Opioid Use After Robotic-Assisted Versus Conventional Total Hip Arthroplasty:A National Database Analysis.

BACKGROUND: In this study, we tested the null hypothesis that robotic-assisted total hip arthroplasty (THA) vs conventional THA was not associated with (1) the amount of postoperative opioid use and (2) the incidence of new, persistent opioid use. MATERIALS AND METHODS: We used a large, national administrative database to identify patients 50 years and older undergoing primary robotic or conventional THA. Patients with hip fractures or a history of malignancy, hip infection, or opioid use disorder were excluded. Patients who filled an opioid prescription within 1 year to 30 days preoperatively or who underwent a subsequent procedure within 1 year after THA were excluded. Outcomes included the morphine milligram equivalents (MMEs) filled within the THA perioperative period and the incidence of new, persistent opioid use. Multivariable logistic regression models were used to evaluate associations between robotic-assisted THA and new, persistent opioid use, adjusting for age, sex, insurance plan, region, location of surgery, and comorbidities. RESULTS: In the postoperative period, robotic-assisted THA, compared with conventional THA, was associated with a lower mean total MMEs filled per patient (452.2 vs 517.1; P<.001) and a lower mean MMEs per patient per day (71.53 vs 74.64; P<.001). Patients undergoing robotic-assisted THA had decreased odds of developing new, persistent opioid use compared with patients undergoing conventional THA (adjusted odds ratio, 0.82 [95% CI, 0.74-0.90]). CONCLUSION: Robotic-assisted THA is associated with lower postoperative opioid use and a decreased odds of developing new, persistent opioid use compared with conventional THA. For the purposes of reducing opioid use, our results support the adoption of robotic-assisted THA. [Orthopedics. 202x;4x(x):xx-xx.].

Performing region-specific tasks does not improve lower extremity patient-reported outcome scores.

BACKGROUND: Patient-reported outcome measures quantify outcomes from patients' perspective with validated instruments. QuickDASH (Quick Disability of Arm, Shoulder and Hand, an upper extremity PROM) scores improve after completing instrument tasks, suggesting patient-reported outcome results can be modified. We hypothesized that performing lower extremity tasks on the knee injury and osteoarthritis outcome score for joint reconstruction (KOOS-JR) and hip disability and osteoarthritis outcome score for joint reconstruction (HOOS-JR) instruments would similarly improve the scores. METHODS: Forty seven hip and 62 knee osteoarthritis patients presenting to a suburban academic center outpatient osteoarthritis and joint replacement clinic were enrolled and randomized to an intervention or a control group. Inclusion criteria were age over 18 years and English competency. Patients completed a HOOS-JR or KOOS-JR instrument, completed tasks similar to those of the instrument (intervention) or the QuickDASH (control), and then repeated instruments again. Paired and unpaired t-tests were used to compare the intervention and control group scores before and after tasks. RESULTS: There was no significant difference in total or individual scores after task completion compared to baseline in either the HOOS-JR or the KOOS-JR groups. There was no significant difference in the scores between the intervention or control groups. CONCLUSIONS: Disability may be less modifiable in the lower extremity than in the upper extremity, perhaps because upper extremity activities are more easily compensated by the contralateral limb, or because lower extremity activities are more frequent. Thorough evaluation of factors influencing patient-reported outcome measures is necessary before their extensive application to quality control and reimbursement models.

Examining effects of a novel estrogenic perfluoro-alcohol, 1H,1H,8H,8H-Perfluorooctane-1,8-diol (FC8-diol), using the fathead minnow EcoToxChip.

