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Williams-Beuren syndrome (WBS) is a rare genetic condition caused by a chromosomal microdeletion at 7q11.23. It is a multisystem disorder characterized by distinct facies, intellectual disability, and supravalvar aortic stenosis (SVAS). Those with WBS are at increased risk of sudden death, but mechanisms underlying this remain poorly understood. We recently demonstrated autonomic abnormalities in those with WBS that are associated with increased susceptibility to arrhythmia and sudden cardiac death (SCD). A recently introduced method for heart rate variability (HRV) analysis called "heart rate fragmentation" (HRF) correlates with adverse cardiovascular events (CVEs) and death in studies where heart rate variability (HRV) failed to identify high-risk subjects. Some argue that HRF quantifies nonautonomic cardiovascular modulators. We, therefore, sought to apply HRF analysis to a WBS cohort to determine 1 ) if those with WBS show differences in HRF compared with healthy controls and 2 ) if HRF helps characterize HRV abnormalities in those with WBS. Similar to studies of those with coronary artery disease (CAD) and atherosclerosis, we found significantly higher HRF (4 out of 7 metrics) in those with WBS compared with healthy controls. Multivariable analyses showed a weak-to-moderate association between HRF and HRV, suggesting that HRF may reflect HRV characteristics not fully captured by traditional HRV metrics (autonomic markers). We also introduce a new metric inspired by HRF methodology, significant acute rate drop (SARD), which may detect vagal activity more directly. HRF and SARD may improve on traditional HRV measures to identify those at greatest risk for SCD both in those with WBS and in other populations. NEW & NOTEWORTHY This work is the first to apply heart rate fragmentation analyses to individuals with Williams syndrome and posits that the heart rate fragmentation parameter W 3 may enable detection and investigation of phenomena underlying the proarrhythmic short-long-short RR interval sequences paradigm known to precede ventricular fibrillation and ventricular tachycardia. It also forwards a novel method for quantifying sinus arrhythmia and sinus pauses that likely correlate with parasympathetic activity.

Objective: To assess the levels of burnout, well-being, and mental health of nonveterinarian employees of veterinary practices and, for context, compare them to veterinarians and the general population by use of validated instruments., Methods: An online survey of 2,271 nonveterinary practice employees drawn from members of the North American Veterinary Technicians Association, members of the Veterinary Hospital Managers Association, referrals from veterinarian respondents to a companion survey, and a large hospital group that owns several hundred US veterinary practices. The study was fielded from September 11 to October 9, 2023., Results: A majority of practice team members were satisfied with their work in veterinary medicine. However, serious psychological distress was twice as prevalent among team members as among veterinarians and well-being was lower than that of veterinarians. Burnout was similar to veterinarians. Personality played a role: team members on average were more likely to score higher in neuroticism than veterinarians and the general population, and neuroticism was a predictor of low well-being, poor mental health, and burnout. There was also evidence of substantial financial stress among team members., Conclusions: Serious psychological distress was common among practice team members. Financial stress may play a role. Burnout and low levels of well-being were also common., Clinical Relevance: This study provided a useful profile of the psychological conditions that many practice employees may be experiencing.

Transcriptomics is a powerful tool for unraveling the molecular effects of genetic variants and disease diagnosis. Prior studies have demonstrated that choice of genome build impacts variant interpretation and diagnostic yield for genomic analyses. To identify the extent genome build also impacts transcriptomics analyses, we studied the effect of the hg19, hg38, and CHM13 genome builds on expression quantification and outlier detection in 386 rare disease and familial control samples from both the Undiagnosed Diseases Network and Genomics Research to Elucidate the Genetics of Rare Disease Consortium. Across six routinely collected biospecimens, 61% of quantified genes were not influenced by genome build. However, we identified 1,492 genes with build-dependent quantification, 3,377 genes with build-exclusive expression, and 9,077 genes with annotation-specific expression across six routinely collected biospecimens, including 566 clinically relevant and 512 known OMIM genes. Further, we demonstrate that between builds for a given gene, a larger difference in quantification is well correlated with a larger change in expression outlier calling. Combined, we provide a database of genes impacted by build choice and recommend that transcriptomics-guided analyses and diagnoses are cross referenced with these data for robustness., Competing Interests: Declaration of interests During this project R.A.U. was employed for an internship by Vertex Pharmaceuticals. P.C.G. is a consultant for BioMarin. S.B.M. is an advisor to BioMarin, MyOme, and Tenaya Therapeutics., (Copyright © 2024 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)

Screening mammography reduces breast cancer mortality, but studies analyzing interval cancers diagnosed after negative screens have shown that many cancers are missed. Supplemental screening using magnetic resonance imaging (MRI) can reduce the number of missed cancers. However, as qualified MRI staff are lacking, the equipment is expensive to purchase and cost-effectiveness for screening may not be convincing, the utilization of MRI is currently limited. An effective method for triaging individuals to supplemental MRI screening is therefore needed. We conducted a randomized clinical trial, ScreenTrustMRI, using a recently developed artificial intelligence (AI) tool to score each mammogram. We offered trial participation to individuals with a negative screening mammogram and a high AI score (top 6.9%). Upon agreeing to participate, individuals were assigned randomly to one of two groups: those receiving supplemental MRI and those not receiving MRI. The primary endpoint of ScreenTrustMRI is advanced breast cancer defined as either interval cancer, invasive component larger than 15 mm or lymph node positive cancer, based on a 27-month follow-up time from the initial screening. Secondary endpoints, prespecified in the study protocol to be reported before the primary outcome, include cancer detected by supplemental MRI, which is the focus of the current paper. Compared with traditional breast density measures used in a previous clinical trial, the current AI method was nearly four times more efficient in terms of cancers detected per 1,000 MRI examinations (64 versus 16.5). Most additional cancers detected were invasive and several were multifocal, suggesting that their detection was timely. Altogether, our results show that using an AI-based score to select a small proportion (6.9%) of individuals for supplemental MRI after negative mammography detects many missed cancers, making the cost per cancer detected comparable with screening mammography. ClinicalTrials.gov registration: NCT04832594 ., (© 2024. The Author(s).)

This paper critiques the restrictive criteria for germline genome editing recently proposed by Chin, Nguma, and Ahmad in this journal. While praising the authors for resisting fervent calls for an outright ban on clinical applications of the technology, this paper argues that their approach is nevertheless unduly restrictive, and may thus hinder technological progress. This response advocates for weighing potential benefits against risks without succumbing to excessive caution, proposing that ethical oversight combined with genetic scrutiny at the embryo stage post-editing can enable responsible use of the technology, ultimately reducing the burden of genetic diseases and enhancing human health, akin to how IVF transformed reproductive medicine despite strong initial opposition., (© 2024. The Author(s).)

Autoimmunity, allergy, and transplant rejection are a collection of chronic diseases that are currently incurable, drastically decrease patient quality of life, and consume considerable health care resources. Underlying each of these diseases is a dysregulated immune system that results in the mounting of an inflammatory response against self or an innocuous antigen. As a consequence, afflicted patients are required to adhere to lifelong regimens of multiple immunomodulatory drugs to control disease and reclaim agency. Unfortunately, current immunomodulatory drugs are associated with a myriad of side effects and adverse events, such as increased risk of cancer and increased risk of serious infection, which negatively impacts patient adherence rates and quality of life. The field of immunoengineering is a new discipline that aims to harness endogenous biological pathways to thwart disease and minimize side effects using novel biomaterial-based strategies. We highlight and discuss polymeric micro/nanoparticles with inherent immunomodulatory properties that are currently under investigation in biomaterial-based therapies for treatment of autoimmunity, allergy, and transplant rejection.

