Search

Weiran Liu,1,* Shumin Xie,2,* Lin Yue,3,* Jiahao Liu,2 Stephanie Mu-Lian Woo,4 Weilin Liu,2 Adam R Miller,5 Jing Zhang,6 Lijun Huang,7 Lei Zhang8,*1Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Department of Anesthesia, Tianjin, People's Republic of China; 2The Xiangya Medical School of Central-South University, Changsha, People's Republic of China; 3Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Outpatient Service, Tianjin, People's Republic of China; 4Harvard University, Cambridge, MA, USA; 5Indiana University School of Medicine, Indianapolis, IN, USA; 6Tianjin Medical University, Tianjin, People's Republic of China; 7Hunan Provincial Tumor Hospital, Department of Lymphoma and Hematology, Changsha, People's Republic of China; 8Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin Lung Cancer Center, Department of Thoracic Surgery, Tianjin, People's Republic of China *These authors contributed equally to this paperPurpose: To examine oncologists' knowledge of cancer pain and morphine's clinical application in the People's Republic of China. In addition, this study analyzes and discusses the negative factors that currently affect the clinical application of morphine.Patients and methods: A questionnaire survey was given to a random sample of 150 oncologists from Tianjin Medical University Cancer Institute and Hospital. The statistical results were analyzed and processed using SPSS version 21.0 and Matlab version 2012a statistical software. Single-factor analysis of variance, Kruskal–Wallis nonparametric test, and independent samples t-test were adopted to analyze the difference in knowledge scores of morphine usage. The study also identified major impediment factors on clinical use of morphine.Results: Among the 127 respondents, morphine controlled-release tablets were the most popular drug chosen to treat severe cancer pain (76 respondents, 35.8%). Participants who reported having received training in cancer pain management and drug use demonstrated a significantly higher mean score of basic knowledge compared with their untrained peers (11.51±2.60 versus 9.28±3.68, t=2.48, P=0.022). The top four barriers to widespread clinical use of morphine for cancer pain were 1) insufficient analgesia administration training for medical personnel, 2) poor patient compliance, 3) drug side effects, and 4) concerns surrounding drug addiction.Conclusion: The oncologists in the People's Republic of China simultaneously lack comprehensive knowledge and harbor misconceptions with regard to cancer pain treatment and morphine's clinical application. Creating professional training initiatives for oncologists is necessary to enhance their awareness and expertise in morphine use for cancer pain treatment.Keywords: pain management, training, clinical application

Purpose. Children with neurodevelopmental disorders (Neuro) pose complex parenting challenges, particularly if the condition co-occurs with behaviour problems. Such challenges are likely to impact caregiver health and well-being. This study explores the extent to which caregivers of children with both 'Neuro' and behaviour problems differ in their physical and psychosocial outcomes from caregivers of children with either condition or neither condition. Method. The first wave of data collected in the National Longitudinal Survey of Children and Youth in Canada (1994) was used to identify four groups of caregivers of 4 to 11-year-old children: caregivers of children with a 'Neuro' disorder and externalising behaviour problems (Both; n = 414), caregivers of children with a 'Neuro' disorder only (Neuro Only; n = 750), caregivers of children with an externalising behaviour problem only (Ext Only; n = 1067), and caregivers of children with neither health condition (Neither; n = 7236). Results. Caregivers in the 'Both' group were least likely to report excellent or very good health, and more frequently reported chronic conditions such as asthma, arthritis, back problems, migraine headaches, and limitations in activities as compared to the 'Neither' group. This group also exhibited higher depression scores, experienced more problematic family functioning, and reported lower social support than the 'Neither' group. Scores for caregivers in the 'Ext Only' and 'Neuro Only' groups tended to lie between the 'Both' and 'Neither' group scores and often did not differ from one another. Conclusions. Caregivers of children with both neurodevelopmental disorders and behaviour problems exhibited a greater number of health and psychosocial problems. While addressing children's behaviour problems, health care professionals should also consider caregiver physical and psychosocial health as this may also have an impact on children's well-being. [ABSTRACT FROM AUTHOR]

This study explored whether a relationship exists between anger among Black adolescents that has been provoked by racial discrimination, and alcohol consumption. Participants consisted of 134 Black adolescents from 14 to 18 years of age, residing in northeast Texas. All participants were administered a questionnaire measuring whether and the extent to which they might be dependent upon alcohol, a background information questionnaire which included questions about their drinking pattern, and a measure designed to assess the extent to which they feel angry either because they had been discriminated against or observed other Blacks being discriminated against or observed other Blacks being discriminated against in various situations. Only gender was found to be predictive of scores on the dependency scale. However gender, age, and racial discrimination anger scores were found to be predictive of the amount of alcohol consumed by the participants. Some implications for theory, research, and intervention are suggested. [ABSTRACT FROM AUTHOR]

OBJECTIVES: To examine selected medical services for children treated for attention-deficit/hyperactivity disorder (ADHD) in a general population setting with universal health insurance. DESIGN: Retrospective analysis of administrative prescription and health services databases spanning from 1990 to 1996. SETTING: British Columbia, Canada. PATIENTS: Children (<19 years of age) who had received the psychostimulant methylphenidate (MPH; Ritalin) on a chronic basis (chronic-MPH group), who had received MPH on any other basis (nonchronic-MPH group), and who were in a no-MPH comparison group. MAIN OUTCOME MEASURES: The number of individuals who received any of the following services based on claims submitted by qualified practitioners: 1) emergency care, 2) critical care, 3) injury-related diagnostic and treatment services, 4) complementary and alternative medical (CAM) care, and 5) other diagnostic and treatment services (audiometry and allergy testing). RESULTS: Prevalence of services users was higher among MPH-treated than nontreated children for all types of services (except critical care services in the chronic-MPH group) after adjusting for effects of age, sex, socioeconomic status, and geographic setting, with odds ratios ranging from 1.49 to 3.17. There were no differences between the 2 MPH-treated groups. CONCLUSIONS: Children treated with MPH for ADHD or presumed ADHD are more frequent users of a wide range of medical services than are other children. Findings support and extend existing evidence of increased use of medical services by this population of children. Findings have implications for service planning, including injury prevention, with these children. High utilization of audiometric, allergy, and CAM services warrants further scrutiny. [ABSTRACT FROM AUTHOR]

