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Unfortunately, only 47.2% of children and young people in the UK are currently meeting the chief medical officer's physical activity guidelines of 60 minutes daily, with 30.1% of children doing less than 30 minutes daily. Reduced physical activity in children is a significant contributor to childhood obesity, a growing paediatric pandemic with 1-in-3 children overweight or obese by the time they leave primary school. The long-term health implications of this and the additional burden on health services are already widely apparent. It is important for GPs and primary care staff to understand the current UK recommendations and evidence on childhood physical activity to empower their support of early engagement of children with measures to improve levels of physical activity. An understanding of childhood obesity is also important. At the other end of the spectrum elite children's sport is becoming increasingly competitive and injuries in developing children can lead to lifelong complications and injury recurrence. It is, therefore, important to understand how much and what types of exercise and training are safe in the paediatric population. [ABSTRACT FROM AUTHOR]

Finally, Schwartz Rounds can assist in improving staff wellbeing and organizational culture in hospitals in the context of COVID-19 related repercussions. Schwartz rounds - An organizational intervention to overcome burnout in hospitals Dear Sir, Staff working in health care environments experience higher rates of work-related stress, burnout, anxiety, depression, and suicidal ideation compared to the general public. [Extracted from the article]

The study of nontraditional model organisms, particularly those exhibiting extreme phenotypes, offers unique insights into adaptive mechanisms of stress response and survival. Snakes, with their remarkable physiological, metabolic, and morphological adaptations, serve as powerful models for investigating these processes. Pythons are a unique model organism that have been studied for their extreme metabolic and physiological plasticity. To date, the Burmese python ( Python bivittatus ) is the only member of the Pythonidae family to have been sequenced. The low contiguity of this genome and rising challenges in obtaining Burmese pythons for study prompted us to sequence, assemble, and annotate the genome of the closely related ball python ( Python regius ). Using a hybrid sequencing approach, we generated a 1.45 Gb genome assembly with a contig N50 greater than 18 Mb and a BUSCO score of 98%, representing the highest quality genome to date for a member of the Pythonidae family. This assembly provides a valuable resource for studying snake-specific traits and evolutionary biology. Furthermore, it enables exploration of the molecular mechanisms underlying the remarkable cardiac and muscular adaptations in pythons, such as their ability to rapidly remodel organs following feeding and resist muscular atrophy during prolonged fasting. These insights have potential applications in human health, particularly in the development of therapies targeting cardiac hypertrophy and muscular atrophy., Competing Interests: Conflict of Interest L.A.L. is a Co-Founder of MyoKardia, acquired by Bristol Myers Squibb. MyoKardia and Bristol Myers Squibb were not involved in this study. The other authors have no competing interests to disclose.