In a previous in vivo study, adult male fathead minnows (Pimephales promelas) were exposed via water for 4 days to 1H,1H,8H,8H-perfluorooctane-1,8-diol (FC8-diol). The present study expands on the evaluation of molecular responses to this perfluoro-alcohol by analyzing 26 male fathead minnow liver RNA samples from that study (five from each test concentration: 0, 0.018, 0.051, 0.171, and 0.463 mg FC8-diol/L) using fathead minnow EcoToxChips Ver. 1.0. EcoToxChips are a quantitative polymerase chain reaction array that allows for simultaneous measurement of >375 species-specific genes of toxicological interest. Data were analyzed with the online tool EcoToxXplorer. Among the genes analyzed, 62 and 96 were significantly up- and downregulated, respectively, by one or more FC8-diol treatments. Gene expression results from the previous study were validated, showing an upregulation of vitellogenin mRNA (vtg) and downregulation of insulin-like growth factor 1 mRNA (igf1). Additional genes related to estrogen receptor activation including esr2a (estrogen receptor 2a) and esrrb (estrogen related receptor beta) were also affected, providing further confirmation of the estrogenic nature of FC8-diol. Furthermore, genes involved in biological pathways related to lipid and carbohydrate metabolism, innate immune response, endocrine reproduction, and endocrine thyroid were significantly affected. These results both add confidence in the use of the EcoToxChip tool for inferring chemical mode(s) of action and provide further insights into the possible biological effects of FC8-diol. Environ Toxicol Chem 2024;00:1-9. © 2024 SETAC. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.

Optimizing the timing of an end-of-outbreak declaration: Ebola virus disease in the Democratic Republic of the Congo.

Following the apparent final case in an Ebola virus disease (EVD) outbreak, the decision to declare the outbreak over must balance societal benefits of relaxing interventions against the risk of resurgence. Estimates of the end-of-outbreak probability (the probability that no future cases will occur) provide quantitative evidence that can inform the timing of an end-of-outbreak declaration. An existing modeling approach for estimating the end-of-outbreak probability requires comprehensive contact tracing data describing who infected whom to be available, but such data are often unavailable or incomplete during outbreaks. Here, we develop a Markov chain Monte Carlo-based approach that extends the previous method and does not require contact tracing data. Considering data from two EVD outbreaks in the Democratic Republic of the Congo, we find that data describing who infected whom are not required to resolve uncertainty about when to declare an outbreak over.

Pain Self-Efficacy Can Improve During a Visit With an Orthopedic Surgeon.

BACKGROUND: Greater pain self-efficacy (PSE) is associated with reduced pain, fewer limitations, and increased quality of life after treatment for orthopedic conditions. The aims of this study were to (1) assess if PSE improves during a visit with an orthopedic surgeon and (2) identify modifiable visit factors that are associated with an increase in PSE. MATERIALS AND METHODS: We performed a prospective observational study of orthopedic clinic visits at a multispecialty clinic from February to May 2022. New patients who presented to one of six orthopedic surgeons were approached for the study. Patients who provided consent completed a pre-visit questionnaire including the Pain Self-Efficacy Questionnaire (PSEQ) and demographic questions. A trained research member recorded the five-item Observing Patient Involvement in Decision Making Instrument (OPTION-5) score, number of questions asked, and visit duration. Immediately after the visit, patients completed a post-visit questionnaire consisting of the PSEQ and Perceived Involvement in Care Scale (PICS). RESULTS: Of 132 patients enrolled, 61 (46%) had improved PSE after the orthopedic visit, with 38 (29%) having improvement above a clinically significant threshold. There were no significant differences between patients with increased PSE and those without increased PSE when comparing the PICS, OPTION-5, questions asked, or visit duration. CONCLUSION: Almost half of the patients had improvement in PSE during an orthopedic visit. The causal pathway to how to improve PSE and the durability of the improved PSE have implications in strategies to improve patient outcomes in orthopedic surgery, such as communication methods and shared decision-making. Future research can focus on studying different interventions that facilitate improving PSE. [Orthopedics. 202x;4x(x):xx-xx.].

Cost-Effectiveness Analysis of Early versus Late Debridement of Superficial Triangular Fibrocartilage Complex Tears.