El artículo analiza el espacio fílmico de la saga cinematográica Star Wars , identiicando cómo se aplican en éste algunos conceptos clave para la geografía que asimismo son relevantes para su análisis multiescalar, como ocurre con el territorio. De igual forma, busca clasiicar los aspectos que hacen de esta galaxia un lugar utópico o distópico. Concluye que, a pesar de su naturaleza de icción, el espacio fílmico de la saga presenta una complejidad que no permite categorizar la galaxia como utopía o distopía, ya que esto varía de acuerdo con la escala y las situaciones examinadas.

Abstract Background The taxis signaling system of the extreme halophilic archaeon Halobacterium (Hbt.) salinarum differs in several aspects from its model bacterial counterparts Escherichia coli and Bacillus subtilis. We studied the protein interactions in the Hbt. salinarum taxis signaling system to gain an understanding of its structure, to gain knowledge about its known components and to search for new members. Results The interaction analysis revealed that the core signaling proteins are involved in different protein complexes and our data provide evidence for dynamic interchanges between them. Fifteen of the eighteen taxis receptors (halobacterial transducers, Htrs) can be assigned to four different groups depending on their interactions with the core signaling proteins. Only one of these groups, which contains six of the eight Htrs with known signals, shows the composition expected for signaling complexes (receptor, kinase CheA, adaptor CheW, response regulator CheY). From the two Hbt. salinarum CheW proteins, only CheW1 is engaged in signaling complexes with Htrs and CheA, whereas CheW2 interacts with Htrs but not with CheA. CheY connects the core signaling structure to a subnetwork consisting of the two CheF proteins (which build a link to the flagellar apparatus), CheD (the hub of the subnetwork), two CheC complexes and the receptor methylesterase CheB. Conclusions Based on our findings, we propose two hypotheses. First, Hbt. salinarum might have the capability to dynamically adjust the impact of certain Htrs or Htr clusters depending on its current needs or environmental conditions. Secondly, we propose a hypothetical feedback loop from the response regulator to Htr methylation made from the CheC proteins, CheD and CheB, which might contribute to adaptation analogous to the CheC/CheD system of B. subtilis.

Abstract Background Archaea share with bacteria the ability to bias their movement towards more favorable locations, a process known as taxis. Two molecular systems drive this process: the motility apparatus and the chemotaxis signal transduction system. The first consists of the flagellum, the flagellar motor, and its switch, which allows cells to reverse the rotation of flagella. The second targets the flagellar motor switch in order to modulate the switching frequency in response to external stimuli. While the signal transduction system is conserved throughout archaea and bacteria, the archaeal flagellar apparatus is different from the bacterial one. The proteins constituting the flagellar motor and its switch in archaea have not yet been identified, and the connection between the bacterial-like chemotaxis signal transduction system and the archaeal motility apparatus is unknown. Results Using protein-protein interaction analysis, we have identified three proteins in Halobacterium salinarum that interact with the chemotaxis (Che) proteins CheY, CheD, and CheC2, as well as the flagella accessory (Fla) proteins FlaCE and FlaD. Two of the proteins belong to the protein family DUF439, the third is a HEAT_PBS family protein. In-frame deletion strains for all three proteins were generated and analyzed as follows: a) photophobic responses were measured by a computer-based cell tracking system b) flagellar rotational bias was determined by dark-field microscopy, and c) chemotactic behavior was analyzed by a swarm plate assay. Strains deleted for the HEAT_PBS protein or one of the DUF439 proteins proved unable to switch the direction of flagellar rotation. In these mutants, flagella rotate only clockwise, resulting in exclusively forward swimming cells that are unable to respond to tactic signals. Deletion of the second DUF439 protein had only minimal effects. HEAT_PBS proteins could be identified in the chemotaxis gene regions of all motile haloarchaea sequenced so far, but not in those of other archaeal species. Genes coding for DUF439 proteins, however, were found to be integral parts of chemotaxis gene regions across the archaeal domain, and they were not detected in other genomic context. Conclusion Altogether, these results demonstrate that, in the archaeal domain, previously unrecognized archaea-specific Che proteins are essential for relaying taxis signaling to the flagellar apparatus.

Abstract Background To determine the tobacco-related knowledge, attitudes, and practice behaviors among US pediatric dentists. Methods A survey was conducted in 1998 among a national, random sample of 1500 American Academy of Pediatric Dentistry members. Chi-square tests and logistic regression with odds ratios (ORs) and 95% confidence intervals assessed factors related to pediatric dentists' tobacco control behaviors. Results Response was 65% for the survey. Only 12% of respondents had prior tobacco prevention/cessation training. Of those untrained, 70% were willing to be trained. Less than two-thirds correctly answered any of four tobacco-related knowledge items. Over one-half agreed pediatric dentists should engage in tobacco control behaviors, but identified patient resistance as a barrier. About 24% of respondents reported always/often asking their adolescent patients about tobacco use; 73% reported always/often advising known tobacco users to quit; and 37% of respondents always/often assisting with stopping tobacco use. Feeling prepared to perform tobacco control behaviors (ORs = 1.9–2.8), a more positive attitude score (4 points) from 11 tobacco-related items (ORs = 1.5–1.8), and a higher statewide tobacco use prevalence significantly predicted performance of tobacco control behaviors. Conclusion Findings suggest thatraining programs on tobacco use and dependence treatment in the pediatric dental setting may be needed to promote tobacco control behaviors for adolescent patients.