We combined synchrotron-based infrared absorbance and Raman scattering spectroscopies with diamond anvil cell techniques and a symmetry analysis to explore the properties of multiferroic (NH 4 ) 2 FeCl 5 ·H 2 O under extreme pressure-temperature conditions. Compression-induced splitting of the Fe-Cl stretching, Cl-Fe-Cl and Cl-Fe-O bending, and NH 4 + librational modes defines two structural phase transitions, and a group-subgroup analysis reveals space group sequences that vary depending upon proximity to the unexpectedly wide order-disorder transition. We bring these findings together with prior high-field work to develop the pressure-temperature-magnetic field phase diagram uncovering competing polar, chiral, and magnetic phases in this system.

Regular exercise has many physical and brain health benefits, yet the molecular mechanisms mediating exercise effects across tissues remain poorly understood. Here we analyzed 400 high-quality DNA methylation, ATAC-seq, and RNA-seq datasets from eight tissues from control and endurance exercise-trained (EET) rats. Integration of baseline datasets mapped the gene location dependence of epigenetic control features and identified differing regulatory landscapes in each tissue. The transcriptional responses to 8 weeks of EET showed little overlap across tissues and predominantly comprised tissue-type enriched genes. We identified sex differences in the transcriptomic and epigenomic changes induced by EET. However, the sex-biased gene responses were linked to shared signaling pathways. We found that many G protein-coupled receptor-encoding genes are regulated by EET, suggesting a role for these receptors in mediating the molecular adaptations to training across tissues. Our findings provide new insights into the mechanisms underlying EET-induced health benefits across organs., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Arterial calcification due to deficiency of CD73 (ACDC; OMIM 211800) is a rare genetic disease resulting in calcium deposits in arteries and small joints causing claudication, resting pain, severe joint pain, and deformities. Currently, there are no standard treatments for ACDC. Our previous work identified etidronate as a potential targeted ACDC treatment, using in vitro and in vivo disease models with patient-derived cells. In this study, we test the safety and effectiveness of etidronate in attenuating the progression of lower-extremity arterial calcification and vascular blood flow based on the computed tomography (CT) calcium score and ankle-brachial index (ABI)., Methods: Seven adult patients with a confirmed genetic diagnosis of ACDC were enrolled in an open-label, nonrandomized, single-arm pilot study for etidronate treatment. They took etidronate daily for 14 days every 3 months and were examined at the NIH Clinical Center bi-annually for 3 years. They received a baseline evaluation as well as yearly follow up after treatment. Study visits included imaging studies, exercise tolerance tests with ABIs, clinical blood and urine testing, and full dental exams., Results: Etidronate treatment appeared to have slowed the progression of further vascular calcification in lower extremities as measured by CT but did not have an effect in reversing vascular and/or periarticular joint calcifications in our small ACDC cohort., Conclusions: Etidronate was found to be safe and well tolerated by our patients and, despite the small sample size, appeared to show an effect in slowing the progression of calcification in our ACDC patient cohort. (ClinicalTrials.gov Identifier NCT01585402) ., Competing Interests: Declaration of conflicting interestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: Mepolizumab is a therapy for severe asthma. We have little knowledge of the characteristics of people in the US that discontinue mepolizumab in clinical care., Objective: To investigate the real-world efficacy and time to clinical discontinuation of mepolizumab, we evaluated individuals with asthma started on mepolizumab at the Cleveland Clinic. We hypothesized that individuals that discontinue mepolizumab have more severe and uncontrolled asthma at baseline., Methods: Between 2016 and 2022, patients who started on mepolizumab consented to be assessed over 18 months. At baseline, a questionnaire including demographic and medical history was collected. Laboratory findings such as ACT score, F E NO (Fractional Excretion of Nitric Oxide), and spirometry were recorded. At the conclusion of the observation period, the participants were divided into two categories: Group A and Group B., Results: Group B [ N  = 28] discontinued mepolizumab ( p  < 0.05) at an average of 5.8 months (SD 4.2 months). Group A [ N  = 129] stayed on the therapy for at least 1 year. A participant with an ACT score less than 13 has an odds ratio of 6.64 (95% CI, 2.1 - 26.0) of discontinuing mepolizumab therapy. For a male, the odds of discontinuing mepolizumab therapy is 3.39 (95% CI, 1.1-11.2)., Conclusion: In this real-world study, we find that high eosinophil count may not be adequate in screening which individuals will benefit from mepolizumab. Up to 17% of patients fail therapy within 6 months, with male sex and low ACT score increasing risk of mepolizumab discontinuation at Cleveland Clinic.

'Embodied cognition' suggests that our bodily experiences broadly shape our cognitive capabilities. We study how embodied experience affects the abstract physical problem-solving styles people use in a virtual task where embodiment does not affect action capabilities. We compare how groups with different embodied experience - 25 children and 35 adults with congenital limb differences versus 45 children and 40 adults born with two hands - perform this task, and find that while there is no difference in overall competence, the groups use different cognitive styles to find solutions. People born with limb differences think more before acting but take fewer attempts to reach solutions. Conversely, development affects the particular actions children use, as well as their persistence with their current strategy. Our findings suggest that while development alters action choices and persistence, differences in embodied experience drive changes in the acquisition of cognitive styles for balancing acting with thinking., (© 2023. The Author(s).)

The synthesis of a new bis-BF 2 tetrafluorobenzo-[α]-fused BOPYPY dye from 4,5,6,7-tetrafluoroisoindole and 2-hydrazinopyrazine is reported. The regioselectivity of nucleophilic substitution reactions at the periphery of the tetrafluorinated BOPYPY and its α-bromo derivative were investigated using N-, O-, S-, and C-based nucleophiles. Among the aromatic fluorine atoms, the F 2 atom is consistently regioselectively substituted, except when the α-position contains a thiophenol group; in this case, F 4 is substituted instead due to stabilizing π-π-stacking between the two aromatic groups. The α-bromo BOPYPY derivative also reacts under Stille cross-coupling reaction conditions to produce the corresponding α-substituted product. The spectroscopic properties of these new fluorinated BOPYPYs were investigated and compared with nonfluorinated analogs.

Purpose: The function of FAM177A1 and its relationship to human disease is largely unknown. Recent studies have demonstrated FAM177A1 to be a critical immune-associated gene. One previous case study has linked FAM177A1 to a neurodevelopmental disorder in 4 siblings., Methods: We identified 5 individuals from 3 unrelated families with biallelic variants in FAM177A1. The physiological function of FAM177A1 was studied in a zebrafish model organism and human cell lines with loss-of-function variants similar to the affected cohort., Results: These individuals share a characteristic phenotype defined by macrocephaly, global developmental delay, intellectual disability, seizures, behavioral abnormalities, hypotonia, and gait disturbance. We show that FAM177A1 localizes to the Golgi complex in mammalian and zebrafish cells. Intersection of the RNA sequencing and metabolomic data sets from FAM177A1-deficient human fibroblasts and whole zebrafish larvae demonstrated dysregulation of pathways associated with apoptosis, inflammation, and negative regulation of cell proliferation., Conclusion: Our data shed light on the emerging function of FAM177A1 and defines FAM177A1-related neurodevelopmental disorder as a new clinical entity., Competing Interests: Conflict of Interest The authors declare no conflicts of interest., (Copyright © 2024 American College of Medical Genetics and Genomics. Published by Elsevier Inc. All rights reserved.)

