The Steep Decline in Reporting to the National Practioner Data Bank, and a Look at Reporting Levels from "Plaintiff-Favorable" and "Defendant-Favorable" States.

The establishment of the National Practitioner Data Bank (NPDB) was authorized in the Health Care Quality Improvement Act of 1986, and it mandated a federal database to collect information related to adverse actions initially against just physicians and dentists throughout the United States, including payments from malpractice lawsuits, restrictions on clinical privileges by hospitals, and medical licensure limitations and revocations by state licensing boards. The aggregate data reports made by this federal data bank began in 1991. The reporting level for the first ten years remained relatively stable in the nationwide range of 16,000 to 18,000 reports per year, but then a steady decline occurred over the second and third decades to under 8,000 reports per year by the year 2021. The researchers in this study explored a theory that might explain at least part of the drop in the states' reporting levels. That is, states that could be called "Plaintiff-Favorable" (Arizona, Kentucky, New York, Pennsylvania, and Washington) would demonstrate a lesser rate of decline or even an increase in the reporting levels, and states that could be characterized as "Defendant-Favorable" (California, Michigan, Nevada, North Carolina, and Texas) would demonstrate a comparatively greater rate of decline in the reporting levels. The decline in reporting to the NPDB proved fairly consistent for both Plaintiff-Favorable and Defendant-Favorable states. The larger question as to why there occurred an overall negative trend in reporting to the NPDB across the United States during the second and third decades remains an intriguing area for future exploration.

Case report: Down syndrome regression disorder, catatonia, and psychiatric and immunomodulatory interventions.

Down syndrome regression disorder (DSRD) is a rare condition involving subacute cognitive decline, loss of previously acquired developmental skills, and prominent neuropsychiatric symptoms, particularly catatonia, in people with Down syndrome. It is thought to involve both autoimmune and neuropsychiatric mechanisms. Research, however, is largely restricted to case studies and retrospective case series and is particularly limited in terms of prospective longitudinal follow-up. We report a case study of a person with DSRD who received both immunomodulatory (intravenous immunoglobulin; IVIG) and psychiatric interventions (electroconvulsive therapy, ECT) over two years with regular assessments using caregiver and clinician ratings. This revealed a small, unsustained response to IVIG and a rapid, sustained response once ECT was introduced. The case highlights the importance of multimodal assessment involving multiple medical specialties, the need to trial different therapies due to the condition's complexity, and the significant barriers that patients and their families face in accessing care.

Automated multifactorial design of experiment and Bayesian optimisation algorithm approaches to method development for the green analysis by supercritical fluid chromatography of a pharmaceutical ingredient.

During drug development, chromatography is frequently used for purity and stability testing of both drug substance and drug product. Reversed phase liquid chromatography (RPLC) is one of the most widely used methodologies due to its wide scope of application. In the later stages of drug development, the specified impurities and degradation products that define the critical quality attribute of the final API, also known as Key Predictive Sample Set (KPSS), are usually well defined and controlled. At this point, a method review enables selecting the most appropriate technique which should be the one providing optimal robustness (ICH-Q14[1]), with the support of Quality by Design (QbD) approaches. Supercritical Fluid Chromatography (SFC) is a preferred technique for its proven diversity in selectivity. The adoption of a technique which presents the most favourable environmental impact, such as, but not limited to, SFC, is also becoming increasingly important as laboratories strive to reduce carbon footprint. Re-developing a method requires high resource-demands in terms of staff, materials, and time. Any step of the process that can be automated can facilitate this approach, speeding up the delivery of the method whilst preserving robustness. In this article we describe how an SFC method was developed for the purity profiling of a late-stage oncology candidate, taking advantage of the superior selectivity of SFC towards structurally similar analytes, owed to the high orthogonality with R2 as low as 0.014 towards the KPSS. We describe two approaches to automate the method development. Firstly, a multifactorial design of experiments (DoE) and secondly, an optimization via a Bayesian algorithm, which was completed in one night, highlighting the potential and limitations, with an insight into the robustness. Both methods achieved baseline separation with varying levels of automation embedded into the process and a large reduction of the resource demands when compared to traditional optimisation methods. Finally, we describe the beneficial environmental impact that implementing SFC methods can yield, with a calculated green score reduced to a value between 17 and 30 % compared to RPLC, depending on the number of runs per sequence.