BACKGROUND: Little is known about general and family practitioners' (GP/FPs') involvement and confidence in dealing with children with common psychosocial problems and mental health conditions. The aims of this study were to ascertain GP/FPs' preferred level of involvement with, and perceived comfort and skill in dealing with children with behavioral problems, social-emotional difficulties, attention-deficit/hyperactivity disorder (ADHD), and mood disorders; and to identify factors associated with GP/FPs' involvement, comfort and skill. METHODS: Postal survey of a representative sample of 801 GP/FPs in British Columbia, Canada, which enquired about level of involvement (from primarily refer out to deal with case oneself); ratings of comfort/skill with assessment/diagnosis and management; beliefs regarding psychosocial problems in children; basic demographics; and practice information. RESULTS: Surveys were completed by 405 of 629 eligible GP/FPs (64.4%). Over 80% of respondents reported collaborative arrangements with specialists across problem and condition types, although for children with behavior problems or ADHD, more physicians primarily refer (chi2 (1) = 9.0; P < 0.005; and chi2 (1) = 103.9; P < 0.001, respectively). Comfort/skill levels (mean +/- s.d) were higher for mood disorders (4.4 +/- 1.3) than behavior problems (3.6 +/- 1.1; F [3, 1155] = 84.0, P < .0001; effect size = 0.67), but not different from social-emotional difficulties (3.8 +/- 1.1) or ADHD (3.9 +/- 1.3). Taking primary responsibility for a case was consistently related to self-reported comfort/skill with each condition type (34% to 61% of variance across condition types), while comfort/skill ratings for each condition were related to exposure to relevant continuing medical education (all P < or = 0.001), and beliefs that these problems are significant and that GP/FPs have a role to play in dealing with them (P values ranged from 0.01 to < 0.001). CONCLUSION: Supporting GP/FPs in their care for children with common psychosocial and mental health problems should include efforts to bolster their confidence and modify attitudes in relation towards these problems, especially behavior problems and ADHD, possibly within innovative continuing education programs. [ABSTRACT FROM AUTHOR]

Alcohol is a known teratogen and prenatal alcohol exposure remains a major ongoing public health concern. Fetal alcohol spectrum disorder has become the diagnosis for describing individuals who have been affected by prenatal alcohol exposure. In this Viewpoint, we raise major concerns about its continued use as a diagnostic term in how it perpetuates a misleading and outdated narrative about child development and maternal health. We argue that the term fetal alcohol spectrum disorder has contributed to a culture of racism and discrimination for many who are diagnosed with it. The term fetal alcohol spectrum disorder fails to capture the progress made in our collective understanding of neurodevelopment through advancements in the field of genetics and in understanding the effects of trauma and adversity. We call for urgent international collaborative action to review the use of it as a diagnostic term and, more broadly, to reconsider the practice of diagnosing disabilities as medical illnesses. We suggest that this practice fails to recognise that outcomes of functioning and participation in individuals are not only the results of health conditions, but are also the products of complex interactions and experiences of individuals within the families and societies in which they live., Competing Interests: Declaration of interests ARM has a service contract with the Provincial Health Services Authority of British Columbia to attend conferences and receives support from Sunny Hill Foundation for academic activities. WBG has a contract with Elsevier to edit a book and write a chapter regarding the harms of assessment and diagnosis for neurodevelopmental disorders. He received payment for this work. All other authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

Background: A significant factor for the high prevalence of traumatic brain injury (TBI) among U.S. service members is their exposure to explosive munitions leading to blast-related TBI. Our understanding of the specific clinical effects of mild TBI having a component of blast mechanism remains limited compared to pure blunt mechanisms., Objective: The purpose of this review is to provide a synopsis of clinical research findings on the long-term effects of blast-related mild TBI derived to date from the Long-Term Impact of Military-Relevant Brain Injury Consortium - Chronic Effects of Neurotrauma Consortium (LIMBIC-CENC)., Methods: Publications on blast-related mild TBI from LIMBIC-CENC and the LIMBIC-CENC prospective longitudinal study (PLS) cohort were reviewed and their findings summarized. Findings from the broader literature on blast-related mild TBI that evaluate similar outcomes are additionally reviewed for a perspective on the state of the literature., Results: The most consistent and compelling evidence for long-term effects of blast-related TBI is for poorer psychological health, greater healthcare utilization and disability levels, neuroimaging impacts on brain structure and function, and greater headache impact on daily life. To date, evidence for chronic cognitive performance deficits from blast-related mild TBI is limited, but futher research including crucial longitudinal data is needed., Conclusion: Commentary is provided on: how LIMBIC-CENC findings assimilate with the broader literature; ongoing research gaps alongside future research needs and priorities; how the scientific community can utilize the LIMBIC-CENC database for independent or collaborative research; and how the evidence from the clinical research should be assimilated into clinical practice.

Background: Use of immune checkpoint inhibitors is growing, but clinical trial data may not apply to Indigenous patients or patients living in remote areas., Aims: To provide real-world incidence of immune-related adverse events (irAE) in the Top End of the Northern Territory and compare incidence between demographic subgroups., Methods: This retrospective, observational, cohort study collected data from electronic records of patients living in the Top End with solid organ cancer treated with immunotherapy between January 2016 and December 2021. The primary outcome was cumulative incidence of any-grade and severe irAE. Secondary outcomes were overall survival, treatment duration and reason for treatment discontinuation., Results: Two hundred and twenty-six patients received immunotherapy. Forty-eight (21%) lived in a remote or very remote area, and 36 (16%) were Indigenous. Cumulative incidence of any-grade irAE was 54% (122/226 patients); incidence of severe irAE was 26% (59/226 patients). Rates were similar between Indigenous and non-Indigenous patients of any-grade (42% vs 56%, P = 0.11) and severe (11% vs 18%, P = 0.29) irAE. However, Indigenous patients had shorter treatment duration, more frequently discontinued treatment due to patient preference and appeared to have shorter median overall survival than non-Indigenous patients (17.1 vs 30.4 months; hazard ratio (HR) = 1.5, 95% confidence interval (CI) = 0.92-2.66). There was no difference in mortality between remote and urban patients (median overall survival 27.5 vs 30.2 months; HR = 1.1, 95% CI = 0.7-1.7)., Conclusions: Rates of irAE in our cohort are comparable to those in the published literature. There was no significant difference in any-grade or severe irAE incidence observed between Indigenous and non-Indigenous patients., (© 2024 The Author(s). Internal Medicine Journal published by John Wiley & Sons Australia, Ltd on behalf of Royal Australasian College of Physicians.)

