Miracle-dz/UniFAR-FTUs huggingface dataset:
Effects of State Opioid Prescribing Laws on Use of Opioid and Other Pain Treatments Among Commercially Insured U.S. Adults

BACKGROUND There is concern that state laws to curb opioid prescribing may adversely affect patients with chronic noncancer pain, but the laws' effects are unclear because of challenges in disentangling multiple laws implemented around the same time. OBJECTIVE To study the association between state opioid prescribing cap laws, pill mill laws, and mandatory prescription drug monitoring program query or enrollment laws and trends in opioid and guideline-concordant nonopioid pain treatment among commercially insured adults, including a subgroup with chronic noncancer pain conditions. DESIGN Thirteen treatment states that implemented a single law of interest in a 4-year period and unique groups of control states for each treatment state were identified. Augmented synthetic control analyses were used to estimate the association between each state law and outcomes. SETTING United States, 2008 to 2019. PATIENTS 7 694 514 commercially insured adults aged 18 years or older, including 1 976 355 diagnosed with arthritis, low back pain, headache, fibromyalgia, and/or neuropathic pain. MEASUREMENTS Proportion of patients receiving any opioid prescription or guideline-concordant nonopioid pain treatment per month, and mean days' supply and morphine milligram equivalents (MME) of prescribed opioids per day, per patient, per month. RESULTS Laws were associated with small-in-magnitude and non-statistically significant changes in outcomes, although CIs around some estimates were wide. For adults overall and those with chronic noncancer pain, the 13 state laws were each associated with a change of less than 1 percentage point in the proportion of patients receiving any opioid prescription and a change of less than 2 percentage points in the proportion receiving any guideline-concordant nonopioid treatment, per month. The laws were associated with a change of less than 1 in days' supply of opioid prescriptions and a change of less than 4 in average monthly MME per day per patient prescribed opioids. LIMITATIONS Results may not be generalizable to non-commercially insured populations and were imprecise for some estimates. Use of claims data precluded assessment of the clinical appropriateness of pain treatments. CONCLUSION This study did not identify changes in opioid prescribing or nonopioid pain treatment attributable to state laws. PRIMARY FUNDING SOURCE National Institute on Drug Abuse.
Effect of center of rotation of angulation‐based leveling osteotomy on ex vivo stifle joint stability following cranial cruciate ligament transection and medial meniscal release with and without a hamstring load

Abstract Objective To evaluate the effect of center of rotation of angulation (CORA)‐based leveling osteotomy (CBLO) and hamstring load on stifle stability following cranial cruciate ligament transection (CCLx) and medial meniscal release (MMR). Study design Ex vivo experimental study. Sample population Cadaver hind limb preparations (n = 7). Methods After instrumentation, constant quadriceps and gastrocnemius loads with an optional hamstring load in a 3:1:0.6 ratio were applied, and stifles were extended from fully flexed using an electrical motor during fluoroscopic recording. The recording process was repeated after each of CCLx, MMR and CBLO and the extracted landmark coordinates were used for calculation of cranial tibial translation (CTT) and patellar ligament angle (PTA). Results Mean initial tibial plateau angle was 28.1°: post‐CBLO the mean was 9.7°. Cranial tibial translation developed from 50° and 75° with CCLx and MMR respectively (p < .04, < .02) without hamstring loading. Hamstring loading mitigated CTT due to CCLx and delayed CTT until 120° for MMR (P < .02) in this model. CBLO prevented CTT, except at 140° without hamstring loading (P = .01). Similar results were seen for PTA, but CBLO curves were parallel to and lower than intact values at all tested angles (P < .04), consistent with induced effective joint flexion. Conclusion CBLO to a target tibial plateau angle of 10° largely eliminated CTT induced by CCLx and MMR. Hamstring loads of 20% quadriceps load improved stifle stability in this model. Impact Stifle stability following CBLO appears to be multifactorial and depends on meniscal integrity, joint angle, and hamstring strength.
Neuronal mechanism of a BK channelopathy in absence epilepsy and dyskinesia