Diagnostic and prognostic value of the left atrial myopathy evaluation in cardiac amyloidosis using echocardiography.

BACKGROUND: Cardiac amyloidosis (CA) is an under-recognized cause of heart failure. Left atrial (LA) myopathy contributes to a worse prognosis in heart failure and is a feature of transthyretin (ATTR) and light-chain (AL) CA. LA mechanical dispersion (LA-MD) is a novel marker of intra-atrial dyssynchrony implicated in LA myopathy and the future development of atrial fibrillation (AF). AIMS: This study aimed to determine the characteristics and prognostic value of LA myopathy in ATTR and AL cardiomyopathy through a comprehensive LA echocardiographic evaluation. METHODS: ATTR (n = 86) and AL (n = 86) CA patients were compared with hypertensive heart disease (HHT) patients (n = 58). Transthoracic echocardiographic measurements including LA strain and LA-MD were obtained with patient follow-up for mortality. RESULTS: ATTR and AL patients had a median follow-up of 66 months, with 26 mortality events. Left ventricular (LV) mass, diastolic function (average-e' and E/e'), LV global longitudinal strain, and LA volume and function (LA function index and strain) were more impaired in ATTR versus AL; these echocardiographic parameters were more impaired in both amyloid groups compared to HHT patients (P < 0.05). LA-MD was increased in ATTR versus AL [median 72.2 (inter-quartile range 55-88.9) vs. 54 (43.5-64.2), respectively, P < 0.001]. Multivariable logistic regression adjusted for age, presence of AF, LV mass, global and basal strain, and E/e' demonstrated that LA-MD was an independent determinant of ATTR CA (P = 0.014). On multivariable analysis, LA reservoir strain was independently associated with the presence of heart failure in the CA group (P < 0.001). LA minimum volume (cut-off ≥18 mL/m2) was a determinant of mortality in AL CA [Cox proportional hazard ratio (HR) 1.042 (1.003-1.082), P = 0.034 and Kaplan-Meier analysis, P = 0.016]. CONCLUSION: Characterizing LA myopathy has significant diagnostic and prognostic utility in CA. ATTR patients have increased atrial dyssynchrony, which may have implications for AF development. LA reservoir strain was associated with heart failure in CA, whilst LA minimum volume was a predictor of mortality in AL CA.

Portable X-ray fluorescence spectrometry: a cost-effective method for analysing trace metals in deposited dust.

For projects requiring extensive environmental sampling and rapid decision-making to identify trace metal contamination using dust wipes, the cost and time required for wet chemistry analysis can be prohibitive. Under such circumstances there is a need for a suitable screening method that is cost-effective, efficient, and portable. To address this need, this study investigated the utility of portable X-ray fluorescence (pXRF) for the analysis of trace metals in dust wipes. Here, 316 dust wipe samples from three different geographical settings co-located with mining and smelting operations were investigated for their trace metal loadings (µg m-2) of arsenic (As), chromium (Cr), copper (Cu), iron (Fe), manganese (Mn), nickel (Ni), lead (Pb), and zinc (Zn) using pXRF. Results collected using pXRF were compared against inductively coupled plasma mass spectrometry (ICP-MS) concentrations using matched dust wipes (n = 87) to assess reproducibility. A subset of dust wipes (n = 4) were subject to different pXRF analytical scenarios (ranging from 1 to 12 pXRF measurements) using a standardised test duration of 30 seconds to identify the most efficient number of tests for analytical precision. Conducting four pXRF tests on a single wipe (total exposure time of 120 seconds) returned comparable results to ICP-MS and was adopted for analysis of all samples. Results from dust wipes analysed with both ICP-MS and pXRF (n = 87) showed moderate to strong Spearman Rho correlations (rs = 0.489-0.956, p < 0.01) and linear regression coefficients of variation demonstrated good agreement between methods (R2 = 0.432-0.989, p < 0.05). Linear regression equations were used to correct pXRF data to the ICP-MS dust wipe data for samples analysed by both approaches, and applied to pXRF data that were not subject to ICP-MS analysis (n = 229). Application of the correction formula resulted in a substantial improvement of pXRF's accuracy and precision, confirming its effectiveness for assessing trace metals in dust wipes.