Background and Objective: Cyclin-dependent kinase (CDK)4/6 inhibitors in combination with endocrine therapy (ET) significantly enhance progression-free survival and overall survival in patients diagnosed with HR+/HER2- metastatic breast cancer (MBC). However, they are highly expensive, and their economic impact has not been fully evaluated. This is a retrospective secondary analysis evaluating the cost effectiveness of these drugs, differentiating between medication-related and non-medication costs from a healthcare perspective., Methods: We identified 3879 patients diagnosed with MBC who received either CDK4/6i+ET (N = 2137) or ET alone (N = 1742) as first-line treatment between February 2015 and November 2021 using a USA-wide electronic health record-derived de-identified database. SEER-Medicare claims spending data were used to quantify monthly costs as a supplement to the database. Relevant costs included prescribed medications (ET and/or CDK4/6i) and overall other costs. The effectiveness was measured as progression-free duration in months. The incremental cost effectiveness ratio (ICER) analysis was conducted to examine the cost effectiveness of first-line CDK4/6i as compared with first-line ET alone., Results: For medication costs, CDK4/6i+ET (mean cost: $240,723.7; mean effect: 19.2 months of delayed progression) compared with ET alone (mean cost: $5159.7; mean effect: 16 months without progression) resulted in an ICER of $73,098 per month of delayed progression. For non-medication costs, CDK4/6i+ET (mean cost: $43,656.6) compared with ET alone (mean cost: $66,083.5) resulted in an ICER of - $7178 per month of delayed progression., Conclusion: The cost of treating HR+/HER2- MBC is driven by the cost of CDK4/6i. Using CDK4/6i+ET reduces non-medication costs compared to ET alone, but these savings are offset by high CDK4/6i medication costs. Lowering the market cost of CDK4/6i or targeting those who can benefit the most could improve the cost effectiveness of CDK4/6i from Medicare perspective., Competing Interests: Declarations. Funding: This work/study was supported by the American Cancer Society/Flatiron Health, grant number “RWIA-21-123-01-RWIA”. Conflict of interest: GK reports associations with Novartis (Piqray) and Pfizer. All the other authors have no conflict of interest to declare. Ethics approval: All procedures in this study were in accordance with the 1964 Helsinki declaration (and its amendments), and this study is approved by the University of Virginia’s Institutional Review Board (IRB-HSR 23533). Consent to participate: Not applicable. Consent for publication: Not applicable. Availability of data and material: The data used in this study are confidential and cannot be shared. Code availability: Not applicable. Author contributions: A.P. contributed to conceptualization, data analysis, and drafted the first version of the manuscript. W.Y. was involved in conceptualization, manuscript writing, and editing. G.K. contributed to conceptualization, assessed clinical importance, provided consultations, and edited the draft. G.B. handled IRB application, data acquisition, and participated in writing and revising the manuscript. R.A. contributed to conceptualization, secured funding, and provided supervision for the study. All authors read and approved the final manuscript., (© 2025. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Purpose: While previous research has highlighted treatment delay inequities in early-stage breast cancer and identified potential contributing factors, there is limited research on disparities in treatment delays for metastatic breast cancer (MBC). This study investigates these disparities in MBC treatment initiation, aiming to identify key factors crucial for improving timely access to care., Method: Nationwide Flatiron Health electronic health records-derived deidentified database, including females aged 18+ diagnosed with either De novo or relapsed MBC in the U.S. between 2011 and 2022. Treatment delay, defined as > 60 days between diagnosis and first-line treatment, was assessed as a binary variable. T-tests and chi-squared tests analyzed patient characteristics (age, race, insurance, diagnosis stage, metastasis site, phenotypes, etc.) among delayed and non-delayed groups. Logistic regression evaluated the association between clinical and non-clinical factors and treatment delays., Results: Among 20,617 patients with MBC, nearly 27% experienced treatment delays. These patients were generally younger, uninsured, historically marginalized, and newly diagnosed. Risk ratio analysis showed patients with only Medicare without secondary coverage (RR: 2.34, 95% CI [1.06, 5.16]) and uninsured (RR: 2.18, 95% CI [1.01, 4.76]) had higher risk of delays compared to those with commercial insurance. Historically marginalized patients had higher delay risk, ranging from 6% for Black patients to 12% for patients with not documented race/ethnicity background (p = 0.03) compared to White patients.", Conclusion: Our study highlights significant disparities in MBC treatment delays. Patients from historically marginalized groups and those without health insurance coverage or with only Medicare coverage are highly likely to experience delays. Addressing these disparities is essential for equitable healthcare and improved outcomes., Competing Interests: Declarations. Conflict of interest: GK reports associations with Novartis (Piqray) and Pfizer. All the other authors have no conflict of interest to declare. Ethical approval: The study was approved by the institutional review board at UVA., (© 2025. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: We examined the added value of serologic testing for estimating influenza virus infection incidence based on illness surveillance with molecular testing versus periodic serologic testing., Methods: Pregnant persons unvaccinated against influenza at <28 weeks gestation were enrolled before the 2017 and 2018 influenza seasons in Peru and Thailand. Blood specimens were collected at enrollment and ≤14 days postpartum for testing by hemagglutination inhibition assay for antibodies against influenza reference viruses. Seroconversion was defined as a ≥4-fold rise in antibody titers from enrollment to postpartum with the second specimen's titer of ≥40. Throughout pregnancy, participants responded to twice weekly surveillance contacts asking about influenza vaccination and influenza-like symptoms (ILS). A mid-turbinate swab was collected with each ILS episode for influenza real-time reverse transcription polymerase chain reaction (rRT-PCR)., Results: Of 1,466 participants without evidence of influenza vaccination during pregnancy, 296 (20.2%) had evidence of influenza virus infections. Fifteen (5.1%) were detected by rRT-PCR only, 250 (84.4%) by serologic testing only, and 31 (10.5%) by both methods., Conclusions: Influenza virus infections during pregnancy occurred in 20% of cohort participants; >80% were not detected by a broad illness case definition coupled with rRT-PCR., Competing Interests: Declarations 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 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