Multicomponent oxides are intriguing materials in heterogeneous catalysis, and the interface between various components often plays an essential role in oxidations. However, the underlying principles of how the hetero-interface affects the catalytic process remain largely unexplored. Here we report a unique structure design of MnCoO x catalysts by chemical reduction, specifically for ethane oxidation. Part of the Mn ions incorporates with Co oxides to form spinel Mn x Co 3-x O 4 , while the rests stay as MnO 2 domains to create the MnO 2 -Mn x Co 3-x O 4 interface. MnCoO x with Mn/Co ratio of 0.5 exhibits an excellent activity and stability up to 1000 h under humid conditions. The synergistic effects between MnO 2 and Mn x Co 3-x O 4 are elucidated, in which the C 2 H 6 tends to be adsorbed on the interfacial Co sites and subsequently break the C-H bonds on the reactive lattice O of MnO 2 layer. Findings from this study provide valuable insights for the rational design of efficient catalysts for alkane combustion., (© 2024. The Author(s).)

Recently, there has been growing interest in the concept of political anxiety. One important question that remains unanswered is whether political anxiety is just a symptom of general anxiety-that those reporting anxiety tied to politics are the same individuals who would already score highly on measures of general anxiety. Using survey data collected in 2023 ( N = 436), we find that measures of political and generalized anxiety do not appear to be tapping into a single underlying construct. In addition, the systematic correlates of these measures identified by previous literature are not equivalent predictors of the different types of anxiety. Politics seems to be a source of apprehensiveness and worry that affects individuals who are not necessarily suffering from general anxiety.

Objective: To assess levels of burnout, well-being, and mental health of veterinarians and compare them to those of nonveterinarians by use of validated instruments, and to identify the predictive values of techniques individuals can use to help reduce burnout and/or improve well-being and mental health., Sample: An online survey of 4,636 veterinarians from a random sample of 40,000 US veterinarians provided by the AVMA., Methods: The study was fielded from September 11 to October 9, 2023., Results: Burnout and well-being of veterinarians were generally consistent with that of employed US adults. Serious psychological distress was more common among veterinarians than in the general population. Veterinarians on average were more likely to score higher in neuroticism than nonveterinarians, and neuroticism was a predictor of low well-being, poor mental health, and burnout. Work-life balance, an effective coping mechanism for stress, and working in a positive clinic culture were among the significant factors that predicted good well-being and mental health and reduced burnout., Clinical Relevance: The higher percentage than the norm of veterinarians with serious psychological distress was a concern. Focusing on maintaining a good work-life balance and adopting a reliable coping mechanism can potentially help reduce distress. Veterinary medicine is an inherently stressful profession. The purpose of this study was to identify key factors that contribute to burnout, well-being, and mental health and to determine what behaviors and management techniques help reduce stress and burnout and contribute to well-being and mental health, thus improving job satisfaction and personal fulfillment.

Nosocomial infections are relatively common in the NICU. These infections increase morbidity and mortality, particularly in the smallest and most fragile infants. The impact of these infections on long-term outcomes and health-care costs is devastating. Worldwide efforts to decrease the incidence of nosocomial infections have focused on implementing specific prevention protocols such as handwashing, central line teams, care bundles, and antimicrobial stewardship. This review summarizes common nosocomial infections in patients in the NICU., (Copyright © 2024 by the American Academy of Pediatrics.)

The 2022 mpox (formerly monkeypox) outbreak affected predominantly men who have sex with men (MSM), likely through sexual transmission, which resulted in institutions specializing in sexual health being at the frontlines of the mpox outbreak. Fenway Health in Boston serves close to 10 000 MSM annually, which includes more than 2400 MSM who are living with HIV and 3320 MSM with active HIV preexposure prophylaxis (PrEP) prescriptions. We report on the programs implemented and changes to clinical practice at Fenway Health during the mpox outbreak. Fenway Health diagnosed its first case of mpox in June 2022 and treated this patient with tecovirimat. In early July 2022, Fenway Health administered its first dose of the Jynneos vaccine under the Emergency Use Authorization for protection against mpox. As of October 6, 2022, 69 people had tested positive for the mpox virus at Fenway Health. Among the 69 people who tested positive, 43 (62.3%) self-identified as male, with the remaining not reporting a sex or gender identity, and 40 (58.0%) reported their sexual orientation as gay or bisexual. Twenty-five people (36.2%) were treated with tecovirimat. As of October 30, 2022, Fenway Health had administered 6376 doses of the Jynneos vaccine. The programmatic changes involved in rollout and scale-up of vaccination, treatment, and community outreach services at Fenway Health during the 2022 mpox outbreak that we describe here could inform strategies to address subsequent outbreaks., Competing Interests: Declaration of Conflicting InterestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background:  Studies have shown that documentation burden experienced by clinicians may lead to less direct patient care, increased errors, and job dissatisfaction. Implementing effective strategies within health care systems to mitigate documentation burden can result in improved clinician satisfaction and more time spent with patients. However, there is a gap in the literature regarding evidence-based interventions to reduce documentation burden., Objectives:  The objective of this review was to identify and comprehensively summarize the state of the science related to documentation burden reduction efforts., Methods:  Following Joanna Briggs Institute Manual for Evidence Synthesis and Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews (PRISMA-ScR) guidelines, we conducted a comprehensive search of multiple databases, including PubMed, Medline, Embase, CINAHL Complete, Scopus, and Web of Science. Additionally, we searched gray literature and used Google Scholar to ensure a thorough review. Two reviewers independently screened titles and abstracts, followed by full-text review, with a third reviewer resolving any discrepancies. Data extraction was performed and a table of evidence was created., Results:  A total of 34 articles were included in the review, published between 2016 and 2022, with a majority focusing on the United States. The efforts described can be categorized into medical scribes, workflow improvements, educational interventions, user-driven approaches, technology-based solutions, combination approaches, and other strategies. The outcomes of these efforts often resulted in improvements in documentation time, workflow efficiency, provider satisfaction, and patient interactions., Conclusion:  This scoping review provides a comprehensive summary of health system documentation burden reduction efforts. The positive outcomes reported in the literature emphasize the potential effectiveness of these efforts. However, more research is needed to identify universally applicable best practices, and considerations should be given to the transfer of burden among members of the health care team, quality of education, clinician involvement, and evaluation methods., Competing Interests: None declared., (Thieme. All rights reserved.)

Governments recently adopted new global targets to halt and reverse the loss of biodiversity. It is therefore crucial to understand the outcomes of conservation actions. We conducted a global meta-analysis of 186 studies (including 665 trials) that measured biodiversity over time and compared outcomes under conservation action with a suitable counterfactual of no action. We find that in two-thirds of cases, conservation either improved the state of biodiversity or at least slowed declines. Specifically, we find that interventions targeted at species and ecosystems, such as invasive species control, habitat loss reduction and restoration, protected areas, and sustainable management, are highly effective and have large effect sizes. This provides the strongest evidence to date that conservation actions are successful but require transformational scaling up to meet global targets.