Targeting a microbiota Wolbachian aminoacyl-tRNA synthetase to block its pathogenic host.

The interplay between humans and their microbiome is crucial for various physiological processes, including nutrient absorption, immune defense, and maintaining homeostasis. Microbiome alterations can directly contribute to diseases or heighten their likelihood. This relationship extends beyond humans; microbiota play vital roles in other organisms, including eukaryotic pathogens causing severe diseases. Notably, Wolbachia, a bacterial microbiota, is essential for parasitic worms responsible for lymphatic filariasis and onchocerciasis, devastating human illnesses. Given the lack of rapid cures for these infections and the limitations of current treatments, new drugs are imperative. Here, we disrupt Wolbachia's symbiosis with pathogens using boron-based compounds targeting an unprecedented Wolbachia enzyme, leucyl-tRNA synthetase (LeuRS), effectively inhibiting its growth. Through a compound demonstrating anti-Wolbachia efficacy in infected cells, we use biophysical experiments and x-ray crystallography to elucidate the mechanism behind Wolbachia LeuRS inhibition. We reveal that these compounds form adenosine-based adducts inhibiting protein synthesis. Overall, our study underscores the potential of disrupting key microbiota to control infections.

Current status of immunodeficient mouse models as substitutes to reduce cat and dog use in heartworm preclinical research.

Chemoprophylactic prevention of veterinary heartworm disease in companion animals, caused by the vector-borne nematode parasite Dirofilaria immitis, is a multi-billion-dollar global market. Experimental use of cats and dogs in preclinical heartworm drug testing is increasing due to evolving drug-resistance to frontline macrocyclic lactones and renewed investment in alternative preventative drug research. We and others recently published data demonstrating proof-of-concept of utilising lymphopenic severe-combined immunodeficient (SCID) or Recombination Activating Gene (RAG)2 deficient mice with additional knockout of the IL-2/7 receptor gamma chain (γc) as alternative preventative drug screening research models of dirofilariasis. Here we summarise the current knowledge of candidate immunodeficient mouse models tested, including a comparison of susceptibility using different background strains of mice, different D. immitis isolates, following use of anti-inflammatory treatments to further suppress residual innate immunity, and efficacies achieved against different reference anthelmintics. We supplement this precis with new data on treatment response to the veterinary anthelmintic, oxfendazole, and initial evaluation of D. immitis susceptibility in CB.17 SCID and C57BL/6 RAG2 -/-γc -/- mice. We conclude that in addition to NSG and NXG mice, RAG2 -/-γc -/- mice on either a BALB/c or C57BL/6 background offer an alternative screening model option, widening access to academic and commercial laboratories wishing to pursue initial rapid in vivo drug screening whilst avoiding potentially unnecessary cat or dog testing.

Perinatal risk factors and subclinical hypomania: A prospective community study.

BACKGROUND: Perinatal risk factors are implicated in the development of psychopathology, but their role in bipolar disorder (BD) and hypomania is unclear. Using data from a prospective community cohort, this is the first study to investigate the association between a range of perinatal risk factors, hypomanic symptoms, and 'high-risk' for BD in the general population. METHODS: Parent report of perinatal events were available for 26,040 eighteen-month-olds from the Twins Early Development Study. Subsequent self-report hypomania was measured at ages 16 (Hypomania Checklist-16; N = 2943) and 26 (Mood Disorders Questionnaire; N = 7748). Participants were categorised as 'high-risk' for BD using established classifications. Linear and logistic regressions were conducted within a generalised estimating equations framework to account for relatedness in the sample. RESULTS: Prenatal alcohol exposure (ß = 0.08, SE = 0.04, p = .0002) and number of alcohol units consumed (ß = 0.09, SE = 0.02, p < .0001) were associated with hypomanic symptoms at age 16, and number of alcohol units (OR = 1.13, 95 % CI:1.06-1.21, p = .0003) and maternal stress (OR = 1.68, 95 % CI:1.21-2.34, p = .002) were associated with 'high-risk' for BD age 16. Prenatal tobacco exposure (ß = 0.10, SE = 0.04, p < .0001) and number of cigarettes smoked (ß = 0.10, SE = 0.01, p < .0001) were associated with hypomanic symptoms and 'high-risk' for BD at age 26, although these result were attenuated controlling for parental psychiatric history. LIMITATIONS: Familial confounding could not be fully adjusted for. Rater reports include some biases. CONCLUSIONS: These findings show perinatal risk factors to be associated with subclinical hypomania and 'high-risk' for BD. Future work should explore the mechanisms underlying these longitudinal associations, which could shed light on prevention and intervention efforts.