In a previous study, we observed decreased 1,25-dihydroxyvitamin D levels, secondary hyperparathyroidism, and increased bone turnover markers in living kidney donors (LKDs) at 3 months and 36 months after kidney donation. In our recent survey-based study, we found no increased risk of fractures of all types but observed significantly more vertebral fractures in LKDs compared with matched controls. To elucidate the long-term effects of kidney donation on bone health, we recruited 139 LKDs and 139 age and sex matched controls from the survey-based participants for further mechanistic analyses. Specifically, we assessed whether LKDs had persistent abnormalities in calcium- and phosphorus-regulating hormones and related factors, in bone formation and resorption markers, and in density and microstructure of bone compared with controls. We measured serum markers, bone mineral density (BMD), bone microstructure and strength (via high-resolution peripheral quantitative computed tomography and micro-finite element analysis [HRpQCT]), and advanced glycation end-products in donors and controls. LKDs had decreased 1,25-dihydroxyvitamin D concentrations (donors mean 33.89 pg/mL vs. controls 38.79 pg/mL, percent difference = -12.6%; P  < .001), increases in both parathyroid hormone (when corrected for ionized calcium; donors mean 52.98 pg/mL vs. controls 46.89 pg/mL,% difference 13%; P  = .03) and ionized calcium levels (donors mean 5.13 mg/dL vs. controls 5.04 mg/dL; P  < .001), and increases in several bone resorption and formation markers versus controls. LKDs and controls had similar measures of BMD; however, HRpQCT suggested that LKDs have a statistically insignificant tendency toward thinner cortical bone and lower failure loads as measured by micro-finite element analysis. Our findings suggest that changes in the hormonal mileu after kidney donation and the long-term cumulative effects of these changes on bone health persist for decades after kidney donation and may explain later-life increased rates of vertebral fractures., Competing Interests: R.K. reported receiving grants from Mayo Clinic Rochester during the conduct of the study and nonfinancial support from Bridge Bio outside the submitted work. No other disclosures were reported. The current clinical investigation is an original full-length submission., (© The Author(s) 2024. Published by Oxford University Press on behalf of the American Society for Bone and Mineral Research.)

Objective: Automated surgical step recognition (SSR) using AI has been a catalyst in the "digitization" of surgery. However, progress has been limited to laparoscopy, with relatively few SSR tools in endoscopic surgery. This study aimed to create a SSR model for transurethral resection of bladder tumors (TURBT), leveraging a novel application of transfer learning to reduce video dataset requirements., Materials and Methods: Retrospective surgical videos of TURBT were manually annotated with the following steps of surgery: primary endoscopic evaluation, resection of bladder tumor, and surface coagulation. Manually annotated videos were then utilized to train a novel AI computer vision algorithm to perform automated video annotation of TURBT surgical video, utilizing a transfer-learning technique to pre-train on laparoscopic procedures. Accuracy of AI SSR was determined by comparison to human annotations as the reference standard., Results: A total of 300 full-length TURBT videos (median 23.96 min; IQR 14.13-41.31 min) were manually annotated with sequential steps of surgery. One hundred and seventy-nine videos served as a training dataset for algorithm development, 44 for internal validation, and 77 as a separate test cohort for evaluating algorithm accuracy. Overall accuracy of AI video analysis was 89.6%. Model accuracy was highest for the primary endoscopic evaluation step (98.2%) and lowest for the surface coagulation step (82.7%)., Conclusion: We developed a fully automated computer vision algorithm for high-accuracy annotation of TURBT surgical videos. This represents the first application of transfer-learning from laparoscopy-based computer vision models into surgical endoscopy, demonstrating the promise of this approach in adapting to new procedure types., Competing Interests: AA, MZ, OB, TW, and DA were employed by Theator Inc. The remaining 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 Deol, Tollefson, Antolin, Zohar, Bar, Ben-Ayoun, Mynderse, Lomas, Avant, Miller, Elliott, Boorjian, Wolf, Asselmann and Khanna.)

