Miracle-dz/UniFAR-FTUs huggingface dataset:
Quantitating Age‐Related BMD Textural Variation from DXA Region‐Free‐Analysis: A Study of Hip Fracture Prediction in Three Cohorts

The risk of osteoporotic fracture is inversely related to bone mineral density (BMD), but how spatial BMD pattern influences fracture risk remains incompletely understood. This study used a pixel‐level spatiotemporal atlas of proximal femoral BMD in 13,338 white European women (age 20–97 years) to quantitate age‐related texture variation in BMD maps and generate a “reference” map of bone aging. We introduce a new index, called Densitometric Bone Age (DBA), as the age at which an individual site‐specific BMD map (the proximal femur is studied here) best matches the median aging trajectory at that site in terms of the root mean squared error (RMSE). The ability of DBA to predict incident hip fracture and hip fracture pattern over 5 years following baseline BMD was compared against conventional region‐based BMD analysis in a subset of 11,899 women (age 45–97 years), for which follow‐up fracture records exist. There were 208 subsequent incident hip fractures in the study populations (138 femoral necks [FNs], 52 trochanteric [TR], 18 sites unspecified). DBA had modestly better performance compared to the conventional FN‐BMD, TR‐BMD, and total hip (TOT)‐BMD in identifying hip fractures measured as the area under the curve (AUC) using receiver operating characteristics (ROC) curve analysis by 2% (95% confidence interval [CI], −0.5% to 3.5%), 3% (95% CI, 1.0% to 4.0%), and 1% (95% CI, 0.4% to 1.6%), respectively. Compared to FN‐BMD T‐score, DBA improved the ROC‐AUC for predicting TR fractures by ~5% (95% CI, 1.1% to 9.8%) with similar performance in identifying FN fractures. Compared to TR‐BMD T‐score, DBA improved the ROC‐AUC for the prediction of FN fractures by ~3% (95% CI, 1.1% to 4.9%), with similar performance in identifying TR fractures. Our findings suggest that DBA may provide a spatially sensitive measure of proximal femoral fragility that is not captured by FN‐BMD or TR‐BMD alone. © 2022 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).
Reconstructing dropout: Building from multiple definitions, therapist effects, and center effects

Abstract Objective: The literature regarding dropout from psychotherapy has suffered from issues of diverse operationalization of the construct. Some have called for a more uniform definition to aid in generalization across research; this study aimed to assess the viability of such a definition by examining the rate of occurrence for three distinct definitions simultaneously. In addition, therapist and center level variances are explored to further understand the differences between definitions. Method: We compared the prevalence rates and overlap of three distinct operationalizations of dropout (based on last session attendance, therapist judgment, and symptom change) using data gathered from a national practice research network (N = 2977). Higher-order therapist and center-level effects were assessed for each definition. Results: There was very little overlap among definitions, with less than one percent of clients simultaneously meeting criteria for all three definitions. Additionally, therapist and center effects were found for each definition, especially notable for therapist-rated and last-session attendance definitions of dropout. Conclusion: Rather than a singular definition of dropout, these results instead suggest that multiple, specific, and unique definitions more accurately depict clinical reality, and future research might benefit from uncovering predictors of different “classes” of dropouts and examining the different practices of therapists and centers.
The late I Na Inhibitor Ranolazine Attenuates Effects of Palmitoyl-L-Carnitine to Increase Late I Na and Cause Ventricular Diastolic Dysfunction

