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Choledochal malformation (CM) is a rare disease that can lead to malignancy and potential long-term sequelae despite surgical resection. There is no long-term follow-up data on patients after CM resection in Germany. We aimed to determine the long-term outcome of our patients with a duration of follow-up >10 years and focused on long-term sequelae and health-related quality of life (HRQOL).

Biliary atresia (BA) is still an enigmatic disease of unknown etiology and cryptic pathomechanism. Despite the fact that BA is rated among rare diseases, it represents the most frequent indication for pediatric liver transplantation. Although every effort is made to elucidate the origin of the ongoing deterioration of liver function, no breakthrough has so far been achieved, which switches the surgical but symptomatic therapy to a cause-oriented approach. The nowadays leading hypothesis focuses on hepatotropic virus as a triggering agent for an autoimmunological self-limiting inflammatory process along the entire biliary tree. The present review highlights the current state of research on the factor “viruses in biliary atresia” in both patients undergoing the Kasai procedure and the virus-induced BA mouse model.

The pullout methods LOK- TEST and CAPO-TEST for in-place compressive strength are presented with their theoretical analysis’ background and correlations from 30 major studies, made worldwide, showing robust general correlations between pullout force and strength by cylinders or cubes/ cores. The coefficient of variation of the systems are shown, reported in 1984. Practical cases using the systems are described: Case 1. In-Situ compressive strength testing of quarantined precast concrete tunnel lining segments using CAPO-TEST, UK; Case 2. Strength testing with CAPO-TEST on old bridges for further loading, Poland; Case 3. Safe and early form stripping with LOK-TEST, Canada; Case 4. Curing of the cover layer evaluated by pullout and bulk resistivity, Denmark.

When low muscle mass and impaired strength and physical function coexist with excess adiposity, it is termed sarcopenic obesity (SO). Handgrip strength (HGS) is a predictor of disability and mortality. Asymmetry in HGS, particularly ≥ 10% strength differences between hands, may indicate neuromuscular dysfunction observable prior to declines in maximal strength are detectedand therefore could be incorporated to identify those at risk of physical limitations and SO. This study compares HGS values and asymmetry in older adults with excess adiposity and evaluates their relationships with physical function. Baseline data from two previous pilot weight loss studies in 85 older adults with body mass index values ≥ 30 kg m -2 are included with measures of body composition, walking speed, and chair stand ability. Sixty-three participants met the criteria for SO. HGS correlated to gait speed (r = 0.22), distance walked (r = 0.40), chair stand time for 5 repetitions (r = 0.42) and during 30 s (r = 0.31). HGS asymmetry is only correlated to gait speed (r = 0.31) and there are no differences in physical function between those with and without asymmetry. Maximal HGS tests should continue to be used to screen for functional decline and disability., (© 2024 Wiley‐VCH GmbH.)

We present two patients who developed multiple lower limb stress fractures. Potential causes, such as osteoporosis, malignancies and disturbances in calcium metabolism were investigated. This led the physicians to consider whether methotrexate (MTX) exposure posed a risk of atypical fractures.The association between MTX and lower limb fractures has been described in at least 80 cases in the literature. Stress fractures associated with MTX treatment are atypical of osteoporosis and located in the lower extremities, most often the tibia. The limited data suggest that discontinuation of MTX may improve symptoms and chances of fracture healing, while antiresorptive or osteoanabolic therapies have not proven clinically efficient. It seems evident, however, that the benefits of MTX treatment in rheumatological disease clearly outweigh the risk of MTX osteopathy and related fractures., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: The nucleus accumbens (NAc) mediates reward learning and motivation. Despite an abundance of neuropeptides, peptidergic neurotransmission from the NAc has not been integrated into current models of reward learning. The existence of a sparse population of neurons containing corticotropin-releasing factor (CRF) has been previously documented. Here, we provide a comprehensive analysis of their identity and functional role in shaping reward learning., Methods: Our multidisciplinary approach included fluorescent in situ hybridization (n = ≥3 mice), tract tracing (n = 5 mice), ex vivo electrophysiology (n = ≥30 cells), in vivo calcium imaging with fiber photometry (n = ≥4 mice), and use of viral strategies in transgenic lines to selectively delete CRF peptide from NAc neurons (n = ≥4 mice). Behaviors used were instrumental learning, sucrose preference, and spontaneous exploration in an open field., Results: We showed that the vast majority of NAc CRF-containing neurons are spiny projection neurons (SPNs) comprising dopamine D 1 -, D 2 -, or D 1 /D 2 -containing SPNs that primarily project and connect to the ventral pallidum and to a lesser extent the ventral midbrain. As a population, they display mature and immature SPN firing properties. We demonstrated that NAc CRF-containing neurons track reward outcomes during operant reward learning and that CRF release from these neurons acts to constrain initial acquisition of action-outcome learning and at the same time facilitates flexibility in the face of changing contingencies., Conclusions: CRF release from this sparse population of SPNs is critical for reward learning under normal conditions., (Copyright © 2024 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Background: The nucleus accumbens (NAc) mediates reward learning and motivation. Despite an abundance of neuropeptides, peptidergic neurotransmission from the NAc has not been integrated into current models of reward learning. The existence of a sparse population of neurons containing corticotropin releasing factor (CRF) has been previously documented. Here we provide a comprehensive analysis of their identity and functional role in shaping reward learning., Methods: To do this, we took a multidisciplinary approach that included florescent in situ hybridization (N mice ≥ 3), tract tracing (N mice = 5), ex vivo electrophysiology (N cells ≥ 30), in vivo calcium imaging with fiber photometry (N mice ≥ 4) and use of viral strategies in transgenic lines to selectively delete CRF peptide from NAc neurons (N mice ≥ 4). Behaviors used were instrumental learning, sucrose preference and spontaneous exploration in an open field., Results: Here we show that the vast majority of NAc CRF-containing (NAc CRF ) neurons are spiny projection neurons (SPNs) comprised of dopamine D1-, D2- or D1/D2-containing SPNs that primarily project and connect to the ventral pallidum and to a lesser extent the ventral midbrain. As a population, they display mature and immature SPN firing properties. We demonstrate that NAc CRF neurons track reward outcomes during operant reward learning and that CRF release from these neurons acts to constrain initial acquisition of action-outcome learning, and at the same time facilitates flexibility in the face of changing contingencies., Conclusion: We conclude that CRF release from this sparse population of SPNs is critical for reward learning under normal conditions.

