross-modal) recognition for four objects. Results: Significantly lower performance for older adults was found in spatial location recognition [task 2, p = 0.03], bound object-location recognition [task 3, p = 0.001], object recognition with location priming [task 4, p = 0.02], and bound name-location recognition [task 5, p = 0.001, independent samples t-test] tasks. A significant age group-task interaction was found (p = 0.02). Conclusion: Performance for all tests except test 1 was impaired in older adults. Lower performance for older adults was most significant in VSTM tasks requiring object-location (visual only) or name-location (auditory and visual) binding. The findings are compatible with the ‘memory source’ model, demonstrating that age-related binding performance is influenced by spatial coding and location priming deficits.
Spatially Detailed 3D Quantification of Improved Facial Symmetry After Surgery in Children With Unicoronal Synostosis

Objective: To assess improvement of soft-tissue facial symmetry in children surgically treated for unicoronal synostosis (UCS) in infancy, to correlate pre- and postsurgical facial asymmetry and to evaluate whether the improvement was visually recognizable. Design: Case–controlled follow-up. Patients/Settings: Eleven Danish children diagnosed with UCS were included, 3 of whom had tested positive for Muenke mutation. Preoperative computed tomography scans and postoperative 3dMD surfaces were available for measurements. A control group of healthy children matched for age and sex was employed. Main Outcome Measures: Pre- and postsurgical facial asymmetry was analyzed using a computerized method capable of objective and spatially detailed quantification in 3-dimension (transverse, vertical, and sagittal directions). Asymmetry was evaluated in the facial region and 6 subregions (forehead, mouth, eyes, nose, cheek, and chin). Results: The largest significant improvement was seen in the sagittal direction of the facial (1.9 mm), forehead (2.0 mm), and cheek (3.4 mm) regions. Small but significant improvements were also seen in the mouth, chin, and eye regions. No significant improvement was seen in the nose region. Significant correlations were found between the pre- and postsurgically calculated facial asymmetry and between calculated asymmetry and clinical validation scores. Conclusions: All patients presented with improved facial symmetry after surgery and the improvements were visually recognizable. However, only 1 (9.1%) of the 11 patients reached a level of facial asymmetry as low as that seen in the control group. The best outcome was, in general, seen in cases with mild facial asymmetry presurgically.
D3Oncoprint: Stand-Alone Software to Visualize and Dynamically Explore Annotated Genomic Mutation Files.

PURPOSE Advances in next-generation sequencing technologies have led to a reduction in sequencing costs, which has increased the availability of genomic data sets to many laboratories. Increasing amounts of sequencing data require effective analysis tools to use genomic data for biologic discovery and patient management. Available packages typically require advanced programming knowledge and system administration privileges, or they are Web services that force researchers to work on outside servers. METHODS To support the interactive exploration of genomic data sets on local machines with no programming skills required, we developed D3Oncoprint, a standalone application to visualize and dynamically explore annotated genomic mutation files. D3Oncoprint provides links to curated variants lists from CIViC, My Cancer Genome, OncoKB, and Food and Drug Administration-approved drugs to facilitate the use of genomic data for biomedical discovery and application. D3Oncoprint also includes curated gene lists from BioCarta pathways and FoundationOne cancer panels to explore commonly investigated biologic processes. RESULTS This software provides a flexible environment to dynamically explore one or more variant mutation profiles provided as input. The focus on interactive visualization with biologic and medical annotation significantly lowers the barriers between complex genomics data and biomedical investigators. We describe how D3Oncoprint helps researchers explore their own data without the need for an extensive computational background. CONCLUSION D3Oncoprint is free software for noncommercial use. It is available for download from the Web site of the Biometric Research Program of the Division of Cancer Treatment and Diagnosis at the National Cancer Institute ( https://brb.nci.nih.gov/d3oncoprint ). We believe that this tool provides an important means of empowering researchers to translate information from collected data sets to biologic insights and clinical development.
Frequency and risk factors for mental disorders following pancreatitis: a nationwide cohort study