Palmitoyl-L-carnitine (PC), an ischemic metabolite, causes cellular Na + and Ca 2+ overload and cardiac dysfunction. This study determined if ranolazine attenuates PC-induced Na + current and ventricular contractile dysfunction of the isolated heart. PC (4 µmol/L, 30 minutes) increased late Na + current by 1,034+/-349% in guinea pig isolated ventricular myocytes; ranolazine (10 μ mol/L) and tetrodotoxin (TTX, 3 μ mol/L) significantly attenuated this effect of PC. PC increased left ventricular end-diastolic pressure (LVEDP), coronary perfusion pressure (CPP), wall stiffness, and cardiac lactate and adenosine release from the isolated heart. Ranolazine (10 µmol/L) significantly reduced the PC-induced increase in LVEDP by 72 ± 6 % (n=6, p<0.001) , reduced left ventricular wall stiffness, and attenuated the PC-induced increase of CPP by 53 ± 10% (n=6-7, p<0.05). Ranolazine (10 µmol/L) reduced the PC-induced increases of lactate and adenosine release by 70 ± 8 and 81 ± 5 %, respectively (n=6, p ≤ 0.05 for both). TTX (2 µmol/L) significantly (p<0.05) reduced PC- induced increases of CPP and LVEDP. free radical reduced the effects of PC to cause increases of late Na + current and LVEDP, respectively, TTX, Tiron reverse late Na + current and LVEDP by coronary two-way ANOVA with repeated measures of one variable, unless stated otherwise. For analysis of data from myocyte electrophysiology experiments, the one-way repeated measures ANOVA followed by Student-Newman-Keuls test for multiple comparisons was used. The percentage inhibition by ranolazine (Ran) of the effects of PC was calculated using the formula [(PC – Ran)/(PC – control)] x 100, where PC, Ran and control indicate measurements obtained in the presence of PC alone, PC plus Ran, and in the absence of drugs, respectively. Differences among measure values were considered to be significant when the probability of their chance occurrence was < 0.05. Values of n indicate the number of cells or hearts studied. Data are expressed as mean ± SEM.
Characterization of Virologic Rebound Following Nirmatrelvir-Ritonavir Treatment for Coronavirus Disease 2019 (COVID-19)

Abstract We enrolled 7 individuals with recurrent symptoms or antigen test conversion following nirmatrelvir-ritonavir treatment. High viral loads (median 6.1 log10 copies/mL) were detected after rebound for a median of 17 days after initial diagnosis. Three had culturable virus for up to 16 days after initial diagnosis. No known resistance-associated mutations were identified.
Synthesis and biological evaluation of sulfonamide‐based compounds as inhibitors of carbonic anhydrase from Vibrio cholerae

This study reports our continued efforts to identify inhibitors capable of targeting carbonic anhydrases (CAs) expressed in bacteria. Based on previously identified chemotypes, we designed and synthesized new analogs that were screened toward the α, β, and γ classes encoded in Vibrio cholerae (Vch). The Ki values measured in the stopped‐flow hydrase assay revealed that very simple structural modifications might induce a relevant impact on the inhibitory effects as well as the selectivity profile over ubiquitous human isozymes (hCA I/II). Unfortunately, the best active VchCA inhibitors demonstrated a dramatic loss of hCA II selectivity when compared to previously reported compounds. Among the new series of sulfonamides, several molecules proved to be about sevenfold more potent against VchCAγ than the reference compound acetazolamide, thus furnishing new insights for further development of inhibitors targeting CAs expressed in bacteria.
Virtual McKenzie extension exercises for low back and leg pain: a prospective pilot exploratory case series

ABSTRACT Introduction Current evidence supports the inclusion of directional preference exercises for a subgroup of patients with low back (LBP) and leg pain. Recent pain neuroscience strategies have suggested that cortical restructuring associated with movement activating the body map representation in the brain might account for the observed improvement with the directional preference approach. Objectives To explore whether or not a motor imagery directional preference approach would result in any changes in patients with LBP and leg pain. Methods A consecutive convenience sample of patients with LBP and leg pain were recruited at two outpatient physical therapy clinics. Measurements of LBP, leg pain, fear-avoidance beliefs (FABQ), pain catastrophizing (PCS), active lumbar flexion, and straight leg raise (SLR) were compared before and immediately after a virtual (motor imagery) directional preference exercise. Results Statistically significant differences for LBP, FABQ, PCS, active lumbar flexion, and SLR were observed, but only SLR changes met or exceeded the minimally clinically important difference (MCID). Conclusions A brief virtual motor imagery extension treatment yielded some immediate positive shifts in patients presenting to physical therapy with LBP and leg pain. Our results indicate that randomized comparison trials are needed to determine the effect of this intervention on the short- and longer-term outcomes in patients with LBP and leg pain.
MOF-derived nitrogen-doped carbon-based trimetallic bifunctional catalysts for rechargeable zinc-air batteries