Background: While initial nonoperative management is the conventional approach for superficial triangular fibrocartilage complex (TFCC) tears, a substantial portion of these cases go on to require surgery, and the optimal duration of nonoperative treatment is unknown. In this study, we evaluate the cost-effectiveness of early versus late arthroscopic debridement for the treatment of superficial TFCC tears without distal radioulnar joint (DRUJ) instability. Methods: We created a decision tree to compare the following strategies from a healthcare payer perspective: immediate arthroscopic debridement versus immobilization for 4 or 6 weeks with late debridement as needed. Costs were obtained from the Centers for Medicaid and Medicare Services and a national administrative claims database. Probabilities and health-related quality-of-life measures were obtained from published sources. We conducted sensitivity analyses on model inputs, including a probabilistic sensitivity analysis consisting of 10,000 Monte Carlo simulations. Results: Immobilization for 6 weeks while reserving arthroscopic debridement for refractory cases was both the least costly and most effective strategy. Immediate arthroscopic debridement became cost-effective when success rates of immobilization for 4 or 6 weeks were less than 7.7 or 10.5%, respectively. Our probabilistic sensitivity analysis showed that immobilization for 6 weeks was preferred 97.6% of the time, and immobilization for 4 weeks was preferred 2.4% of the time. Conclusion: Although various early and late debridement strategies can be used to treat superficial TFCC tears without DRUJ instability, immobilization for 6 weeks while reserving arthroscopic debridement for refractory cases is the optimal strategy from a cost-effectiveness standpoint.

The Association Between Social Determinants of Health and Distal Radius Fracture Outcomes.

PURPOSE: The purpose of this study was to determine if adverse social determinants of health (SDOH) are associated with differential complication rates following surgical fixation of distal radius fractures and assess which SDOH domain (economic, educational, social, health care, or environmental) is most associated with postoperative complications. METHODS: Using a national administrative claims database, we conducted a retrospective cohort analysis of patients undergoing open treatment for an isolated distal radius fracture between 2010 and 2020. Patients were stratified based on the presence/absence of at least one SDOH code and propensity score matched to create two cohorts balanced by age, sex (male or female), insurance type, and comorbidities. Social determinants of health examined included economic, educational, social, health care, and environmental factors. Multivariable logistic regression analyses were performed to assess the isolated effect of SDOH on 90-day and 1-year complication rates. RESULTS: After propensity matching, 57,025 patients in the adverse SDOH cohort and 57,025 patients in the control cohort were included. Patients facing an adverse SDOH were significantly more likely to experience 90-day complications, including emergency department visits (Odds ratio (OR): 3.18 [95% confidence interval (CI): 3.07-3.29]), infection (OR: 2.37 [95% CI: 2.12-2.66]), wound dehiscence (OR: 2.06 [95% CI: 1.72-2.49]), and 1-year complications, including complex regional pain syndrome (OR: 1.35 [95% CI: 1.15-1.58]), malunion/nonunion (OR: 1.18 [95% CI: 1.08-1.29]), and hardware removal (OR: 1.13 [95% CI: 1.07-1.20]). Additionally, patients facing an adverse SDOH had a significantly increased risk of 90-day complications, regardless of fracture severity, and patients with economic and social challenges had the highest odds of both 90-day and 1-year postoperative complications. CONCLUSIONS: Social determinants of health are associated with increased complications following distal radius fracture fixation, even when controlling for demographic and clinical factors. We recommend routine screening for adverse SDOH and inclusion of SDOH data into health records to not only inform quality improvement initiatives and risk adjustment for outcome-based quality measurements but also to allow providers to begin to discuss and address such barriers during the perioperative period. TYPE OF STUDY/LEVEL OF EVIDENCE: Prognosis II.

Referral Patterns and Diagnostic Concordance in Pediatric Skin Disorders.

IMPORTANCE: This study explores referral patterns in pediatric dermatology and assesses the diagnostic concordance between referring and dermatology providers. METHOD: This retrospective cross-sectional study utilized referrals to an outpatient pediatric dermatology clinic. The review included patients referred between July 1, 2018 and June 30, 2019. Only patients who completed a clinic visit were included in the diagnostic concordance. Referral and first visit diagnoses were compared to determine concordance. RESULTS: A total of 8,682 charts were reviewed, and 3,738 completed a clinic visit. The most common referral diagnoses included atopic dermatitis, rash, lesion, melanocytic nevus, and warts. Physicians (78.5%) and APRNs (18.1%) most frequently referred patients. The diagnostic concordance of physicians was 67.1% vs 66.3% for APRNs. CONCLUSION: Physicians and APRNs showed similar rates of diagnostic concordance, yet a large proportion of diagnoses were discordant. Primary care providers may benefit from focused education around the most commonly referred and missed diagnoses.

