Variants in ZFX are associated with an X-linked neurodevelopmental disorder with recurrent facial gestalt.

Pathogenic variants in multiple genes on the X chromosome have been implicated in syndromic and non-syndromic intellectual disability disorders. ZFX on Xp22.11 encodes a transcription factor that has been linked to diverse processes including oncogenesis and development, but germline variants have not been characterized in association with disease. Here, we present clinical and molecular characterization of 18 individuals with germline ZFX variants. Exome or genome sequencing revealed 11 variants in 18 subjects (14 males and 4 females) from 16 unrelated families. Four missense variants were identified in 11 subjects, with seven truncation variants in the remaining individuals. Clinical findings included developmental delay/intellectual disability, behavioral abnormalities, hypotonia, and congenital anomalies. Overlapping and recurrent facial features were identified in all subjects, including thickening and medial broadening of eyebrows, variations in the shape of the face, external eye abnormalities, smooth and/or long philtrum, and ear abnormalities. Hyperparathyroidism was found in four families with missense variants, and enrichment of different tumor types was observed. In molecular studies, DNA-binding domain variants elicited differential expression of a small set of target genes relative to wild-type ZFX in cultured cells, suggesting a gain or loss of transcriptional activity. Additionally, a zebrafish model of ZFX loss displayed an altered behavioral phenotype, providing additional evidence for the functional significance of ZFX. Our clinical and experimental data support that variants in ZFX are associated with an X-linked intellectual disability syndrome characterized by a recurrent facial gestalt, neurocognitive and behavioral abnormalities, and an increased risk for congenital anomalies and hyperparathyroidism.

SOX9 maintains human foetal lung tip progenitor state by enhancing WNT and RTK signalling.

The balance between self-renewal and differentiation in human foetal lung epithelial progenitors controls the size and function of the adult organ. Moreover, progenitor cell gene regulation networks are employed by both regenerating and malignant lung cells, where modulators of their effects could potentially be of therapeutic value. Details of the molecular networks controlling human lung progenitor self-renewal remain unknown. We performed the first CRISPRi screen in primary human lung organoids to identify transcription factors controlling progenitor self-renewal. We show that SOX9 promotes proliferation of lung progenitors and inhibits precocious airway differentiation. Moreover, by identifying direct transcriptional targets using Targeted DamID, we place SOX9 at the centre of a transcriptional network, which amplifies WNT and RTK signalling to stabilise the progenitor cell state. In addition, the proof-of-principle CRISPRi screen and Targeted DamID tools establish a new workflow for using primary human organoids to elucidate detailed functional mechanisms underlying normal development and disease.

The Drosophila homologue of CTIP1 (Bcl11a) and CTIP2 (Bcl11b) regulates neural stem cell temporal patterning.

In the developing nervous system, neural stem cells (NSCs) use temporal patterning to generate a wide variety of different neuronal subtypes. In Drosophila, the temporal transcription factors, Hunchback, Kruppel, Pdm and Castor, are sequentially expressed by NSCs to regulate temporal identity during neurogenesis. Here, we identify a new temporal transcription factor that regulates the transition from the Pdm to Castor temporal windows. This factor, which we call Chronophage (or 'time-eater'), is homologous to mammalian CTIP1 (Bcl11a) and CTIP2 (Bcl11b). We show that Chronophage binds upstream of the castor gene and regulates its expression. Consistent with Chronophage promoting a temporal switch, chronophage mutants generate an excess of Pdm-specified neurons and are delayed in generating neurons associated with the Castor temporal window. In addition to promoting the Pdm to Castor transition, Chronophage also represses the production of neurons generated during the earlier Hunchback and Kruppel temporal windows. Genetic interactions with Hunchback and Kruppel indicate that Chronophage regulates NSC competence to generate Hunchback- and Kruppel-specified neurons. Taken together, our results suggest that Chronophage has a conserved role in temporal patterning and neuronal subtype specification.

Neuropathy target esterase activity defines phenotypes among PNPLA6 disorders.