Zinc-air battery (ZAB) is a promising new metal-air energy system, but the large overpotentials of oxygen evolution reaction (OER) and oxygen reduction reaction (ORR) around the air electrode lead to their poor energy efficiency. Herein, a novel bifunctional oxygen electrocatalyst is reported with the preparation of a zeolite imidazolate framework (ZIF-67) derived trimetallic composites decorated nitrogen-doped carbon, which consist of NiFe alloy and Co nanoparticles. The ZIF-derived porous N-doped carbon shell can speed up the mass transfer efficiency. Whereas the electronic effect between the formed NiFe alloy and Co nanoparticles, as well as the N-doped carbon framework can enrich the active centers and enhance the electrical conductivity. As a result, the NiFe-Co@NC-450 catalyst shows superior performance manifested as a small potential gap (ΔE = 0.857 V) between the overpotential at 10 mA cm−2 (E j=10) for OER (460 mV) and half-wave potential (E 1/2) for ORR (0.833 V). The liquid ZABs exhibit a high specific capacity reaching 798 mAh/gZn and a stable cycling performance at 10 mA cm−2 for more than 200 h. Meanwhile, the NiFe-Co@NC-450 based flexible ZABs also presents robust flexibility and stability. This study has certain implications for the development of economical, powerful and stable bifunctional catalysts for ZABs.
A pathologically confirmed case of combined amyotrophic lateral sclerosis with C9orf72 mutation and multiple system atrophy

Hexanucleotide repeat expansions in C9orf72 account for a large proportion of cases of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration. There have been occasional reported cases associated with this expansion but also additional extrapyramidal clinical features. However, only very rarely has there been pathological confirmation of a parkinsonian syndrome associated with a C9orf72 repeat expansion. To date, as far as we are aware, there have been no reported pathologically confirmed cases of ALS with C9orf72 mutation and multiple system atrophy (MSA). We report a case of a man who initially presented with extrapyramidal features, including cogwheel rigidity, and, therefore, was clinically considered likely to have Parkinson's disease or a parkinsonian syndrome. Subsequent examination six months later revealed additional abnormal upper and lower motor neuron signs, raising the strong possibility of ALS. He had a rapid clinical decline and died 16 months after the first presentation. It was noted that his father also had ALS, and that his mother had a parkinsonian syndrome, suggestive of progressive supranuclear palsy. The macroscopic and microscopic examination of the brain and spinal cord revealed ALS pathology with neuronal loss, especially of the anterior horns of the cord and the motor cortex. This was associated with numerous neuronal cytoplasmic inclusions immunoreactive for phosphorylated transactivation response DNA‐binding protein of 43 Da (TDP43). There were additional pathological features, including p62‐immunoreactive cerebellar neuronal cytoplasmic inclusions, fully in keeping with a C9orf72 repeat expansion, and this was confirmed on molecular analysis. However, there was also α‐synuclein pathology in the form of oligodendroglial cytoplasmic inclusions in the basal ganglia, cerebellum, and brainstem, indicative of MSA. To our knowledge, this is the first reported case of pathologically confirmed combined ALS‐C9orf72 and MSA.
Total Postprandial Hepatic Nonesterified and Dietary Fatty Acid Uptake Is Increased and Insufficiently Curbed by Adipose Tissue Fatty Acid Trapping in Prediabetes With Overweight