Identifying active compounds for a target is a time- and resource-intensive task in early drug discovery. Accurate bioactivity prediction using morphological profiles could streamline the process, enabling smaller, more focused compound screens. We investigate the potential of deep learning on unrefined single-concentration activity readouts and Cell Painting data, to predict compound activity across 140 diverse assays. We observe an average ROC-AUC of 0.744 ± 0.108 with 62% of assays achieving ≥0.7, 30% ≥0.8, and 7% ≥0.9. In many cases, the high prediction performance can be achieved using only brightfield images instead of multichannel fluorescence images. A comprehensive analysis shows that Cell Painting-based bioactivity prediction is robust across assay types, technologies, and target classes, with cell-based assays and kinase targets being particularly well-suited for prediction. Experimental validation confirms the enrichment of active compounds. Our findings indicate that models trained on Cell Painting data, combined with a small set of single-concentration data points, can reliably predict the activity of a compound library across diverse targets and assays while maintaining high hit rates and scaffold diversity. This approach has the potential to reduce the size of screening campaigns, saving time and resources, and enabling primary screening with more complex assays., (© 2024. The Author(s).)

Physical activity, including structured exercise, is associated with favorable health-related chronic disease outcomes. While there is evidence of various molecular pathways that affect these responses, a comprehensive molecular map of these molecular responses to exercise has not been developed. The Molecular Transducers of Physical Activity Consortium (MoTrPAC) is a multi-center study designed to isolate the effects of structured exercise training on the molecular mechanisms underlying the health benefits of exercise and physical activity. MoTrPAC contains both a pre-clinical and human component. The details of the human studies component of MoTrPAC that include the design and methods are presented here. The human studies contain both an adult and pediatric component. In the adult component, sedentary participants are randomized to 12 weeks of Control, Endurance Exercise Training, or Resistance Exercise Training with outcomes measures completed before and following the 12 weeks. The adult component also includes recruitment of highly active endurance trained or resistance trained participants who only complete measures once. A similar design is used for the pediatric component; however, only endurance exercise is examined. Phenotyping measures include weight, body composition, vital signs, cardiorespiratory fitness, muscular strength, physical activity and diet, and other questionnaires. Participants also complete an acute rest period (adults only) or exercise session (adults, pediatrics) with collection of biospecimens (blood only for pediatrics) to allow for examination of the molecular responses. The design and methods of MoTrPAC may inform other studies. Moreover, MoTrPAC will provide a repository of data that can be used broadly across the scientific community.

Objective: The objective of this study is to investigate safety and effectiveness of a fluoroscopy-guided high-intensity focused ultrasound (HIFU) system for thermal ablation of the lumbar medial branch nerves., Methods: This dual center prospective cohort study enrolled 30 participants with lumbar zygapophyseal joint syndrome. Each participant previously had a positive response to either a single diagnostic analgesic block or radiofrequency ablation (RFA). The primary effectiveness outcome was individual responder rate, defined as a reduction of two points or more on the pain intensity numerical rating scale without an increase in opioid intake, or a reduction in opioid intake without an increase in pain at 6 months after the intervention. The primary safety outcome was procedure-related or device-related adverse events (AEs). Secondary outcome variables included MRI evidence of tissue ablation, Oswestry Disability Index, 12-Item Short Form Health Survey, Brief Pain Inventory, and Patient Global Impression of Change., Results: The individual responder rate was 89.7% at 2 days, 89.7% at 7 days, 72.4% at 14 days, 82.1% at 30 days, 59.3% at 90 days and 82.6% at 180 days. The average Numeric Rating Scale for pain severity decreased from 7.1 at baseline to 3.0 (N=29) after 2 days, 3.0 (N=29) after 7 days, 3.1 (N=29) after 14 days, 3.2 (N=28) after 30 days, 4.3 (N=27) after 90 days, and 3.3 (N=23) after 180 days. All participants tolerated the procedure well with no significant side effects or complications., Conclusions: Fluoroscopy-guided HIFU neurotomy achieved clinical responses comparable with RFA, and there were no significant device-related or procedure-related AEs., Trial Registration Number: NCT04129034., Competing Interests: Competing interests: AH and RA are the founders of FUSMobile. MG is the chief medical officer of FUSMobile and holds an option to buy ordinary shares. EM and BS are employees of FUSMobile and hold an option to buy ordinary shares. EM and SL hold shares and ordinary options in FUSMobile., (© American Society of Regional Anesthesia & Pain Medicine 2024. Re-use permitted under CC BY-NC. No commercial re-use. Published by BMJ.)

The Environmental Impact Classification for Alien Taxa (EICAT) is an important tool for biological invasion policy and management and has been adopted as an International Union for Conservation of Nature (IUCN) standard to measure the severity of environmental impacts caused by organisms living outside their native ranges. EICAT has already been incorporated into some national and local decision-making procedures, making it a particularly relevant resource for addressing the impact of non-native species. Recently, some of the underlying conceptual principles of EICAT, particularly those related to the use of the precautionary approach, have been challenged. Although still relatively new, guidelines for the application and interpretation of EICAT will be periodically revisited by the IUCN community, based on scientific evidence, to improve the process. Some of the criticisms recently raised are based on subjectively selected assumptions that cannot be generalized and may harm global efforts to manage biological invasions. EICAT adopts a precautionary principle by considering a species' impact history elsewhere because some taxa have traits that can make them inherently more harmful. Furthermore, non-native species are often important drivers of biodiversity loss even in the presence of other pressures. Ignoring the precautionary principle when tackling the impacts of non-native species has led to devastating consequences for human well-being, biodiversity, and ecosystems, as well as poor management outcomes, and thus to significant economic costs. EICAT is a relevant tool because it supports prioritization and management of non-native species and meeting and monitoring progress toward the Kunming-Montreal Global Biodiversity Framework (GBF) Target 6., (© 2023 The Authors. Conservation Biology published by Wiley Periodicals LLC on behalf of Society for Conservation Biology.)

Background Mammographic density measurements are used to identify patients who should undergo supplemental imaging for breast cancer detection, but artificial intelligence (AI) image analysis may be more effective. Purpose To assess whether AISmartDensity-an AI-based score integrating cancer signs, masking, and risk-surpasses measurements of mammographic density in identifying patients for supplemental breast imaging after a negative screening mammogram. Materials and Methods This retrospective study included randomly selected individuals who underwent screening mammography at Karolinska University Hospital between January 2008 and December 2015. The models in AISmartDensity were trained and validated using nonoverlapping data. The ability of AISmartDensity to identify future cancer in patients with a negative screening mammogram was evaluated and compared with that of mammographic density models. Sensitivity and positive predictive value (PPV) were calculated for the top 8% of scores, mimicking the proportion of patients in the Breast Imaging Reporting and Data System "extremely dense" category. Model performance was evaluated using area under the receiver operating characteristic curve (AUC) and was compared using the DeLong test. Results The study population included 65 325 examinations (median patient age, 53 years [IQR, 47-62 years])-64 870 examinations in healthy patients and 455 examinations in patients with breast cancer diagnosed within 3 years of a negative screening mammogram. The AUC for detecting subsequent cancers was 0.72 and 0.61 ( P < .001) for AISmartDensity and the best-performing density model (age-adjusted dense area), respectively. For examinations with scores in the top 8%, AISmartDensity identified 152 of 455 (33%) future cancers with a PPV of 2.91%, whereas the best-performing density model (age-adjusted dense area) identified 57 of 455 (13%) future cancers with a PPV of 1.09% ( P < .001). AISmartDensity identified 32% (41 of 130) and 34% (111 of 325) of interval and next-round screen-detected cancers, whereas the best-performing density model (dense area) identified 16% (21 of 130) and 9% (30 of 325), respectively. Conclusion AISmartDensity, integrating cancer signs, masking, and risk, outperformed traditional density models in identifying patients for supplemental imaging after a negative screening mammogram. © RSNA, 2024 Supplemental material is available for this article. See also the editorial by Kim and Chang in this issue.