Biallelic pathogenic variants in the PNPLA6 gene cause a broad spectrum of disorders leading to gait disturbance, visual impairment, anterior hypopituitarism and hair anomalies. PNPLA6 encodes neuropathy target esterase (NTE), yet the role of NTE dysfunction on affected tissues in the large spectrum of associated disease remains unclear. We present a systematic evidence-based review of a novel cohort of 23 new patients along with 95 reported individuals with PNPLA6 variants that implicate missense variants as a driver of disease pathogenesis. Measuring esterase activity of 46 disease-associated and 20 common variants observed across PNPLA6-associated clinical diagnoses unambiguously reclassified 36 variants as pathogenic and 10 variants as likely pathogenic, establishing a robust functional assay for classifying PNPLA6 variants of unknown significance. Estimating the overall NTE activity of affected individuals revealed a striking inverse relationship between NTE activity and the presence of retinopathy and endocrinopathy. This phenomenon was recaptured in vivo in an allelic mouse series, where a similar NTE threshold for retinopathy exists. Thus, PNPLA6 disorders, previously considered allelic, are a continuous spectrum of pleiotropic phenotypes defined by an NTE genotype:activity:phenotype relationship. This relationship, and the generation of a preclinical animal model, pave the way for therapeutic trials, using NTE as a biomarker.

Nutrition-responsive glia control exit of neural stem cells from quiescence.

The systemic regulation of stem cells ensures that they meet the needs of the organism during growth and in response to injury. A key point of regulation is the decision between quiescence and proliferation. During development, Drosophila neural stem cells (neuroblasts) transit through a period of quiescence separating distinct embryonic and postembryonic phases of proliferation. It is known that neuroblasts exit quiescence via a hitherto unknown pathway in response to a nutrition-dependent signal from the fat body. We have identified a population of glial cells that produce insulin/IGF-like peptides in response to nutrition, and we show that the insulin/IGF receptor pathway is necessary for neuroblasts to exit quiescence. The forced expression of insulin/IGF-like peptides in glia, or activation of PI3K/Akt signaling in neuroblasts, can drive neuroblast growth and proliferation in the absence of dietary protein and thus uncouple neuroblasts from systemic control.

Paradoxical cancer cell proliferation after FGFR inhibition through decreased p21 signaling in FGFR1-amplified breast cancer cells.

Fibroblast growth factors (FGFs) control various cellular functions through fibroblast growth factor receptor (FGFR) activation, including proliferation, differentiation, migration, and survival. FGFR amplification in ER + breast cancer patients correlate with poor prognosis, and FGFR inhibitors are currently being tested in clinical trials. By comparing three-dimensional spheroid growth of ER + breast cancer cells with and without FGFR1 amplification, our research discovered that FGF2 treatment can paradoxically decrease proliferation in cells with FGFR1 amplification or overexpression. In contrast, FGF2 treatment in cells without FGFR1 amplification promotes classical FGFR proliferative signaling through the MAPK cascade. The growth inhibitory effect of FGF2 in FGFR1 amplified cells aligned with an increase in p21, a cell cycle inhibitor that hinders the G1 to S phase transition in the cell cycle. Additionally, FGF2 addition in FGFR1 amplified cells activated JAK-STAT signaling and promoted a stem cell-like state. FGF2-induced paradoxical effects were reversed by inhibiting p21 or the JAK-STAT pathway and with pan-FGFR inhibitors. Analysis of patient ER + breast tumor transcriptomes from the TCGA and METABRIC datasets demonstrated a strong positive association between expression of FGF2 and stemness signatures, which was further enhanced in tumors with high FGFR1 expression. Overall, our findings reveal a divergence in FGFR signaling, transitioning from a proliferative to stemness state driven by activation of JAK-STAT signaling and modulation of p21 levels. Activation of these divergent signaling pathways in FGFR amplified cancer cells and paradoxical growth effects highlight a challenge in the use of FGFR inhibitors in cancer treatment.

Detailed Analysis of ITPR1 Missense Variants Guides Diagnostics and Therapeutic Design.