Significance BK channelopathy has been increasingly implicated in diverse neurological disorders, including epilepsy and movement, cognitive, and neurodevelopmental disorders. However, precision medicine to treat BK channelopathy is lacking. We characterized a mouse model carrying a gain-of-function BK channelopathy D434G from a large family of patients with absence epilepsy and paroxysmal dyskinesia. The BK-D434G mice manifest the clinical features of absence seizures and exhibit severe locomotor defects including involuntary dyskinesia-like behavior. Pharmacological inhibition of BK channels suppresses neuronal hyperactivity and mitigates absence seizure and the locomotor defects. The BK-D434G mice thus serve as a model to understand the pathogenic mechanisms of absence epilepsy and dyskinesia. Our study also suggests that BK inhibition is a promising strategy for treating BK gain-of-function channelopathy.
Thematic analysis of therapists' experiences integrating EMDR and EFT in couple therapy: Theoretical and clinical complementarity, and benefits to client couples

Abstract In this article, we present partial findings from a thematic analysis study that examined integrating emotionally focused therapy (EFT) and eye‐movement desensitization and reprocessing (EMDR) as clinical frameworks in couple therapy. The purpose of the study is to better understand how therapists integrate EFT and EMDR therapy in their clinical work. Thirteen licensed therapists (n = 13) trained in EFT and EMDR were interviewed about their experiences integrating these two models in their couple therapy practice. The findings included in this article are related to how these models complement each other as well as the clinical benefits associated with their integration. Findings provide preliminary evidence that there are benefits and challenges when integrating both models, although we emphasize complementarity in this article. Limitations and implications for future research on the integration and efficacy of these two models are also discussed.
A Smartphone Application Using Artificial Intelligence Is Superior To Subject Self-Reporting When Assessing Stool Form

INTRODUCTION: Stool form assessment relies on subjective patient reports using the Bristol Stool Scale (BSS). In a novel smartphone application (app), trained artificial intelligence (AI) characterizes digital images of users' stool. In this study, we evaluate this AI for accuracy in assessing stool characteristics. METHODS: Subjects with diarrhea-predominant irritable bowel syndrome image-captured every stool for 2 weeks using the app, which assessed images for 5 visual characteristics (BSS, consistency, fragmentation, edge fuzziness, and volume). In the validation phase, using 2 expert gastroenterologists as a gold standard, sensitivity, specificity, accuracy, and diagnostic odds ratios of subject-reported vs AI-graded BSS scores were compared. In the implementation phase, agreements between AI-graded and subject-reported daily average BSS scores were determined, and subject BSS and AI stool characteristics scores were correlated with diarrhea-predominant irritable bowel syndrome symptom severity scores. RESULTS: In the validation phase (n = 14), there was good agreement between the 2 experts and AI characterizations for BSS (intraclass correlation coefficients [ICC] = 0.782–0.852), stool consistency (ICC = 0.873–0.890), edge fuzziness (ICC = 0.836–0.839), fragmentation (ICC = 0.837–0.863), and volume (ICC = 0.725–0.851). AI outperformed subjects' self-reports in categorizing daily average BSS scores as constipation, normal, or diarrhea. In the implementation phase (n = 25), the agreement between AI and self-reported BSS scores was moderate (ICC = 0.61). AI stool characterization also correlated better than subject reports with diarrhea severity scores. DISCUSSION: A novel smartphone application can determine BSS and other visual stool characteristics with high accuracy compared with the 2 expert gastroenterologists. Moreover, trained AI was superior to subject self-reporting of BSS. AI assessments could provide more objective outcome measures for stool characterization in gastroenterology.
Recombinant pro-CTSD (cathepsin D) enhances SNCA/α-Synuclein degradation in α-Synucleinopathy models

