Miracle-dz/UniFAR-FTUs huggingface dataset:
Valgus alignment and lateral compartment knee OA: A biomechanical paradox or new insight into knee OA? Why has the adduction moment been found to be such a consistent marker of medial compartment disease?

The paper by Felson and colleagues (1) in this issue reports that valgus malalignment increases the risk of knee osteoarthritis (OA) x-ray progression, and incidence of lateral cartilage damage. Furthermore the paper suggests that even a relatively slight valgus alignment may cause lateral compartment osteoarthritis (OA), in part, by increasing the risk of meniscal damage. Given that the major percentage of the ambulatory load during walking is transferred to the medial compartment of the knee even for knees with slight valgus alignment, this study raises some important questions regarding the role of static frontal plane alignment and more specifically of ambulatory forces in the natural course of knee OA. Does this study present a possible biomechanical paradox or do these results point to the need for a deeper understanding of the role of ambulatory load in the pathomechanics of knee OA? This editorial will address this potential paradox by examining the role of mechanical factors in OA across scales ranging from full body ambulation to cell biology.
CDC 37 Is Required for p 60 vsrc Activity in Yeast

Mutations in genes encoding the molecular chaperones Hsp9O and Ydjlp suppress the toxicity of the protein tyrosine kinase p6Ov-src in yeast by reducing its levels or its kinase activity. We describe isolation and characterization of novel p60v-src-resistant, temperature-sensitive cdc37 mutants, cdc37-34 and cdc37-17, which produce less p6Ov-src than the parental wild-type strain at 23°C. However, p6Ov-src levels are not low enough to account for the resistance of these strains. Asynchronously growing cdc37-34 and cdc37-17 mutants arrest in G1 and G2/M when shifted from permissive temperatures (23°C) to the restrictive temperature (370C), but hydroxyurea-synchronized cdc37-34 and cdc37-17 mutants arrest in G2/M when released from the hydroxyurea block and shifted from 23 to 37°C. The previously described temperature-sensitive cdc37-1 mutant is p6Ov-src_ sensitive and produces wild-type amounts of p6ov-src at permissive temperatures but becomes p60v-src-resistant at its restrictive temperature, 38°C. In all three cdc37 mutants, inactivation of Cdc37p by incubation at 38°C reduces p60v-src-dependent tyrosine phosphorylation of yeast proteins to low or undetectable levels. Also, p6Ov-src levels are enriched in urea-solubilized extracts and depleted in detergent-solubilized extracts of all three cdc37 mutants prepared from cells incubated at the restrictive temperature. These results suggest that Cdc37p is required for maintenance of p6ov-src in a soluble, biologically active form.
Stereotactic Radiotherapy combined with Immunotherapy: Augmenting Radiation’s Role in Local and Systemic Treatment

2 study of MEDI4736 (anti-PD-L1) combined with radiation in patients with Glioblastoma (NCT02336165). This multi-center study sponsored by the Ludwig Institute for Cancer Research aims to enroll over 80 patients with GBM into three cohorts. Cohort A is planned to enroll patients with newly diagnosed unmethylated MGMT GBM who will receive MEDI4736 every 2 weeks in combination with standard radiotherapy; Cohort B will include bevacizumab-naïve patients with recurrent GBM who will receive MEDI4736 every 2 weeks as monotherapy; and Cohort C will enroll bevacizumab-refractory patients with recurrent GBM who will receive MEDI4736 every 2 weeks in combination with continued bevacizumab. The primary endpoint includes overall survival and progression free survival. Secondary objectives include safety, tolerability and biological activity as assessed by immunologic markers. This study will investigate the efficacy of anti-PD-L1 monotherapy in GBM patients and radiation combined with anti-PD-L1 in patients with newly diagnosed GBM with unmethylated MGMT.
Improving Adjuvant Liver-Directed Treatment Recommendations for Unresectable Hepatocellular Carcinoma: An Artificial Intelligence–Based Decision-Making Tool