BACKGROUND: The ITPR1 gene encodes the inositol 1,4,5-trisphosphate (IP3 ) receptor type 1 (IP3 R1), a critical player in cerebellar intracellular calcium signaling. Pathogenic missense variants in ITPR1 cause congenital spinocerebellar ataxia type 29 (SCA29), Gillespie syndrome (GLSP), and severe pontine/cerebellar hypoplasia. The pathophysiological basis of the different phenotypes is poorly understood. OBJECTIVES: We aimed to identify novel SCA29 and GLSP cases to define core phenotypes, describe the spectrum of missense variation across ITPR1, standardize the ITPR1 variant nomenclature, and investigate disease progression in relation to cerebellar atrophy. METHODS: Cases were identified using next-generation sequencing through the Deciphering Developmental Disorders study, the 100,000 Genomes project, and clinical collaborations. ITPR1 alternative splicing in the human cerebellum was investigated by quantitative polymerase chain reaction. RESULTS: We report the largest, multinational case series of 46 patients with 28 unique ITPR1 missense variants. Variants clustered in functional domains of the protein, especially in the N-terminal IP3 -binding domain, the carbonic anhydrase 8 (CA8)-binding region, and the C-terminal transmembrane channel domain. Variants outside these domains were of questionable clinical significance. Standardized transcript annotation, based on our ITPR1 transcript expression data, greatly facilitated analysis. Genotype-phenotype associations were highly variable. Importantly, while cerebellar atrophy was common, cerebellar volume loss did not correlate with symptom progression. CONCLUSIONS: This dataset represents the largest cohort of patients with ITPR1 missense variants, expanding the clinical spectrum of SCA29 and GLSP. Standardized transcript annotation is essential for future reporting. Our findings will aid in diagnostic interpretation in the clinic and guide selection of variants for preclinical studies. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Standards of NGS Data Sharing and Analysis in Ataxias: Recommendations by the NGS Working Group of the Ataxia Global Initiative.

The Ataxia Global Initiative (AGI) is a worldwide multi-stakeholder research platform to systematically enhance trial-readiness in degenerative ataxias. The next-generation sequencing (NGS) working group of the AGI aims to improve methods, platforms, and international standards for ataxia NGS analysis and data sharing, ultimately allowing to increase the number of genetically ataxia patients amenable for natural history and treatment trials. Despite extensive implementation of NGS for ataxia patients in clinical and research settings, the diagnostic gap remains sizeable, as approximately 50% of patients with hereditary ataxia remain genetically undiagnosed. One current shortcoming is the fragmentation of patients and NGS datasets on different analysis platforms and databases around the world. The AGI NGS working group in collaboration with the AGI associated research platforms-CAGC, GENESIS, and RD-Connect GPAP-provides clinicians and scientists access to user-friendly and adaptable interfaces to analyze genome-scale patient data. These platforms also foster collaboration within the ataxia community. These efforts and tools have led to the diagnosis of > 500 ataxia patients and the discovery of > 30 novel ataxia genes. Here, the AGI NGS working group presents their consensus recommendations for NGS data sharing initiatives in the ataxia field, focusing on harmonized NGS variant analysis and standardized clinical and metadata collection, combined with collaborative data and analysis tool sharing across platforms.

Quantitative Oculomotor Assessment in Hereditary Ataxia: Discriminatory Power, Correlation with Severity Measures, and Recommended Parameters for Specific Genotypes.