House Sparrows as Sentinels of Childhood Lead Exposure.

Our understanding of connections between human and animal health has advanced substantially since the canary was introduced as a sentinel of toxic conditions in coal mines. Nonetheless, the development of wildlife sentinels for monitoring human exposure to toxins has been limited. Here, we capitalized on a three-decade long child blood lead monitoring program to demonstrate that the globally ubiquitous and human commensal house sparrow (Passer domesticus) can be used as a sentinel of human health risks in urban environments impacted by lead mining. We showed that sparrows are a viable proxy for the measurement of blood lead levels in children at a neighborhood scale (0.28 km2). In support of the generalizability of this approach, the blood lead relationship established in our focal mining city enabled us to accurately predict elevated blood lead levels in children from another mining city using only sparrows from the second location. Using lead concentrations and lead isotopic compositions from environmental and biological matrices, we identified shared sources and pathways of lead exposure in sparrows and children, with strong links to contamination from local mining emissions. Our findings showed how human commensal species can be used to identify and predict human health risks over time and space.

Overarching Priorities for Health and Care Research in the United Kingdom: A Coproduced Synthesis of James Lind Alliance 'Top 10s'.

INTRODUCTION: James Lind Alliance (JLA) Priority Setting Partnerships (PSPs) produce 'Top 10' lists of health and care research priorities through a structured, shared decision-making process with patients or service users, carers and health or care professionals who identify questions that are most important to them. To date, over 150 PSPs in different areas of health and care have published research priorities. Some PSPs share similar priorities, which could be combined, promoted and addressed through collaborative research to increase value and reduce research waste. AIM: The aim of this study was to identify overarching themes common to JLA PSP priorities across different areas of health and care. METHODS: Our analysis included 'Top 10' research priorities produced by UK-based JLA PSPs between 2016 and 2020. The priorities were coded deductively by the Health Research Classification System (HRCS) health category and research activity. We then carried out online workshops with patients, service users and carers to generate new codes not already captured by this framework. Within each code, multistakeholder inductive thematic analysis was used to identify overarching themes, defined as encompassing priorities from three or more PSPs covering two or more health categories. We used codesign methods to produce an interactive tool for end users to navigate the overarching themes. RESULTS: Five hundred and fifteen research priorities from 51 PSPs were included in our analysis. The priorities together encompassed 20 of 21 HRCS health categories, the most common being 'generic health relevance' (22%), 'mental health' (18%) and 'musculoskeletal' (14%). We identified 89 overarching themes and subthemes, which we organised into a hierarchy with seven top-level themes: quality of life, caregivers and families, causes and prevention, screening and diagnosis, treatment and management, services and systems and social influences and impacts. CONCLUSION: There are many overarching themes common to research priorities across multiple areas of health and care. To facilitate new research and research funding, we have developed an interactive tool to help researchers, funders and patients or service users to explore these priority topics. This is freely available to download online. PATIENT OR PUBLIC CONTRIBUTION: Patients or service users and carers were involved throughout the study, including deciding the aims, designing the study, analysing priorities to identify themes, interpreting and reporting the findings.

Assessing screw length impact on bone strain in proximal humerus fracture fixation via surrogate modelling.

