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Objective: To evaluate associations of wildfire fine particulate matter ≤2.5 mm in diameter (PM2.5) with diabetes across multiple countries and territories., Research Design and Methods: We collected data on 3,612,135 diabetes hospitalizations from 1,008 locations in Australia, Brazil, Canada, Chile, New Zealand, Thailand, and Taiwan during 2000-2019. Daily wildfire-specific PM2.5 levels were estimated through chemical transport models and machine-learning calibration. Quasi-Poisson regression with distributed lag nonlinear models and random-effects meta-analysis were applied to estimate associations between wildfire-specific PM2.5 and diabetes hospitalization. Subgroup analyses were by age, sex, location income level, and country or territory. Diabetes hospitalizations attributable to wildfire-specific PM2.5 and nonwildfire PM2.5 were compared., Results: Each 10 µg/m3 increase in wildfire-specific PM2.5 levels over the current day and previous 3 days was associated with relative risks (95% CI) of 1.017 (1.011-1.022), 1.023 (1.011-1.035), 1.023 (1.015-1.032), 0.962 (0.823-1.032), 1.033 (1.001-1.066), and 1.013 (1.004-1.022) for all-cause, type 1, type 2, malnutrition-related, other specified, and unspecified diabetes hospitalization, respectively. Stronger associations were observed for all-cause, type 1, and type 2 diabetes in Thailand, Australia, and Brazil; unspecified diabetes in New Zealand; and type 2 diabetes in high-income locations. An estimate of 0.67% (0.16-1.18%) and 1.02% (0.20-1.81%) for all-cause and type 2 diabetes hospitalizations were attributable to wildfire-specific PM2.5. Compared with nonwildfire PM2.5, wildfire-specific PM2.5 posed greater risks of all-cause, type 1, and type 2 diabetes and were responsible for 38.7% of PM2.5-related diabetes hospitalizations., Conclusions: We show the relatively underappreciated links between diabetes and wildfire air pollution, which can lead to a nonnegligible proportion of PM2.5-related diabetes hospitalizations. Precision prevention and mitigation should be developed for those in advantaged communities and in Thailand, Australia, and Brazil., (© 2024 by the American Diabetes Association.)

Objectives: The focus of this review was to systematically review and meta-analyse the prevalence of ACEs among university students in the UK., Method: The systematic searching of six electronic databases (conducted February 2024) identified ten relevant articles (peer-reviewed articles of a quantitative nature that included ACE prevalence). PROSPERO reference: CRD42022364799., Results: Pooled prevalence for number of ACEs endured was 55.4% (95% CI: 32.4% - 78.4%; I2 > 99.5%) for one or more, and 31.6% (7.5% - 55.6%; I2 > 99.5%) for three or more. Pooled prevalence was: 15.9% (7.0% - 24.7%; I2 > 94.5%) for physical abuse; 27.0% (18.1% - 35.9%; I2 > 94.5%) for emotional abuse; 12.1% (5.2% - 19.0%; I2 > 94.5%) for sexual abuse; 8.4% (1.7% - 15.1%; I2 > 95.4%) for physical neglect, and 30.0% (21.5% - 38.5%; I2 > 95.4%) for emotional neglect. Pooled prevalence for household dysfunction categories were: 34.4% (22.8% - 46.0%) for parental separation; 18.4% (10.1% - 26.8%) for domestic violence; 35.2% (23.6% - 46.8%) for mental health difficulties; 21.4% (12.9% - 29.9%) for substance use; and 5.7% (2.3% - 9.1%) for incarceration (I2 > 88.8% for all household dysfunction items). Significant heterogeneity was observed between studies for most categories of adversity, and it was not possible to explain/reduce this variance by removing small numbers of influential/discrepant studies. Further analyses suggested potential influences of measurement tool used, country of data collection, and age and sex of participants., Conclusion: Results demonstrate considerable, largely unaccounted-for, heterogeneity in estimates of the prevalence of ACEs, impeding confidence in any summary statistics. Conclusions must be tentative due to analyses being underpowered given small numbers of papers, as well as potential confounds, meaning results may not be truly representative. However, results do suggest high prevalence rates which warrant further investigation, with appropriate support offered to students., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Hamilton et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

The aggregation pathway of transthyretin (TTR) proceeds through rate-limiting dissociation of the tetramer (a dimer of dimers) and partial misfolding of the resulting monomer, which assembles into amyloid structures through a downhill polymerization mechanism. The structural features of the aggregation-prone monomeric intermediate are poorly understood. NMR relaxation dispersion offers a unique opportunity to characterize amyloidogenic intermediates when they exchange on favorable timescales with NMR-visible ground states. Here we use NMR to characterize the structure and conformational dynamics of the monomeric F87E mutant of human TTR. Chemical shifts derived from analysis of multinuclear relaxation dispersion data provide insights into the structure of a low-lying excited state that exchanges with the ground state of the F87E monomer at a rate of 3800 s -1 . Disruption of the subunit interfaces of the TTR tetramer leads to destabilization of edge strands in both β-sheets of the F87E monomer. Conformational fluctuations are propagated through the entire hydrogen bonding network of the DAGH β-sheet, from the inner β-strand H, which forms the strong dimer-dimer interface in the TTR tetramer, to outer strand D which is unfolded in TTR fibrils. Fluctuations are also propagated from the AB loop in the weak dimer-dimer interface to the EF helix, which undergoes structural remodeling in fibrils. The conformational fluctuations in both regions are enhanced at acidic pH where amyloid formation is most favorable. The relaxation dispersion data provide insights into the conformational dynamics of the amyloidogenic state of monomeric TTR that predispose it for structural remodeling and progression to amyloid fibrils., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Measurement of overall survival (OS) remains the gold standard for interpreting the impact of new therapies for multiple myeloma in phase 3 trials. However, as outcomes have improved, it is increasingly challenging to use OS as the primary endpoint if timely approval of novel agents is to be ensured to enable maximum benefit for patients. Surrogate endpoints of OS, such as progression-free survival (PFS) and response to treatment, have contributed to approval decisions by the Food and Drug Administration (FDA) and European Medicines Agency as endpoints demonstrating clinical benefit, and the FDA has recently supported the use of minimal residual disease (MRD) as an accelerated approval endpoint in multiple myeloma. This review aims to address situations in which the use of PFS as a surrogate endpoint warrants careful interpretation especially for specific subgroups of patients and considers ways to ensure that studies can be designed to account for possible discordance between PFS and OS. The utility of subgroup analyses, including the potential for those not pre-specified, to identify target populations for new agents is also discussed., (© 2024. The Author(s).)

Multiple myeloma (MM) is an incurable malignancy of plasma cells. Epidemiological studies indicate a substantial heritable component, but the underlying mechanisms remain unclear. Here, in a genome-wide association study totaling 10,906 cases and 366,221 controls, we identify 35 MM risk loci, 12 of which are novel. Through functional fine-mapping and Mendelian randomization, we uncover two causal mechanisms for inherited MM risk: longer telomeres; and elevated levels of B-cell maturation antigen (BCMA) and interleukin-5 receptor alpha (IL5RA) in plasma. The largest increase in BCMA and IL5RA levels is mediated by the risk variant rs34562254-A at TNFRSF13B. While individuals with loss-of-function variants in TNFRSF13B develop B-cell immunodeficiency, rs34562254-A exerts a gain-of-function effect, increasing MM risk through amplified B-cell responses. Our results represent an analysis of genetic MM predisposition, highlighting causal mechanisms contributing to MM development., (© 2024. The Author(s).)

The high diversity and global distribution of heterotrophic bacterial diazotrophs (HBDs) in the ocean has recently become apparent. However, understanding the role these largely uncultured microorganisms play in marine N 2 fixation poses a challenge due to their undefined growth requirements and the complex regulation of the nitrogenase enzyme. We isolated and characterized Candidatus Thalassolituus haligoni, a member of a widely distributed clade of HBD belonging to the Oceanospirillales. Analysis of its nifH gene via amplicon sequencing revealed the extensive distribution of Cand. T. haligoni across the Pacific, Atlantic, and Arctic Oceans. Pangenome analysis indicates that the isolate shares >99% identity with an uncultured metagenome-assembled genome called Arc-Gamma-03, recently recovered from the Arctic Ocean. Through combined genomic, proteomic, and physiological approaches, we confirmed that the isolate fixes N 2 gas. However, the mechanisms governing nitrogenase regulation in Cand. T. haligoni remain unclear. We propose Cand. T. haligoni as a globally distributed, cultured HBD model species within this understudied clade of Oceanospirillales.