Characterizing bedside oculomotor deficits is a critical factor in defining the clinical presentation of hereditary ataxias. Quantitative assessments are increasingly available and have significant advantages, including comparability over time, reduced examiner dependency, and sensitivity to subtle changes. To delineate the potential of quantitative oculomotor assessments as digital-motor outcome measures for clinical trials in ataxia, we searched MEDLINE for articles reporting on quantitative eye movement recordings in genetically confirmed or suspected hereditary ataxias, asking which paradigms are most promising for capturing disease progression and treatment response. Eighty-nine manuscripts identified reported on 1541 patients, including spinocerebellar ataxias (SCA2, n = 421), SCA3 (n = 268), SCA6 (n = 117), other SCAs (n = 97), Friedreich ataxia (FRDA, n = 178), Niemann-Pick disease type C (NPC, n = 57), and ataxia-telangiectasia (n = 85) as largest cohorts. Whereas most studies reported discriminatory power of oculomotor assessments in diagnostics, few explored their value for monitoring genotype-specific disease progression (n = 2; SCA2) or treatment response (n = 8; SCA2, FRDA, NPC, ataxia-telangiectasia, episodic-ataxia 4). Oculomotor parameters correlated with disease severity measures including clinical scores (n = 18 studies (SARA: n = 9)), chronological measures (e.g., age, disease duration, time-to-symptom onset; n = 17), genetic stratification (n = 9), and imaging measures of atrophy (n = 5). Recurrent correlations across many ataxias (SCA2/3/17, FRDA, NPC) suggest saccadic eye movements as potentially generic quantitative oculomotor outcome. Recommendation of other paradigms was limited by the scarcity of cross-validating correlations, except saccadic intrusions (FRDA), pursuit eye movements (SCA17), and quantitative head-impulse testing (SCA3/6). This work aids in understanding the current knowledge of quantitative oculomotor parameters in hereditary ataxias, and identifies gaps for validation as potential trial outcome measures in specific ataxia genotypes.

Predicting novel candidate human obesity genes and their site of action by systematic functional screening in Drosophila.

The discovery of human obesity-associated genes can reveal new mechanisms to target for weight loss therapy. Genetic studies of obese individuals and the analysis of rare genetic variants can identify novel obesity-associated genes. However, establishing a functional relationship between these candidate genes and adiposity remains a significant challenge. We uncovered a large number of rare homozygous gene variants by exome sequencing of severely obese children, including those from consanguineous families. By assessing the function of these genes in vivo in Drosophila, we identified 4 genes, not previously linked to human obesity, that regulate adiposity (itpr, dachsous, calpA, and sdk). Dachsous is a transmembrane protein upstream of the Hippo signalling pathway. We found that 3 further members of the Hippo pathway, fat, four-jointed, and hippo, also regulate adiposity and that they act in neurons, rather than in adipose tissue (fat body). Screening Hippo pathway genes in larger human cohorts revealed rare variants in TAOK2 associated with human obesity. Knockdown of Drosophila tao increased adiposity in vivo demonstrating the strength of our approach in predicting novel human obesity genes and signalling pathways and their site of action.

Impact of feedback generation and presentation on self-monitoring behaviors, dietary intake, physical activity, and weight: a systematic review and meta-analysis.

Self-monitoring of dietary intake, physical activity, and weight is a key strategy in behavioral interventions, and some interventions provide self-monitoring feedback to facilitate goal setting and promote engagement. This systematic review aimed to evaluate whether feedback increases intervention effectiveness, and which forms of feedback presentation (e.g., personalized vs. not personalized) and generation (i.e., human vs. algorithm-generated) are most effective. To achieve this aim, 5 electronic databases (PubMed/MEDLINE, Web of Science, CINAHL, PsycINFO, and Google Scholar) were searched in April 2022 and yielded 694 unique records, out of which 24 articles reporting on 19 studies were included (with a total of 3261 participants). Two reviewers independently screened titles and abstracts and then full texts and categorized articles as eligible or excluded according to the pre-registered criteria (i.e., availability of full text, peer reviewed manuscript in English; adult participants in a randomized controlled trial that included both self-monitoring and feedback; comparisons of different forms of feedback or comparisons of feedback vs. no feedback; primary outcomes of diet, physical activity, self-monitoring behavior, and/or weight). All included studies were assessed for methodological quality independently by two reviewers using the revised Cochrane risk-of-bias tool for randomized studies (version 2). Ten studies compared feedback to no feedback, 5 compared human- vs. algorithm-generated feedback, and the remaining 4 studies compared formats of feedback presentation (e.g., frequency, richness). A random effects meta-analysis indicated that physical activity interventions with feedback provision were more effective than physical activity interventions without feedback (d = 0.73, 95% CI [0.09;1.37]). No meta-analysis could be conducted for other comparisons due to heterogeneity of study designs and outcomes. There were mixed results regarding which form of feedback generation and presentation is superior. Limitations of the evidence included in this review were: lack of details about feedback provided, the brevity of most interventions, the exclusion of studies that did not isolate feedback when testing intervention packages, and the high risk of bias in many studies. This systematic review underlines the importance of including feedback in behavioral interventions; however, more research is needed to identify most effective forms of feedback generation and presentation to maximize intervention effectiveness.Trial registration (PROSPERO)CRD42022316206.