A high failure rate is associated with fracture plates in proximal humerus fractures. The causes of failure remain unclear due to the complexity of the problem including the number and position of the screws, their length and orientation in the space. Finite element (FE) analysis has been used for the analysis of plating of proximal humeral fractures, but due to computational costs is unable to fully explore all potential screw combinations. Surrogate modelling is a viable solution, having the potential to significantly reduce the computational cost whilst requiring a moderate number of training sets. This study aimed to develop adaptive neural network (ANN)-based surrogate models to predict the strain in the humeral bone as a result of changing the length of the screws. The ANN models were trained using data from FE simulations of a single humerus, and after defining the best training sample size, multiple and single-output models were developed. The best performing ANN model was used to predict all the possible screw length configurations. The ANN predictions were compared with the FE results of unseen data, showing a good correlation (R2 = 0.99) and low levels of error (RMSE = 0.51%-1.83% strain). The ANN predictions of all possible screw length configurations showed that the screw that provided the medial support was the most influential on the predicted strain. Overall, the ANN-based surrogate model accurately captured bone strains and has the potential to be used for more complex problems with a larger number of variables.

Substance use-related problems in mild intellectual disability: A Swedish nationwide population-based cohort study with sibling comparison.

Background: Evidence for substance use-related problems in individuals with mild intellectual disability is sparse and mainly limited to selected psychiatric populations. We evaluated the risk of substance use-related problems in individuals with mild intellectual disability compared to the general population. Additionally, we have performed secondary sibling comparison analyses to account for familial confounding. Methods: We conducted a population-based cohort study of individuals born in Sweden between 1973 and 2003. A total of 18,307 individuals with mild intellectual disability were compared to 915,350 reference individuals from the general population and 18,996 full siblings of individuals with mild intellectual disability. Information on mild intellectual disability and substance use-related problems was obtained from several Swedish national and regional school and healthcare registers. Substance use-related problems were measured via corresponding diagnostic and legal codes and included alcohol use disorder, drug use disorder, alcohol-related somatic disease, conviction for a substance-related crime, and substance-related death. Results: Individuals with mild intellectual disability had a higher risk of any substance use-related problem compared to the general population (HR, 1.81; 95% CI, 1.72-1.91), both in males (HR, 1.76; 95% CI, 1.65-1.89) and females (HR, 1.89; 95% CI, 1.74-2.05). The risks of substance use-related problems were particularly elevated among individuals with mild intellectual disability and psychiatric comorbidities (HR, 2.21-8.24). The associations were attenuated in the sibling comparison models. Conclusions: Individuals with mild intellectual disability, especially those with psychiatric comorbidity, are at an elevated risk of substance use-related problems. Familial factors shared by full siblings contribute considerably to the association between mild intellectual disability and substance use-related problems.

A Phase 1, Randomized, Double-Blind, Placebo-Controlled, Single Ascending Dose Trial of AWZ1066S, an Anti-Wolbachia Candidate Macrofilaricide.

AWZ1066S has been developed as a potential treatment for the neglected tropical diseases lymphatic filariasis and onchocerciasis. AWZ1066S targets the Wolbachia bacterial endosymbiont present in the causative nematode parasites. This phase 1, first-in-human study aimed to assess the safety and pharmacokinetics of AWZ1066S in healthy human participants. In a randomized double-blind, placebo-controlled, single ascending dose study, healthy adults received a single oral dose of AWZ1066S (or placebo) and were followed up for 10 days. The planned single doses of AWZ1066S ranged from 100 to 1600 mg, and each dose was administered to a cohort of 8 participants (6 AWZ1066S and 2 placebo). In total 30 people participated, 18 (60%) female, median age 30.0 years (minimum 20, maximum 61). The cohorts administered 100, 200, 300, and 400 mg of AWZ1066S progressed unremarkably. After single 700-mg doses all 4 participants developed symptoms of acute gastritis and transient increases in liver enzymes. The severity of these adverse events ranged from mild to severe, with 1 participant needing hospital admission. Pharmacokinetic analysis indicated that AWZ1066S is rapidly absorbed with predictable pharmacokinetics. In conclusion, safety concerns prevented this study from reaching the human exposures needed for AWZ1066S to be clinically effective against lymphatic filariasis and onchocerciasis.

Blood lead increases and haemoglobin decreases in urban birds along a soil contamination gradient in a mining city.