Background: Nonalcoholic steatohepatitis (NASH) is the fastest-growing indication for liver transplantation (LT). Sex disparities among patients with cirrhosis on the LT waitlist are well known. We wanted to understand these disparities further in women with end-stage liver disease patients listed for NASH cirrhosis in a contemporary cohort., Methods: We used data from the Scientific Registry of Transplant Recipients to assess sex racial, and ethnic differences in NASH patients listed for LT. Adults transplanted from August 1997 to June 2021 were included. Inferential statistics were used to evaluate differences with univariate and multivariate comparisons, including competitive risk analysis., Results: During the study time period, we evaluated 12 844 LT for NASH cirrhosis. Women were transplanted at a lower rate (46.5% versus 53.5%; P  < 0.001) and higher model for end-stage liver disease (MELD) (23.8 versus 22.6; P < 0.001) than men. Non-White women were transplanted at a higher MELD (26.1 versus 23.1; P  < 0.001) than White women and non-White male patients (26.1 versus 24.8; P  < 0.001). Graft and patient survivals were significantly different ( P  < 0.001) between non-White women and White women and men (White and non-White)., Conclusions: Evaluation of LT candidates in the United States demonstrates women with NASH cirrhosis have a higher MELD than men at LT. Additional disparities exist among non-White women with NASH as they have higher MELD and creatinine at LT compared with White women. After LT, non-White women have worse graft and patient survival compared with men or White women. These data indicate that non-White women with NASH are the most vulnerable on the LT waitlist., Competing Interests: The authors declare no funding or conflicts of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

During the coronavirus 2019 (COVID-19) pandemic, children suffered severe lung injury resulting in acute respiratory distress syndrome requiring support with extracorporeal membrane oxygenation (ECMO). In this case series, we described our center's experience employing a rehabilitation-focused ECMO strategy including extubation during ECMO support in four pediatric patients with acute COVID-19 pneumonia hospitalized from September 2021 to January 2022. All four patients tolerated extubation within 30 days of ECMO initiation and achieved mobility while on ECMO support. Duration of ECMO support was 35-152 days and hospital lengths of stay were 52-167 days. Three of four patients survived. Two of three survivors had normal functional status at discharge except for ongoing respiratory support. The third survivor had significant motor deficits due to critical illness polyneuropathy and was supported with daytime oxygen and nocturnal noninvasive support. Overall, these patients demonstrated good outcomes and tolerance of a rehabilitation-focused ECMO strategy., Competing Interests: Disclosure: The authors have no conflicts of interest to report., (Copyright © ASAIO 2024.)

Background: Respiratory tract infections are readily transmitted in care homes. Airborne transmission of pathogens causing respiratory tract illness is largely unmitigated. Portable high-efficiency-particulate-air (HEPA) filtration units capture microbial particles from the air, but it is unclear whether this is sufficient to reduce infections in care home residents. The Air Filtration to prevent symptomatic winter Respiratory Infections (including COVID-19) in care homes (AFRI-c) randomized controlled trial will determine whether using HEPA filtration units reduces respiratory infection episodes in care home residents., Methods: AFRI-c is a cluster randomized controlled trial that will be delivered in residential care homes for older people in England. Ninety-one care homes will be randomised to take part for one winter period. The intervention care homes will receive HEPA filtration units for use in communal areas and private bedrooms. Normal infection control measures will continue in all care homes. Anonymised daily data on symptoms will be collected for up to 30 residents. Ten to 12 of these residents will be invited to consent to a primary care medical notes review and (in intervention homes) to having an air filter switched on in their private room. The primary outcome will be number of symptomatic winter respiratory infection episodes. Secondary outcomes include specific clinical measures of infection, number of falls / near falls, number of laboratory confirmed infections, hospitalisations, staff sickness and cost-effectiveness. A mixed methods process evaluation will assess intervention acceptability and implementation., Discussion: The results of AFRI-c will provide vital information about whether portable HEPA filtration units reduce symptomatic winter respiratory infections in older care home residents. Findings about effectiveness, fidelity, acceptability and cost-effectiveness will support stakeholders to determine the use of HEPA filtration units as part of infection control policies., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Brierley et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Individual differences in reward salience may relate to the difficulty in regulating the effects of multiple substances (e.g., nicotine and food). Increased brain activation in reward and self-regulation (SR) regions has been evidenced while adults view appetitive cues (e.g., food pictures) to test substance use disorder treatment response. Enhancing SR with behavioral interventions may increase brain activation in SR regions and reduce responses in reward regions. Our primary analysis demonstrated increased brain activation in SR regions to smoking cues among individuals who practiced SR by delaying their first cigarette of the day for 2 weeks. However, little is known about the generalizability of SR between appetitive cues. This secondary analysis explored the influence of adherence to a SR behavioral intervention by examining the impact of practicing smoking SR on brain activation to food cues among adults who smoke. Participants ( N  = 65) were randomly assigned to practice SR by delaying their first daily cigarette or smoking as usual for 2-weeks. Functional magnetic resonance imaging data were collected while people were told to think of "negative" or "positive" associations with the cue. The results indicated that practicing smoking SR was linked with increased activation in the dorsolateral prefrontal cortex (dlPFC) when viewing food cues. There was no correlation between delaying smoking adherence and brain activation in the dlPFC. Exploratory analyses suggested higher dlPFC activation when people thought about "positive" associations with the food cues instead of "negative" ones. We concluded that practicing smoking SR is related to increased brain activation to food cues, suggesting potential generalizability of SR practice from smoking cues to food cues., 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 © 2024 Torres Morillo, Pasqualini, Brucks and Martin.)

The Child Depression Inventory (CDI) is often used to assess change in depression over time, but no studies estimate the reliability of CDI change scores nor its five subscores. Our study investigated the reliability of change scores for both the total score on the CDI as well as its five subscores. We examined CDI responses from 186 maltreated children and estimated change score reliability for relative (e.g., comparison) and absolute (e.g., diagnosis) purposes. We also conducted subscore utility analysis, which determines if subscores have adequate reliability and provide information beyond the total score. We found that the total change score had acceptable reliability of .70 for our sample for both relative and absolute interpretations. In addition, the total score was a better predictor of true subscore values than the observed subscores-suggesting subscores did not add value over the total score, and that the reliability of changes in subscores was too low to be useful for any purpose. In summary, we found that the total CDI change scores were useful for assessing change in studies that examine relative or absolute change, and we advise caution when interpreting CDI subscores based on our analysis., 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.

Juvenile Dermatomyositis (JDM) is the most common inflammatory myopathy in pediatrics. This study evaluates the role of Natural Killer (NK) cells in Juvenile Dermatomyositis (JDM) pathophysiology. The study included 133 untreated JDM children with an NK cell count evaluation before treatment. NK cell subsets (CD56 low/dim vs. CD 56 bright ) were examined in 9 untreated children. CD56 and perforin were evaluated in situ in six untreated JDM and three orthopedic, pediatric controls. 56% of treatment-naive JDM had reduced circulating NK cell counts, designated "low NK cell". This low NK group had more active muscle disease compared to the normal NK cell group. The percentage of circulating CD56 low/dim NK cells was significantly lower in the NK low group than in controls (0.55% vs. 4.6% p < 0.001). Examination of the untreated JDM diagnostic muscle biopsy documented an increased infiltration of CD56 and perforin-positive cells ( p = 0.023, p = 0.038, respectively). Treatment-naive JDM with reduced circulating NK cell counts exhibited more muscle weakness and higher levels of serum muscle enzymes. Muscle biopsies from treatment-naive JDM displayed increased NK cell infiltration, with increased CD56 and perforin-positive cells.