Abstract Objective: To investigate the frequency and risk factors for mental disorders following pancreatitis. Methods: Patients with acute pancreatitis (AP) and chronic pancreatitis (CP) were identified (n = 18,074) from a nationwide database in New Zealand (1998–2015). They were followed from their first hospital admissions for AP or CP to incident mental disorders. Hazard ratios (HR) and 95% confidence intervals (CI) were estimated using multivariable Cox regression analyses. Results: CP (vs AP) was associated with a significantly higher risk of mental disorders (adjusted HR = 2.00 [95% CI = 1.53–2.62]). Pre-existing diabetes (adjusted HR = 8.99 [95% CI = 6.23–12.96] for AP and adjusted HR = 3.42 [95% CI = 2.37–4.96] for CP) and post-pancreatitis diabetes mellitus (adjusted HR = 7.10 [95% CI = 4.14–12.19] for AP and adjusted HR = 2.97 [95% CI = 1.83–4.82] for CP) were risk factors for mental disorders in individuals following pancreatitis. Severe (adjusted HR = 2.07 [95% CI = 1.39–3.06] vs mild) and recurrent (adjusted HR = 1.62 [95% CI = 1.07–2.45] vs single episode) attacks were associated with significantly higher risks of mental disorders following AP. Conclusions: Patients following CP, recurrent AP, severe AP, and those with diabetes are at high risk for developing mental disorders.
Burkitt lymphoma in a patient with Kabuki syndrome carrying a novel KMT2D mutation

Kabuki syndrome (KS) is an extremely rare genetic disorder, mainly caused by germline mutations at specific epigenetic modifier genes, including KMT2D. Because the tumor suppressor gene KMT2D is also frequently altered in many cancer types, it has been suggested that KS may predispose to the development of cancer. However, KS being a rare disorder, few data are available on the incidence of cancer in KS patients.
A phase I dose-escalation study of XL147 (SAR245408), a PI3K inhibitor administered orally to patients (pts) with advanced malignancies.

3004 Background: XL147 is a selective inhibitor of class I PI3K isoforms. In preclinical cancer models, XL147 is cytostatic or cytoreductive as monotherapy and enhances the efficacy of targeted agents and chemotherapeutics. This open label, phase I dose escalation study assesses the safety, pharmacokinetics, pharmacodynamics and activity of XL147 in pts with advanced solid tumors and lymphoma. Methods: Using a standard 3 + 3 design, pts with solid tumors receive once daily XL147 on days 1-21 (21/7) or as a continuous daily dose (CDD) in 28-day cycles. Cycle 1 safety data determine dose-limiting toxicities (DLTs). Disease assessments occur every 8 weeks. The potential utility of pan-Class I PI3K inhibition in lymphoma pts will be explored. Results: 68 solid tumor pts have been treated: 41 on 21/7, 21 on CDD using capsules, and 6 on CDD using tablets. The MTD for 21/7 and preliminary MTD for CDD was 600 mg; MTD expansion in NSCLC and other solid tumor pts at 600 mg XL147 CDD is ongoing. Drug-related skin ra.
Effects of a Rugby League Match Simulation on Decision-Making in Elite Junior Rugby League

Abstract Redman, K, Steel, K, Kelly, V, and Siegler, J. Effects of a rugby league match simulation on decision-making in elite junior rugby league. J Strength Cond Res 35(7): 1972–1980, 2021—The paucity of research on decision-making in Rugby league within the context of a match, and the potential for age and playing experience to influence decision-making ability, warrants further investigation. Therefore, the aim of this study was to determine the effects of a simulated rugby league match on decision-making in elite junior rugby league players. Twenty male junior rugby league players (age 15.9 ± 0.9 years, body mass 87.3 ± 14.3 kg, height 1.82 ± 0.07 m, playing experience 10.2 ± 2.4 years) completed a match simulation protocol that replicated the physiological demands of an elite junior rugby league match. Decision-making performance was measured prematch, midmatch, and postmatch simulation through a reactive agility test and video-based temporal occlusion task. Upper- and lower-body neuromuscular measures as well as ratings of perceived exertion were obtained before decision-making assessments to quantify fatigue. A 2-way mixed analysis of variance with Bonferroni corrections was used to assess changes during the simulation, and significance was accepted at p < 0.05. The main finding of this study was despite observing a decline in neuromuscular function during the match simulation protocol (countermovement jump declined 1.9 ± 0.6 cm [95% confidence intervals 0.4–3.5]; p < 0.05), this decline did not significantly affect decision-making performance (reactive agility test [p = 0.58]; temporal occlusion [p = 0.88]). These results suggest elite junior rugby league players are capable of sustaining performance during a progressively fatiguing match simulation.
The role of dose escalation and proton therapy in perioperative or definitive treatment of chondrosarcoma and chordoma: An analysis of the National Cancer Data Base

Chordomas and chondrosarcomas are a rare but challenging subset of tumors to treat; however, previous studies have shown benefits from proton therapy, which are thought to be primarily driven by prescription conformality permitting homogeneous tumor dosing and the allowance of higher doses. No retrospective studies to date have directly compared the outcomes of conventional and particle therapy or examined the role of high doses (specifically ≥70 Gy) in definitive radiotherapy (DRT) or perioperative radiotherapy (PRT) for both types of malignancies.
Frailty is an independent risk factor for mortality, cardiovascular disease, bone disease and diabetes among aging adults with HIV.