As ambush-hunting predators that consume large prey after long intervals of fasting, Burmese pythons evolved with unique adaptations for modulating organ structure and function. Among these is cardiac hypertrophy that develops within three days following a meal (Andersen et al., 2005, Secor, 2008), which we previously showed was initiated by circulating growth factors (Riquelme et al., 2011). Postprandial cardiac hypertrophy in pythons also rapidly regresses with subsequent fasting (Secor, 2008); however, the molecular mechanisms that regulate the dynamic cardiac remodeling in pythons during digestion are largely unknown. In this study, we employed a multiomics approach coupled with targeted molecular analyses to examine remodeling of the python ventricular transcriptome and proteome throughout digestion. We found that forkhead box protein O1 (FoxO1) signaling was suppressed prior to hypertrophy development and then activated during regression, which coincided with decreased and then increased expression, respectively, of FoxO1 transcriptional targets involved in proteolysis. To define the molecular mechanistic role of FoxO1 in hypertrophy regression, we used cultured mammalian cardiomyocytes treated with postfed python plasma. Hypertrophy regression both in pythons and in vitro coincided with activation of FoxO1-dependent autophagy; however, the introduction of a FoxO1-specific inhibitor prevented both regression of cell size and autophagy activation. Finally, to determine whether FoxO1 activation could induce regression, we generated an adenovirus expressing a constitutively active FoxO1. FoxO1 activation was sufficient to prevent and reverse postfed plasma-induced hypertrophy, which was partially prevented by autophagy inhibition. Our results indicate that modulation of FoxO1 activity contributes to the dynamic ventricular remodeling in postprandial Burmese pythons., Competing Interests: Competing interests statement:L.A.L. is a Co-Founder of MyoKardia, acquired by Bristol Myers Squibb. MyoKardia and Bristol Myers Squibb were not involved in this study. The other authors have no competing interests to disclose.

Background: While circulating metabolites have been increasingly linked to cancer risk, the causality underlying these associations remains largely uninterrogated., Methods: We conducted a comprehensive 2-sample Mendelian randomization (MR) study to evaluate the potential causal relationship between 913 plasma metabolites and the risk of seven cancers among European-ancestry individuals. Data on variant-metabolite associations were obtained from a genome-wide association study (GWAS) of plasma metabolites among 14,296 subjects. Data on variant-cancer associations were gathered from large-scale GWAS consortia for breast (N = 266,081), colorectal (N = 185,616), lung (N = 85,716), ovarian (N = 63,347), prostate (N = 140,306), renal cell (N = 31,190), and testicular germ cell (N = 28,135) cancers. MR analyses were performed with the inverse variance-weighted (IVW) method as the primary strategy to identify significant associations at Bonferroni-corrected P < 0.05 for each cancer type separately. Significant associations were subjected to additional scrutiny via weighted median MR, Egger regression, MR-Pleiotropy RESidual Sum and Outlier (MR-PRESSO), and reverse MR analyses. Replication analyses were performed using an independent dataset from a plasma metabolite GWAS including 8,129 participants of European ancestry., Results: We identified 94 significant associations, suggesting putative causal associations between 66 distinct plasma metabolites and the risk of seven cancers. Remarkably, 68.2% (45) of these metabolites were each associated with the risk of a specific cancer. Among the 66 metabolites, O-methylcatechol sulfate and 4-vinylphenol sulfate demonstrated the most pronounced positive and negative associations with cancer risk, respectively. Genetically proxied plasma levels of these two metabolites were significantly associated with the risk of lung cancer and renal cell cancer, with an odds ratio and 95% confidence interval of 2.81 (2.33-3.37) and 0.49 (0.40-0.61), respectively. None of these 94 associations was biased by weak instruments, horizontal pleiotropy, or reverse causation. Further, 64 of these 94 were eligible for replication analyses, and 54 (84.4%) showed P < 0.05 with association patterns consistent with those shown in primary analyses., Conclusions: Our study unveils plausible causal relationships between 66 plasma metabolites and cancer risk, expanding our understanding of the role of circulating metabolites in cancer genetics and etiology. These findings hold promise for enhancing cancer risk assessment and prevention strategies, meriting further exploration., (© 2024. The Author(s).)