Purpose: This article summarizes emerging nontraditional therapies administered via the nebulization route for use in the emergency department (ED)., Summary: Although traditional routes of medication administration (eg, intravenous) have been the mainstay of administration modalities for decades, these routes may not be appropriate for all patients. Nowhere is this more readily apparent than in the ED setting, where patients with a variety of presentations receive care. One unique route for medication administration that has increasingly gained popularity in the ED is that of aerosolized drug delivery. This route holds promise as direct delivery of medications to the site of action could yield a more rapid and effective therapeutic response while also minimizing systemic adverse effects by utilizing a fraction of the systemic dose. Medication administration via nebulization also provides an alternative that is conducive to rapid, less invasive access, which is advantageous in the emergent setting of the ED. This review is intended to analyze the existing literature regarding this route of administration, including the nuances that can impact drug efficacy, as well as the available literature regarding novel, noncommercial nebulized medication therapy given in the ED., Conclusion: Multiple medications have been investigated for administration via this route, and when implementing any of these therapies several practical considerations must be taken into account, from medication preparation to administration, to ensure optimal efficacy while minimizing adverse effects. The pharmacist is an essential bedside team member in these scenarios to assist with navigating unique and complex nuances of this therapy as they develop., (© American Society of Health-System Pharmacists 2023. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Cancers exhibit complex transcriptomes with aberrant splicing that induces isoform-level differential expression compared to non-diseased tissues. Transcriptomic profiling using short-read sequencing has utility in providing a cost-effective approach for evaluating isoform expression, although short-read assembly displays limitations in the accurate inference of full-length transcripts. Long-read RNA sequencing (Iso-Seq), using the Pacific Biosciences (PacBio) platform, can overcome such limitations by providing full-length isoform sequence resolution which requires no read assembly and represents native expressed transcripts. A constraint of the Iso-Seq protocol is due to fewer reads output per instrument run, which, as an example, can consequently affect the detection of lowly expressed transcripts. To address these deficiencies, we developed a concatenation workflow, PacBio Full-Length Isoform Concatemer Sequencing (PB&#95;FLIC-Seq), designed to increase the number of unique, sequenced PacBio long-reads thereby improving overall detection of unique isoforms. In addition, we anticipate that the increase in read depth will help improve the detection of moderate to low-level expressed isoforms., Results: In sequencing a commercial reference (Spike-In RNA Variants; SIRV) with known isoform complexity we demonstrated a 3.4-fold increase in read output per run and improved SIRV recall when using the PB&#95;FLIC-Seq method compared to the same samples processed with the Iso-Seq protocol. We applied this protocol to a translational cancer case, also demonstrating the utility of the PB&#95;FLIC-Seq method for identifying differential full-length isoform expression in a pediatric diffuse midline glioma compared to its adjacent non-malignant tissue. Our data analysis revealed increased expression of extracellular matrix (ECM) genes within the tumor sample, including an isoform of the Secreted Protein Acidic and Cysteine Rich (SPARC) gene that was expressed 11,676-fold higher than in the adjacent non-malignant tissue. Finally, by using the PB&#95;FLIC-Seq method, we detected several cancer-specific novel isoforms., Conclusion: This work describes a concatenation-based methodology for increasing the number of sequenced full-length isoform reads on the PacBio platform, yielding improved discovery of expressed isoforms. We applied this workflow to profile the transcriptome of a pediatric diffuse midline glioma and adjacent non-malignant tissue. Our findings of cancer-specific novel isoform expression further highlight the importance of long-read sequencing for characterization of complex tumor transcriptomes., (© 2024. The Author(s).)

Importance: Living kidney donors may have an increased risk of fractures due to reductions in kidney mass, lower concentrations of serum 1,25-dihydroxyvitamin D, and secondary increases in serum parathyroid hormone., Objective: To compare the overall and site-specific risk of fractures among living kidney donors with strictly matched controls from the general population who would have been eligible to donate a kidney but did not do so., Design, Setting, and Participants: This survey study was conducted between December 1, 2021, and July 31, 2023. A total of 5065 living kidney donors from 3 large transplant centers in Minnesota were invited to complete a survey about their bone health and history of fractures, and 16 156 population-based nondonor controls without a history of comorbidities that would have precluded kidney donation were identified from the Rochester Epidemiology Project and completed the same survey. A total of 2132 living kidney donors and 2014 nondonor controls responded to the survey. Statistical analyses were performed from May to August 2023., Exposure: Living kidney donation., Main Outcomes and Measures: The rates of overall and site-specific fractures were compared between living kidney donors and controls using standardized incidence ratios (SIRs)., Results: At the time of survey, the 2132 living kidney donors had a mean (SD) age of 67.1 (8.9) years and included 1245 women (58.4%), and the 2014 controls had a mean (SD) age of 68.6 (7.9) years and included 1140 women (56.6%). The mean (SD) time between donation or index date and survey date was 24.2 (10.4) years for donors and 27.6 (10.7) years for controls. The overall rate of fractures among living kidney donors was significantly lower than among controls (SIR, 0.89; 95% CI, 0.81-0.97). However, there were significantly more vertebral fractures among living kidney donors than among controls (SIR, 1.42; 95% CI, 1.05-1.83)., Conclusions and Relevance: This survey study found a reduced rate of overall fractures but an excess of vertebral fractures among living kidney donors compared with controls after a mean follow-up of 25 years. Treatment of excess vertebral fractures with dietary supplements such as vitamin D3 may reduce the numbers of vertebral fractures and patient morbidity.

Retinoblastoma is an ocular cancer associated with genomic variation in the RB1 gene. In individuals with bilateral retinoblastoma, a germline variant in RB1 is identified in virtually all cases. We describe herein an individual with bilateral retinoblastoma for whom multiple clinical lab assays performed by outside commercial laboratories failed to identify a germline RB1 variant. Paired tumor/normal exome sequencing, long-read whole genome sequencing, and long-read isoform sequencing was performed on a translational research basis ultimately identified a germline likely de novo Long Interspersed Nuclear Element (LINE)-1 mediated deletion resulting in a premature stop of translation of RB1 as the underlying genetic cause of retinoblastoma in this individual. Based on these research findings, the LINE-1 mediated deletion was confirmed via Sanger sequencing in our clinical laboratory, and results were reported in the patient's medical record to allow for appropriate genetic counseling., Competing Interests: None declared., (© The Author(s) 2023. Published by Oxford University Press, the Society for Neuro-Oncology and the European Association of Neuro-Oncology.)