ABSTRACT Parkinson disease (PD) is a neurodegenerative disorder characterized by the abnormal intracellular accumulation of SNCA/α-synuclein. While the exact mechanisms underlying SNCA pathology are not fully understood, increasing evidence suggests the involvement of autophagy as well as lysosomal deficiencies. Because CTSD (cathepsin D) has been proposed to be the major lysosomal protease involved in SNCA degradation, its deficiency has been linked to the presence of insoluble SNCA conformers in the brain of mice and humans as well as to the transcellular transmission of SNCA aggregates. We here postulate that SNCA degradation can be enhanced by the application of the recombinant human proform of CTSD (rHsCTSD). Our results reveal that rHsCTSD is efficiently endocytosed by neuronal cells, correctly targeted to lysosomes and matured to an enzymatically active protease. In dopaminergic neurons derived from induced pluripotent stem cells (iPSC) of PD patients harboring the A53T mutation within the SNCA gene, we confirm the reduction of insoluble SNCA after treatment with rHsCTSD. Moreover, we demonstrate a decrease of pathological SNCA conformers in the brain and within primary neurons of a ctsd-deficient mouse model after dosing with rHsCTSD. Boosting lysosomal CTSD activity not only enhanced SNCA clearance in human and murine neurons as well as tissue, but also restored endo-lysosome and autophagy function. Our findings indicate that CTSD is critical for SNCA clearance and function. Thus, enzyme replacement strategies utilizing CTSD may also be of therapeutic interest for the treatment of PD and other synucleinopathies aiming to decrease the SNCA burden. Abbreviations: aa: amino acid; SNCA/α-synuclein: synuclein alpha; APP: amyloid beta precursor protein; BBB: blood brain barrier; BF: basal forebrain; CBB: Coomassie Brilliant Blue; CLN: neuronal ceroid lipofuscinosis; CNL10: neuronal ceroid lipofuscinosis type 10; Corr. : corrected; CTSD: cathepsin D; CTSB: cathepsin B; DA: dopaminergic; DA-iPSn: induced pluripotent stem cell-derived dopaminergic neurons; dox: doxycycline; ERT: enzyme replacement therapy; Fx: fornix, GBA/β-glucocerebrosidase: glucosylceramidase beta; h: hour; HC: hippocampus; HT: hypothalamus; i.c. : intracranially; IF: immunofluorescence; iPSC: induced pluripotent stem cell; KO: knockout; LAMP1: lysosomal associated membrane protein 1; LSDs: lysosomal storage disorders; MAPT: microtubule associated protein tau; M6P: mannose-6-phosphate; M6PR: mannose-6-phosphate receptor; MB: midbrain; mCTSD: mature form of CTSD; neurofil. : neurofilament; PD: Parkinson disease; proCTSD: proform of CTSD; PRNP: prion protein; RFU: relative fluorescence units; rHsCTSD: recombinant human proCTSD; SAPC: Saposin C; SIM: structured illumination microscopy; T-insol: Triton-insoluble; T-sol: Triton-soluble; TEM: transmission electron microscopy, TH: tyrosine hydroxylase; Thal: thalamus
Copper Induces Protein Aggregation, a Toxic Process Compensated by Molecular Chaperones

With the increase of antibiotic drug resistance, alternative antibacterial treatment strategies are needed. Copper is a well-known antimicrobial and antiviral agent; however, the underlying molecular mechanisms by which copper causes cell death are not yet fully understood. ABSTRACT Copper is well known for its antimicrobial and antiviral properties. Under aerobic conditions, copper toxicity relies in part on the production of reactive oxygen species (ROS), especially in the periplasmic compartment. However, copper is significantly more toxic under anaerobic conditions, in which ROS cannot be produced. This toxicity has been proposed to arise from the inactivation of proteins through mismetallations. Here, using the bacterium Escherichia coli, we discovered that copper treatment under anaerobic conditions leads to a significant increase in protein aggregation. In vitro experiments using E. coli lysates and tightly controlled redox conditions confirmed that treatment with Cu+ under anaerobic conditions leads to severe ROS-independent protein aggregation. Proteomic analysis of aggregated proteins revealed an enrichment of cysteine- and histidine-containing proteins in the Cu+-treated samples, suggesting that nonspecific interactions of Cu+ with these residues are likely responsible for the observed protein aggregation. In addition, E. coli strains lacking the cytosolic chaperone DnaK or trigger factor are highly sensitive to copper stress. These results reveal that bacteria rely on these chaperone systems to protect themselves against Cu-mediated protein aggregation and further support our finding that Cu toxicity is related to Cu-induced protein aggregation. Overall, our work provides new insights into the mechanism of Cu toxicity and the defense mechanisms that bacteria employ to survive. IMPORTANCE With the increase of antibiotic drug resistance, alternative antibacterial treatment strategies are needed. Copper is a well-known antimicrobial and antiviral agent; however, the underlying molecular mechanisms by which copper causes cell death are not yet fully understood. Herein, we report the finding that Cu+, the physiologically relevant copper species in bacteria, causes widespread protein aggregation. We demonstrate that the molecular chaperones DnaK and trigger factor protect bacteria against Cu-induced cell death, highlighting, for the first time, the central role of these chaperones under Cu+ stress. Our studies reveal Cu-induced protein aggregation to be a central mechanism of Cu toxicity, a finding that will serve to guide future mechanistic studies and drug development.
Risk characterization of dietary acrylamide exposure and associated factors in the Portuguese population