Background: Ross River virus (RRV), Australia's most notifiable vector-borne disease transmitted through mosquito bites, has seen increased transmission due to rising temperatures. Quantifying the burden of RRV infection attributable to increasing temperatures (both current and future) is pivotal to inform prevention strategies in the context of climate change., Methods: As RRV-related deaths are rare in Australia, we utilised years lived with disability (YLDs) associated with RRV infection data from the Australian Institute of Health and Welfare (AIHW) Burden of Disease database between 2003 and 2018. We obtained relative risks per 1 °C temperature increase in RRV infection from a previous meta-analysis. Exposure distributions for each Köppen-Geiger climate zone were calculated separately and compared with the theoretical-minimum-risk exposure distribution to calculate RRV burden attributable to increasing temperatures during the baseline period (2003-2018), and projected future burdens for the 2030s and 2050s under two greenhouse gas emission scenarios (Representative Concentration Pathways, RCP 4.5 and RCP 8.5), two adaptation scenarios, and different population growth series., Findings: During the baseline period (2003-2018), increasing mean temperatures contributed to 35.8 (±0.5) YLDs (19.1%) of the observed RRV burden in Australia. The mean temperature attributable RRV burden varied across climate zones and jurisdictions. Under both RCP scenarios, the projected RRV burden is estimated to increase in the future despite adaptation scenarios. By the 2050s, without adaptation, the RRV burden could reach 45.8 YLDs under RCP4.5 and 51.1 YLDs under RCP8.5. Implementing a 10% adaptation strategy could reduce RRV burden to 41.8 and 46.4 YLDs, respectively., Interpretation: These findings provide scientific evidence for informing policy decisions and guiding resource allocation for mitigating the future RRV burden. The current findings underscore the need to develop location-specific adaptation strategies for climate-sensitive disease control and prevention., Funding: Australian Research Council Discovery Program., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors.)

We discuss the use of two empirically validated behavior-change methods-checklists and goal setting-and designed a checklist to assist behavior analysts in improving their behavioral services to be more culturally responsive and trauma informed. We also present pilot data evaluating the use of the checklist and goal setting on the inclusion of culturally responsive and trauma-informed practices in behavior support plans designed for students in a public school. The training package was effective for both participants, and the participants' weekly goals corresponded to the observed changes in their behavior plans. Moreover, both participants strongly agreed that the checklist was valuable and easy to use and reported increases in their perceived abilities to implement culturally responsive and trauma-informed practices posttraining., (© 2024 Society for the Experimental Analysis of Behavior (SEAB).)

Enterovirus genomic replication initiates at a predicted RNA cloverleaf (5'CL) at the 5' end of the RNA genome. The 5'CL contains one stem (SA) and three stem-loops (SLB, SLC, SLD). Here, we present an analysis of 5'CL conservation and divergence for 209 human health-related serotypes from the enterovirus genus, including enterovirus and rhinovirus species. Phylogenetic analysis indicates six distinct 5'CL serotypes that only partially correlate with the species definition. Additional findings include that 5'CL sequence conservation is higher between the EV species than between the RV species, the 5'CL of EVA and EVB are nearly identical, and RVC has the lowest 5'CL conservation. Regions of high conservation throughout all species include SA and the loop and nearby bases of SLB, which is consistent with known protein interactions at these sites. In addition to the known protein binding site for the Poly-C binding protein in the loop of SLB, other conserved consecutive cytosines in the stems of SLB and SLC provide additional potential interaction sites that have not yet been explored. Other sites of conservation, including the predicted bulge of SLD and other conserved stem, loop, and junction regions, are more difficult to explain and suggest additional interactions or structural requirements that are not yet fully understood. This more intricate understanding of sequence and structure conservation and variability in the 5'CL may assist in the development of broad-spectrum antivirals against a wide range of enteroviruses , while better defining the range of virus isotypes expected to be affected by a particular antiviral.

Humoral primary immunodeficiencies are the most prevalent form of primary immunodeficiency (PID). Currently, there is no convenient method to quantify newly formed B cells. The aim of this proof-of-concept study was to quantitate the ratio of coding joints (CJs) to Kappa-deleting recombination excision circles (KRECs) and serum B cell activating factor (BAFF) in patients with humoral primary immunodeficiency and assess if they correlate with disease severity. This IRB-approved study was conducted at one academic children's hospital. Patients with humoral PIDs and healthy controls were included. CJ and KREC levels were measured via qPCR. Serum BAFF levels were measured using Mesoscale. 16 patients with humoral PID and 5 healthy controls were included. The mean CJ:KREC ratio in the CVID, antibody deficiency syndromes, and controls groups, respectively were 13.04 ± 9.5, 5.25 ± 4.1, and 4.38 ± 2.5 (p = 0.059). The mean serum BAFF levels in CVID, antibody deficiency syndromes and controls were 216.3 ± 290 pg/mL, 107.9 ± 94 pg/mL and 50.9 ± 12 pg/mL, respectively (p = 0.271). When the CVID patients were subdivided into CVID with or without lymphoproliferative features, the BAFF level was substantially higher in the CVID with lymphoproliferation cohort (mean 372.4 ± 361 pg/mL, p = 0.031). Elevated CJ:KREC ratio was observed in CVID, although statistical significance was not achieved, likely due to the small sample size. Serum BAFF levels were significantly higher in CVID patients with lymphoproliferative features. We speculate that the CJ:KREC ratio and serum BAFF levels can be utilized in patients with humoral PID, once more extensive studies confirm this exploratory investigation., (© 2024. The Author(s).)

Nitric oxide can covalently modify cysteine thiols on target proteins to alter that protein's function in a process called S-nitrosylation (SNO). S-nitrosylation of synaptic proteins plays an integral part in neurotransmission. Here we review the function of the SNO-proteome at the synapse and whether clusters of SNO-modification may predict synaptic dysfunction associated with disease. We used a systematic search strategy to concatenate SNO-proteomic datasets from normal human or murine brain samples. Identified SNO-modified proteins were then filtered against proteins reported in the Synaptome Database, which provides a detailed and experimentally verified annotation of all known synaptic proteins. Subsequently, we performed an unbiased network analysis of all known SNO-synaptic proteins to identify clusters of SNO proteins commonly involved in biological processes or with known disease associations. The resulting SNO networks were significantly enriched in biological processes related to metabolism, whereas significant gene-disease associations were related to Schizophrenia, Alzheimer's, Parkinson's and Huntington's disease. Guided by an unbiased network analysis, the current review presents a thorough discussion of how clustered changes to the SNO-proteome influence health and disease., Competing Interests: Declaration of competing interest The authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

This study investigates HLA-DR expression on activated T cells and serum neopterin levels in Juvenile Dermatomyositis (JDM) children pre- and post-treatment. Sixty-nine JDM children (less than 18 years) were included. Elevated HLA-DR+ T cells (>7 %) were observed in 19 % of untreated cases. Post-treatment, mean HLA-DR+ T cells decreased from 5.1 to 2.9 ( P < 0.001), and serum neopterin levels declined from 19.3 to 9.1 nmol/L ( P < 0.0001). A positive correlation between serum neopterin and HLA-DR T cell percentage was observed ( r = 0.39, P = 0.01). Intravenous steroid treatment exhibited a 47.4 % improvement in HLA-DR+ T cells and a 50.5 % reduction in serum neopterin levels, in contrast to 14.8 % and 34.1 % in the oral steroid group. In conclusion, treatment, particularly with IV steroids, significantly improved HLA-DR+ T cells percentage and neopterin levels. A correlation between HLA-DR+ T cells percentage and serum neopterin was noted in untreated JDM patients., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Multiple Myeloma is an incurable plasma cell malignancy with a poor survival rate that is usually treated with immunomodulatory drugs (iMiDs) and proteosome inhibitors (PIs). The malignant plasma cells quickly become resistant to these agents causing relapse and uncontrolled growth of resistant clones. From whole genome sequencing (WGS) and RNA sequencing (RNA-seq) studies, different high-risk translocation, copy number, mutational, and transcriptional markers can be identified. One of these markers, PHF19, epigenetically regulates cell cycle and other processes and is already studied using RNA-seq. In this study, we generate a large (325,025 cells and 49 patients) single cell multi-omic dataset and jointly quantify ATAC- and RNA-seq for each cell and matched genomic profiles for each patient. We identify an association between one plasma cell subtype with myeloma progression that we call relapsed/refractory plasma cells (RRPCs). These cells are associated with chromosome 1q alterations, TP53 mutations, and higher expression of PHF19. We also identify downstream regulation of cell cycle inhibitors in these cells, possible regulation by the transcription factor (TF) PBX1 on chromosome 1q, and determine that PHF19 may be acting primarily through this subset of cells., (© 2024. The Author(s).)