Background: Despite the prevalence of mental health disorders rising worldwide, physio-therapists' perceptions of their role and ability to holistically treat people with anxiety and depression remain unclear., Purpose: This research aimed to understand the physiotherapists' perception of their role in treating and managing people with anxiety and depression while revealing barriers and facilitators in practice., Methods: PubMed, PsycInfo, CINAHL, EMBASE, Web of Science, and Google Scholar were searched systematically for mixed-method, quantitative, or qualitative designs. Using the Joanna Briggs Institute (JBI) Methodology for Systematic Reviews, data was extracted, critically appraised, assigned quality grades, and synthesized through meta-aggregation., Results: A total of 2991 records were initially sourced, with eleven studies included in the systematic review. The studies were published worldwide between 2016 and 2021, with the majority (n = 8) published in 2020-2021. Participating physiotherapists most frequently had a Bachelor's degree (35.7-62.6%), followed by a Master's degree (28.4-37.4%). Meta-aggregation revealed the synthesized finding that physiotherapists perceived their role to include treating people with anxiety and depression despite feeling underprepared. Physiotherapists perceive many barriers and facilitators, such as education, when treating people with anxiety and depression., Conclusion: Physiotherapists have positive perceptions toward anxiety and depression, despite feeling underprepared in their ability to implement psychosocial strategies.

Aims: The primary aim of this study was to report the radiological outcomes of patients with a dorsally displaced distal radius fracture who were randomized to a moulded cast or surgical fixation with wires following manipulation and closed reduction of their fracture. The secondary aim was to correlate radiological outcomes with patient-reported outcome measures (PROMs) in the year following injury., Methods: Participants were recruited as part of DRAFFT2, a UK multicentre clinical trial. Participants were aged 16 years or over with a dorsally displaced distal radius fracture, and were eligible for the trial if they needed a manipulation of their fracture, as recommended by their treating surgeon. Participants were randomly allocated on a 1:1 ratio to moulded cast or Kirschner wires after manipulation of the fracture in the operating theatre. Standard posteroanterior and lateral radiographs were performed in the radiology department of participating centres at the time of the patient's initial assessment in the emergency department and six weeks postoperatively. Intraoperative fluoroscopic images taken at the time of fracture reduction were also assessed., Results: Patients treated with surgical fixation with wires had less dorsal angulation of the radius versus those treated in a moulded cast at six weeks after manipulation of the fracture; the mean difference of -4.13° was statistically significant (95% confidence interval 5.82 to -2.45). There was no evidence of a difference in radial shortening. However, there was no correlation between these radiological measurements and PROMs at any timepoint in the 12 months post-injury., Conclusion: For patients with a dorsally displaced distal radius fracture treated with a closed manipulation, surgical fixation with wires leads to less dorsal angulation on radiographs at six weeks compared with patients treated in a moulded plaster cast alone. However, the difference in dorsal angulation was small and did not correlate with patient-reported pain and function., Competing Interests: The authors disclose that the UK National Institute for Health Research (NIHR) provided grant funding for the DRAFFT2 trial. The research was supported by the NIHR Oxford Biomedical Research Centre (BRC). In addition, M. L. Costa declares that the University of Oxford receives research grant funding from the NIHR and Wellcome for research into musculoskeletal trauma., (© 2024 Costa et al.)

We conducted a secondary analysis of the evaluations of 22 sites participating in four primary care redesign initiatives funded by the Centers for Medicare and Medicaid Services or the Center for Medicare and Medicaid Innovation. Our objectives were to determine the overall impact of the initiatives on Medicare expenditures and whether specific site-level program features influenced expenditure findings. Averaged over sites, the mean intervention effect was a statistically insignificant US$26 per beneficiary per year. Policy implications from meta-regression results suggest that funders should consider supporting technical assistance efforts and pay for performance incentives to increase savings. There was no evidence that paying for medical home transformation produced savings in total cost of care. We estimate that in future evaluations, data from 35 sites would be needed to detect feature effects of US$300 per beneficiary per year., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: Systematic reviews of observational studies can be affected by biases that lead to under- or over-estimates of true intervention effects. Several tools have been reported in the literature that attempt to characterize potential bias. Our objective in this study was to determine the extent to which study-specific bias may have influenced intervention impacts on total costs of care (TCOC) in round 1 of the Health Care Innovation Awards., Methods: We reviewed 82 statistical evaluations of innovation impacts on Medicare TCOC. We developed five risk-of-bias measures and assessed their influence on TCOC impacts using meta-regression., Results: The majority of evaluations used propensity score matching to create their comparison groups. One third of the non-randomized interventions were judged to have some risk of biased effects due largely to the way they recruited their treatment groups, and 35% had some degree of covariate imbalance remaining after propensity score adjustments. However, in the multivariable analysis of TCOC effects, none of the bias threats we examined (comparison group construction method, risk of bias, or degree of covariate imbalance) had a major impact on the magnitude of HCIA1 innovation effects. Evaluations using propensity score weighting produced larger but imprecise savings effects compared to propensity score matching., Discussion: Our results suggest that it is unlikely that HCIA1 TCOC effect sizes were systematically affected by the types of bias we considered. Assessing the risk of bias based on specific study design features is likely to be more useful for identifying problematic characteristics than the subjective quality ratings used by existing risk tools., (© 2024. The Author(s).)