Abstract Acrylamide exposure, mainly resulting from food cooking and processing, has been associated with a higher risk of health problems, due to genotoxic effects. This study aims to estimate acrylamide dietary exposure of the Portuguese population and its associated factors. Dietary data collected through 2 non-consecutive 24 hour recalls or food diaries from a representative sample of the Portuguese population from the National Food, Nutrition and Physical Activity Survey was used (n = 5811; 3–84 years). Occurrence data of acrylamide in food were obtained from EFSA. The margins of exposure (MOE) were calculated for peripheral neuropathy and neoplastic effects. The association between acrylamide and socio-demographic characteristics was estimated through linear regression models. For the total population, the estimated median daily dietary exposure per body weight to acrylamide was 0.38 µg/kg/day, ranging from 0.14 to 0.88 µg/kg/day for the 5th and 95th percentile, respectively. Children aged between 1–2 years had the highest acrylamide exposure (median 0.75 µg/kg/day, 95th percentile 1.41 µg/kg/day). For the peripheral neuropathy and neoplastic effects, the median MOE estimated was 1140 and 451, respectively. Men compared to women had a higher acrylamide dietary exposure, as well as smokers compared to non-smokers. Elderly and less educated individuals were inversely associated with acrylamide exposure. ‘Bread and rusks’ (24.2%) were the main source of acrylamide, followed by ‘coffee’ (21.3%). The current dietary exposure to acrylamide in the Portuguese population is of concern mainly regarding neoplastic effects. Our results point to the need to reduce exposure to acrylamide, especially in men, young children, higher educated individuals and smokers.
Gender and family structures affecting intergenerational support from adult children to older parents: A cross-national study in a developing country

Abstract In Latin America, informal support from adult children to their older parents (“upward support”) is crucial with an aging population and insufficient coverage of social protection systems. This article examines variables associated with upward support, distinguishing by gender of parents and their children. The research design is quantitative, correlational, and cross-sectional. It is based on primary survey data collected by the authors for the study. The authors hypothesized that upward support depends on children’s opportunities to provide support and on the needs of parents. The results show that upward support depends more on children’s opportunities than on parents’ needs, although upward support is higher for parents with poorer health. Daughters are more supportive than sons, but sibling characteristics do not moderate associations between children’s gender and receipt of support. Cohabiting with the parent, receiving support from the parent, and having a good relationship were also associated with greater upward support. Therefore, policies should consider the gender of adult children when allocating resources to older people.
Comparative study of 1064 nm nanosecond, 1064 nm picosecond, 755 nm, and 595 nm lasers for tattoo removal: An essential role by macrophage

Tattoo removal is in high demand, and many types of lasers can be used for tattoo removal. Macrophages play an important role in the persistence of tattoos. However, comparative studies of the efficacy of tattoo removal with different lasers versus the relationship between the destruction of pigment particles or recruitment of macrophages after laser treatment are lacking.
Classification of adult‐type diffuse gliomas: Impact of the World Health Organization 2021 update