Smoking cessation among sexual minority women: Differences in cigarette quit ratios across age, race/ethnicity, and sexual orientation.

OBJECTIVE: Sexual minority (SM) women experience tobacco-related disparities and report a higher prevalence of cigarette use, as well as subgroup differences in use, but little is known about their quitting behavior. This study used data from a national sample of United States SM women to examine cigarette quit ratios overall and by age, race/ethnicity, and sexual orientation. METHODS: Using baseline survey data from the Generations Study (2016-2017, N = 812), we calculated quit ratios among SM women reporting lifetime smoking (100+ cigarettes) who reported currently smoking "not at all" relative to those reporting smoking "every day or some days." Quitting was compared across cohort, race/ethnicity, and sexual orientation, controlling for household income. RESULTS: SM women reporting lifetime smoking in the older cohort were significantly more likely to report quitting than those in the younger cohort. Bisexual women also reported a greater likelihood of quitting than gay/lesbian women. There was no association between race/ethnicity and the probability of quitting smoking. CONCLUSIONS: SM women remain a priority for tobacco prevention and cessation efforts. There is evidence that the probability of quitting cigarettes differs across sexual orientation and age cohorts, which has implications for tailoring of interventions and tobacco communications.

Race/ethnicity-based discrimination, depressive symptoms, and smoking-related variables among people with HIV participating in a randomized clinical trial for cigarette smoking cessation.

People with HIV smoke cigarettes at a high prevalence, and it is important to identify modifiable variables related to smoking in this population. Race/ethnicity-based discrimination is common among people with HIV from minoritized racial and ethnic groups and results in significant adverse effects. The goal of this study was to examine the relationship between race/ethnicity-based discrimination, depression, and smoking-related variables among people with HIV who smoke. This was a secondary analysis of data from a prospective, randomized controlled smoking cessation trial for people with HIV. Participants were recruited from three HIV clinical care sites and randomly assigned to an HIV-tailored group therapy intervention or a control condition. Participants completed measures of demographics, smoking-related variables, race/ethnicity-based discrimination, and depressive symptoms at baseline and were followed up 3- and 6-months after study completion. Depressive symptoms had an indirect effect on the relationship between race/ethnicity-based discrimination and self-efficacy to quit smoking at 3-month follow-up. Depressive symptoms mediated the relationship between race/ethnicity-based discrimination and both nicotine dependence and self-efficacy to quit smoking at 6-month follow-up. Findings highlight the importance of considering race/ethnicity-based discrimination and depressive symptoms in the development and implementation of smoking cessation treatment interventions for people with HIV.

Hepatitis C and Cigarette Smoking Behavior: Themes From Focus Groups.