Purpose: Self-service interactive devices allow users to access information or services without directly interacting with service personnel. As the prevalence of disability increases, it is important to consider the barriers individuals face in using these devices and explore opportunities to increase accessibility through assistive and adaptive technologies. This study aimed to establish recommendations to enhance the accessibility of self-service interactive devices, with the objective of understanding users' experiences with these devices., Materials and Methods: Nineteen semi-structured interviews were held with stakeholders focusing on accessible design for people with disabilities, categorized as (a) persons with lived experiences with disability, (b) disability advocates, or (c) assistive technology industry experts. The study used content analysis to identify recurring concepts and opportunities to improve accessibility. Participants discussed the potential benefits of updating or incorporating additional accessibility technologies into self-service devices and proposed solutions to existing deficiencies., Results: Common concerns expressed among participants included the privacy and security of self-service devices, protection of personal information, and the consistency and usability of devices. Participants also suggested how this inconsistency could be mitigated and how to improve existing accessibility functionalities. Accessible functionalities in self-service devices have the potential to help address the unmet needs of Canadians with disabilities., Conclusions: With the breadth of available accessible and adaptive technologies, the study concludes that it is imperative to understand (1) what technologies are useful to people with disabilities, (2) whether the inclusion of these technologies is feasible in self-service devices, and (3) how user experience can be improved.

Background: Avascular necrosis (AVN) remains the most dreaded complication of unstable slipped capital femoral epiphysis (SCFE) treatment. Newer closed reduction techniques (with perfusion monitoring) have emerged as a technically straightforward means to address residual SCFE deformity while still minimizing the risk of osteonecrosis. However, limited data exists regarding the reliability of intraoperative epiphyseal perfusion monitoring to predict the development of AVN. The purpose of this study was to evaluate its reliability., Methods: We retrospectively reviewed all patients with unstable SCFE who underwent closed or open reduction with epiphyseal perfusion monitoring using an intracranial pressure (ICP) probe from 2015 to 2023 at a single institution with a minimum 6-month radiographic follow-up. Demographic, clinical, and radiographic data were recorded, including duration of symptoms, type of reduction, capsulotomy performed, presence of a waveform on ICP monitoring after epiphyseal fixation, and development of AVN on follow-up radiographs., Results: Our cohort included 33 hips (32 patients), of which 60.6% (n=20) were male. The average age was 12.5±1.8 years, with a median follow-up of 15.8 months. Eleven hips were treated with open reduction using the modified Dunn technique (10 hips) or anterior approach (1 hip), and 22 hips were treated with inadvertent (5 hips) or purposeful closed reduction using the Leadbetter technique (17 hips). Overall, 8 of the 33 hips in our series (24.2%) developed AVN, 6 of which (20%) had a pulsatile waveform on intraoperative epiphyseal perfusion monitoring. The overall rate of AVN after closed reductions was 31.8% (7 of 22 hips); the incidence of AVN after closed reduction with a detectable waveform was 30% (6 of 20 hips). There was no significant association between time to surgery ( P =0.416) or type of reduction ( P =0.218) and the incidence of AVN., Conclusions: In this series, intraoperative epiphyseal perfusion monitoring did not reliably predict the development of osteonecrosis. To our knowledge, this is the first study to report AVN after demonstrable intraoperative epiphyseal perfusion following closed reduction of unstable slips., Level of Evidence: Level IV: case series-therapeutic study., Competing Interests: W.N.S. is a consultant for Orthopediatrics, Medivir, and Siemens and receives royalties from Wolter Kluwer Health. The remaining authors declare no conflicts of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Introduction: Most deaf babies are born to hearing families who do not yet have the skills to communicate effectively with their child. Adaptations to communication are important because the quality of parent-child interaction (PCI) predicts how a deaf child develops language. Teachers of Deaf children and Speech and Language Therapists support families with communication in the home. Currently, there are no assessments that appraise how a parent interacts with their deaf baby. Previous research has identified which parent behaviours and approaches are used in PCI assessments in research and practice. The current paper forms consensus on the core content and best practices of a new PCI tool for deaf children aged 0-3 years., Methods: An international sample of expert academics and practitioners (n = 83) were recruited to take part in a two-round modified electronic Delphi study. Participants were presented with 69 statements focusing on (i) which parent behaviours were important in assessment (ii) the methods to be used in PCI assessment. Participants rated the extent to which they agreed or disagreed with each statement on a five-point Likert scale and gave comments to support their response. Consensus was defined as >80% of participants rating the statement as a (4) 'highly important' or a (5) 'essential'. If consensus was not reached, participant comments were used to generate new statements which were rated in the second round. This project involved a patient and public involvement (PPI) group of hearing and deaf parents and professionals to design and guide the study., Results: Consensus was achieved on 52 statements and ranged from 80-99%. A further six statements were additionally included. Within the 58 statements included, 36 were parent behaviours which centred on the parent's observation of, and response to, their child's behaviour and/or language. The remaining 22 statements focused on methods used in the assessment such as parents having their PCI filmed, parents having the opportunity to review the video and assess themselves alongside a professional, and parents being involved in subsequent goal setting., Conclusions: This e-Delphi presented the parent behaviours and methods of assessment to be included in a new PCI tool for deaf children. Future co-production work and acceptability and feasibility testing are discussed., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Curtin et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

This study aimed to assess the association between the oral microbiome, age, and frailty. Data and saliva samples were obtained from male and female participants aged 35-70 years (n = 1357). Saliva samples were analysed by 16S rRNA gene sequencing and differences in microbial diversity and community compositions were examined in relation to chronological age and the frailty index (FI). Most alpha diversity measures (Richness, Shannon Diversity, Faith's Phylogenetic Diversity) showed an inverse association with frailty, whereas a positive association was observed with age and Shannon Diversity and Evenness. A further sex-stratified analysis revealed differences in measures of microbial diversity and composition. Multiple genera were detected as significantly differentially abundant with increasing frailty and age by at least two methods. With age, the relative abundance of Veillonella was reduced in both males and females, whereas increases in Corynebacterium appeared specific to males and Aggregatibacter, Fusobacterium, Neisseria, Stomatobaculum, and Porphyromonas specific to females. Beta diversity was significantly associated with multiple mental health components of the FI. This study shows age and frailty are differentially associated with measures of microbial diversity and composition, suggesting the oral microbiome may be a useful indicator of increased risk of frailty or a potential target for improving health in ageing adults., (© 2024. The Author(s).)

Purpose: Early intervention for High-Risk Smoldering Multiple Myeloma (HR-SMM) achieves deep and prolonged responses. It is unclear if beneficial outcomes are due to treatment of less complex, susceptible disease or inaccuracy in clinical definition of cases entered., Experimental Design: Here, we interrogated whole genome and whole exome sequencing for 54 patients across two HR-SMM interventional studies (NCT01572480, NCT02279394)., Results: We reveal that the genomic landscape of treated HR-SMM is generally simple as compared to Newly Diagnosed (ND)MM counterparts with less inactivation of tumor suppressor genes, RAS pathway mutations, MYC disruption, and APOBEC contribution. The absence of these events parallels that of indolent precursor conditions, possibly explaining overall excellent outcomes. However, some patients harboring genomic complexity fail to sustain response and experience resistant, progressive disease. Overall, clinical risk scores do not effectively discriminate between genomically indolent and aggressive disease., Conclusions: Genomic profiling can contextualize the advantage of early intervention in SMM and guide personalization of therapy.

Background: GENCOV is a prospective, observational cohort study of COVID-19-positive adults. Here, we characterize and compare side effects between COVID-19 vaccines and determine whether reactogenicity is exacerbated by prior SARS-CoV-2 infection., Methods: Participants were recruited across Ontario, Canada. Participant-reported demographic and COVID-19 vaccination data were collected using a questionnaire. Multivariable logistic regression was performed to assess whether vaccine manufacturer, type, and previous SARS-CoV-2 infection are associated with reactogenicity., Results: Responses were obtained from n = 554 participants. Tiredness and localized side effects were the most common reactions across vaccine doses. For most participants, side effects occurred and subsided within 1-2 days. Recipients of Moderna mRNA and AstraZeneca vector vaccines reported reactions more frequently compared to recipients of a Pfizer-BioNTech mRNA vaccine. Previous SARS-CoV-2 infection was independently associated with developing side effects., Conclusions: We provide evidence of relatively mild and short-lived reactions reported by participants who have received approved COVID-19 vaccines., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Jennifer Taher reports financial support was provided by Canadian Institutes of Health Research for this study. JT also received in-kind funding from Roche for projects unrelated to the current manuscript. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Ltd.)