Over the last decade, developments in molecular profiling have radically altered the diagnosis, classification, and management of numerous cancer types, with primary brain tumors being no exception. Although historically brain tumors have been classified based on their morphological characteristics, recent advances have allowed refinement of tumor classification based on molecular alterations. This shift toward molecular classification of primary brain tumors is reflected in the 2021 5th edition of the WHO classification of central nervous system tumors (WHO 2021). In this review, we will discuss the most recent updates to the classification of adult‐type diffuse gliomas, a group of highly infiltrative and largely incurable CNS malignancies. It is our hope continued that refinement of molecular criteria will improve diagnosis, prognostication, and eventually treatment of these devastating tumors.
A new early branching armored dinosaur from the Lower Jurassic of southwestern China

The early evolutionary history of the armoured dinosaurs (Thyreophora) is obscured by its patchily distributed fossil record and by conflicting views on the relationships of its Early Jurassic representatives. Here, we describe an early-diverging thyreophoran from the Lower Jurassic Fengjiahe Formation of Yunnan Province, China, on the basis of an associated partial skeleton that includes skull, axial, limb and armour elements. It can be diagnosed as a new taxon based on numerous cranial and postcranial autapomorphies and is further distinguished from all other thyreophorans by a unique combination of character states. Although the robust postcranium is similar to that of more deeply nested ankylosaurs and stegosaurs, phylogenetic analysis recovers it as either the sister taxon of Emausaurus or of the clade Scelidosaurus+Eurypoda. This new taxon, XXXX XXXX, represents the first valid thyreophoran dinosaur to be described from the Early Jurassic of Asia and confirms the rapid geographic spread and diversification of the clade after its first appearance in the Hettangian. Its heavy build and distinctive armour also hint at previously unrealised morphological diversity early in the clade’s history.
Video‐evoked fMRI BOLD responses are highly consistent across different data acquisition sites

Naturalistic imaging paradigms, in which participants view complex videos in the scanner, are increasingly used in human cognitive neuroscience. Videos evoke temporally synchronized brain responses that are similar across subjects as well as within subjects, but the reproducibility of these brain responses across different data acquisition sites has not yet been quantified. Here, we characterize the consistency of brain responses across independent samples of participants viewing the same videos in functional magnetic resonance imaging (fMRI) scanners at different sites (Indiana University and Caltech). We compared brain responses collected at these different sites for two carefully matched datasets with identical scanner models, acquisition, and preprocessing details, along with a third unmatched dataset in which these details varied. Our overall conclusion is that for matched and unmatched datasets alike, video‐evoked brain responses have high consistency across these different sites, both when compared across groups and across pairs of individuals. As one might expect, differences between sites were larger for unmatched datasets than matched datasets. Residual differences between datasets could in part reflect participant‐level variability rather than scanner‐ or data‐ related effects. Altogether our results indicate promise for the development and, critically, generalization of video fMRI studies of individual differences in healthy and clinical populations alike.
Immunohistochemical Panels to Evaluate Important Immunophenotypes of Human Mesonephros

Abstract Background. The immunophenotypes and potential excretory function of human mesonephros are not well studied. Methods. Five mesonephros specimens of human embryos from the 6th to 10th weeks of gestation were stained with immunohistochemical markers. Results. PAX8 was universally expressed in all renal tubules, while α-methyacyl-CoA racemase (AMACAR) was positive in proximal tubules and GATA3 was positive in distal tubular mesonephric structures. At the 8th weeks of gestation, the mesonephric glomeruli were characterized by opened glomerular capillary loops with Periodic Acid Schiff (PAS)-positive glomerular basement membranes and GATA3-positive mesangial-like cells. By the 8th week, proximal tubules showed PAS-positive brush borders, indicating reabsorption capacity, and the proximal tubules also demonstrated positivity with kidney injury molecule-1 (KIM-1), representing tubular response to injury. Conclusion. Our overall findings show detailed phenotypes of the glomerular and tubular structures of the mesonephros and indicate that at the 8th week of gestation, the mesonephros may carry out temporary excretory function before metanephros becomes fully functional.
Comparison of Patients Infected With Delta Versus Omicron COVID-19 Variants Presenting to Paris Emergency Departments

At the end of 2021, infections with the B.1. 1.529 SARS-CoV-2 variant (Omicron) superseded those with the B.1. 617.2 variant (Delta). This study compares baseline characteristics and in-hospital outcomes of patients who presented to 13 emergency departments in Paris from 29 November 2021 to 10 January 2022.