Somatic mosaicism is a known cause of neurological disorders, including developmental brain malformations and epilepsy. Brain mosaicism is traditionally attributed to post-zygotic genetic alterations arising in fetal development. Here we describe post-zygotic rescue of meiotic errors as an alternate origin of brain mosaicism in patients with focal epilepsy who have mosaic chromosome 1q copy number gains. Genomic analysis showed evidence of an extra parentally derived chromosome 1q allele in the resected brain tissue from five of six patients. This copy number gain is observed only in patient brain tissue, but not in blood or buccal cells, and is strongly enriched in astrocytes. Astrocytes carrying chromosome 1q gains exhibit distinct gene expression signatures and hyaline inclusions, supporting a novel genetic association for astrocytic inclusions in epilepsy. Further, these data demonstrate an alternate mechanism of brain chromosomal mosaicism, with parentally derived copy number gain isolated to brain, reflecting rescue in other tissues during development., (© 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Introduction: Advancements in vascularized composite allotransplantation have made hand transplants possible for persons living with upper limb loss. Hand transplantation is not a life-saving procedure, but rather a quality-of-life enhancing procedure; hence the risk of morbidity and mortality must be weighed against improvements in function and appearance. This study explored the decision-making process of patients evaluated for hand transplantation., Methods/approach: A qualitative case series study using retrospective chart data of evaluations was conducted between January 1, 2011 and February 28, 2020. Notes were extracted and read by three reviewers. Each case was summarized noting similarities and differences., Findings: Nine patients underwent evaluation. Eight were no longer under evaluation and did not receive transplant; one was still undergoing evaluation. Patient motivations for evaluation were dissatisfaction with prostheses or self-image, chronic pain, performing activities of daily living, occupation, burden placed on caregivers, and concerns about overuse of non-affected limbs. Patients chose not to pursue transplantation due to rehabilitation time, immunosuppression, alternative treatments, and social and financial challenges. The clinical team discontinued evaluations due to unmet evaluation requirements, medical contraindications, or treatment alternatives. Different modes of shared decision-making were present depending on the party most heavily featured in the charts as driving decisions., Discussion: This was an examination of shared decision-making with hand transplant candidates who did not proceed to transplant. Reasons for choosing alternative strategies for management were multifactorial. Lessons learned regarding patient motivations and shared decision-making can inform future interventions to better support patients.

Background: To bring evidence-based interventions (EBIs) to individuals with behavioral health needs, psychosocial interventions must be delivered at scale. Despite an increasing effort to implement effective treatments in communities, most individuals with mental health and behavioral problems do not receive EBIs. We posit that organizations that commercialize EBIs play an important role in disseminating EBIs, particularly in the USA. The behavioral health and implementation industry is growing, bringing the implementation field to an important inflection point: how to scale interventions to improve access while maintaining EBI effectiveness and minimizing inequities in access to psychosocial intervention., Main Body: We offer a first-hand examination of five illustrative organizations specializing in EBI implementation: Beck Institute for Cognitive Behavioral Therapy; Incredible Years, Inc.; the PAXIS Institute; PracticeWise, LLC; and Triple P International. We use the Five Stages of Small Business Growth framework to organize themes. We discuss practical structures (e.g., corporate structures, intellectual property agreements, and business models) and considerations that arise when trying to scale EBIs including balancing fidelity and reach of the intervention. Business models consider who will pay for EBI implementation and allow organizations to scale EBIs., Conclusion: We propose research questions to guide scaling: understanding the level of fidelity needed to maintain efficacy, optimizing training outcomes, and researching business models to enable organizations to scale EBIs., (© 2023. The Author(s).)

Research on the associations between the built environment and COVID-19 outcomes has mostly focused on incidence and mortality. Also, few studies on the built environment and COVID-19 have controlled for individual-level characteristics across large samples. In this study, we examine whether neighborhood built environment characteristics are associated with hospitalization in a cohort of 18,042 individuals who tested positive for SARS-CoV-2 between May and December 2020 in the Denver metropolitan area, USA. We use Poisson models with robust standard errors that control for spatial dependence and several individual-level demographic characteristics and comorbidity conditions. In multivariate models, we find that among individuals with SARS-CoV-2 infection, those living in multi-family housing units and/or in places with higher particulate matter (PM2.5) have a higher incident rate ratio (IRR) of hospitalization. We also find that higher walkability, higher bikeability, and lower public transit access are linked to a lower IRR of hospitalization. In multivariate models, we did not find associations between green space measures and the IRR of hospitalization. Results for non-Hispanic white and Latinx individuals highlight substantial differences: higher PM2.5 levels have stronger positive associations with the IRR of hospitalization for Latinx individuals, and density and overcrowding show stronger associations for non-Hispanic white individuals. Our results show that the neighborhood built environment might pose an independent risk for COVID-19 hospitalization. Our results may inform public health and urban planning initiatives to lower the risk of hospitalization linked to COVID-19 and other respiratory pathogens., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Rigolon 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.)

An accurate understanding of boar temperature preferences may allow the swine industry to design and utilize environmental control systems in boar facilities more precisely. Therefore, the study objective was to determine the temperature preferences of sexually mature Duroc, Landrace, and Yorkshire boars. Eighteen, 8.57 ± 0.10-mo-old boars ( N = 6 Duroc, 6 Landrace, and 6 Yorkshire; 186.25 ± 2.25 kg) were individually tested in thermal apparatuses (12.20 m × 1.52 m × 1.86 m) that allowed free choice of their preferred temperature within a 8.92 to 27.92 ºC range. For analyses, the apparatuses were divided into five thermal zones (3.71 m 2 /thermal zone) with temperature recorded 1.17 m above the floor in the middle of each zone. Target temperatures for thermal zones 1 to 5 were 10, 15, 20, 25, and 30 ºC, respectively. All boars were given a 24-h acclimation phase followed by a 24-h testing phase within the thermal apparatuses. Daily feed allotments (3.63 kg/d) were provided to each boar and all boars were allowed to consume all feed prior to entering the thermal apparatus. Water was provided ad libitum within the thermal apparatuses with 1 waterer per thermal zone. During testing, boars were video recorded continuously to evaluate behavior (inactive, active, or other), posture (lying, standing, or other), and thermal zone the boar occupied. All parameters were recorded in 15 min intervals using instantaneous scan sampling. Data were analyzed using GLM in JMP 15. For the analyses, only time spent lying or inactive were used because they were observed most frequently (lying 80.02%, inactive 77.64%) and were deemed to be associated with comfort based on previous research. Percent time spent active (19.73%) or standing (15.87%) were associated with latrine or drinking activity and were too low to accurately analyze as an indicator of thermal preference. Breed did not affect temperature preference ( P > 0.05). A cubic regression model determined that boars spent the majority of their time inactive at 25.50 ºC ( P < 0.01) and lying (both sternal and lateral) at 25.90 ºC ( P < 0.01). These data suggest that boar thermal preferences did not differ by breed and that boars prefer temperatures at the upper end of current guidelines (10.00 to 25.00 ºC)., (Published by Oxford University Press for the American Society of Animal Science 2023.)