Air pollution is the leading environmental risk factor for mortality worldwide. In Australia, residential wood heating is the single largest source of pollution in many regions of the country. Estimates around the world and in some limited locations across Australia have shown that the health burden attributable to wood heating PM 2.5 is considerable, and that there is great potential to reduce this burden. Here, we aimed to calculate the mortality burden attributable to wood heating emissions (WHE)-related PM 2.5 throughout Australia and estimate the potential health benefits of reducing WHE-related air pollution, by replacing wood heaters with cleaner heating technologies. In summary, we used a four-stage process to (1) compile a nationwide WHE inventory, (2) generate annual exposure estimates of WHE-PM 2.5 , (3) estimate the annual mortality burden attributable to wood heater use across Australia for the year 2015, and (4) assess the potential health benefits of replacing existing wood heaters with cleaner heating technologies. We estimated that population weighted WHE-PM 2.5 exposure across Australia for 2015 ranged between 0.62 μg/m 3 and 1.35 μg/m 3 , with differing exposures across State/Territories. We estimated a considerable mortality burden attributable to WHE-PM 2.5 ranging between 558 (95 % CI, 364-738) and 1555 (95 % CI, 1180-1740) deaths annually, depending on the scenario assessed. We calculated that replacing 50 % of the current wood heater stock, with zero or lower emission technologies could produce relevant health benefits, of between $AUD 1.61 and $AUD 1.93 billion per year (303-364 attributable deaths). These findings provide a preliminary and likely conservative assessment of the health burden of wood heater smoke across Australia, and an estimation of the potential benefits from replacing the current wood heater stock with cleaner technologies. The results presented here underscore the magnitude of the health burden attributable to wood heating in Australia., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Nicolas Borchers-Arriagada reports financial support was provided by The Centre for Air pollution, energy and health Research (CAR). Stephen Vander Hoorn reports financial support was provided by The Centre for Air pollution, energy and health Research (CAR)., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Purpose: Outcomes for patients with newly diagnosed multiple myeloma (NDMM) are heterogenous, with overall survival (OS) ranging from months to over 10 years., Methods: To decipher and predict the molecular and clinical heterogeneity of NDMM, we assembled a series of 1,933 patients with available clinical, genomic, and therapeutic data., Results: Leveraging a comprehensive catalog of genomic drivers, we identified 12 groups, expanding on previous gene expression-based molecular classifications. To build a model predicting individualized risk in NDMM (IRMMa), we integrated clinical, genomic, and treatment variables. To correct for time-dependent variables, including high-dose melphalan followed by autologous stem-cell transplantation (HDM-ASCT), and maintenance therapy, a multi-state model was designed. The IRMMa model accuracy was significantly higher than all comparator prognostic models, with a c-index for OS of 0.726, compared with International Staging System (ISS; 0.61), revised-ISS (0.572), and R2-ISS (0.625). Integral to model accuracy was 20 genomic features, including 1q21 gain/amp, del 1p, TP53 loss, NSD2 translocations, APOBEC mutational signatures, and copy-number signatures (reflecting the complex structural variant chromothripsis). IRMMa accuracy and superiority compared with other prognostic models were validated on 256 patients enrolled in the GMMG-HD6 (ClinicalTrials.gov identifier: NCT02495922) clinical trial. Individualized patient risks were significantly affected across the 12 genomic groups by different treatment strategies (ie, treatment variance), which was used to identify patients for whom HDM-ASCT is particularly effective versus patients for whom the impact is limited., Conclusion: Integrating clinical, demographic, genomic, and therapeutic data, to our knowledge, we have developed the first individualized risk-prediction model enabling personally tailored therapeutic decisions for patients with NDMM.

Parkinson's disease (PD) is a debilitating neurodegenerative disease characterized by the loss of midbrain dopaminergic neurons (DaNs) and the abnormal accumulation of α-Synuclein (α-Syn) protein. Currently, no treatment can slow nor halt the progression of PD. Multiplications and mutations of the α-Syn gene (SNCA) cause PD-associated syndromes and animal models that overexpress α-Syn replicate several features of PD. Decreasing total α-Syn levels, therefore, is an attractive approach to slow down neurodegeneration in patients with synucleinopathy. We previously performed a genetic screen for modifiers of α-Syn levels and identified CDK14, a kinase of largely unknown function as a regulator of α-Syn. To test the potential therapeutic effects of CDK14 reduction in PD, we ablated Cdk14 in the α-Syn preformed fibrils (PFF)-induced PD mouse model. We found that loss of Cdk14 mitigates the grip strength deficit of PFF-treated mice and ameliorates PFF-induced cortical α-Syn pathology, indicated by reduced numbers of pS129 α-Syn-containing cells. In primary neurons, we found that Cdk14 depletion protects against the propagation of toxic α-Syn species. We further validated these findings on pS129 α-Syn levels in PD patient neurons. Finally, we leveraged the recent discovery of a covalent inhibitor of CDK14 to determine whether this target is pharmacologically tractable in vitro and in vivo. We found that CDK14 inhibition decreases total and pathologically aggregated α-Syn in human neurons, in PFF-challenged rat neurons and in the brains of α-Syn-humanized mice. In summary, we suggest that CDK14 represents a novel therapeutic target for PD-associated synucleinopathy., (© 2024. The Author(s).)

Objectives: To evaluate for associations between a child's neighborhood, as categorized by Child Opportunity Index (COI 2.0), and 1) PICU mortality, 2) severity of illness at PICU admission, and 3) PICU length of stay (LOS)., Design: Retrospective cohort study., Setting: Fifteen PICUs in the United States., Patients: Children younger than 18 years admitted from 2019 to 2020, excluding those after cardiac procedures. Nationally-normed COI category (very low, low, moderate, high, very high) was determined for each admission by census tract, and clinical features were obtained from the Virtual Pediatric Systems LLC (Los Angeles, CA) data from each site., Interventions: None., Measurements and Main Results: Among 33,901 index PICU admissions during the time period, median patient age was 4.9 years and PICU mortality was 2.1%. There was a higher percentage of admissions from the very low COI category (27.3%) than other COI categories (17.2-19.5%, p < 0.0001). Patient admissions from the high and very high COI categories had a lower median Pediatric Index of Mortality 3 risk of mortality (0.70) than those from the very low, low, and moderate COI groups (0.71) ( p < 0.001). PICU mortality was lowest in the very high (1.7%) and high (1.9%) COI groups and highest in the moderate group (2.5%), followed by very low (2.3%) and low (2.2%) ( p = 0.001 across categories). Median PICU LOS was between 1.37 and 1.50 days in all COI categories. Multivariable regression revealed adjusted odds of PICU mortality of 1.30 (95% CI, 0.94-1.79; p = 0.11) for children from a very low versus very high COI neighborhood, with an odds ratio [OR] of 0.996 (95% CI, 0.993-1.00; p = 0.05) for mortality for COI as an ordinal value from 0 to 100. Children without insurance coverage had an OR for mortality of 3.58 (95% CI, 2.46-5.20; p < 0.0001) as compared with those with commercial insurance., Conclusions: Children admitted to a cohort of U.S. PICUs were often from very low COI neighborhoods. Children from very high COI neighborhoods had the lowest risk of mortality and observed mortality; however, odds of mortality were not statistically different by COI category in a multivariable model. Children without insurance coverage had significantly higher odds of PICU mortality regardless of neighborhood., Competing Interests: Dr. McCrory received funding from the Wake Forest Department of Anesthesiology. Dr. Maddux’s institution received funding from the National Institute of Child Health and Human Development (K23HD096018) and the Francis Family Foundation. The remaining authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2024 by the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies.)

Improving the outcome of high-risk myeloma (HRMM) is a key therapeutic aim for the next decade. To achieve this aim, it is necessary to understand in detail the genetic drivers underlying this clinical behavior and to target its biology therapeutically. Advances have already been made, with a focus on consensus guidance and the application of novel immunotherapeutic approaches. Cases of HRMM are likely to have impaired prognosis even with novel strategies. However, if disease eradication and minimal disease states are achieved, then cure may be possible., Competing Interests: Disclosures X. Chen, G. Varma declare no related conflict of interests., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Alzheimer's disease (AD) is characterised by age-related cognitive decline. Brain accumulation of amyloid-β plaques and tau tangles is required for a neuropathological AD diagnosis, yet up to one-third of AD-pathology positive community-dwelling elderly adults experience no symptoms of cognitive decline during life. Conversely, some exhibit chronic cognitive impairment in absence of measurable neuropathology, prompting interest into cognitive resilience-retained cognition despite significant neuropathology-and cognitive frailty-impaired cognition despite low neuropathology. Synapse loss is widespread within the AD-dementia, but not AD-resilient, brain. Recent evidence points towards critical roles for synaptic proteins, such as neurosecretory VGF, in cognitive resilience. However, VGF and related proteins often signal as peptide derivatives. Here, nontryptic peptidomic mass spectrometry was performed on 102 post-mortem cortical samples from individuals across cognitive and neuropathological spectra. Neuropeptide signalling proteoforms derived from VGF, somatostatin (SST) and protachykinin-1 (TAC1) showed higher abundance in AD-resilient than AD-dementia brain, whereas signalling proteoforms of cholecystokinin (CCK) and chromogranin (CHG) A/B and multiple cytoskeletal molecules were enriched in frail vs control brain. Integrating our data with publicly available single nuclear RNA sequencing (snRNA-seq) showed enrichment of cognition-related genes in defined cell-types with established links to cognitive resilience, including SST interneurons and excitatory intratelencephalic cells., (© 2024. The Author(s).)