Background: Cesarean delivery rates have increased globally resulting in a public health concern. We estimate rates of cesarean deliveries among Thai women using the World Health Organization (WHO) Robson Classification system and compare rates by Robson group to the Robson guideline for acceptable rates to identify groups that might benefit most from interventions for rate reduction., Methods: In 2017 and 2018, we established cohorts of pregnant women aged ≥ 18 years seeking prenatal care at two tertiary Thai hospitals and followed them until 6-8 weeks postpartum. Three in-person interviews (enrollment, end of pregnancy, and postpartum) were conducted using structured questionnaires to obtain demographic characteristics, health history, and delivery information. Cesarean delivery indication was classified based on core obstetric variables (parity, previous cesarean delivery, number of fetuses, fetal presentation, gestational week, and onset of labor) assigned to 10 groups according to the Robson Classification. Logistic regression was used to identify factors associated with cesarean delivery among nulliparous women with singleton, cephalic, term pregnancies., Results: Of 2,137 participants, 970 (45%) had cesarean deliveries. The median maternal age at delivery was 29 years (interquartile range, 25-35); 271 (13%) participants had existing medical conditions; and 446 (21%) had pregnancy complications. The cesarean delivery rate varied by Robson group. Multiparous women with > 1 previous uterine scar, with a single cephalic pregnancy, ≥ 37 weeks gestation (group 5) contributed the most (14%) to the overall cesarean rate, whereas those with a single pregnancy with a transverse or oblique lie, including women with previous uterine scars (group 9) contributed the least (< 1%). Factors independently associated with cesarean delivery included age ≥ 25 years, pre-pregnancy obesity, new/worsen medical condition during pregnancy, fetal distress, abnormal labor, infant size for gestational age ≥ 50 th percentiles, and self-pay for delivery fees. Women with existing blood conditions were less likely to have cesarean delivery., Conclusions: Almost one in two pregnancies among women in our cohorts resulted in cesarean deliveries. Compared to WHO guidelines, cesarean delivery rates were elevated in selected Robson groups indicating that tailored interventions to minimize non-clinically indicated cesarean delivery for specific groups of pregnancies may be warranted., (© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

The heart is a highly plastic organ that responds to diverse stimuli to modify form and function. The molecular mechanisms of adaptive physiological cardiac hypertrophy are well-established; however, the regulation of hypertrophy regression is poorly understood. To identify molecular features of regression, we studied Burmese pythons which experience reversible cardiac hypertrophy following large, infrequent meals. Using multi-omics screens followed by targeted analyses, we found forkhead box protein O1 (FoxO1) transcription factor signaling, and downstream autophagy activity, were downregulated during hypertrophy, but re-activated with regression. To determine whether these events were mechanistically related to regression, we established an in vitro platform of cardiomyocyte hypertrophy and regression from treatment with fed python plasma. FoxO1 inhibition prevented regression in this system, while FoxO1 activation reversed fed python plasma-induced hypertrophy in an autophagy-dependent manner. We next examined whether FoxO1 was implicated in mammalian models of reversible hypertrophy from exercise and pregnancy and found that in both cases FoxO1 was activated during regression. In these models, as in pythons, activation of FoxO1 was associated with increased expression FoxO1 target genes involved in autophagy. Taken together, our findings suggest FoxO1-dependent autophagy is a conserved mechanism for regression of physiological cardiac hypertrophy across species., Competing Interests: COMPETING INTERESTS LAL is a Co-Founder of MyoKardia, acquired by Bristol Myers Squibb. MyoKardia and Bristol Myers Squibb were not involved in this study. The other authors have no competing interests to disclose.

Tuberculosis (TB) is a bacterial infection that is well-known in the palaeopathological record because it can affect the skeleton and consequently leaves readily identifiable macroscopic alterations. Palaeopathological case studies provide invaluable information about the spatio-temporal distribution of TB in the past. This is true for those archaeological periods and geographical regions from when and where no or very few TB cases have been published until now-as in the Sarmatian period (1st-5th centuries CE) in the Barbaricum of the Carpathian Basin. The aim of our paper is to discuss five newly discovered TB cases (HK199, HK201, HK225, HK253, and HK309) from the Sarmatian-period archaeological site of Hódmezővásárhely-Kenyere-ér, Bereczki-tanya (Csongrád-Csanád county, Hungary). Detailed macromorphological evaluation of the skeletons focused on the detection of bony changes likely associated with different forms of TB. In all five cases, the presence of endocranial alterations (especially TB-specific granular impressions) suggests that these individuals suffered from TB meningitis. Furthermore, the skeletal lesions observed in the spine and both hip joints of HK225 indicate that this juvenile also had multifocal osteoarticular TB. Thanks to the discovery of HK199, HK201, HK225, HK253, and HK309, the number of TB cases known from the Sarmatian-period Carpathian Basin doubled, implying that the disease was likely more frequent in the Barbaricum than previously thought. Without the application of granular impressions, the diagnosis of TB could not have been established in these five cases. Thus, the identification of TB in these individuals highlights the importance of diagnostics development, especially the refinement of diagnostic criteria. Based on the above, the systematic macromorphological (re-)evaluation of osteoarchaeological series from the Sarmatian-period Carpathian Basin would be advantageous to provide a more accurate picture of how TB may have impacted the ancestral human communities of the Barbaricum., Competing Interests: The authors have declared that no competing interests exist., (Copyright: This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.)