Acute myeloid leukemia is a poor-prognosis cancer commonly stratified by genetic aberrations, but these mutations are often heterogeneous and fail to consistently predict therapeutic response. Here, we combine transcriptomic, proteomic, and phosphoproteomic datasets with ex vivo drug sensitivity data to help understand the underlying pathophysiology of AML beyond mutations. We measure the proteome and phosphoproteome of 210 patients and combine them with genomic and transcriptomic measurements to identify four proteogenomic subtypes that complement existing genetic subtypes. We build a predictor to classify samples into subtypes and map them to a "landscape" that identifies specific drug response patterns. We then build a drug response prediction model to identify drugs that target distinct subtypes and validate our findings on cell lines representing various stages of quizartinib resistance. Our results show how multiomics data together with drug sensitivity data can inform therapy stratification and drug combinations in AML., Competing Interests: Declaration of interests J.W.T. has received research support from Agios, Aptose, Array, AstraZeneca, Constellation, Genentech, Gilead, Incyte, Janssen, Petra, Seattle Genetics, Syros, and Takeda and is on the Scientific Advisory Board of Recludix. C.E.T. has received support from Notable Labs. B.J.D. is/was on the Scientific Advisory Board of Adela Bio, Aileron Therapeutics (inactive), Celgene, Cepheid, DNA SEQ, Nemucore Medical Innovations, Novartis, RUNX1 Research Program, Therapy Architects/ALLCRON (inactive), and Vivid Biosciences (inactive); is/was on the Scientific Advisory Board of and owns/owned stock in Aptose Biosciences, Blueprint Medicines, Enliven Therapeutics, GRAIL, Iterion Therapeutics, and Recludix Pharma; is/was on the Board of Directors and owns/owned stock in Amgen and Vincerx Pharma; is/was on the Board of Directors of Burroughs Wellcome Fund, CureOne; is/was on the Joint Steering Committee of Beat AML (Leukemia & Lymphoma Society); is/was on the Advisory Committee of Multicancer Early Detection Consortium; is the Founder of VB Therapeutics; has/had sponsored research agreements with Enliven Therapeutics and Recludix Pharma; receives/received clinical trial funding from AstraZeneca and Novartis; receives/received royalties from Patent 6958335 (Novartis exclusive license), the Oregon Health & Science University, and the Dana-Farber Cancer Institute (one Merck exclusive license, one CytoImage, Inc. exclusive license, and one Sun Pharma Advanced Research Company nonexclusive license); and holds US Patents 4326534, 6958335, 7416873, 7592142, 10473667, 10664967, and 11049247., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Environmentally enriched housing (EE) provides a stimulating and species-typical environment that enhances brain plasticity and cognition, while reducing disease severity in laboratory animals. However, standardizing EE protocols has been challenging due to issues such as variability, high pricing, or limited laboratory space. To address these challenges, we present a replicable and cost-efficient cage protocol that is accessible to researchers with limited resources and space constraints. The protocol is designed to provide a stimulating and species-typical environment for the animals. It incorporates elements such as social interaction, physical exercise, cognitive stimulation, manipulable objects, environmental variability, and sensory stimulation. As evidenced in our previous studies using our protocol, users can expect to observe similar neuroplastic and health-wise benefits that accompany EE experimental paradigms. These included straightforward step-by-step guide, which allows for construction of functional EE cages in under 8 hr. Basic knowledge of 3D printing and laser cutting is required, but no advanced skills are necessary. The protocol enables researchers to create stimulating and replicable environments that promote animal welfare, enhance brain plasticity, and yield valuable experimental results for low cost. © 2024 Wiley Periodicals LLC. Basic Protocol: An effective and cost-efficient environmental enrichment cage designed to encourage standardization amongst laboratory protocols., (© 2024 Wiley Periodicals LLC.)

The reaction of Zn ions with β-octaalkylcorroles leads to the air oxidation of the macrocycle, with the formation of a mixture of 5- and 10-oxocorroles. Spectroscopic characterization confirms the antiaromatic character of these macrocycles. A simple synthetic protocol opens the way for more detailed studies of oxocorrole chemistry.

The COVID-19 pandemic has mandated a re-imagination of how healthcare is administered and delivered, with a view towards focusing on person-centred care and advancing population health while increasing capacity, access and equity in the healthcare system. These goals can be achieved through healthcare integration. In 2019, the University Health Network (UHN), a consortium of four quaternary care hospitals in Ontario, Canada, established the first stage of a pilot program to increase healthcare integration at the institutional level and vertically with other primary, secondary and tertiary institutions in the Ontario healthcare system. Implementation of the program was accelerated during the COVID-19 pandemic and demonstrated how healthcare integration improves person-centred care and population health; therefore serving as the foundation for a health system response for the COVID-19 pandemic recovery and beyond., Competing Interests: The authors have no competing interests to declare., (Copyright: © 2023 The Author(s).)

Selection for more nutritious crop plants is an important goal of plant breeding to improve food quality and contribute to human health outcomes. While there are efforts to integrate genomic prediction to accelerate breeding progress, an ongoing challenge is identifying strategies to improve accuracy when predicting within biparental populations in breeding programs. We tested multiple genomic prediction methods for 12 seed fatty acid content traits in oat (Avena sativa L.), as unsaturated fatty acids are a key nutritional trait in oat. Using two well-characterized oat germplasm panels and other biparental families as training populations, we predicted family mean and individual values within families. Genomic prediction of family mean exceeded a mean accuracy of 0.40 and 0.80 using an unrelated and related germplasm panel, respectively, where the related germplasm panel outperformed prediction based on phenotypic means (0.54). Within family prediction accuracy was more variable: training on the related germplasm had higher accuracy than the unrelated panel (0.14-0.16 and 0.05-0.07, respectively), but variability between families was not easily predicted by parent relatedness, segregation of a locus detected by a genome-wide association study in the panel, or other characteristics. When using other families as training populations, prediction accuracies were comparable to the related germplasm panel (0.11-0.23), and families that had half-sib families in the training set had higher prediction accuracy than those that did not. Overall, this work provides an example of genomic prediction of family means and within biparental families for an important nutritional trait and suggests that using related germplasm panels as training populations can be effective., (© 2023 The Authors. The Plant Genome published by Wiley Periodicals LLC on behalf of Crop Science Society of America.)

Objective: This pilot study compared non-medically trained surf lifesavers' (SLS) ability, after infographic training, to occlude the femoral artery using a pressure point (PP) versus an arterial tourniquet (AT)., Methods: Using a crossover design, eight SLS applied PP and AT to a participant's leg to occlude the femoral artery. Arterial flow, application time and perceived difficulty were recorded., Results: PP achieved 89.7% and 50.8% blood flow reduction for PP and AT, respectively. Average application time was 50.63 and 113.5 s for PP and AT, respectively. Perceived difficulty using a Likert scale from 0 to 10 (0 being no difficulty and 10 being maximal difficulty) was 2.75 and 3.50 for PP and AT, respectively., Conclusion: Infographic-trained SLS showed superior blood flow occlusion using PP. This pilot study will inform a larger trial for untrained beachgoers., (© 2023 The Authors. Emergency Medicine Australasia published by John Wiley & Sons Australia, Ltd on behalf of Australasian College for Emergency Medicine.)

Alkylation of one of the inner-core nitrogen atoms is one possible approach to obtain dianionic corrole ligands, suitable for the coordination of divalent metal ions, such as Pd II . Inner-core N-methylation can be obtained by treating the corrole with CH 3 I, but the reaction conditions should be optimized to limit the formation of the dimethylated derivative. Two regioisomers, the N-21 and the N-22 methyl derivatives are obtained from the reaction, with the first product achieved in a higher amount. Structural characterization of the reaction products evidenced the distortion induced by the introduction of the methyl groups; the N-methylcorroles are chiral compounds, and the enantiomers were separated by chromatography, with their absolute configuration assigned by ECD computation. Palladium insertion was achieved in the case of monosubstituted corroles, but not with the dimethylated macrocycle; X-ray characterization of the complexes showed the distortion of the macrocycles. The Pd complexes do not show luminescence emission, but are able to produce singlet oxygen upon irradiation. The Pd II complexes were also inserted in human serum albumin (HSA) and dispersed in water; in this case, the protein protects the corroles from photobleaching, and a switch from the type II to the type I mechanism in reactive oxygen species (ROS) production is observed., (© 2023 Wiley-VCH GmbH.)