Excessive lean tissue uptake of fatty acids (FAs) is important in the development of insulin resistance and may be caused by impaired dietary FA (DFA) storage and/or increased nonesterified FA (NEFA) flux from adipose tissue intracellular lipolysis. Cardiac and hepatic total postprandial FA uptake of NEFA+DFA has, however, never been reported in prediabetes with overweight. In this study, 20 individuals with impaired glucose tolerance (IGT) and 19 participants with normal glucose tolerance (NGT) and normal fasting glucose underwent postprandial studies with whole-body positron emission tomography/computed tomography (PET/CT) with oral [18F]fluoro-thia-heptadecanoic acid and dynamic PET/CT with intravenous [11C]palmitate. Hepatic (97 [range 36–215] mmol/6 h vs. 68 [23–132] mmol/6 h, P = 0.03) but not cardiac (11 [range 4–24] mmol/6 h vs. 8 [3–20] mmol/6 h, P = 0.09) uptake of most sources of postprandial FA (NEFA + DFA uptake) integrated over 6 h was higher in IGT versus NGT. DFA accounted for lower fractions of total cardiac (21% [5–47] vs. 25% [9–39], P = 0.08) and hepatic (19% [6–52] vs. 28% [14–50], P = 0.04) uptake in IGT versus NGT. Increased adipose tissue DFA trapping predicted lower hepatic DFA uptake and was associated with higher total cardiac FA uptake. Hence, enhanced adipose tissue DFA trapping in the face of increased postprandial NEFA flux is insufficient to fully curb increased postprandial lean organ FA uptake in prediabetes with overweight (ClinicalTrials.gov; NCT02808182).
BK channels at dendritic spines: A mechanism for coupling morphology, plasticity and information storage?

Cortical pyramidal neurons receive a constant barrage of temporally and spatially precise information in the form of local and long-range synaptic inputs. These inputs contact microscopic (<1 fL) protrusions called spines, connected to the neuron’s extensive dendritic arborization by a slender neck. These spines express glutamate receptors (AMPARs and NMDARs) on their surface and act as electrical and biochemical compartments upon their excitation by presynaptic inputs. Work over recent decades has shown that the morphological and functional heterogeneity of spines enables them to perform sophisticated, combinatorial computations on incoming synaptic information. Spine morphology can influence synaptic plasticity, with spine neck shape and head volume controlling diffusion of important plasticity-related molecules such as calcium between the spine and the parent dendrite. Concurrently, plasticity can influence spine morphology, with learning-related changes over timescales of minutes to hours; long-term synaptic depression (LTD) can reduce spine head volume and lead to elimination, whereas long-term
Impact of ward pharmacist-led antimicrobial stewardship in intensive care units

Abstract Various outcomes of mortality, medical costs, and antimicrobial usage result from antimicrobial stewardship (AS) programmes. Here, we clarified the effects of AS implementation by a well-trained pharmacist in an open intensive care unit (open ICU) through a retrospective, comparative study of 5123 open ICU patients of Tokai University Hospital. The 12 months before and after AS implementation were considered the control and study periods, respectively. After AS implementation, the number of AS cases increased significantly. The period until the implementation of therapeutic drug monitoring was significantly shortened, and antimicrobial drug usage increased significantly. The methicillin-resistant Staphylococcus aureus (MRSA) detection rate decreased significantly. Earlier and more frequent AS implementation could enhance treatment effects, possibly decreasing the MRSA incidence. Despite active AS implementation, antimicrobial drug usage did not necessarily decrease. ICU pharmacists with experience in AS should take on leadership roles and implement active AS strategies in open ICU settings.
Non-Contributory Pensions, Functional Limitations, and Unpaid Family Care for Older Adults in Mexico

Objectives: We explore the effects of non-contributory pensions on functional limitations and receipt of unpaid family care by gender and frequency of pension payment. Methods: We employ a difference-in-differences estimator to identify the causal effects of non-contributory pension programs disbursed monthly or every two months for adults 70 years and older in the state of Yucatan, Mexico. Results:The monthly payment program led to lower difficulties in functional limitations and less receipt of help from family or relatives for older men and women as compared to the bimonthly program. We found a larger decline on receipt of family care for older women than for men. Discussion:Our results suggest that more frequent pension payments may have greater health benefits for recipients. They also highlight the need for greater understanding of policies that prevent or delay functional limitations and that could indirectly alleviate unpaid caregiver burden.
Orbital myeloid sarcoma treated with low-dose venetoclax and a potent cytochrome P450 inhibitor