Lead contaminated soil is a persistent global threat to the health of animal populations. Nevertheless, links between soil lead and its adverse effects on exposed wildlife remain poorly understood. Here, we explore local geographic patterns of exposure in urban birds along a gradient of lead contamination in Broken Hill, an Australian mining city. Soil lead concentrations are linked to co-located blood lead measurements in rock pigeons (Columba livia), house sparrows (Passer domesticus), crested pigeons (Ocyphaps lophotes) and white-plumed honeyeaters (Lichenostomus ornatus). Median blood lead levels were highest in crested pigeons (59.6 µg/dL), followed by house sparrows (35.2 µg/dL), rock pigeons (35.1 µg/dL), and white-plumed honeyeaters (27.4 µg/dL). Blood lead levels in all species declined away from mining areas, the primary source of lead contamination in Broken Hill. Blood lead increased significantly and at the greatest rate relative to soil lead in the three ground foraging species (crested pigeons, house sparrows, rock pigeons). For these species, soil lead concentrations below 200 mg/kg and 900 mg/kg were needed to maintain a median blood lead concentration under the lower threshold of the subtoxic (20-50 µg/dL) and toxic (≥50 µg/dL) effect ranges previously identified for some bird species. We also investigated the effects of lead exposure on blood haemoglobin levels as a general measure of physiological condition in birds exposed to different levels of soil lead contamination. Overall, for every 1 µg/dL increase in blood lead, haemoglobin decreased by 0.11 g/L. The rate of this decrease was not significantly different between species, which supports the measurement of haemoglobin as a consistent though insensitive measure of physiological condition in chronically lead exposed birds. Our findings reflect the importance of lead contaminated soil as a widespread source of elevated blood lead and supressed haemoglobin levels in birds inhabiting urbanised and mining impacted environments.

Stem-cell states converge in multistage cutaneous squamous cell carcinoma development.

Stem cells play a critical role in cancer development by contributing to cell heterogeneity, lineage plasticity, and drug resistance. We created gene expression networks from hundreds of mouse tissue samples (both normal and tumor) and integrated these with lineage tracing and single-cell RNA-seq, to identify convergence of cell states in premalignant tumor cells expressing markers of lineage plasticity and drug resistance. Two of these cell states representing multilineage plasticity or proliferation were inversely correlated, suggesting a mutually exclusive relationship. Treatment of carcinomas in vivo with chemotherapy repressed the proliferative state and activated multilineage plasticity whereas inhibition of differentiation repressed plasticity and potentiated responses to cell cycle inhibitors. Manipulation of this cell state transition point may provide a source of potential combinatorial targets for cancer therapy.

Doxycycline for the treatment of nodding syndrome: a randomised, placebo-controlled, phase 2 trial.