Introduction: Self-regulated learning (SRL), or learners' ability to monitor and change their own cognitive, affective, metacognitive, and motivational processes, encompasses several operations that should be deployed during learning including Searching, Monitoring, Assembling, Rehearsing, and Translating (SMART). Scaffolds are needed within GBLEs to both increase learning outcomes and promote the accurate and efficient use of SRL SMART operations. This study aims to examine how restricted agency (i.e., control over one's actions) can be used to scaffold learners' SMART operations as they learn about microbiology with Crystal Island, a game-based learning environment., Methods: Undergraduate students ( N  = 94) were randomly assigned to one of two conditions: (1) Full Agency, where participants were able to make their own decisions about which actions they could take; and (2) Partial Agency, where participants were required to follow a pre-defined path that dictated the order in which buildings were visited, restricting one's control. As participants played Crystal Island, participants' multimodal data (i.e., log files, eye tracking) were collected to identify instances where participants deployed SMART operations., Results: Results from this study support restricted agency as a successful scaffold of both learning outcomes and SRL SMART operations, where learners who were scaffolded demonstrated more efficient and accurate use of SMART operations., Discussion: This study provides implications for future scaffolds to better support SRL SMART operations during learning and discussions for future directions for future studies scaffolding SRL during game-based learning., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Dever, Wiedbusch, Romero, Smith, Patel, Sonnenfeld, Lester and Azevedo.)

The 2020 U.S. presidential election saw rising political tensions among ordinary voters and political elites, with fears of election violence culminating in the January 6 riot. We hypothesized that the 2020 election might have been traumatic for some voters, producing measurable symptoms of post-traumatic stress disorder (PTSD). We also hypothesized that negative sentiment toward the opposing party correlates with PTSD. We measured PTSD using a modified version of the PCL-5, a validated PTSD screener, for 573 individuals from a nationally representative YouGov sample. We modeled the association between affective polarization and PTSD, controlling for political, demographic, and psychological traits. We estimate that 12.5% of American adults (95% CI: 9.2% to 15.9%) experienced election-related PTSD, far higher than the annual PTSD prevalence of 3.5%. Additionally, negativity toward opposing partisans correlated with PTSD symptoms. These findings highlight a potential need to support Americans affected by election-related trauma.

Bacterial leaf streak (BLS), caused chiefly by the pathogen Xanthomonas translucens pv. translucens , is becoming an increasingly important foliar disease of barley in the Upper Midwest. The deployment of resistant cultivars is the most economical and practical method of control. To identify sources of BLS resistance, we evaluated two panels of breeding lines from the University of Minnesota (UMN) and Anheuser-Busch InBev (ABI) barley improvement programs for reaction to strain CIX95 in the field at St. Paul and Crookston, MN, in 2020 and 2021. The percentage of resistant lines in the UMN and ABI panels with mid-season maturity was 1.8% (6 of 333 lines) and 5.2% (13 of 251 lines), respectively. Both panels were genotyped with the barley 50K iSelect SNP array, and then a genome-wide association study was performed. A single, highly significant association was identified for BLS resistance on chromosome 6H in the UMN panel. This association was also identified in the ABI panel. Seven other significant associations were detected in the ABI panel: two each on chromosomes 1H, 2H, and 3H and one on chromosome 5H. Of the eight associations identified in the panels, five were novel. The discovery of resistance in elite breeding lines will hasten the time needed to develop and release a BLS-resistant cultivar., Competing Interests: The author(s) declare no conflict of interest.

Objective: We aimed to evaluate the false interpretations between artificial intelligence (AI) and radiologists in screening mammography to get a better understanding of how the distribution of diagnostic mistakes might change when moving from entirely radiologist-driven to AI-integrated breast cancer screening., Methods and Materials: This retrospective case-control study was based on a mammography screening cohort from 2008 to 2015. The final study population included screening examinations for 714 women diagnosed with breast cancer and 8029 randomly selected healthy controls. Oversampling of controls was applied to attain a similar cancer proportion as in the source screening cohort. We examined how false-positive (FP) and false-negative (FN) assessments by AI, the first reader (RAD 1) and the second reader (RAD 2), were associated with age, density, tumor histology and cancer invasiveness in a single- and double-reader setting., Results: For each reader, the FN assessments were distributed between low- and high-density females with 53 (42%) and 72 (58%) for AI; 59 (36%) and 104 (64%) for RAD 1 and 47 (36%) and 84 (64%) for RAD 2. The corresponding numbers for FP assessments were 1820 (47%) and 2016 (53%) for AI; 1568 (46%) and 1834 (54%) for RAD 1 and 1190 (43%) and 1610 (58%) for RAD 2. For ductal cancer, the FN assessments were 79 (77%) for AI CAD; with 120 (83%) for RAD 1 and with 96 (16%) for RAD 2. For the double-reading simulation, the FP assessments were distributed between younger and older females with 2828 (2.5%) and 1554 (1.4%) for RAD 1 + RAD 2; 3850 (3.4%) and 2940 (2.6%) for AI+RAD 1 and 3430 (3%) and 2772 (2.5%) for AI+RAD 2., Conclusion: The most pronounced decrease in FN assessments was noted for females over the age of 55 and for high density-women. In conclusion, AI could have an important complementary role when combined with radiologists to increase sensitivity for high-density and older females., Advances in Knowledge: Our results highlight the potential impact of integrating AI in breast cancer screening, particularly to improve interpretation accuracy. The use of AI could enhance screening outcomes for high-density and older females.

Background: Complete unilateral cleft lip and palate (UCLP) creates a continuity defect on the nasal floor, which contributes to nasal asymmetry. Traditionally, piriform rim symmetry has been evaluated by comparing cleft and noncleft sides. No study has compared the magnitude of perinasal asymmetry in UCLP patients with a control group of patients without clefts., Purpose: To address the following question: In UCLP patients, whose alveolar clefts are reconstructed with alveolar bone grafts (ABGs), is the magnitude of remaining piriform rim asymmetry similar to that of patients without UCLP?, Study Design Setting, Sample: This is a retrospective cohort study that used the cone beam computed tomography of UCLP and non-UCLP patients to evaluate the piriform rim symmetry. The sample was derived from patients who presented for orthognathic surgery between January 2015 and December 2022. To be included, patients had to have a maxillary deficiency. The cleft group had ABG performed with symphyseal bone harvest and bone morphogenetic protein application. Patients were excluded from the control group if they had clinical asymmetry and nasal septum deviation. Patients from the UCLP group were excluded if they failed the first attempt of ABG or had a syndrome. Preorthognathic cone beam computed tomography was used to measure the distance from the inferior and lateral aspects of the piriform rim to reference lines., Predictor Variable: UCLP status grouped as present or absent (control)., Outcome Variables: The magnitude of piriform rim asymmetry defined as the millimetric distance from the inferior and lateral aspects of the piriform rim to reference lines., Covariates: The covariates were age, sex, tissue thickness at the level of the alar base, and turbinate size., Analysis: Welch's two-sample t-test was utilized to compare means. A level of significance of 5% (P < .05) was used for all analyses. To analyze the reliability of the measurements intraexaminer and interexaminer errors were tested using the Weir method., Results: A total of 60 patients were included, 30 in each group. The mean age of UCLP patients was 16.76 (range 13 to 25), and the control group was 17 (range 13 to 25), P = .71. The UCLP group had 12 girls, and the control had 18 girls (P = .12). In the UCLP group, the mean discrepancy between affected and unaffected sides at the inferior aspect of the piriform rim was 3.9 mm (range 0.9 to 7 mm, P < .01), and in the control group the discrepancy between right and left sides was 0.1 mm (0-2.1 mm, P = .87). The mean discrepancy between affected and unaffected sides at the lateral aspect of the piriform rim was 3.6 mm (range 0.7 to 7.6 mm, P < .01) in the UCLP group, and in the control group the discrepancy between right and left sides was 0.1 mm (range 0.1 to 5.8 mm, P = .78) in the control group. The mean alar base soft tissue thickness discrepancy was 3.1 mm (range 0.9 to 7.9 mm, P < .01) in the UCLP group and 0 mm (range -1.8 to 1.9 mm, P = .97) in the control group. The mean difference in the turbinate area in the UCLP group was 314 mm 2 (range 797 to 2,898) and in the control group 35 mm 2 (range 702 to 2,302) (P = .19)., Conclusion: ABG with symphyseal bone and bone morphogenetic protein was not able to provide the same level of piriform symmetry observed in patients without a cleft. Alar base tissue was thicker on the cleft side, and the turbinate size demonstrated greater variability in the UCLP patients., (Copyright © 2023 American Association of Oral and Maxillofacial Surgeons. Published by Elsevier Inc. All rights reserved.)