Case report We report the first case of orbital myeloid sarcoma that was successfully treated with a standard venetoclax dose of 25%. A 38-year-old man with acute myeloid leukemia (AML) post-haplo-hematopoietic stem cell transplantation (HSCT) presented with a nine-month history of progressive right proptosis and a visual acuity deficit. The patient was treated with venetoclax (100 mg orally on days 1–28), cytarabine (40 mg subcutaneously, days 1–10), and itraconazole (100 mg twice daily orally on days 1–28). Management and outcome The present case report shows that using cytochrome P450 (CYP) inhibitors is a helpful strategy to reduce the cost of expensive treatments. Discussion There are limited data on the use of CYP inhibitors as a strategy to reduce the costs of expensive drugs (i.e. venetoclax). This approach has some advantages over standard dose venetoclax (400 mg/day) such as significantly reduced costs (which is relevant for patients in low-income countries). In this case, we used itraconazole—a potent CYP3A4 inhibitor—which can theoretically reduce the dose to 100 mg/day without losing serum therapeutic concentrations.
Patterns, Predictors, and Intercenter Variability in Empiric Gram-Negative Antibiotic Use Across 928 United States Hospitals

Abstract Background Empiric antibiotic use among hospitalized adults in the United States (US) is largely undescribed. Identifying factors associated with broad-spectrum empiric therapy may inform antibiotic stewardship interventions and facilitate benchmarking. Methods We performed a retrospective cohort study of adults discharged in 2019 from 928 hospitals in the Premier Healthcare Database. “Empiric” gram-negative antibiotics were defined by administration before day 3 of hospitalization. Multivariable logistic regression models with random effects by hospital were used to evaluate associations between patient and hospital characteristics and empiric receipt of broad-spectrum, compared to narrow-spectrum, gram-negative antibiotics. Results Of 8 017 740 hospitalized adults, 2 928 657 (37%) received empiric gram-negative antibiotics. Among 1 781 306 who received broad-spectrum therapy, 30% did not have a common infectious syndrome present on admission (pneumonia, urinary tract infection, sepsis, or bacteremia), surgery, or an intensive care unit stay in the empiric window. Holding other factors constant, males were 22% more likely (adjusted odds ratio [aOR], 1.22 [95% confidence interval, 1.22–1.23]), and all non-White racial groups 6%–13% less likely (aOR range, 0.87–0.94), to receive broad-spectrum therapy. There were significant prescribing differences by region, with the highest adjusted odds of broad-spectrum therapy in the US West South Central division. Even after model adjustment, there remained substantial interhospital variability: Among patients receiving empiric therapy, the probability of receiving broad-spectrum antibiotics varied as much as 34+ percentage points due solely to the admitting hospital (95% interval of probabilities: 43%–77%). Conclusions Empiric gram-negative antibiotic use is highly variable across US regions, and there is high, unexplained interhospital variability. Sex and racial disparities in the receipt of broad-spectrum therapy warrant further investigation.
Immature Brain Cortical Neurons Have Low Transcriptional Competence to Activate Antiviral Defences and Control RNA Virus Infections

Virus infections of the central nervous system (CNS) cause important diseases of humans and animals. As in other tissues, innate antiviral responses mediated by type I interferons (IFNs) are crucially important in controlling CNS virus infections. The maturity of neuronal populations is an established critical factor determining the outcome of CNS virus infection. Using primary cultures of mouse cortical neurons, we investigated the relationships between neuronal maturation, type I IFN responses, and the outcome of Semliki Forest virus infection. The virus replicated better, infected more cells, and produced higher titres of infectious viruses in immature neurons. Complete transcriptome analysis demonstrated that resting immature neurons have low transcriptional competence to mount antiviral responses. They had no detectable transcription of the genes Ddx58 and Ifih1, which encode key RNA virus cytoplasmic sensors RIG-I and MDA5, and very low expression of genes encoding key regulators of associated signalling pathways. Upon infection, immature neurons failed to mount an antiviral response as evidenced by their failure to produce chemokines, IFNs, and other cytokines. Treatment of immature neurons with exogenous IFNβ prior to infection resulted in antiviral responses and lower levels of virus replication and infectious virus production. In contrast, resting mature neurons generated a robust antiviral response. This was augmented by pretreatment with IFNβ. Infection of mature neurons derived from IFNAR−/− mice did not make an antiviral response and replicated virus to high levels.