INTRODUCTION: People with chronic hepatitis C virus (HCV; PWHC) use cigarettes at a much higher prevalence than other individuals, and smoking can exacerbate the harms specifically related to HCV (eg, hepatocellular carcinoma). Little is known about factors related to cigarette use among PWHC. AIMS AND METHODS: This study examined focus group data to explore beliefs and behaviors related to cigarette use among PWHC. Qualitative data from two focus groups of PWHC reporting current cigarette smoking (n = 15, 60% male) were collected using a semi-structured interview guide. Participants were asked about reasons for smoking, barriers to quitting smoking, and the relationship of HCV to smoking. Focus groups were transcribed verbatim and coded in NVivo 12. Four coders examined themes that arose in the focus groups. Common themes are described and supported with quotes. RESULTS: Reasons for smoking included addiction to cigarettes, stress, substituting cigarettes for other drugs, and social norms, while reasons for quitting included health and being free from the use of all drugs. Barriers to quitting included concerns about coping with stress, weight gain, and having a lack of support for and education about quitting. Many participants believed there was a link between smoking and HCV and discussed smoking in relation to the stress of an HCV diagnosis. CONCLUSIONS: Participants identified both HCV-related and non-HCV-related aspects of cigarette smoking and cessation-related behaviors that could be targeted in cessation treatment. More research is needed to identify the best treatment approaches that reduce the significant medical consequences of cigarette use among PWHC. IMPLICATIONS: People with chronic hepatitis C virus (HCV; PWHC) smoke cigarettes at a high prevalence, yet little is known about their smoking behaviors. Moreover, there are no cessation treatments targeting PWHC. This is the first study to collect focus group data from PWHC who smoke in order to identify reasons for cigarette use (HCV-related and non-HCV-related), and motivators and barriers to quitting cigarettes. PWHC reports using cigarettes to cope with the stress of an HCV diagnosis and to celebrate HCV cure. These findings suggest there are specific times during the HCV care continuum where providers can aid with cessation efforts.

An Introduction and Practical Guide to Strategies for Analyzing Longitudinal Data in Clinical Trials of Smoking Cessation Treatment: Beyond Dichotomous Point-Prevalence Outcomes.

Conceptualizing tobacco dependence as a chronic relapsing condition suggests the need to use analytic strategies that reflect that premise. However, clinical trials for smoking cessation typically define the primary endpoint as a measure of abstinence at a single timepoint distal to the intervention, typically 3-12 months. This reinforces the concept of tobacco outcomes as a dichotomous state-one is, or is not, abstinent. Fortunately, there are several approaches available to handle longitudinal data that reflect the relapsing and remitting nature of tobacco use during treatment studies. In this paper, sponsored by the Society for Research on Nicotine and Tobacco's Treatment Research Network, we present an introductory overview of these techniques and their application in smoking cessation clinical trials. Topics discussed include models to examine abstinence outcomes (eg, trajectory models of abstinence, models for transitions in smoking behavior, models for time to event), models that examine reductions in tobacco use, and models to examine joint outcomes (eg, examining changes in the use of more than one tobacco product). Finally, we discuss three additional relevant topics (ie, heterogeneity of effects, handling missing data, and power and sample size) and provide summary information about the type of model that can be used based on the type of data collected and the focus of the study. We encourage investigators to familiarize themselves with these techniques and use them in the analysis of data from clinical trials of smoking cessation treatment. Implications Clinical trials of tobacco dependence treatment typically measure abstinence 3-12 months after participant enrollment. However, because smoking is a chronic relapsing condition, these measures of intervention success may not accurately reflect the common trajectories of tobacco abstinence and relapse. Several analytical techniques facilitate this type of outcome modeling. This paper is meant to be an introduction to these concepts and techniques to the global nicotine and tobacco research community including which techniques can be used for different research questions with visual summaries of which types of models can be used for different types of data and research questions.

Normal and pathogenic variation of RFC1 repeat expansions: implications for clinical diagnosis.

Cerebellar ataxia, neuropathy and vestibular areflexia syndrome (CANVAS) is an autosomal recessive neurodegenerative disease, usually caused by biallelic AAGGG repeat expansions in RFC1. In this study, we leveraged whole genome sequencing data from nearly 10 000 individuals recruited within the Genomics England sequencing project to investigate the normal and pathogenic variation of the RFC1 repeat. We identified three novel repeat motifs, AGGGC (n = 6 from five families), AAGGC (n = 2 from one family) and AGAGG (n = 1), associated with CANVAS in the homozygous or compound heterozygous state with the common pathogenic AAGGG expansion. While AAAAG, AAAGGG and AAGAG expansions appear to be benign, we revealed a pathogenic role for large AAAGG repeat configuration expansions (n = 5). Long-read sequencing was used to characterize the entire repeat sequence, and six patients exhibited a pure AGGGC expansion, while the other patients presented complex motifs with AAGGG or AAAGG interruptions. All pathogenic motifs appeared to have arisen from a common haplotype and were predicted to form highly stable G quadruplexes, which have previously been demonstrated to affect gene transcription in other conditions. The assessment of these novel configurations is warranted in CANVAS patients with negative or inconclusive genetic testing. Particular attention should be paid to carriers of compound AAGGG/AAAGG expansions when the AAAGG motif is very large (>500 repeats) or the AAGGG motif is interrupted. Accurate sizing and full sequencing of the satellite repeat with long-read sequencing is recommended in clinically selected cases to enable accurate molecular diagnosis and counsel patients and their families.