BACKGROUND: Nodding syndrome is a poorly understood neurological disorder that predominantly occurs in Africa. We hypothesised that nodding syndrome is a neuroinflammatory disorder, induced by antibodies to Onchocerca volvulus or its Wolbachia symbiont, cross-reacting with host neuronal proteins (HNPs), and that doxycycline can be used as treatment. METHODS: In this randomised, double-blind, placebo-controlled, phase 2 trial, we recruited participants from districts affected by nodding syndrome in northern Uganda. We included children and adolescents aged 8-18 years with nodding syndrome, as defined by WHO consensus criteria. Participants were randomly assigned (1:1) to receive either 100 mg doxycycline daily or placebo for 6 weeks via a computer-generated schedule stratified by skin microscopy results, and all parties were masked to group assignment. Diagnoses of O volvulus and antibodies to HNPs were made using luciferase immunoprecipitation system assays and immunohistochemistry. The primary outcome was change in the proportion with antibodies to HNPs, assessed at 24 months. All participants were included in safety analyses, and surviving participants (those with samples at 24 months) were included in primary analyses. Secondary outcomes were: change in concentrations of antibodies to HNPs at 24 months compared with baseline; proportion of participants testing positive for antibodies to O volvulus-specific proteins and concentrations of Ov16 or OVOC3261 antibodies at 24 months compared with baseline; change in seizure burden, proportion achieving seizure freedom, and the proportions with interictal epileptiform discharges on the diagnostic EEG; overall quality of life; disease severity at 24 months; and incidence of all-cause adverse events, serious adverse events, and seizure-related mortality by 24 months. This trial is registered with ClinicalTrials.gov, NCT02850913. FINDINGS: Between Sept 1, 2016, and Aug 31, 2018, 329 children and adolescents were screened, of whom 240 were included in the study. 140 (58%) participants were boys and 100 (42%) were girls. 120 (50%) participants were allocated to receive doxycycline and 120 (50%) to receive placebo. At recruitment, the median duration of symptoms was 9 years (IQR 6-10); 232 (97%) participants had O volvulus-specific antibodies and 157 (65%) had autoantibodies to HNPs. The most common plasma autoantibodies were to human protein deglycase DJ-1 (85 [35%] participants) and leiomodin-1 (77 [32%] participants) and, in cerebrospinal fluid (CSF), to human DJ-1 (27 [11%] participants) and leiomodin-1 (14 [6%] participants). On immunohistochemistry, 46 (19%) participants had CSF autoantibodies to HNPs, including leiomodin-1 (26 [11%]), γ-aminobutyric acid B receptors (two [<1%]), CASPR2 (one [<1%]), or unknown targets (28 [12%]). At 24 months, 161 (72%) of 225 participants had antibodies to HNPs compared with 157 (65%) of 240 at baseline. 6 weeks of doxycycline did not affect the concentration of autoantibodies to HNPs, seizure control, disease severity, or quality of life at the 24-month follow-up but substantially decreased Ov16 antibody concentrations; the median plasma signal-to-noise Ov16 ratio was 16·4 (95% CI 6·4-38·4), compared with 27·9 (8·2-65·8; p=0·033) for placebo. 14 (6%) participants died and, other than one traffic death, all deaths were seizure-related. Acute seizure-related hospitalisations (rate ratio [RR] 0·43 [95% CI 0·20-0·94], p=0·028) and deaths (RR 0·46 [0·24-0·89], p=0·028) were significantly lower in the doxycycline group. At 24 months, 96 (84%) of 114 participants who received doxycycline tested positive for antibodies to Ov16, compared with 97 (87%) of 111 on placebo (p=0·50), and 74 (65%) participants on doxycycline tested positive for antibodies to OVOC3261, compared with 57 (51%) on placebo (p=0·039). Doxycycline was safe; there was no difference in the incidence of grade 3-5 adverse events across the two groups. INTERPRETATION: Nodding syndrome is strongly associated with O volvulus and the pathogenesis is probably mediated through an O volvulus induced autoantibody response to multiple proteins. Although it did not reverse disease symptoms, doxycycline or another prophylactic antibiotic could be considered as adjunct therapy to antiseizure medication, as it might reduce fatal complications from acute seizures and status epilepticus induced by febrile infections. FUNDING: Medical Research Council (UK). TRANSLATION: For the Luo translation of the abstract see Supplementary Materials section.

Development and validation of a biomechanically fidelic surgical training knee model.

Knee arthroplasty technique is constantly evolving and the opportunity for surgeons to practice new techniques is currently highly dependent on the availability of cadaveric specimens requiring certified facilities. The high cost, limited supply, and heterogeneity of cadaveric specimens has increased the demand for synthetic training models, which are currently limited by a lack of biomechanical fidelity. Here, we aimed to design, manufacture, and experimentally validate a synthetic knee surgical training model which reproduces the flexion dependent varus-valgus (VV) and anterior-posterior (AP) mechanics of cadaveric knees, while maintaining anatomic accuracy. A probabilistic finite element modeling approach was employed to design physical models to exhibit passive cadaveric VV and AP mechanics. Seven synthetic models were manufactured and tested in a six-degree-of-freedom hexapod robot. Overall, the synthetic models exhibited cadaver-like VV and AP mechanics across a wide range of flexion angles with little variation between models. In the extended position, two models showed increased valgus rotation (<0.5°), and three models showed increased posterior tibial translation (<1.7 mm) when compared to the 95% confidence interval (CI) of cadaveric measurements. At full flexion, all models showed VV and AP mechanics within the 95% CI of cadaveric measurements. Given the repeatable mechanics exhibited, the knee models developed in this study can be used to reduce the current reliance on cadaveric specimens in surgical training.

Neurodevelopmental and psychiatric conditions in 600 Swedish Children with the ARFID phenotype.