Hyaluronan (HA), the essential [-3-GlcNAc-1-β-4-GlcA-1-β-]n matrix polysaccharide in vertebrates and molecular camouflage coating in select pathogens, is polymerized by "HA synthase" (HAS) enzymes. The first HAS identified three decades ago opened the window for new insights and biotechnological tools. This review discusses current understanding of HA biosynthesis, its biotechnological utility, and addresses some misconceptions in the literature. HASs are fascinating enzymes that polymerize two different UDP-activated sugars via different glycosidic linkages. Therefore, these catalysts were the first examples to break the "one enzyme/one sugar transferred" dogma. Three distinct types of these bifunctional glycosyltransferases (GTs) with disparate architectures and reaction modes are known. Based on biochemical and structural work, we present an updated classification system. Class I membrane-integrated HASs employ a processive chain elongation mechanism and secrete HA across the plasma membrane. This complex operation is accomplished by functionally integrating a cytosolic catalytic domain with a channel-forming transmembrane region. Class I enzymes, containing a single GT family-2 (GT-2) module that adds both monosaccharide units to the nascent chain, are further subdivided into two groups that construct the polymer with opposite molecular directionalities: Class I-R and I-NR elongate the HA polysaccharide at either the reducing or the non-reducing end, respectively. In contrast, Class II HASs are membrane-associated peripheral synthases with a non-processive, non-reducing end elongation mechanism using two independent GT-2 modules (one for each type of monosaccharide) and require a separate secretion system for HA export. We discuss recent mechanistic insights into HA biosynthesis that promise biotechnological benefits and exciting engineering approaches., (© The Author(s) 2023. Published by Oxford University Press.)

Background: Understanding respiratory syncytial virus (RSV) global epidemiology is important to inform future prevention strategies., Methods: Hospitalized infants <1-year-old with acute illness were enrolled prospectively in Albania, Jordan, Nicaragua, and Philippines during respiratory seasons in 2015-2017. Medical chart review, parental interview, and post-discharge follow up were conducted. Respiratory specimens were tested using real-time RT-PCR for RSV. Infant characteristics associated with very severe illness (intensive care unit [ICU] admission or receipt of supplemental oxygen) were assessed using logistic regression to adjust for potential confounders (age, sex, study site, and preterm birth)., Results: Of 3634 enrolled hospitalized infants, 1129 (31%) tested positive for RSV. The median age of RSV-positive infants was 2.7 (IQR: 1.4-6.1) months and 665 (59%) were male. Very severe illness in 583 (52%) RSV-positive infants was associated with younger age (aOR 4.1, 95% CI: 2.6-6.5 for 0-2 compared to 9-11-months; P < .01), low weight-for-age z-score (aOR 1.9, 95% CI: 1.2-2.8; P < .01), ICU care after birth (aOR 1.6, 95% CI: 1.0-2.5; P = .048), and cesarean delivery (aOR 1.4, 95% CI: 1.0-1.8; P = .03). RSV subgroups A and B co-circulated at all sites with alternating predominance by year; subgroup was not associated with severity (aOR 1.0, 95% CI: 0.8-1.4). Nine (0.8%) RSV-positive infants died during admission or within ≤30 days of discharge, of which 7 (78%) were <6-months-old., Conclusions: RSV was associated with nearly a third of infant acute illness hospitalizations in four middle-income countries during the respiratory season, where, in addition to young age, factors including low weight-for-age might be important predictors of severity. RSV prevention strategies targeting young infants could substantially reduce RSV-associated hospitalizations in middle-income countries., (Published by Oxford University Press on behalf of The Journal of the Pediatric Infectious Diseases Society 2023.)

Objectives: This study compares humeral diaphyseal robusticity and asymmetry between Late Holocene hunter-gatherers from Alaska with the goal of reconstructing habitual activity in relation to culture and environment., Materials and Methods: Ancestral remains from four geographic regions of Alaska were divided into five site groups defined by subsistence strategies and technology: Aleutian Islands, Coastal Bay, Far North Coastal, Inland/Riverine, and Tikeraq. Mid-distal humeral diaphyseal robusticity was quantified using cross-sectional geometric properties standardized by estimated body mass and bone length., Results: Humeral strength and bilateral asymmetry were greatest in Aleutian Island males, moderate in Far North Coastal and Tikeraq males, and reduced in Inland/Riverine males. Left-biased directional asymmetry and reduced humeral strength were found in Coastal Bay males. Aleutian Island males had relatively mediolaterally strengthened humeri compared with other groups. Aleutian Island females had elevated humeral strength, while humeral asymmetry among females was moderate and did not vary between groups. Humeri were relatively round among Aleutian Island and Tikeraq females and anteroposteriorly (A-P) strengthened among Coastal Bay, Far North Coastal, and Inland/Riverine females., Conclusions: These results suggest elevated humeral strength and asymmetry in males that engaged in rowing and unimanual projectile hunting, while reduced humeral strength and asymmetry may reflect bow-and-arrow or ensnarement technologies. Left-biased humeral asymmetry may be associated with net-fishing. Humeral strength and asymmetry are consistent with select instances of unimanual projectile hunting in females, while differences in humeral A-P/mediolateral strength may reflect variation in butchery and processing of prey versus rowing and throwing behaviors., (© 2023 Wiley Periodicals LLC.)