Domesticated yaks endure as iconic symbols of high-altitude frozen landscapes, where herding communities depend on their high-fat milk, transport, dung, and natural fibers. While there is established proteomic evidence for ancient consumption of ruminant and horse milk in the mountains and steppes of northern Eurasia, yak dairy products have yet to be detected. Yak domestication and the species' dispersal from Tibet into the mountainous zones to the north are also poorly resolved due to a paucity of zooarchaeological data. To examine the potential of paleoproteomics to shed light on domesticated yak in Mongolia, we analyzed human dental calculus from Mongol era elite individuals recovered from permafrost burials in Khovsgol province, where people continue to herd yak to this day. We report the first evidence for yak dairy consumption, linked to local resource control. In addition, we confirm a large diversity of recovered whey, curd, tissue, and blood proteins, likely reflecting the excellent preservation conditions found at permafrost sites., (© 2023. The Author(s).)

The nanomachine from the ATPases associated with various cellular activities superfamily, called spastin, severs microtubules during cellular processes. To characterize the functionally important allostery in spastin, we employed methods from evolutionary information, to graph-based networks, to machine learning applied to atomistic molecular dynamics simulations of spastin in its monomeric and the functional hexameric forms, in the presence or absence of ligands. Feature selection, using machine learning approaches, for transitions between spastin states recognizes all the regions that have been proposed as allosteric or functional in the literature. The analysis of the composition of the Markov State Model macrostates in the spastin monomer, and the analysis of the direction of change in the top machine learning features for the transitions, indicate that the monomer favors the binding of ATP, which primes the regions involved in the formation of the inter-protomer interfaces for binding to other protomer(s). Allosteric path analysis of graph networks, built based on the cross-correlations between residues in simulations, shows that perturbations to a hub specific for the pre-hydrolysis hexamer propagate throughout the structure by passing through two obligatory regions: the ATP binding pocket, and pore loop 3, which connects the substrate binding site to the ATP binding site. Our findings support a model where the changes in the terminal protomers due to the binding of ligands play an active role in the force generation in spastin. The secondary structures in spastin, which are found to be highly degenerative within the network paths, are also critical for feature transitions of the classification models, which can guide the design of allosteric effectors to enhance or block allosteric signaling.

Background: Although thermal indices have been proposed for swine, none to our knowledge differentiate by reproductive stage or predict thermal comfort using behavioral and physiological data. The study objective was to develop a behavior and physiology-based decision support tool to predict thermal comfort and stress in multiparous (3.28 ± 0.81) non-pregnant (n = 11), mid-gestation (n = 13), and late-gestation (n = 12) sows., Results: Regression analyses were performed using PROC MIXED in SAS 9.4 to determine the optimal environmental indicator [dry bulb temperature (T DB ) and dew point] of heat stress (HS) in non-pregnant, mid-gestation, and late-gestation sows with respiration rate (RR) and body temperature (T B ) successively used as the dependent variable in a cubic function. A linear relationship was observed for skin temperature (T S ) indicating that T DB rather than the sow HS response impacted T S and so T S was excluded from further analyses. Reproductive stage was significant for all analyses (P < 0.05). Heat stress thresholds for each reproductive stage were calculated using the inflections points of RR for mild HS and T B for moderate and severe HS. Mild HS inflection points differed for non-pregnant, mid-gestation, and late gestation sows and occurred at 25.5, 25.1, and 24.0 °C, respectively. Moderate HS inflection points differed for non-pregnant, mid-gestation, and late gestation sows and occurred at 28.1, 27.8, and 25.5 °C, respectively. Severe HS inflection points were similar for non-pregnant and mid-gestation sows (32.9 °C) but differed for late-gestation sows (30.8 °C). These data were integrated with previously collected behavioral thermal preference data to estimate the T DB that non-pregnant, mid-gestation, and late-gestation sows found to be cool (T DB  < T DB preference range), comfortable (T DB  = T DB preference range), and warm (T DB preference range < T DB  < mild HS)., Conclusions: The results of this study provide valuable information about thermal comfort and thermal stress thresholds in sows at three reproductive stages. The development of a behavior and physiology-based decision support tool to predict thermal comfort and stress in non-pregnant, mid-gestation, and late-gestation sows is expected to provide swine producers with a more accurate means of managing sow environments., (© 2022. The Author(s).)