Deeper responses are associated with improved survival in patients being treated for myeloma. However, the sensitivity of the current blood-based assays is limited. Historical studies suggested that normalisation of the serum free light chain (FLC) ratio in patients who were negative by immunofixation electrophoresis (IFE) was associated with improved outcomes. However, recently this has been called into question. Mass spectrometry (MS)-based FLC assessments may offer a superior methodology for the detection of monoclonal FLC due to greater sensitivity. To test this hypothesis, all available samples from patients who were IFE negative after treatment with carfilzomib and lenalidomide-based induction and autologous stem cell transplantation (ASCT) in the Myeloma XI trial underwent FLC-MS testing. FLC-MS response assessments from post-induction, day+100 post-ASCT and six months post-maintenance randomisation were compared to serum FLC assay results. Almost 40% of patients had discordant results and 28.7% of patients with a normal FLC ratio had residual monoclonal FLC detectable by FLC-MS. FLC-MS positivity was associated with reduced progression-free survival (PFS) but an abnormal FLC ratio was not. This study demonstrates that FLC-MS provides a superior methodology for the detection of residual monoclonal FLC with FLC-MS positivity identifying IFE-negative patients who are at higher risk of early progression., (© 2024. The Author(s).)

Platinum and taxane chemotherapy is associated with the risk of hypersensitivity reactions (HSRs), which may require switching to less effective treatments. Desensitization to platinum and taxane HSRs can be used to complete chemotherapy according to the standard regimen. Therefore, we aimed to investigate the current management of HSRs to platinum and/or taxane chemotherapy in patients with gynecologic cancers. We conducted an online cross-sectional survey among gynecological and medical oncologists consisting of 33 questions. A total of 144 respondents completed the survey, and 133 respondents were included in the final analysis. Most participants were gynecologic oncologists (43.6%) and medical oncologists (33.8%), and 77.4% ( n = 103) were involved in chemotherapy treatment. More than 73% of participants experienced >5 HSRs to platinum and taxane per year. Premedication and a new attempt with platinum or taxane chemotherapy were used in 84.8% and 92.5% of Grade 1-2 HSRs to platinum and taxane, respectively. In contrast, desensitization was used in 49.4% and 41.8% of Grade 3-4 HSRs to platinum and taxane, respectively. Most participants strongly emphasized the need to standardize the management of platinum and taxane HSRs in gynecologic cancer. Our study showed that HSRs in gynecologic cancer are common, but management is variable and the use of desensitization is low. In addition, the need for guidance on the management of platinum- and taxane-induced HSRs in gynecologic cancer was highlighted.

Context: In Colorado children, the prevalence of diabetic ketoacidosis (DKA) at diagnosis of type 1 diabetes (T1D) has been increasing over time., Objective: Evaluate the prevalence of and factors involved in DKA at T1D diagnosis among participants followed in monitoring research studies before diagnosis compared to patients from the community., Setting and Participants: Patients < 18 years diagnosed with T1D between 2005 and 2021 at the Barbara Davis Center for Diabetes., Outcome: Prevalence of and factors associated with DKA at diagnosis among participants in preclinical monitoring studies compared to those diagnosed in the community., Results: Of 5049 subjects, 164 were active study participants, 42 inactive study participants, and 4843 were community patients. Active study participants, compared to community patients, had lower HbA1c (7.3% vs 11.9%]; P < 0.001) and less frequently experienced DKA (4.9% vs 48.5%; P < 0.001), including severe DKA (1.2% vs 16.2%; P < 0.001). Inactive study participants had intermediate levels for both prevalence and severity of DKA. DKA prevalence increased in community patients, from 44.0% to 55%, with less evidence for a temporal trend in study participants. DKA prevalence was highest in children <2 years (13% in active study participants vs 83% in community patients). In community patients, younger age (P = 0.0038), public insurance (P < 0.0001), rural residence (P < 0.0076), higher HbA1c (P < 0.0001), and ethnicity minority status (P < 0.0001) were associated with DKA at diagnosis., Conclusions: While DKA prevalence increases in community patients over time, it stayed <5% in active research participants, who have a 10 times lower prevalence of DKA at diagnosis, including in minorities., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Introduction: Parent child interaction (PCI) is positively associated with deaf children's language development. However, there are no known, deaf-specific tools to observe how a parent interacts with their deaf child aged 0-3 years. Without a framework for professionals to use with families, it is unknown how professionals assess PCI, what they assess, why they assess, and how the assessment results relate to case management., Methods: Eighteen hearing and deaf professionals, who work with deaf and hard of hearing infants aged 0-3 years and their families, attended online focus groups. The aim of the study was to gain insight into the professional assessment of PCI. Data were analyzed using thematic analysis., Findings: Six themes were generated from the dataset. Professionals discussed how central parents were in the support offered to families in the home, the importance of knowing and understanding the individual family, and accounting for and supporting parental wellbeing. Descriptions on how to administer a best practice PCI assessment included which parent behaviors to assess and how to make adaptations for different populations. Professionals shared how the assessment and review process could be used to inform and upskill parents through video reflection and goal setting., Discussion: This study provides insight into the mechanisms and motivations for professionals assessing the interactive behaviors of parents who have deaf children aged 0-3. Professionals acknowledged that family life is multi-faceted, and that support is most meaningful to families when professionals worked with these differences and incorporated them into assessment, goal setting, and intervention plans., 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 © 2024 Curtin, Wakefield, Herman, Morgan and Cruice.)

Background: Biomarkers for idiopathic inflammatory myopathies are difficult to identify and may involve expensive laboratory tests. We assess the potential for artificial intelligence (AI) to differentiate children with juvenile dermatomyositis (JDM) from healthy controls using nailfold capillaroscopy (NFC) images. We also assessed the potential of NFC images to reflect the range of disease activity with JDM., Methods: A total of 1,120 NFC images from 111 children with active JDM, diagnosed between 1990 and 2020, and 321 NFC images from 31 healthy controls were retrieved from the CureJM JDM Registry. We built a lightweight and explainable deep neural network model called NFC-Net. Images were downscaled by interpolation techniques to reduce the computational cost., Results: NFC-Net achieved high performance in differentiating patients with JDM from controls, with an area under the ROC curve (AUROC) of 0.93 (0.84, 0.99) and accuracy of 0.91 (0.82, 0.92). With sensitivity (0.85) and specificity (0.90) resulted in model precision of 0.95. The AUROC and accuracy for predicting clinical disease activity from inactivity were 0.75 (0.61, 0.81) and 0.74 (0.65, 0.79)., Conclusion: The good performance of the NFC-Net demonstrates that NFC images are sufficient for detecting often unrecognized JDM disease activity, providing a reliable indicator of disease status., Impact: Proposed NFC-Net can accurately predict children with JDM from healthy controls using nailfold capillaroscopy (NFC) images. Additionally, it predicts the scores to JDM disease activity versus no activity. Equipped with gradients, NFC-Net is explainable and gives visual information beside the reported accuracies. NFC-Net is computationally efficient since it is applied to substantially downscaled NFC images. Furthermore, the model can be wrapped within an edge-based device like a mobile application that is accessible to both clinicians and patients., (© 2023. The Author(s), under exclusive licence to the International Pediatric Research Foundation, Inc.)