Objective: Avoidant restrictive food intake disorder (ARFID) is a feeding and eating disorder characterized by extremely restricted dietary variety and/or quantity resulting in serious consequences for physical health and psychosocial functioning. ARFID often co-occurs with neurodevelopmental conditions (NDCs) and psychiatric conditions, but previous data are mostly limited to small clinical samples examining a narrow range of conditions. Here, we examined NDCs and psychiatric conditions in a large, population-based group of children with ARFID. Method: In a sample of 30,795 children born 1992-2008 in Sweden, ARFID was assessed using parent reports and clinical diagnoses from national health registers. Parents further reported symptoms of NDCs and psychiatric conditions at child age 9 or 12 years. We conducted regressions for symptom scores and screening diagnoses (identified using validated cut offs) on ARFID and examined interactions with sex. Results: Children with ARFID had significantly increased odds of all 17 screening diagnoses with odds ratios ranging from 3.3 for visual hallucinations to 13.7 for autism (all p<.0001). The most common NDCs were oppositional defiant disorder (19.4%), ADHD (16.9%), tic disorders (14.8%), and autism (12.1%). Among psychiatric conditions, separation anxiety disorder (29.0%) and sleep problems (20.0%) had the highest prevalence. We did not find any sex-specific differences in co-occurring conditions. Conclusion: This study highlights the co-occurrence of a broad range of NDCs and psychiatric conditions with ARFID in a large, non-clinical cohort. Our findings underscore that children with ARFID face significant burden from multiple co-existing conditions which should be considered during assessment and treatment.

Genetics of environmental sensitivity to psychiatric and neurodevelopmental phenotypes: evidence from GWAS of monozygotic twins.

Individual sensitivity to environmental exposures may be genetically influenced. This genotype-by-environment interplay implies differences in phenotypic variance across genotypes. However, environmental sensitivity genetic variants have proven challenging to detect. GWAS of monozygotic twin differences is a family-based variance analysis method, which is more robust to systemic biases that impact population-based methods. We combined data from up to 21,792 monozygotic twins (10,896 pairs) from 11 studies to conduct the largest GWAS meta-analysis of monozygotic phenotypic differences in children and adolescents/adults for seven psychiatric and neurodevelopmental phenotypes: attention deficit hyperactivity disorder (ADHD) symptoms, autistic traits, anxiety and depression symptoms, psychotic-like experiences, neuroticism, and wellbeing. The SNP-heritability of variance in these phenotypes were estimated (h2: 0% to 18%), but were imprecise. We identified a total of 13 genome-wide significant associations (SNP, gene, and gene-set), including genes related to stress-reactivity for depression, growth factor-related genes for autistic traits and catecholamine uptake-related genes for psychotic-like experiences. Monozygotic twins are an important new source of evidence about the genetics of environmental sensitivity.

Determination of preoperative risk factors for iliopsoas tendonitis after total hip arthroplasty: A simulation study.

This study aims to identify preoperative risk factors for iliopsoas tendonitis after total hip arthroplasty, a complication typically attributed to acetabular cup position and orientation, using a validated iliopsoas impingement detection simulation. Analyzing CT scans and X-rays of 448 patients using a validated preoperative planning protocol, patients were simulated for iliopsoas impingement and categorized into at-risk and not at-risk groups based on a prior validation study, with a 23% at-risk incidence. Implementing a propensity score matching algorithm to reduce covariate imbalance, we identified factors that may exacerbate risk of iliopsoas tendonitis. Parameters that were investigated included standing pelvic tilt, functional femoral rotation, and the difference between the planned acetabular cup diameter and native femoral head diameter (ΔC-NFH). Comparing pelvic tilt, we found a significant difference between the groups (at-risk: -6.0°, not at-risk: -0.7°; p << 0.01). A similar trend was noted for ΔC-NFH (at-risk: +5.7 mm, not at-risk: +5.1 mm; p = 0.01). Additional simulations of at-risk patients indicated increased anteversion of the acetabular cup reduces impingement risk more effectively than medialisation. These findings suggest that spinopelvic parameters may exacerbate iliopsoas irritation risk, underscoring their importance in preoperative planning and patient expectation management. Similar findings of a greater than 6 mm difference between cup size and native femoral head diameter being a significant risk for iliopsoas tendonitis have been observed before, underscoring its potential veracity. These results may provide surgeons with a simple threshold that can be used in determining a cup size to reduce the risk of iliopsoas tendonitis.