Platinum(II) Phenylpyridyl Schiff Base Complexes as Latent, Photoactivated, Alkene Hydrosilylation Catalysts.

Photoactivated catalysts for the hydrosilylation of alkenes with silanes offer temporal control in manufacturing processes that require silicone curing. We report the development of a range of air-stable Pt(II) (salicylaldimine)(phenylpyridyl), [Pt(sal)(ppy)], complexes as photoinitiated hydrosilylation catalysts. Some of these catalysts show appreciable latency in thermal catalysis and can also be rapidly (10 s) activated by a LED UV-light source (365 nm), to give systems that selectively couple trimethylvinylsilane and hexamethylsiloxymethylsilane to give the linear hydrosilylation product. Although an undetectable (by NMR spectroscopy) amount of precatalyst is converted to the active form under UV-irradiation in the timescale required to initiate hydrosilylation, clean and reliable kinetics can be measured for these systems that allow for a detailed mechanism to be developed for Pt(sal)(ppy)-based photoactivated hydrosilylation. The suggested mechanism is shown to have close parallels with, but also subtle differences from, those previously proposed for thermally-activated Karstedt-type Pt(0) systems.

Clinical Practice Guidelines to Support Capacity Building in Orthopaedic Surgical Outreach: An International Consensus Building Approach.

BACKGROUND: Surgical outreach to low- and middle-income countries (LMICs) by organizations from high- income countries is on the rise to help address the growing burden of conditions warranting surgery. However, concerns remain about the impact and sustainability of such outreach. Leading organizations (e.g., the World Health Organization) advocate for a capacity-building approach to ensure the safety, quality, and sustainability of the local health-care system. Despite this, to our knowledge, no guidelines exist to inform such efforts. We aimed to develop clinical practice guidelines (CPGs) to support capacity-building in orthopaedic surgical outreach utilizing a multistakeholder and international voting panel. METHODS: We followed a modified American Academy of Orthopaedic Surgeons (AAOS) CPG development process. We systematically reviewed the existing literature across 7 predefined capacity-building domains (partnership, professional development, governance, community impact, finance, coordination, and culture). A writing panel composed of 6 orthopaedic surgeons with extensive experience in surgical outreach reviewed the existing literature and developed a consensus-based CPG for each domain. We created an international voting panel of orthopaedic surgeons and administrators who have leadership roles in outreach organizations or hospitals with which outreach organizations partner. Members individually reviewed the CPGs and voted to approve or disapprove each guideline. A CPG was considered approved if >80% of panel members voted to approve it. RESULTS: An international voting panel of 14 surgeons and administrators from 6 countries approved all 7 of the CPGs. Each CPG provides recommendations for capacity-building in a specific domain. For example, in the domain of partnership, the CPG recommends the development of a documented plan for ongoing, bidirectional partnership between the outreach organization and the local team. In the domain of professional development, the CPG recommends the development of a needs-based curriculum focused on both surgical and nonsurgical patient care utilizing didactic and hands-on techniques. CONCLUSIONS: As orthopaedic surgical outreach grows, best-practice CPGs to inform capacity-building initiatives can help to ensure that resources and efforts are optimized to support the sustainability of care delivery at local sites. These guidelines can be reviewed and updated in the future as evidence that supports capacity-building in LMICs evolves.The global burden of disease warranting surgery is substantial, and morbidity and mortality from otherwise treatable conditions remain disproportionately high in low- and middle-income countries (LMICs)1,2. It is estimated that up to 2 million (about 40%) of injury-related deaths in LMICs could be avoided annually if mortality rates were reduced to the level of those in high-income countries (HICs)3. Despite this, progress toward improved access to safe, timely surgery in resource-poor areas has been slow. Historically, nongovernmental organizations (NGOs) have tried to address unmet surgical needs through short-term outreach trips; however, growing criticism has highlighted the limitations of short-term trips, including limited follow-up, an increased burden on the local workforce, and further depletion of local resources4-6. In light of ongoing concerns, public health priorities have shifted toward models that emphasize long-term capacity-building rather than short-term care delivery. Capacity-building is an approach to health-care development that builds independence through infrastructure development, sustainability, and enhanced problem-solving while taking context into account7,8.