Purpose: To assess the effect of lung volume on measured values and repeatability of xenon 129 ( 129 Xe) gas uptake metrics in healthy volunteers and participants with chronic obstructive pulmonary disease (COPD)., Materials and Methods: This Health Insurance Portability and Accountability Act-compliant prospective study included data (March 2014-December 2015) from 49 participants (19 with COPD [mean age, 67 years ± 9 (SD)]; nine women]; 25 older healthy volunteers [mean age, 59 years ± 10; 20 women]; and five young healthy women [mean age, 23 years ± 3]). Thirty-two participants underwent repeated 129 Xe and same-breath-hold proton MRI at residual volume plus one-third forced vital capacity (RV+FVC/3), with 29 also undergoing one examination at total lung capacity (TLC). The remaining 17 participants underwent imaging at TLC, RV+FVC/3, and residual volume (RV). Signal ratios between membrane, red blood cell (RBC), and gas-phase compartments were calculated using hierarchical iterative decomposition of water and fat with echo asymmetry and least-squares estimation (ie, IDEAL). Repeatability was assessed using coefficient of variation and intraclass correlation coefficient, and volume relationships were assessed using Spearman correlation and Wilcoxon rank sum tests., Results: Gas uptake metrics were repeatable at RV+FVC/3 (intraclass correlation coefficient = 0.88 for membrane/gas; 0.71 for RBC/gas, and 0.88 for RBC/membrane). Relative ratio changes were highly correlated with relative volume changes for membrane/gas ( r = -0.97) and RBC/gas ( r = -0.93). Membrane/gas and RBC/gas measured at RV+FVC/3 were significantly lower in the COPD group than the corresponding healthy group ( P ≤ .001). However, these differences lessened upon correction for individual volume differences ( P = .23 for membrane/gas; P = .09 for RBC/gas)., Conclusion: Dissolved-phase 129 Xe MRI-derived gas uptake metrics were repeatable but highly dependent on lung volume during measurement. Keywords: Blood-Air Barrier, MRI, Chronic Obstructive Pulmonary Disease, Pulmonary Gas Exchange, Xenon Supplemental material is available for this article © RSNA, 2023., Competing Interests: Disclosures of conflicts of interest: W.J.G. No relevant relationships. K.Q. No relevant relationships. M.H. No relevant relationships. L.Z. National Key R&D Program of China 2022ZD0118004, the Alzheimer’s Association through AARF-18-566347, the Zhejiang Provincial Natural Science Foundation of China under grant no. LGJ22H180004, 2020R01003, 2022C03057, the Fundamental Research Funds for the Central Universities 2021FZZX002-05, MOE Frontier Science Center for Brain Science & Brain-Machine Integration, Zhejiang University, DOBI Medical; systems and methods for accelerated MR thermometry. US10722137B2. Samuel Fielden, Li Zhao, Wilson Miller, Xue Feng, Max Wintermark, Kim Butts Pauly, Craig H. Meyer. 2020-07-28 System and Method for Improved Spin-Echo-Based Magnetic Resonance Imaging. US16498672. David C. Alsop, Li Zhao. 2021-11-02. N.J.T. No relevant relationships. J.T.P. No relevant relationships. J.F.M. No relevant relationships. Y.M.S. NIH funding HL132177. A.M.R. No relevant relationships. T.A.A. Grant/contract for Polarean Clinical Trial, consultant for Polarean, speaker for Polarean. J.P.M. NIH-NHLBI R01 HL109618 grants; research grant from Siemens Medical Solutions not related to the content of this manuscript. G.W.M. Grants from National Institutes of Health (R01 HL109618, R01 HL105586, R01 CA172595; payments paid to University of Virginia)., (© 2023 by the Radiological Society of North America, Inc.)