Axenfeld-Rieger syndrome: more than meets the eye.

BACKGROUND: Axenfeld-Rieger syndrome (ARS) is characterised by typical anterior segment anomalies, with or without systemic features. The discovery of causative genes identified ARS subtypes with distinct phenotypes, but our understanding is incomplete, complicated by the rarity of the condition. METHODS: Genetic and phenotypic characterisation of the largest reported ARS cohort through comprehensive genetic and clinical data analyses. RESULTS: 128 individuals with causative variants in PITX2 or FOXC1, including 81 new cases, were investigated. Ocular anomalies showed significant overlap but with broader variability and earlier onset of glaucoma for FOXC1-related ARS. Systemic anomalies were seen in all individuals with PITX2-related ARS and the majority of those with FOXC1-related ARS. PITX2-related ARS demonstrated typical umbilical anomalies and dental microdontia/hypodontia/oligodontia, along with a novel high rate of Meckel diverticulum. FOXC1-related ARS exhibited characteristic hearing loss and congenital heart defects as well as previously unrecognised phenotypes of dental enamel hypoplasia and/or crowding, a range of skeletal and joint anomalies, hypotonia/early delay and feeding disorders with structural oesophageal anomalies in some. Brain imaging revealed highly penetrant white matter hyperintensities, colpocephaly/ventriculomegaly and frequent arachnoid cysts. The expanded phenotype of FOXC1-related ARS identified here was found to fully overlap features of De Hauwere syndrome. The results were used to generate gene-specific management plans for the two types of ARS. CONCLUSION: Since clinical features of ARS vary significantly based on the affected gene, it is critical that families are provided with a gene-specific diagnosis, PITX2-related ARS or FOXC1-related ARS. De Hauwere syndrome is proposed to be a FOXC1opathy.

Biceps femoris long head muscle and aponeurosis geometry in males with and without a history of hamstring strain injury.

OBJECTIVES: Hamstring strain injuries (HSIs) commonly affect the proximal biceps femoris long head (BFlh) musculotendinous junction. Biomechanical modeling suggests narrow proximal BFlh aponeuroses and large muscle-to-aponeurosis width ratios increase localized tissue strains and presumably risk of HSI. This study aimed to determine if BFlh muscle and proximal aponeurosis geometry differed between limbs with and without a history of HSI. METHODS: Twenty-six recreationally active males with (n = 13) and without (n = 13) a history of unilateral HSI in the last 24 months underwent magnetic resonance imaging of both thighs. BFlh muscle and proximal aponeurosis cross-sectional areas, length, volume, and interface area between muscle and aponeurosis were extracted. Previously injured limbs were compared to uninjured contralateral and control limbs for discrete variables and ratios, and along the relative length of tissues using statistical parametric mapping. RESULTS: Previously injured limbs displayed significantly smaller muscle-to-aponeurosis volume ratios (p = 0.029, Wilcoxon effect size (ES) = 0.43) and larger proximal BFlh aponeurosis volumes (p = 0.019, ES = 0.46) than control limbs with no history of HSI. No significant differences were found between previously injured and uninjured contralateral limbs for any outcome measure (p = 0.216-1.000, ES = 0.01-0.36). CONCLUSIONS: Aponeurosis geometry differed between limbs with and without a history of HSI. The significantly larger BFlh proximal aponeuroses and smaller muscle-to-aponeurosis volume ratios in previously injured limbs could alter the strain experienced in muscle adjacent to the musculotendinous junction during active lengthening. Future research is required to determine if geometric differences influence the risk of re-injury and whether they can be altered via targeted training.