Incubation Period and Serial Interval of Mpox in 2022 Global Outbreak Compared with Historical Estimates.

Understanding changes in the transmission dynamics of mpox requires comparing recent estimates of key epidemiologic parameters with historical data. We derived historical estimates for the incubation period and serial interval for mpox and contrasted them with pooled estimates from the 2022 outbreak. Our findings show the pooled mean infection-to-onset incubation period was 8.1 days for the 2022 outbreak and 8.2 days historically, indicating the incubation periods remained relatively consistent over time, despite a shift in the major mode of transmission. However, we estimated the onset-to-onset serial interval at 8.7 days using 2022 data, compared with 14.2 days using historical data. Although the reason for this shortening of the serial interval is unclear, it may be because of increased public health interventions or a shift in the mode of transmission. Recognizing such temporal shifts is essential for informed response strategies, and public health measures remain crucial for controlling mpox and similar future outbreaks.

Implementation of an electronic health record system during global surgical outreach: A prospective evaluation of success and sustainability.

BACKGROUND: The burden of musculoskeletal conditions continues to grow in low- and middle-income countries. Among thousands of surgical outreach trips each year, few organizations electronically track patient data to inform real-time care decisions and assess trip impact. We report the implementation of an electronic health record (EHR) system utilized at point of care during an orthopedic surgical outreach trip. METHODS: In March 2023, we implemented an EHR on an orthopedic outreach trip to guide real-time care decisions. We utilized an effectiveness-implementation hybrid type 3 design to evaluate implementation success. Success was measured using outcomes adopted by the World Health Organization, including acceptability, appropriateness, feasibility, adoption, fidelity, and sustainability. Clinical outcome measures included adherence to essential quality measures and follow-up numerical rating system (NRS) pain scores. RESULTS: During the 5-day outreach trip, 76 patients were evaluated, 25 of which underwent surgery beforehand. The EHR implementation was successful as defined by: mean questionnaire ratings of acceptability (4.26), appropriateness (4.12), feasibility (4.19), and adoption (4.33) at least 4.00, WHO behaviorally anchored rating scale ratings of fidelity (6.8) at least 5.00, and sustainability (80%) at least 60% follow-up at 6 months. All clinical quality measures were reported in greater than 80% of cases with all measures reported in 92% of cases. NRS pain scores improved by an average of 2.4 points. CONCLUSIONS: We demonstrate successful implementation of an EHR for real-time clinical use on a surgical outreach trip. Benefits of EHR utilization on surgical outreach trips may include improved documentation, minimization of medical errors, and ultimately improved quality of care.

Are Clinical Practice Guidelines Representative of Patients With Distal Radius Fractures? A Review of Patient Demographics and Patient-Reported Outcome Measures Used to Inform Guidelines.