Proximal fifth metatarsal fractures are the most common foot fractures in children. Attempts to classify these injuries are misapplied and inadequately predict outcomes. This is the first study to identify factors associated with healing in pediatric fifth metatarsal fractures. In this retrospective cohort study (N = 305), proximal fifth metatarsal fractures were classified on radiographs by location on the bone, alignment (transverse or oblique), displacement (>2 mm), and completion through the bone. Based on the literature, they were secondarily sorted by category: apophyseal, intra-articular metaphyseal, extra-articular metaphyseal, and diaphyseal. Primary outcomes included times to healing, indicated by clinical symptoms, immobilization, and return to sports, as well as radiographic callus formation, bridging, and remodeling. Healing times were compared by ANOVA and linear regression. Location had a significant effect on times of immobilization and return to sports, but alignment, displacement, and completion were not associated with healing. When re-classified, the categories were also associated with immobilization and return to sports. Apophyseal fractures healed fastest and diaphyseal fractures required the most time to heal. There was no difference between extra- and intra-articular fractures. For every year of age, symptoms resolved about 2 days sooner. Neither gender nor body mass index (BMI) was positively or negatively associated with healing times. In conclusion, classifying fractures by apophyseal, metaphyseal, and diaphyseal is the most concise, accurate, and useful system. This is the largest series of nonoperatively treated proximal fifth metatarsal fractures in children and a robust standard to which surgical management can be compared., (Copyright © 2024. Published by Elsevier Inc.)

The Internet of Things (IoT) has emerged as an important concept, bridging the physical and digital worlds through interconnected devices. Although the idea of interconnected devices predates the term "Internet of Things", which was coined in 1999 by Kevin Ashton, the vision of a seamlessly integrated world of devices has been accelerated by advancements in wireless technologies, cost-effective computing, and the ubiquity of mobile devices. This study aims to provide an in-depth review of existing and emerging IoT simulators focusing on their capabilities and real-world applications, and discuss the current challenges and future trends in the IoT simulation area. Despite substantial research in the IoT simulation domain, many studies have a narrow focus, leaving a gap in comprehensive reviews that consider broader IoT development metrics, such as device mobility, energy models, Software-Defined Networking (SDN), and scalability. Notably, there is a lack of literature examining IoT simulators' capabilities in supporting renewable energy sources and their integration with Vehicular Ad-hoc Network (VANET) simulations. Our review seeks to address this gap, evaluating the ability of IoT simulators to simulate complex, large-scale IoT scenarios and meet specific developmental requirements, as well as examining the current challenges and future trends in the field of IoT simulation. Our systematic analysis has identified several significant gaps in the current literature. A primary concern is the lack of a generic simulator capable of effectively simulating various scenarios across different domains within the IoT environment. As a result, a comprehensive and versatile simulator is required to simulate the diverse scenarios occurring in IoT applications. Additionally, there is a notable gap in simulators that address specific security concerns, particularly battery depletion attacks, which are increasingly relevant in IoT systems. Furthermore, there is a need for further investigation and study regarding the integration of IoT simulators with traffic simulation for VANET environments. In addition, it is noteworthy that renewable energy sources are underrepresented in IoT simulations, despite an increasing global emphasis on environmental sustainability. As a result of these identified gaps, it is imperative to develop more advanced and adaptable IoT simulation tools that are designed to meet the multifaceted challenges and opportunities of the IoT domain.

Introduction: The addition of taxanes to anthracycline-based chemotherapy is considered standard of care in the treatment of breast cancer. However, there are insufficient data regarding the safety of taxanes during pregnancy. The aim of this study was to describe the incidence of obstetric and neonatal adverse events associated with the use of taxane-containing chemotherapy regimens for the treatment of breast cancer during pregnancy., Methods: This is a multicenter, international cohort study of breast cancer patients treated with taxanes during pregnancy. A descriptive analysis was undertaken to synthetize available data., Results: A total of 103 patients were included, most of whom were treated with paclitaxel and anthracyclines given in sequence during gestation (90.1%). The median gestational age at taxane initiation was 28 weeks (range = 12-37 weeks). Grade 3-4 adverse events were reported in 7 of 103 (6.8%) patients. The most common reported obstetric complications were intrauterine growth restriction (n = 8 of 94, 8.5%) and preterm premature rupture of membranes (n = 5 of 94, 5.3%). The live birth rate was 92 of 94 (97.9%), and the median gestational age at delivery was 37 weeks (range = 32-40 weeks). Admission to an intensive care unit was reported in 14 of 88 (15.9%) neonates, and 17 of 70 (24.3%) live births resulted in small for gestational age neonates. Congenital malformations were reported in 2 of 93 (2.2%)., Conclusion: Obstetric and neonatal outcomes after taxane exposure during pregnancy were generally favorable and did not seem to differ from those reported in the literature with standard anthracycline-based regimens. This study supports the use of taxanes during gestation when clinically indicated., (© The Author(s) 2023. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

How individual animals respond to climate change is key to whether populations will persist or go extinct. Yet, few studies investigate how changes in individual behavior underpin these population-level phenomena. Shifts in the distributions of migratory animals can occur through adaptation in migratory behaviors, but there is little understanding of how selection and plasticity contribute to population range shift. Here, we use long-term geolocator tracking of Balearic shearwaters ( Puffinus mauretanicus ) to investigate how year-to-year changes in individual birds' migrations underpin a range shift in the post-breeding migration. We demonstrate a northward shift in the post-breeding range and show that this is brought about by individual plasticity in migratory destination, with individuals migrating further north in response to changes in sea-surface temperature. Furthermore, we find that when individuals migrate further, they return faster, perhaps minimizing delays in return to the breeding area. Birds apparently judge the increased distance that they will need to migrate via memory of the migration route, suggesting that spatial cognitive mechanisms may contribute to this plasticity and the resulting range shift. Our study exemplifies the role that individual behavior plays in populations' responses to environmental change and highlights some of the behavioral mechanisms that might be key to understanding and predicting species persistence in response to climate change., Competing Interests: Competing interests statement:The authors declare no competing interest.

Background: The Pavlik harness (PH) is the most common treatment for infants with developmental dysplasia of the hip. Although success rates are high when used appropriately, brace treatment may impact family function and parental bonding. The purpose of this study was to prospectively determine how PH treatment affected these psychosocial variables., Methods: This is a prospective, single-surgeon study at a tertiary-care, urban, academic children's hospital between November 2022 and March 2023. All patients newly treated with a Pavlik were eligible. Caregivers were administered the Postpartum Bonding Questionnaire and the Revised Impact on Family Scale (rIOFS) at the baseline visit and 2- and 6 weeks following treatment initiation. Demographic and treatment-specific information was collected through surveys and retrospective chart review. Descriptive statistics and bivariate analysis were used., Results: A total of 55 caregiver-child dyads were included in the final analysis. Most patients were female (89%) and/or first-born (73%). Forty (73%) hips were diagnosed as having stable dysplasia. rIOFS scores steadily improved from baseline, through 2- and 6 weeks posttreatment initiation. Six-week rIOFS scores were significantly lower than both baseline ( P= 0.002) and 2 weeks ( P =0.018). Average parental bonding scores also improved steadily throughout treatment and did not surpass the threshold of clinical concern at any time. Neither full-time harness use (24 h/d vs. 23 h/d based upon clinical stability) nor age at treatment initiation had a statistically significant effect on parental bonding or family functioning (all P >0.05). Additional demographic variables such as birth order, parental history of anxiety/depression, and relative socioeconomic disadvantage also had no significant effect on psychosocial outcomes., Conclusion: PH treatment did not significantly impact maternal-fetal bonding or family dynamics. Relative to other pediatric diseases, PH treatment has an impact on family life greater than that of single-leg spica, but less than that of school-age children with chronic medical illnesses. As PH treatment is a widely used treatment for infantile developmental dysplasia of the hip, this study provides information that clinicians may use to more accurately counsel families and assuage parental concerns., Levels of Evidence: Level IV-prospective uncontrolled cohort study., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Debates exist regarding the validity and utility of functional psychiatric diagnoses. How mental health diagnoses are understood has real impacts for service users and service delivery., Aims: To investigate different attitudes about the utility of psychiatric diagnoses., Methods: Forty-one stakeholders sorted 57 statements related to the usefulness of psychiatric diagnoses. Using q-methodology, four viewpoints were identified and interpreted., Results: Viewpoint 1 ( Pathologising human experience ) regarded diagnoses as pseudo-scientific constructs that lacked validity and obscured the relationships between lived experience and distress. Viewpoint 2 ( Illnesses like any other ) held that labels reflected real disorders and diagnosis offered important benefits for service users and services. Viewpoint 3 ( Stigmatised conditions ) similarly regarded diagnoses as reflecting real disorders, but diagnostic criteria were viewed as biased and the impacts of applying labels seen as causing problems for service users. Conversely, Viewpoint 4 ( Useful short-hands ) viewed diagnostic processes as imperfect but necessary for supporting communication and structuring service delivery., Conclusions: While not all viewpoints are in keeping with empirical evidence, we hope results will enable professionals and service users to take meta-positions in relation to their own and others' attitudes, and to reflect on the impacts of privileging certain viewpoints over others.