A patient activation intervention in primary care for patients with chronic pain on long term opioid therapy: results from a randomized control trial.

BACKGROUND: Given significant risks associated with long-term prescription opioid use, there is a need for non-pharmacological interventions for treating chronic pain. Activating patients to manage chronic pain has the potential to improve health outcomes. The ACTIVATE study was designed to evaluate the effectiveness of a 4-session patient activation intervention in primary care for patients on long-term opioid therapy. METHODS: The two-arm, pragmatic, randomized trial was conducted in two primary care clinics in an integrated health system from June 2015-August 2018. Consenting participants were randomized to the intervention (n = 189) or usual care (n = 187). Participants completed online and interviewer-administered surveys at baseline, 6- and 12- months follow-up. Prescription opioid use was extracted from the EHR. The primary outcome was patient activation assessed by the Patient Activation Measure (PAM). Secondary outcomes included mood, function, overall health, non-pharmacologic pain management strategies, and patient portal use. We conducted a repeated measure analysis and reported between-group differences at 12 months. RESULTS: At 12 months, the intervention and usual care arms had similar PAM scores. However, compared to usual care at 12 months, the intervention arm demonstrated: less moderate/severe depression (odds ratio [OR] = 0.40, 95%CI 0.18-0.87); higher overall health (OR = 3.14, 95%CI 1.64-6.01); greater use of the patient portal's health/wellness resources (OR = 2.50, 95%CI 1.42-4.40) and lab/immunization history (OR = 2.70, 95%CI 1.29-5.65); and greater use of meditation (OR = 2.72; 95%CI 1.61-4.58) and exercise/physical therapy (OR = 2.24, 95%CI 1.29-3.88). At 12 months, the intervention arm had a higher physical health measure (mean difference 1.63; 95%CI: 0.27-2.98). CONCLUSION: This trial evaluated the effectiveness of a primary care intervention in improving patient activation and patient-reported outcomes among adults with chronic pain on long-term opioid therapy. Despite a lack of improvement in patient activation, a brief intervention in primary care can improve outcomes such as depression, overall health, non-pharmacologic pain management, and engagement with the health system. TRIAL REGISTRATION: The study was registered on 10/27/14 on ClinicalTrials.gov (NCT02290223).

Same-Day Discharge Does Not Increase Resource Utilization Within One Year of Total Joint Arthroplasty.

BACKGROUND: While the safety of rapid recovery total joint arthroplasty is well established, less is known about its impact on postoperative care utilization patterns. We wished to examine whether same-day discharge-and its associated presumed reduction in hospital-based postoperative care and education-translates to the need for more postoperative support during the 1-year recovery period. METHODS: A retrospective review of 1,237 total hip arthroplasty (THA) and 1,710 total knee arthroplasty (TKA) patients who had 0- or 1-day length of stay (LOS) from January 2020 to October 2023 was conducted. The primary outcome was the number of follow-up visits with total joint arthroplasty providers at our institution during the 1-year postoperative period. Secondary outcomes included 30-day emergency department returns, readmissions, 1-year physical therapy utilization, and improvement in Patient-Reported Outcomes Measurement Information System Physical Function scores at 6 to 12 months postoperatively. Bivariate and multivariable analyses were performed to compare outcomes between 0-day and 1-day LOS THA and TKA patients. RESULTS: In both the THA and TKA populations, 0-day LOS patients were younger, had a lower average body mass index, were more likely to be White, men, and had an American Society of Anesthesiologists score < 3 than 1-day LOS patients. After controlling for differences between groups, no significant differences in the number of one-year follow-up visits, physical therapy visits, emergency department returns, or readmissions were seen between 0 and 1-day THA or TKA patients. In TKA patients, 1-day LOS was associated with lower improvements in Patient-Reported Outcomes Measurement Information System Physical Function scores. CONCLUSIONS: After risk adjustment, same-day discharge of THA and TKA patients did not result in increased resource utilization during the one-year postoperative period. In the setting of a coordinated joint arthroplasty program with nurse navigator support, same-day discharge can be safely performed without increasing the need for postoperative care in appropriately selected patients undergoing both THA and TKA.