PURPOSE: Clinical practice guidelines (CPGs) are recommendations developed for broad application to optimize high-quality care and decision-making. The composition of patients and outcome measures used in studies informing CPGs; however, has not been rigorously evaluated. With growing evidence that outcomes in musculoskeletal surgery vary by sociocultural factors, we aimed to: (1) review the linguistic, racial, and ethnic representation of the patients in the studies informing CPGs for distal radius fractures and (2) assess their use of linguistically and culturally adapted patient-reported outcome measures (PROMs). METHODS: The American Academy of Orthopaedic Surgeons website was used to identify relevant studies. Key variables were extracted, including inclusion and exclusion criteria, language of study, patient language and proficiency, patient race and ethnicity, and use of translated or culturally adapted PROMs. If provided, the clinical trial registration page for the study was evaluated. Descriptive statistics were used to describe the frequency of each variable. RESULTS: Fifty-four published texts were evaluated. Participant language was reported in four (7%) of the published texts and six (11%) when including the clinical trial registration information. Of the published texts, one (2%) reported ethnic group/race data and 40 (74%) used PROMs. Of those using PROMs, eight (20%) of 40 reported the use of translated PROMs, and three (8%) of 40 reported the use of culturally adapted PROMs. CONCLUSIONS: There is a lack of reporting of linguistic, racial, and ethnic data and inconsistent use of PROMs, particularly those that are translated and culturally adapted, in studies included in the American Academy of Orthopaedic Surgeons CPG for distal radius fractures. As sociocultural characteristics and PROMs are associated with outcomes, ensuring they are broadly represented in studies, may improve equity and shared decision-making. CLINICAL RELEVANCE: Greater inclusion and reporting of demographic data and PROMs are required in musculoskeletal studies to ensure broad applicability and advance health equity.

Influence of disease course and comprehensive management on blood glucose level in children and adolescents with type 2 diabetes mellitus.

AIMS/INTRODUCTION: The aim of the present study was to evaluate the status of glycemic control, and assess the effects of the disease course and comprehensive management measures on the blood glucose level in children and adolescents with type 2 diabetes mellitus. MATERIALS AND METHODS: The study collected the clinical data of type 2 diabetes patients in Beijing Children's Hospital from January 2015 to September 2020. Patients were grouped based on the disease course to compare their glycated hemoglobin (HbA1c) level, islet ß-cell function, insulin resistance and comprehensive management measures. RESULTS: Of the 170 participants, the median disease course was 2.0 years (interquartile range [IQR] 1.0-4.0 years). The baseline HbA1c was 11.2% (IQR 9.2-12.4%). According to the grouping by the disease course, the median HbA1c was the lowest (5.7% [IQR 5.3-6.1%]) in the half-year course group and the highest in the 4-year course group (9.0 [IQR 6.8%-11.3%]). Compared with the group with a disease duration <2 years, patients in the >4 years group had a lower proportion of patients with HbA1c <7% (29.2% vs 66.2%), a lower homeostasis model assessment of ß-cell function, and a lower proportion with a controlled diet, moderate-intensity exercise, regular follow up and no drug treatment. We deemed HbA1c as the dependent variable, and found that disease duration, homeostasis model assessment of ß-cell function at follow up, continuous moderate-intensity exercise, regular review and treatment regimen were significant influencing factors for glycemic control. CONCLUSIONS: Children and adolescents with type 2 diabetes and a prolonged disease course showed poor glycemic control and decreased islet ß-cell function. A good lifestyle, especially moderate-intensity exercise, can help such cases better control their blood glucose level.

Applications of Transition Metal-Catalyzed ortho-Fluorine-Directed C-H Functionalization of (Poly)fluoroarenes in Organic Synthesis.

The synthesis of organic compounds efficiently via fewer steps but in higher yields is desirable as this reduces energy and reagent use, waste production, and thus environmental impact as well as cost. The reactivity of C-H bonds ortho to fluorine substituents in (poly)fluoroarenes with metal centers is enhanced relative to meta and para positions. Thus, direct C-H functionalization of (poly)fluoroarenes without prefunctionalization is becoming a significant area of research in organic chemistry. Novel and selective methodologies to functionalize (poly)fluorinated arenes by taking advantage of the reactivity of C-H bonds ortho to C-F bonds are continuously being developed. This review summarizes the reasons for the enhanced reactivity and the consequent developments in the synthesis of valuable (poly)fluoroarene-containing organic compounds.

Genetic modifiers of rare variants in monogenic developmental disorder loci.