PURPOSE Liver-directed therapy after transarterial chemoembolization (TACE) can lead to improvement in survival for selected patients with unresectable hepatocellular carcinoma (HCC). However, there is uncertainty in the appropriate application and modality of therapy in current clinical practice guidelines. The aim of this study was to develop a proof-of-concept, machine learning (ML) model for treatment recommendation in patients previously treated with TACE and select patients who might benefit from additional treatment with combination stereotactic body radiotherapy (SBRT) or radiofrequency ablation (RFA). METHODS This retrospective observational study was based on data from an urban, academic hospital system selecting for patients diagnosed with stage I-III HCC from January 1, 2008, to December 31, 2018, treated with TACE, followed by adjuvant RFA, SBRT, or no additional liver-directed modality. A feedforward, ML ensemble model provided a treatment recommendation on the basis of pairwise assessments evaluating each potential treatment option and estimated benefit in survival. RESULTS Two hundred thirty-seven patients met inclusion criteria, of whom 54 (23%) and 49 (21%) received combination of TACE and SBRT or TACE and RFA, respectively. The ML model suggested a different consolidative modality in 32.7% of cases among patients who had previously received combination treatment. Patients treated in concordance with model recommendations had significant improvement in progression-free survival (hazard ratio 0.5; P = .007). The most important features for model prediction were cause of cirrhosis, stage of disease, and albumin-bilirubin grade (a measure of liver function). CONCLUSION In this proof-of-concept study, an ensemble ML model was able to provide treatment recommendations for HCC who had undergone prior TACE. Additional treatment in line with model recommendations was associated with significant improvement in progression-free survival, suggesting a potential benefit for ML-guided medical decision making. Proof of concept #ML decision support tool for adjuvant therapy selection for unresectable HCC.
Translating the Observational Medical Outcomes Partnership - Common Data Model (OMOP-CDM) Electronic Health Records to an OWL Ontology

The heterogeneity of electronic health records model is a major problem: it is necessary to gather data from various models for clinical research, but also for clinical decision support. The Observational Medical Outcomes Partnership - Common Data Model (OMOP-CDM) has emerged as a standard model for structuring health records populated from various other sources. This model is proposed as a relational database schema. However, in the field of decision support, formal ontologies are commonly used. In this paper, we propose a translation of OMOP-CDM into an ontology, and we explore the utility of the semantic web for structuring EHR in a clinical decision support perspective, and the use of the SPARQL language for querying health records. The resulting ontology is available online.
mHealth Research for Weight Loss, Physical Activity, and Sedentary Behavior: Bibliometric Analysis

Background Research into mobile health (mHealth) technologies on weight loss, physical activity, and sedentary behavior has increased substantially over the last decade; however, no research has been published showing the research trend in this field. Objective The purpose of this study was to provide a dynamic and longitudinal bibliometric analysis of recent trends of mHealth research for weight loss, physical activity, and sedentary behavior. Methods A comprehensive search was conducted through Web of Science to retrieve all existing relevant documents published in English between January 1, 2010, and November 1, 2021. We developed appropriate research questions; based on the proven bibliometric approaches, a search strategy was formulated to screen the title for eligibility. Finally, we conducted bibliometric analyses to explore the growth rate of publications; publication patterns; and the most productive authors, institutions, and countries, and visualized the trends in the field using a keyword co-occurrence network. Results The initial search identified 8739 articles, of which 1035 were included in the analyses. Our findings show an exponential growth trend in the number of annual publications of mHealth technology research in these fields. JMIR mHealth and uHealth (n=214, 20.67%), Journal of Medical Internet Research (n=71, 6.86%), and BMC Public Health (n=36, 3.47%) were the top 3 journals, publishing higher numbers of articles. The United States remained the leading contributor in these areas (n=405, 39.13%), followed by Australia (n=154, 14.87%) and England (n=125, 12.07%). Among the universities, the University of Sydney (n=36, 3.47%) contributed the most mHealth technology research in these areas; however, Deakin University (n=25, 2.41%) and the National University of Singapore (n=23, 2.22%) were in the second and third positions, respectively. Conclusions Although the number of papers published on mobile technologies for weight loss, physical activity, and sedentary behavior was initially low, there has been an overall increase in these areas in recent years. The findings of the study indicate that mobile apps and technologies have substantial potential to reduce weight, increase physical activity, and change sedentary behavior. Indeed, this study provides a useful overview of the publication trends and valuable guidance on future research directions and perspectives in this rapidly developing field.
Behavior Analytic Feeding Interventions: Current State of the Literature