Purpose of Review: The underlying molecular mechanisms that direct stem cell differentiation into fully functional, mature cells remain an area of ongoing investigation. Cell state is the product of the combinatorial effect of individual factors operating within a coordinated regulatory network. Here, we discuss the contribution of both gene regulatory and splicing regulatory networks in defining stem cell fate during differentiation and the critical role of protein isoforms in this process., Recent Findings: We review recent experimental and computational approaches that characterize gene regulatory networks, splice regulatory networks, and the resulting transcriptome and proteome they mediate during differentiation. Such approaches include long-read RNA sequencing, which has demonstrated high-resolution profiling of mRNA isoforms, and Cas13-based CRISPR, which could make possible high-throughput isoform screening. Collectively, these developments enable systems-level profiling of factors contributing to cell state., Summary: Overall, gene and splice regulatory networks are important in defining cell state. The emerging high-throughput systems-level approaches will characterize the gene regulatory network components necessary in driving stem cell differentiation., Competing Interests: Conflict of interest: Madison M. Mehlferber, Muge Kuyumcu, Gloria M. Sheynkman declare they have no conflict of interest. Clint L. Miller has received funding support from AstraZeneca for work unrelated to the current study.

Polysaccharides are essential biopolymers produced in all kingdoms of life. On the cell surface, they represent versatile architectural components, forming protective capsules and coats, cell walls, or adhesives. Extracellular polysaccharide (EPS) biosynthesis mechanisms differ based on the cellular localization of polymer assembly. Some polysaccharides are first synthesized in the cytosol and then extruded by ATP powered transporters [1]. In other cases, the polymers are assembled outside the cell [2], synthesized and secreted in a single step [3], or deposited on the cell surface via vesicular trafficking [4]. This review focuses on recent insights into the biosynthesis, secretion, and assembly of EPS in microbes, plants and vertebrates. We focus on comparing the sites of biosynthesis, secretion mechanisms, and higher-order EPS assemblies., Competing Interests: Conflict of interest statement Nothing declared., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Background: Few studies have examined influenza vaccine effectiveness (VE) among women during pregnancy in middle-income countries. We used data from a prospective cohort of women who were pregnant in Peru to estimate effectiveness of the 2018 Southern Hemisphere influenza vaccine., Methods: Women at <28 weeks gestation were enrolled from 4 tertiary level hospitals in Lima, Peru at the start of the 2018 influenza season and followed until the end of their pregnancies. Participants had mid-turbinate nasal swabs collected and tested for influenza by reverse-transcription polymerase chain reaction (RT-PCR) with onset of ≥1 of myalgia, cough, runny nose or nasal congestion, sore throat, or difficulty breathing. Time-varying Cox proportional hazard regression models were used to estimate the risk of RT-PCR-confirmed influenza infection after adjusting for inverse probability treatment weight., Results: We followed 1896 women for a median of 127 days (interquartile range [IQR], 86-174). Participants had a median age of 29 years (IQR, 24-34). Among the 1896 women, 49% were vaccinated with the 2018 influenza vaccine and 1039 (55%) developed influenza-like illness, 76 (7%) of whom had RT-PCR-confirmed influenza. Incidence rates of RT-PCR-confirmed influenza were 36.6 and 15.3 per 100 000 person-days among women who were unvaccinated and vaccinated, respectively. Adjusted influenza VE was 22% (95% confidence interval, -64.1% to 62.9%)., Conclusions: Participants vaccinated against influenza had more than 50% lower incidence of RT-PCR-confirmed influenza illness. Although the VE estimated through propensity weight-adjusted time-varying Cox regression did not reach statistical significance, our findings provide additional evidence about the value of maternal influenza vaccination in middle-income countries., (Published by Oxford University Press on behalf of Infectious Diseases Society of America 2023.)

The macromorphological examination of identified human osteological collections from the pre-antibiotic era (e.g., Terry Collection) can provide invaluable information about the skeletal manifestations of tuberculosis (TB) in individuals who did not receive pharmaceutical therapy. With analysis of such collections, new diagnostic criteria for TB can be recognised which can be used in palaeopathological interpretation. The aim of our paper is to provide a reference and aid for the identification of TB in past populations by demonstrating and discussing in detail the vertebral alterations indicative of one of its rare skeletal manifestations, lumbosacral TB. These changes were detected in two individuals from the Terry Collection (Terry No. 760 and Terry No. 1093). These two case studies furnish palaeopathologists with a stronger basis for diagnosing lumbosacral TB in skeletons which exhibit similar vertebral lesions from osteoarchaeological series. To illustrate this, an archaeological case from Hungary (KK146) is also presented, displaying vertebral alterations resembling that of the two cases from the Terry Collection. Through the demonstrated case studies, we can derive a better insight into the disease experience of people who lived in the past and suffered from TB., Competing Interests: Declaration of competing interest None., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Mixed-linkage (1,3;1,4)-β-glucans, which are widely distributed in cell walls of the grasses, are linear glucose polymers containing predominantly (1,4)-β-linked glucosyl units interspersed with single (1,3)-β-linked glucosyl units. Their distribution in cereal grains and unique structures are important determinants of dietary fibers that are beneficial to human health. We demonstrate that the barley cellulose synthase-like CslF6 enzyme is sufficient to synthesize a high-molecular weight (1,3;1,4)-β-glucan in vitro. Biochemical and cryo-electron microscopy analyses suggest that CslF6 functions as a monomer. A conserved "switch motif" at the entrance of the enzyme's transmembrane channel is critical to generate (1,3)-linkages. There, a single-point mutation markedly reduces (1,3)-linkage formation, resulting in the synthesis of cellulosic polysaccharides. Our results suggest that CslF6 monitors the orientation of the nascent polysaccharide's second or third glucosyl unit. Register-dependent interactions with these glucosyl residues reposition the polymer's terminal glucosyl unit to form either a (1,3)- or (1,4)-β-linkage.