Rare damaging variants in a large number of genes are known to cause monogenic developmental disorders (DDs) and have also been shown to cause milder subclinical phenotypes in population cohorts. Here, we show that carrying multiple (2-5) rare damaging variants across 599 dominant DD genes has an additive adverse effect on numerous cognitive and socioeconomic traits in UK Biobank, which can be partially counterbalanced by a higher educational attainment polygenic score (EA-PGS). Phenotypic deviators from expected EA-PGS could be partly explained by the enrichment or depletion of rare DD variants. Among carriers of rare DD variants, those with a DD-related clinical diagnosis had a substantially lower EA-PGS and more severe phenotype than those without a clinical diagnosis. Our results suggest that the overall burden of both rare and common variants can modify the expressivity of a phenotype, which may then influence whether an individual reaches the threshold for clinical disease.

Rare variant associations with birth weight identify genes involved in adipose tissue regulation, placental function and insulin-like growth factor signalling.

Investigating the genetic factors influencing human birth weight may lead to biological insights into fetal growth and long-term health. Genome-wide association studies of birth weight have highlighted associated variants in more than 200 regions of the genome, but the causal genes are mostly unknown. Rare genetic variants with robust evidence of association are more likely to point to causal genes, but to date, only a few rare variants are known to influence birth weight. We aimed to identify genes that harbour rare variants that impact birth weight when carried by either the fetus or the mother, by analysing whole exome sequence data in UK Biobank participants. We annotated rare (minor allele frequency <0.1%) protein-truncating or high impact missense variants on whole exome sequence data in up to 234,675 participants with data on their own birth weight (fetal variants), and up to 181,883 mothers who reported the birth weight of their first child (maternal variants). Variants within each gene were collapsed to perform gene burden tests and for each associated gene, we compared the observed fetal and maternal effects. We identified 8 genes with evidence of rare fetal variant effects on birth weight, of which 2 also showed maternal effects. One additional gene showed evidence of maternal effects only. We observed 10/11 directionally concordant associations in an independent sample of up to 45,622 individuals (sign test P=0.01). Of the genes identified, IGF1R and PAPPA2 (fetal and maternal-acting) have known roles in insulin-like growth factor bioavailability and signalling. PPARG, INHBE and ACVR1C (all fetal-acting) have known roles in adipose tissue regulation and rare variants in the latter two also showed associations with favourable adiposity patterns in adults. We highlight the dual role of PPARG in both adipocyte differentiation and placental angiogenesis. NOS3, NRK, and ADAMTS8 (fetal and maternal-acting) have been implicated in both placental function and hypertension. Analysis of rare coding variants has identified regulators of fetal adipose tissue and fetoplacental angiogenesis as determinants of birth weight, as well as further evidence for the role of insulin-like growth factors.

Clustering of predicted loss-of-function variants in genes linked with monogenic disease can explain incomplete penetrance.

BACKGROUND: Genetic variants that severely alter protein products (e.g. nonsense, frameshift) are often associated with disease. For some genes, these predicted loss-of-function variants (pLoFs) are observed throughout the gene, whilst in others, they occur only at specific locations. We hypothesised that, for genes linked with monogenic diseases that display incomplete penetrance, pLoF variants present in apparently unaffected individuals may be limited to regions where pLoFs are tolerated. To test this, we investigated whether pLoF location could explain instances of incomplete penetrance of variants expected to be pathogenic for Mendelian conditions. METHODS: We used exome sequence data in 454,773 individuals in the UK Biobank (UKB) to investigate the locations of pLoFs in a population cohort. We counted numbers of unique pLoF, missense, and synonymous variants in UKB in each quintile of the coding sequence (CDS) of all protein-coding genes and clustered the variants using Gaussian mixture models. We limited the analyses to genes with ≥ 5 variants of each type (16,473 genes). We compared the locations of pLoFs in UKB with all theoretically possible pLoFs in a transcript, and pathogenic pLoFs from ClinVar, and performed simulations to estimate the false-positive rate of non-uniformly distributed variants. RESULTS: For most genes, all variant classes fell into clusters representing broadly uniform variant distributions, but genes in which haploinsufficiency causes developmental disorders were less likely to have uniform pLoF distribution than other genes (P < 2.2 × 10-6). We identified a number of genes, including ARID1B and GATA6, where pLoF variants in the first quarter of the CDS were rescued by the presence of an alternative translation start site and should not be reported as pathogenic. For other genes, such as ODC1, pLoFs were located approximately uniformly across the gene, but pathogenic pLoFs were clustered only at the end, consistent with a gain-of-function disease mechanism. CONCLUSIONS: Our results suggest the potential benefits of localised constraint metrics and that the location of pLoF variants should be considered when interpreting variants.