Background We characterized associations between frailty and incidence of cardiovascular disease (CVD), diabetes mellitus (DM), bone disease and mortality within a cohort of aging persons with HIV (PWH). Methods Participants underwent frailty evaluations using the Fried's frailty assessment at baseline and then annually. Frailty was defined as having ≥3 frailty criteria. Clinical outcomes of mortality, incident CVD events, DM, and bone disease events were recorded throughout the study period (baseline to most recent study or clinic visit, or date of clinical outcome occurrence, whichever came first). Poisson regression models evaluated associations between baseline frailty, change in frailty score over 48 weeks, and each clinical outcome. Results Among 821 men and 195 women (median age 51 years), 62 (6%) were frail at baseline. Frailty scores increased in one or more components among 194 participants (19%) from baseline to 48 weeks. Baseline frailty was associated with an increased risk of incident CVD and DM with a trend towards a significant association with incident bone events. Among the components of frailty, slow gait speed was associated with incident DM and borderline-associated with incident CVD. An increase in frailty from baseline to week 48 was associated with mortality, but not with the other clinical outcomes. Conclusions Baseline frailty was associated with multiple adverse health outcomes (incident CVD, DM and bone disease), while increase in frailty score was associated with mortality among PWH engaged in care. Incorporation of frailty assessments into the routine care of PWH may assist in improvement of functional status and risk stratification for age-related chronic diseases.
REDUCING LUNG LIQUID VOLUME INCREASES BIVENTRICULAR OUTPUTS AND SYSTEMIC ARTERIAL BLOOD FLOWS DESPITE DECREASED CARDIAC FILLING PRESSURES IN FETAL LAMBS

As prior work has shown that reducing lung liquid volume 1) increases pulmonary arterial (PA) blood flow, 2) augments right ventricular (RV) output/power, and 3) decreases left atrial (LA) pressure, we tested the hypothesis that this perturbation has global cardiovascular effects. Ten anesthetized, open-chest fetal lambs (128 ± 2 days gestation, full term = 147 days) were acutely instrumented with 1) LA and right atrial (RA) catheters, 2) aortic and pulmonary trunk catheters, 3) brachiocephalic trunk, aortic isthmus, ductal, and left PA flow probes to obtain left ventricular (LV) and RV outputs and hydraulic power and flow in the descending thoracic aorta, and 4) an endotracheal tube to remove lung liquid. A 17 ± 7 ml/kg reduction of lung liquid volume 1) decreased LA and RA pressures similarly (1.5-1.6 mmHg, P < 0.001), 2) augmented LV and RV outputs (21-24%, P < 0.001) and total power (27-28%, P < 0.005), 3) increased systolic flows in the brachiocephalic trunk (18%, P < 0.001), aortic isthmus (29%, P < 0.005), ductus (12%, P < 0.005), and descending thoracic aorta (16%, P < 0.001), 4) increased mean PA flow via a higher systolic inflow (37%, P < 0.001) and lower diastolic backflow (-16%, P < 0.05), and 5) did not change systemic vascular conductance or arterial compliance but increased both pulmonary vascular conductance and arterial compliance (1.8-fold, P < 0.001). These data suggest that hemodynamic effects of lung liquid volume reduction are not confined to the lungs but extend to all cardiac chambers via rises in LV and RV outputs and power, despite falls in cardiac filling pressures, as well as the systemic circulation, via downstream increases in systolic flows of major central arteries.
Prosthetic dental restorations in Swedish samples: prevalence and agreement between self-report, clinical findings, and influence on quality of life

Abstract Objective: To determine the prevalence of dental prosthetic restorations in an adult population, to study the agreement between self-reports and clinical findings of prosthetic restorations, and to study answers from a questionnaire in relation to the prevalence of prosthetic restorations. Material and methods: A questionnaire was sent to a sample of 10,000 adults. A further sample of 1000 individuals was invited to answer the questionnaire and also participate in a clinical study. The agreement between self-report and clinical findings was analyzed, as were the associations between prosthetic restorations and questionnaire responses, using the chi2 test. Results: A total of 40% of the sample had fixed dental prostheses (FDP), 2.7% had removable dentures. The agreement between self-report and clinical findings was 93%. 34.7% of the individuals with no prosthetic restorations were university graduates and 4% of individuals with removable complete dentures. Oral health had the greatest impact on the quality of life of younger individuals with FDP, with an OHIP-14 (Oral Health Impact Profile) score of 7.3 for the age group 20–39 years compared to 4.9 for the age group 65–89 years. Conclusion: The questionnaire method can be a cost-effective way to determine the prevalence of prosthetic restorations.