Genomic profiling using short-read sequencing has utility in detecting disease-associated variation in both DNA and RNA. However, given the frequent occurrence of structural variation in cancer, molecular profiling using long-read sequencing improves the resolution of such events. For example, the Pacific Biosciences long-read RNA-sequencing (Iso-Seq) transcriptome protocol provides full-length isoform characterization, discernment of allelic phasing, and isoform discovery, and identifies expressed fusion partners. The Pacific Biosciences Fusion and Long Isoform Pipeline (PB&#95;FLIP) incorporates a suite of RNA-sequencing software analysis tools and scripts to identify expressed fusion partners and isoforms. In addition, sequencing of a commercial reference (Spike-In RNA Variants) with known isoform complexity was performed and demonstrated high recall of the Iso-Seq and PB&#95;FLIP workflow to benchmark our protocol and analysis performance. This study describes the utility of Iso-Seq and PB&#95;FLIP analysis in improving deconvolution of complex structural variants and isoform detection within an institutional pediatric and adolescent/young adult translational cancer research cohort. The exemplar case studies demonstrate that Iso-Seq and PB&#95;FLIP discover novel expressed fusion partners, resolve complex intragenic alterations, and discriminate between allele-specific expression profiles., (Copyright © 2022 Association for Molecular Pathology and American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

Importance: The rapid proliferation of COVID-19 has left governments scrambling, and several data aggregators are now assisting in the reporting of county cases and deaths. The different variables affecting reporting (e.g., time delays in reporting) necessitates a well-documented reliability study examining the data methods and discussion of possible causes of differences between aggregators., Objective: To statistically evaluate the reliability of COVID-19 data across aggregators using case fatality rate (CFR) estimates and reliability statistics., Design, Setting, and Participants: Cases and deaths were collected daily by volunteers via state and local health departments, as primary sources and newspaper reports, as secondary sources. In an effort to begin comparison for reliability statistical analysis, BroadStreet collected data from other COVID-19 aggregator sources, including USAFacts, Johns Hopkins University, New York Times, The COVID Tracking Project., Main Outcomes and Measures: COVID-19 cases and death counts at the county and state levels., Results: Lower levels of inter-rater agreement were observed across aggregators associated with the number of deaths, which manifested itself in state level Bayesian estimates of COVID-19 fatality rates., Conclusions and Relevance: A national, publicly available data set is needed for current and future disease outbreaks and improved reliability in reporting., Competing Interests: The specific roles of these authors are articulated in the ‘author contributions’ section. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Introduction: LUN17-139 evaluated the safety and efficacy of Atezolizumab (A) plus Carboplatin (C) plus Pemetrexed (Pem) plus Bevacizumab (B) (ACBPem) in treatment naïve patients with stage IV non-squamous non-small cell lung cancer (Ns-NSCLC)., Patients and Methods: In this multicenter, single-arm phase II trial, all patients received A (1200-mg, D1) + C (AUC 5, D1) + Pem (500-mg/m2, D1) + B (15-mg/kg D1) q3 week x4. If no PD (progressive disease), patients received maintenance ABPem until PD or intolerable side effects. The primary endpoint was progression-free survival (PFS). The positive PFS result was considered as PFS>6m (historical control). Secondary endpoints included objective response rate (ORR), disease control rate (DCR) defined by complete response (CR) + partial response (PR) + stable disease (SD) ≥ 2 months, overall survival (OS), and safety., Results: Thirty patients were enrolled from November 2018 to October 2020. The study was closed early due to 3 patient deaths, possibly related to treatment. Median age 64 (range 38-83); Men/Women 20/10; PD-L1 TPS < 1%/1-49%/ ≥ 50% (8/15/7). The median follow-up was 20.3 months ( 1-28.1). ORR 42.9% (95% CI, 24.5-62.8%), DCR 96.4% (95% CI, 81.7-99.9%). The median PFS and OS were 11.3m (5.5-14.9,P > .05) and 22.4m (22.4-NR), respectively. Four patients had G4 toxicity (anemia, febrile-neutropenia, severe neutropenia, sepsis), and 3 patients had G5 toxicity (thromboembolism, sepsis, colonic perforation)., Conclusion: ABCPem was associated with increased PFS compared to historical controls but this difference did not meet the statistical significance. Three on-treatment deaths and 5 thromboembolic events prompted early closure., 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 © 2022. Published by Elsevier Inc.)

Objective: To assess in-vivo cross-sectional and 3D morphology of human motor units in hand, forearm and lower leg muscles using magnetic resonance imaging (MRI)., Methods: Diffusion weighted MRI was used with in-scanner electrical stimulation in healthy controls to image motor units at a single slice in lower leg, forearm and hand muscles (n = 6) and multiple slices in the lower leg for 3D assessment (n = 7)., Results: Motor unit cross-sectional area (CSA) and maximum Feret diameter (FD max ) did not differ between the lower leg (CSA: 22.4 ± 8.4 mm 2 ; FD max : 8.7 ± 2.4 mm), forearm (CSA: 23.6 ± 14.1 mm 2 ; FD max : 9.0 ± 3.3 mm) and hand (CSA: 26.8 ± 12.8 mm 2 and FD max : 9.6 ± 2.7 mm) (ANOVA; p = 0.487 and p = 0.587, respectively). Lower leg motor units were 8.0 ± 3.8 cm long with largest CSA in the motor unit's middle section. 3D motor unit imaging revealed a complex structure with several units splitting and re-forming along their length., Conclusions: Motor unit MRI (MUMRI) can be applied to upper limb muscles, and can reveal the 3D structure of human motor units in-vivo., Significance: MUMRI provides the first in-vivo 2D images of upper limb motor units and 3D images of lower leg motor units. 3D imaging suggest a more complex human motor unit structure than previously thought., 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 © 2022 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved.)

We empirically investigate the impact of COVID-19 shutdowns on domestic violence using incident-level data on both domestic-related calls for service and crime reports of domestic violence assaults from the 18 major US police departments for which both types of records are available. Although we confirm prior reports of an increase in domestic calls for service at the start of the pandemic, we find that the increase preceded mandatory shutdowns, and there was an incremental decline following the government imposition of restrictions. We also find no evidence that domestic violence crimes increased. Rather, police reports of domestic violence assaults declined significantly during the initial shutdown period. There was no significant change in intimate partner homicides during shutdown months and victimization survey reports of intimate partner violence were lower. Our results fail to support claims that shutdowns increased domestic violence and suggest caution before drawing inference or basing policy solely on data from calls to police., (© 2022 Published by Elsevier Inc.)