The purpose of this paper was to review the current state of the behavior analytic feeding intervention literature. We highlight studies that we found to be important contributions to the recent literature in the following areas: food selectivity, chewing, packing, and food refusal/tube weaning and provide suggestions for future research and clinical work in these areas. We also discuss several current topics relevant to the field in hopes to further advance research and clinical practice. These topics include considering the benefits of innovative models of service delivery such as telehealth and caregiver-implemented interventions, the importance of evaluating long-term outcomes of behavioral feeding interventions, and lastly, ethical issues to consider in the designing and implementation of behavioral feeding interventions and training of practitioners in our field.
Microbially-derived cocktail of carbohydrases as an anti-biofouling agents: a ‘green approach’

Abstract Enzymes, also known as biocatalysts, display vital properties like high substrate specificity, an eco-friendly nature, low energy inputs, and cost-effectiveness. Among their numerous known applications, enzymes that can target biofilms or their components are increasingly being investigated for their anti-biofouling action, particularly in healthcare, food manufacturing units and environmental applications. Enzymes can target biofilms at different levels like during the attachment of microorganisms, formation of exopolymeric substances (EPS), and their disruption thereafter. In this regard, a consortium of carbohydrases that can target heterogeneous polysaccharides present in the EPS matrix may provide an effective alternative to conventional chemical anti-biofouling methods. Further, for complete annihilation of biofilms, enzymes can be used alone or in conjunction with other antimicrobial agents. Enzymes hold the promise to replace the conventional methods with greener, more economical, and more efficient alternatives. The present article explores the potential and future perspectives of using carbohydrases as effective anti-biofilm agents.
Old World Vultures Reflect Effects of Environmental Pollutants Through Human Encroachment

African wildlife face challenges from many stressors including current and emerging contaminants, habitat and resource loss, poaching, intentional and unintentional poisoning, and climate‐related environmental change. The plight of African vultures exemplifies these challenges due to environmental contaminants and other stressors acting on individuals and populations that are already threatened or endangered. Many of these threats emanate from increasing human population size and settlement density, habitat loss from changing land use for agriculture, residential areas, and industry, and climate‐related changes in resource availability. Environmental chemicals that are hazardous include legacy chemicals, emerging chemicals of concern, and high‐volume‐use chemicals that are employed as weed killers and in other agricultural applications. Furthermore, there are differences in risk for species living in close proximity to humans or in areas affected by habitat loss, climate, and industry. Monitoring programs are essential to track the status of nesting pairs, offspring survival, longevity, and lifetime productivity. This is important for long‐lived birds, such as vultures, that may be especially vulnerable to chronic exposure to chemicals as obligate scavengers. Furthermore, their position in the food web may increase risk due to biomagnification of chemicals. We review the primary chemical hazards to Old World vultures and the interacting stressors affecting these and other birds. Habitat is a major consideration for vultures, with tree‐nesters and cliff‐nesters potentially experiencing different risks of exposure to environmental chemicals. The present review provides information from long‐term monitoring programs and discusses a range of these threats and their effects on vulture populations. Environ Toxicol Chem 2022;41:1586–1603. © 2022 SETAC
Heavy Chain Constant Region Usage in Antibodies to Peptidylarginine Deiminase 4 as a Marker of Disease Subsets in Rheumatoid Arthritis