Purpose of Review: Pain medicine is rapidly expanding. The gap in treatment for patients with chronic pain in between traditional conservative therapy and major invasive surgery is closing. Neuromodulation is one therapeutic area that has continued to show promise for treatment of chronic pain. Our aim is to review updates in non-invasive neuromodulation (NIN) techniques as an adjunct for various chronic pain conditions., Recent Findings: Overall, the literature suggests that NIN techniques such as tCDS, TMS, TENS, tVNS, and HIFUS/LIFUS have utility in treating various types of chronic pain and have a promising future. There is a better understanding of the mechanistic basis for pain relief from NIN, as well as refinement in technology improving NIN therapy success. Future studies will need to focus on continuing to refine protocols for optimal benefit from NIN as well as implementing larger RCTs to improve the quality of data being generated in the field., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Aims: To evaluate psychosocial outcomes for adults with type 1 diabetes (T1D) using the tubeless Omnipod® 5 Automated Insulin Delivery (AID) System., Methods: A single-arm, multicenter (across the United States), prospective safety and efficacy study of the tubeless AID system included 115 adults with T1D. Participants aged 18-70 years completed questionnaires assessing psychosocial outcomes - diabetes distress (T1-DDS), hypoglycemic confidence (HCS), well-being (WHO-5), sleep quality (PSQI), insulin delivery satisfaction (IDSS), diabetes treatment satisfaction (DTSQ), and system usability (SUS) - before and after 3 months of AID use. Associations among participant characteristics, psychosocial measures and glycemic outcomes were evaluated using linear regression analyses., Results: Adults using the tubeless AID system demonstrated improvements in diabetes-specific psychosocial measures, including diabetes distress, hypoglycemic confidence, insulin delivery satisfaction, diabetes treatment satisfaction, and system usability after 3 months (all P < 0.001). No changes in general well-being or sleep quality were observed. The psychosocial outcomes assessed were not consistently associated with baseline participant characteristics (i.e., age, sex, diabetes duration, glycemic outcomes including percent time in range 70-180 mg/dL, percent time below range < 70 mg/dL, hemoglobin A1c, or insulin regimen)., Conclusions: Use of the Omnipod 5 AID system was associated with significant improvements in diabetes-related psychosocial outcomes for adults with T1D., Clinical Trials Registration Number: NCT04196140., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

While short stems in total shoulder arthroplasty (TSA) preserve bone stock and facilitate revision surgery, they have been associated with higher rates of malalignment and loosening in some cases compared to standard length stems. The purpose of this study was to analyze the intramedullary canal in progressive increments distal to the greater tuberosity to provide anatomic information about the optimal length of press-fit short stems for alignment and stability in TSA. We hypothesized that the humeral canal diameter will remain variable for the first 50 to 75 mm distal to the greater tuberosity and will become consistent thereafter. A retrospective review of 99 consecutive patients undergoing TSA with CT scans was performed. Intramedullary anterior-posterior (AP) and medial-lateral (ML) width as well as diameter were analyzed on two-dimensional computed tomography following multiplanar reconstruction. Measurements were taken at consistent distances distal to the greater tuberosity (GT). The transition point was measured at the proximal level of the humerus where endosteal borders of the medial and lateral cortices became parallel. The mean transition point was 73 mm from the GT (range: 53 to 109 mm). ML and AP widths became consistent 80 mm distal to the GT. IM diameter became consistent after 90 mm distal to the GT and a stem length of 90 mm extended past the transition point in 91.9% of cases. In TSA, a humeral stem length of 90 mm is required to predictably reach points at which the humeral canal becomes cylindrical and consistent in diameter. This information may aid data-driven decisions on humeral stem length during press-fit fixation, assuring consistency of alignment and implant stability, while maintaining ease of revision associated with a short stem implant. Level of evidence: III.