How a general vulnerability for psychopathology during adolescence manifests in young adults' daily lives.

BACKGROUND: There is widespread interest in the general factor of psychopathology or 'p factor', which has been proposed to reflect vulnerability to psychopathology. We examined to what extent this 'vulnerability' is associated with dysregulations in affect and behavior that occur in daily life. As such we hoped to provide an account of how this vulnerability may be maintained. METHODS: We used data from the Tracking Adolescents' Individual Lives Survey (TRAILS; N = 2,772) collected at ages 11, 14, 16, 19, and 22 years to fit a bifactor model with a general psychopathology factor, alongside internalizing, externalizing (EXT), attention-deficit/hyperactivity, and autism spectrum problem domains. Following the fifth TRAILS assessment, a subsample of participants (n = 133, age = 22.6, 43% women) with heightened risk for psychopathology completed a 6-month daily diary protocol with one assessment each day. Using a dynamic structural equation approach, we examined to what extent mean intensity, variability, inertia, and within-day co-occurrence of EXT, anxious-tense, and depressed-withdrawn affects and behaviors were associated with general factor scores. RESULTS: Unexpectedly, higher general factor scores were not associated with higher mean intensity of any of the three types of daily negative affects and behaviors, but were associated with higher variability and less carryover (inertia) EXT affects and behaviors. CONCLUSIONS: We showed that individual differences in general factor scores do not manifest as differences in average levels of daily affects and behaviors, but instead were related to a type of EXT reactivity to the environment. Future research is necessary to investigate whether reactive irritable moods may be involved in or signal vulnerability sustained psychopathology.

Site of Service Disparities Exist for Total Joint Arthroplasty.

BACKGROUND: The rate of outpatient total joint arthroplasty procedures, including those performed at ambulatory surgical centers (ASCs) and hospital outpatient departments, is increasing. The purpose of this study was to analyze if type of insurance is associated with site of service (in-patient vs outpatient) for total joint arthroplasty and adverse outcomes. MATERIALS AND METHODS: We identified patients undergoing unicompartmental knee arthroplasty (UKA), total knee arthroplasty (TKA), or total hip arthroplasty (THA) using Current Procedural Terminology codes in a national administrative claims database. Eligible patients were stratified by type of insurance (Medicaid, Medicare, private). The primary outcome was site of service. Secondary outcomes included general complications, procedural complications, and revision procedures. We evaluated the associations using adjusted multivariable logistic regression models. RESULTS: We identified 951,568 patients for analysis; 46,703 (4.9%) patients underwent UKA, 607,221 (63.8%) underwent TKA, and 297,644 (31.3%) underwent THA. Overall, 9.6% of procedures were outpatient. Patients with Medicaid were less likely than privately insured patients to receive outpatient UKA or THA (UKA: odds ratio [OR], 0.729 [95% CI, 0.640-0.829]; THA: OR, 0.625 [95% CI, 0.557-0.702]) but more likely than patients with Medicare to receive outpatient TKA or THA (TKA: OR, 1.391 [95% CI, 1.315-1.472]; THA: OR, 1.327 [95% CI, 1.166-1.506]). Patients with Medicaid were more likely to experience complications and revision procedures. CONCLUSION: Differences in site of service and complication rates following hip and knee arthroplasty exist based on type of insurance, suggesting a disparity in care. Further exploration of drivers of this disparity is warranted and can inform interventions (eg, progressive value-based payments) to support equity in orthopedic services. [Orthopedics. 2024;47(3):179-184.].