The study of autoantibody isotypes in autoimmune diseases is useful for identifying clinically relevant endotypes. This study was undertaken to study the prevalence and clinical significance of different isotypes and IgG subclasses of anti–peptidylarginine deiminase 4 (anti‐PAD4) autoantibodies in individuals with rheumatoid arthritis (RA).
Hemophagocytosis on ascitic fluid cytology: Diagnosis of HLH

Hemophagocytic lymphohistiocytosis (HLH) is a life‐threatening syndrome of pathologic immune response characterized by excessive activation of macrophages. Hemophagocytosis is one of the diagnostic criteria for HLH, and it usually involves the bone marrow, spleen, lymph nodes, or any part of the reticuloendothelial system. Hemophagocytosis in the ascitic fluid has rarely been reported in HLH. Here, we report the case of a patient who presented with fever and abdominal distention and ascites. Ascitic fluid cytology showed hemophagocytosis which was the clue for HLH diagnosis. We also review the literature for this rare cytological occurrence.
In Vivo Measurement of and Field Inhomogeneity Maps in the Human Heart at 1.5 T

Cardiac echo-planar imaging suffers invariably from regions of severe distortion and decay in the myocardium. The purpose of this work was to perform local measurements of and field inhomogeneities in the myocardium and to identify the sources of focal signal loss and distortion. Field inhomogeneity maps and were measured in five normal volunteers in short-axis slices spanning from base to apex. It was found that ranged from 26 ms (SD = 7 ms, n = 5) to 41 ms (SD = 11 ms, n = 5) over most of the heart, and peak-to-peak field inhomogeneity differences were 71 Hz (SD = 14 Hz, n = 5). In all hearts, regions of severe signal loss were consistently adjacent to the posterior vein of the left ventricle; in these regions was 12 ms (SD = 2 ms, n = 5), and the difference in resonance frequency with the surrounding myocardium was 70-100 Hz. These effects may be caused by increased magnetic susceptibility from deoxygenated blood in these veins.
Metabolic Actions of IGF-I in Normal Physiology and Diabetes

Synopsis Insulin-like growth factor-I (IGF-I) is closely related to insulin but has distinct metabolic actions. IGF-I is an important stimulant of protein synthesis in muscle but it also stimulates free fatty acid utilization. Important indirect effects of IGF-I that influence metabolism include suppression of growth hormone secretion and at supraphysiologic concentrations suppression of insulin secretion. IGF-I actions are regulated by IGF binding proteins and in obesity and metabolic syndrome there is major dysregulation of IGF binding protein secretion resulting in alterations in the concentration of free IGF-I and IGF-I actions. In type 1 diabetes, IGF-I synthesis is markedly impaired and in type 2 diabetes multiple changes occur in IGF-I actions including sensitization to its mitogenic actions in some target tissues. Administration of IGF-I to patients with extreme insulin resistance results in improvement in glycemic control and IGF-I has been shown to be associated with lowering glucose and enhancing insulin sensitivity in both type 1 and type 2 diabetes. However diabetics are also quite sensitive to stimulation of side effects in response to IGF-I and this has greatly limited its usefulness as a hypoglycemic agent. IGF-I coordinately links growth hormone and insulin actions as well as having direct effects on intermediary metabolism.
SHORT COMMUNICATION IL-1 b and Caspase-1 Drive Autoin ﬂ ammatory Disease Independently of IL-1 a or Caspase-8 in a Mouse Model of Familial Mediterranean Fever