Purpose: Multiple vendors are currently offering artificial intelligence (AI) computer-aided systems for triage detection, diagnosis, and risk prediction of breast cancer based on screening mammography. There is an imminent need to establish validation platforms that enable fair and transparent testing of these systems against external data., Approach: We developed validation of artificial intelligence for breast imaging (VAI-B), a platform for independent validation of AI algorithms in breast imaging. The platform is a hybrid solution, with one part implemented in the cloud and another in an on-premises environment at Karolinska Institute. Cloud services provide the flexibility of scaling the computing power during inference time, while secure on-premises clinical data storage preserves their privacy. A MongoDB database and a python package were developed to store and manage the data on-premises. VAI-B requires four data components: radiological images, AI inferences, radiologist assessments, and cancer outcomes., Results: To pilot test VAI-B, we defined a case-control population based on 8080 patients diagnosed with breast cancer and 36,339 healthy women based on the Swedish national quality registry for breast cancer. Images and radiological assessments from more than 100,000 mammography examinations were extracted from hospitals in three regions of Sweden. The images were processed by AI systems from three vendors in a virtual private cloud to produce abnormality scores related to signs of cancer in the images. A total of 105,706 examinations have been processed and stored in the database., Conclusions: We have created a platform that will allow downstream evaluation of AI systems for breast cancer detection, which enables faster development cycles for participating vendors and safer AI adoption for participating hospitals. The platform was designed to be scalable and ready to be expanded should a new vendor want to evaluate their system or should a new hospital wish to obtain an evaluation of different AI systems on their images., (© 2023 The Authors.)

People make fast and reasonable predictions about the physical behavior of everyday objects. To do so, people may use principled mental shortcuts, such as object simplification, similar to models developed by engineers for real-time physical simulations. We hypothesize that people use simplified object approximations for tracking and action (the body representation), as opposed to fine-grained forms for visual recognition (the shape representation). We used three classic psychophysical tasks (causality perception, time-to-collision, and change detection) in novel settings that dissociate body and shape. People's behavior across tasks indicates that they rely on coarse bodies for physical reasoning, which lies between convex hulls and fine-grained shapes. Our empirical and computational findings shed light on basic representations people use to understand everyday dynamics, and how these representations differ from those used for recognition. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Mutations in SOD1 cause amyotrophic lateral sclerosis (ALS) through gain-of-function effects, yet the mechanisms by which misfolded mutant SOD1 (mutSOD1) protein impairs human motor neurons (MNs) remain unclear. Here, we use induced-pluripotent-stem-cell-derived MNs coupled to metabolic stable isotope labeling and mass spectrometry to investigate proteome-wide degradation dynamics. We find several proteins, including the ALS-causal valosin-containing protein (VCP), which predominantly acts in proteasome degradation and autophagy, that degrade slower in mutSOD1 relative to isogenic control MNs. The interactome of VCP is altered in mutSOD1 MNs in vitro, while VCP selectively accumulates in the affected motor cortex of ALS-SOD1 patients. Overexpression of VCP rescues mutSOD1 toxicity in MNs in vitro and in a C. elegans model in vivo, in part due to its ability to modulate the degradation of insoluble mutSOD1. Our results demonstrate that VCP contributes to mutSOD1-dependent degeneration, link two distinct ALS-causal genes, and highlight selective protein degradation impairment in ALS pathophysiology., Competing Interests: Declaration of interests J.K.I. is a co-founder of AcuraStem and Modulo Bio, SAB member of Spinogenix, Vesalius, and Synapticure, and employee of BioMarin Pharmaceutical. E.K. is a co-founder of NeuronGrow, SAB member of Axion Biosystems, ResQ Biotech, and Synapticure, and a consultant for Confluence Therapeutics; named companies were not involved in this project., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

The increasing demand for fertility treatments has led to the rise of private clinics offering complementary and alternative medicine (CAM) treatments. The most frequently offered CAM infertility treatment is acupuncture. However, there is no good evidence to support the effectiveness of acupuncture in treating infertility. This study evaluates the scope of information provided by CAM fertility clinics in the UK. A content analysis was conducted on 200 websites of CAM fertility clinics in the UK that offer acupuncture as a treatment for infertility. Of the 48 clinics that met the eligibility criteria, the majority of the websites did not provide sufficient information on the efficacy, risks and success rates of acupuncture for infertility. This has the potential to infringe on patient autonomy, provide false hope and reduce the chances of pregnancy ever being achieved as fertility declines during the time course of ineffective acupuncture treatment., (© 2023. The Author(s).)

Chinese hamster ovary (CHO) cells are used extensively to produce protein therapeutics, such as monoclonal antibodies (mAbs), in the biopharmaceutical industry. MAbs are large proteins that are energetically demanding to synthesize and secrete; therefore, high-producing CHO cell lines that are engineered for maximum metabolic efficiency are needed to meet increasing demands for mAb production. Previous studies have identified that high-producing cell lines possess a distinct metabolic phenotype when compared to low-producing cell lines. In particular, it was found that high mAb production is correlated to lactate consumption and elevated TCA cycle flux. We hypothesized that enhancing flux through the mitochondrial TCA cycle and oxidative phosphorylation would lead to increased mAb productivities and final titers. To test this hypothesis, we overexpressed peroxisome proliferator-activated receptor γ co-activator-1⍺ (PGC-1⍺), a gene that promotes mitochondrial metabolism, in an IgG-producing parental CHO cell line. Stable cell pools overexpressing PGC-1⍺ exhibited increased oxygen consumption, indicating increased mitochondrial metabolism, as well as increased mAb specific productivity compared to the parental line. We also performed 13 C metabolic flux analysis (MFA) to quantify how PGC-1⍺ overexpression alters intracellular metabolic fluxes, revealing not only increased TCA cycle flux, but global upregulation of cellular metabolic activity. This study demonstrates the potential of rationally engineering the metabolism of industrial cell lines to improve overall mAb productivity and to increase the abundance of high-producing clones in stable cell pools., (Copyright © 2023 International Metabolic Engineering Society. Published by Elsevier Inc. All rights reserved.)