Purpose: Whole-genome sequencing (WGS) of patients with newly diagnosed multiple myeloma (NDMM) has shown recurrent structural variant (SV) involvement in distinct regions of the genome (i.e., hotspots) and causing recurrent copy-number alterations. Together with canonical immunoglobulin translocations, these SVs are recognized as "recurrent SVs." More than half of SVs were not involved in recurrent events. The significance of these "rare SVs" has not been previously examined., Experimental Design: In this study, we utilize 752 WGS and 591 RNA sequencing data from patients with NDMM to determine the role of rare SVs in myeloma pathogenesis., Results: Ninety-four percent of patients harbored at least one rare SV event. Rare SVs showed an SV class-specific enrichment within genes and superenhancers associated with outlier gene expression. Furthermore, known myeloma driver genes recurrently impacted by point mutations were dysregulated by rare SVs., Conclusions: Overall, we demonstrate the association of rare SVs with aberrant gene expression supporting a potential driver role in myeloma pathogenesis., (©2023 American Association for Cancer Research.)

Sickle cell disease (SCD) is an inherited, progressively debilitating blood disorder. Emerging gene therapies (GTx) may lead to a complete remission, the benefits of such can only be realized if GTx is affordable and accessible in the low-and middle-income countries (LMIC) with the greatest SCD burden. To estimate the health impacts and country-specific value-based prices (VBP) of a future gene therapy for SCD using a cost-utility model framework. We developed a lifetime Markov model to compare the costs and health outcomes of GTx versus standard of care for SCD. We modeled populations in seven LMICs and six high-income countries (HICs) estimating lifetime costs and disability-adjusted life-years (DALYs) in comparison to estimates of a country's cost-effectiveness threshold. Each country's unique VBP for GTx was calculated via threshold analysis. Relative to SOC treatment alone, we found that hypothetical GTx reduced the number of people symptomatic with SCD over time leading to fewer DALYs. Across countries, VBPs ranged from $3.6 million (US) to $700 (Uganda). Our results indicate a wide range of GTx prices are required if it is to be made widely available and may inform burden and affordability for 'target product profiles' of GTx in SCD., (© 2024. The Author(s).)

Air pollution poses a threat to children's respiratory health. This study aims to quantify the association between short-term air pollution exposure and respiratory hospital admissions among children in Hanoi, Vietnam, and estimate the population-attributable burden using local data. A case-crossover analysis was conducted based on the individual records where each case is their own control. The health data was obtained from 13 hospitals in Hanoi and air pollution data was collected from four monitoring stations from 2007 to 2019. We used conditional logistic regression to estimate Percentage Change (PC) and 95% Confidence Interval (CI) in odd of hospital admissions per 10 μg/m 3 increase in daily average particulate matter (e.g. PM 1 , PM 2.5 , PM 10 ), Sulfur Dioxide (SO 2 ), Nitrogen Dioxide (NO 2 ), 8-h maximum Ozone and per 1000 μg/m 3 increase in daily mean of Carbon Monoxide (CO). We also calculated the number and fraction of admissions attributed to air pollution in Hanoi by using the coefficient at lag 0. A 10 μg/m 3 increase in the concentration of PM 10 , PM 2.5 , PM 1 , SO 2 , NO 2 , O 3 8-h maximum and 1000 μg/m 3 increase in CO concentration was associated with 0.6%, 1.2%, 1.4%, 0.8%, 1.6%, 0.3%, and 1.7% increase in odd of admission for all respiratory diseases among children under 16 years at lag 0-2. All PM metrics and NO 2 are associated with childhood admission for pneumonia and bronchitis. Admissions due to asthma and upper respiratory diseases are related to increments in NO 2 and CO. For attributable cases, PM 2.5 concentrations in Hanoi exceeding the World Health Organization Air Quality Guidelines accounted for 1619 respiratory hospital admissions in Hanoi children in 2019. Our findings show that air pollution has a detrimental impact on the respiratory health of Hanoi children and there will be important health benefits from improved air quality management planning to reduce air pollution in Vietnam., Competing Interests: Declaration of competing interest NO., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Raw meat diets (RMD) for dogs are an increasingly popular alternative pet food choice, however studies worldwide have demonstrated them to be contaminated with zoonotic and antimicrobial resistant (AMR) bacteria, including bacteria resistant to critically important antibiotics. Despite this, few data exist surrounding the presence of these bacteria in RMD in the United Kingdom. The present study aimed to identify the most commonly selected RMD and non-raw diets (NRMD) by United Kingdom dog owners. Additionally, it investigated the presence of AMR- Enterobacteriaceae in samples of pre-prepared RMD and cooked commercial kibble dog foods. An online survey investigating diet preferences of United Kingdom dog owners was open for 6 weeks between February-March 2020. From this, the top 10 brands of pre-prepared raw and cooked kibble diets were ascertained and 134 samples purchased (110 RMD, 24 kibble) and subjected to microbiological testing. Bacterial enumeration of E. coli and other Enterobacteriaceae was undertaken, and the presence of Salmonella spp. and AMR- E. coli within samples determined. Whole genome sequencing was undertaken on Salmonella spp. and third-generation cephalosporin-resistant 3GCR- E. coli isolates. Pre-prepared RMD was most commonly selected by dog owners who fed RMD, and cooked commercial complete dry food was most frequently fed by owners who fed NRMD. Damaged and leaking packaging was observed in samples of RMD, alongside variability in information provided surrounding product traceability. Counts of E. coli and other Enterobacteriaceae exceeding >5,000 CFU/g were identified in samples of RMD. AMR-, extended-spectrum beta-lactamase (ESBL)-producing and 3GCR- E. coli was isolated from 39, 14 and 16% of RMD samples, respectively. Multiple antimicrobial resistance genes were identified in 3GCR- E. coli isolates. Of the ESBL encoding genes, bla CTX-M-15 was most commonly identified. S. enterica was isolated from 5% of RMD samples. No Enterobacteriaceae were isolated from any of the cooked kibble samples. The present study suggests that pre-prepared RMD available for dogs in the United Kingdom can be contaminated with zoonotic and AMR- Enterobacteriaceae . RMDs, therefore, are potentially an important One Health concern. Veterinary and medical professionals, pet food retailers and pet owners should be aware of these risks; and stringent hygiene measures should be practiced if owners choose to feed RMD., 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 © 2024 Morgan, Pinchbeck, Taymaz, Chattaway, Schmidt and Williams.)

Objectives: Emissions from road traffic, power generation and industry were substantially reduced during pandemic lockdown periods globally. Thus, we analysed reductions in traffic-related air pollution in Australian capital cities during March-April 2020 and then modelled the mortality benefits that could be realised if similar reductions were sustained by structural policy interventions., Study Design: Satellite, air pollution monitor and land use observations were used to estimate ground-level nitrogen dioxide (NO 2 ) concentrations in all Australian capital cities during: (a) a typical year with no prolonged air pollution events; (b) a hypothetical sustained reduction in NO 2 equivalent to the COVID-19 lockdowns., Methods: We use the WHO recommended NO 2 exposure-response coefficient for mortality (1.023, 95 % CI: 1.008-1.037, per 10 μg/m 3 annual average) to assess gains in life expectancy and population-wide years of life from reduced exposure to traffic-related air pollution., Results: We attribute 1.1 % of deaths to anthropogenic NO 2 exposures in Australian cities, corresponding to a total of 13,340 years of life lost annually. Although COVID-19-related reductions in NO 2 varied widely between Australian cities during April 2020, equivalent and sustained reductions in NO 2 emissions could reduce NO 2 -attributable deaths by 27 %, resulting in 3348 years of life gained annually., Conclusions: COVID-19 mobility restrictions reduced NO 2 emissions and population-wide exposures in Australian cities. When sustained to the same extent by policy interventions that reduce fossil fuel consumption by favouring the uptake of electric vehicles, active travel and public transport, the health, mortality and economic benefits will be measurable in Australian cities., (Copyright © 2023 The Royal Society for Public Health. Published by Elsevier Ltd. All rights reserved.)