Mutations in the gene encoding pyrin are associated with autoin ﬂ ammatory disorder Familial Mediterranean Fever (FMF). A FMF-knock-in mouse strain that expresses chimeric pyrin protein with a V726A mu-tation ( Mefv V726A/V726A ) was generated to model human FMF. This mouse strain shows an autoin ﬂ ammatory disorder that is prevented by genetic deletion of IL-1 (IL-1) receptor or apoptosis-associated speck-like protein containing a caspase activation and recruitment domain (ASC). ASC-mediated cell death leads to the release of IL-1 a and IL-1 b , both of which signal through IL-1 receptor. Furthermore, caspase-1 and caspase-8 can interact with ASC to mediate secretion of IL-1 cytokines. The speci ﬁ c IL-1 cytokine instigating development of FMF and the enzymatic caspase involved in its secretion currently are unknown. In this study, we show that the autoin ﬂ ammation observed in Mefv V726A/V726A mice is mediated speci ﬁ cally by IL-1 b and not IL-1 a . Furthermore, the disorder is dependent on the caspase-1 e ASC axis, whereas caspase-8 is dispensable. Concurrently, aberrant IL-1 b release by Mefv V726A/V726A monocytes in response to stimulation with lipopolysaccharide also is dependent on the caspase-1 e ASC axis. In conclusion, our studies have uncovered a speci ﬁ c role for caspase-1 e mediated IL-1 b release in the manifestation of FMF. (Am
Acidifying endolysosomes prevented LDL-induced amyloidogenesis

, Abstract Cholesterol dyshomeostasis has been linked to the pathogenesis of sporadic Alzheimer’s disease (AD). In furthering the understanding of mechanisms by which increased levels of circulating cholesterol augments the risk of developing sporadic AD, others and we have reported that LDL enters brain parenchyma by disrupting the blood-brain barrier and that endolysosome deacidification plays a role in LDL-induced amyloidogenesis in neurons. Here, we tested the hypothesis that endolysosome de-acidification was central to amyloid beta (A β ) generation and that acidifying endolysosomes protects against LDL-induced increases in A β levels in neurons. We demonstrated that LDL, but not HDL, de-acidified endolysosomes and increased intraneuronal and secreted levels of A β . ML-SA1, an agonist of endolysosome-resident TRPML1 channels, acidified endolysosomes, and TRPML1 knockdown attenuated MLSA1-induced endolysosome acidification. ML-SA1 blocked LDL-induced increases in intraneuronal and secreted levels of A β as well as A β accumulation in endolysosomes, prevented BACE1 accumulation in endolysosomes, and decreased BACE1 activity levels. LDL down regulated TRPML1 protein levels, and TRPML1 knockdown worsens LDL-induced increases in A β . Our findings suggest that endolysosome acidification by activating TRPML1 may represent a protective strategy against sporadic AD.
Functional Expression of g –Amino Butyric Acid Transporter 2 in Human and Guinea Pig Airway Epithelium and Smooth Muscle

g 2 Amino butyric acid (GABA) is a primary inhibitory neurotransmitter in the central nervous system, and is classically released by fusion of synaptic vesicles with the plasma membrane or by egress via GABA transporters (GATs). Recently, a GABAergic system com- prised of GABA A and GABA B receptors has been identiﬁed on airway epithelialandsmoothmusclecellsthatregulatemucussecretionand contractile tone of airway smooth muscle (ASM). In addition, the enzyme that synthesizes GABA, glutamic acid decarboxylase, has beenidentiﬁedinairwayepithelialcells;however,themechanism(s)bywhichthissynthesizedGABAisreleasedfromepithelialintracel-lular stores is unknown. We questioned whether any of the four known isoforms of GATs are functionally expressed in ASM or epithelial cells. We detected mRNA and protein expression of GAT2 and -4, and isoforms of glutamic acid decarboxylase in native and cultured human ASM and epithelial cells. In contrast, mRNA encod- ing vesicular GAT (VGAT), the neuronal GABA transporter, was not detected. Functional inhibition of 3 H-GABA uptake was demonstrated using GAT2 and GAT4/betaine–GABA transporter 1 (BGT1) inhibitors in both human ASM and epithelial cells. These results demonstratethattwoisoformsofGATs,butnotVGAT,areexpressedinbothairwayepithelialandsmoothmusclecells.Theyalsoprovide a mechanism by which locally synthesized GABA can be released from these cells into the airway to activate GABA A channels and GABA B receptors, with subsequent autocrine and/or paracrine signaling effects on airway epithelium and ASM.
Emotions in sport coaching: Introduction to the special issue

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