In this case report, a 19-year-old woman suffered a high-energy trauma to her left side with multiple left-sided fractures, including ribs 8-12, with no pneumothorax on the left side, but a large right-sided pneumothorax. Contralateral pneumothorax is extremely rare in primarily unilateral trauma, especially when no contralateral rib fractures are present. A possible explanation is that of a barotrauma due to increased intrathoracic pressure with external compression. Careful examination of both sides of the body is necessary when evaluating patients with unilateral trauma, as serious organ injury may occur contralaterally., (Published under Open Access CC-BY-NC-BD 4.0. https://creativecommons.org/licenses/by-nc-nd/4.0/.)

Importance: Triptans are contraindicated in patients with ischemic heart disease or previous myocardial infarction, and caution is advised when prescribing these drugs to patients with vascular risk factors. However, controlled observational studies have either shown no association or an apparent lower risk, possibly owing to a channeling of triptans to individuals at low risk of cardiovascular outcomes, and it remains unclear whether avoiding triptan treatment for these patients is meaningful., Objective: To establish whether an association between triptans and ischemic events could be demonstrated using a self-controlled design because this type of design is robust to the previously mentioned type of confounding., Design, Setting, and Participants: All people in nationwide Danish registries who were initiating triptans and all the ischemic events that they experienced were identified. A case-crossover design was used to estimate odds ratios (OR) for associations between first-ever triptan use and ischemic outcomes, comparing triptan exposure in the 2-week period up to the event with four 2-week reference periods. Data were obtained for the period January 1995 to August 2022. Included from the population of Denmark were individuals redeeming a prescription for any triptan and experiencing at least 1 of 3 predefined ischemic outcomes. No one was excluded., Exposure: Initiation of any triptan., Main Outcomes and Measures: Acute myocardial infarction, ischemic stroke, or nonspecified stroke., Results: Identified were a total of 429 612 individuals (median [IQR] age, 38 [28-48] years; 325 687 female [75.8%]) who redeemed a first prescription for a triptan in the study period. Of these patients, 11 (0.003%) had a myocardial infarction with the first triptan prescription in either a focal or referent window (odds ratio [OR], 3.3; 95% CI, 1.0-10.9), 18 (0.004%) had ischemic stroke (OR, 3.2; 95% CI, 1.3-8.1), and 35 (0.008%) had ischemic/nonspecified stroke (OR, 3.0; 95% CI, 1.5-5.9). Case patients had a median age of approximately 60 years and had a high-risk cardiovascular profile., Conclusions and Relevance: Results of this case-crossover study suggest that triptan initiation was associated with higher risk of ischemic stroke and myocardial infarction. For the individual patient with low background cardiovascular risk, the risk of an ischemic event after triptan initiation was very low.

Background: Sarcopenic Obesity is the co-existence of increased adipose tissue (obesity) and decreased muscle mass or strength (sarcopenia) and is associated with worse outcomes than obesity alone. The new EASO/ESPEN consensus provides a framework to standardize its definition. This study sought to evaluate whether there are preliminary differences observed in weight loss or physical function in older adults with and without sarcopenic obesity taking part in a multicomponent weight loss intervention using these new definitions., Methods: A 6-month, non-randomized, non-blinded, single-arm pilot study was conducted from 2018 to 2020 in adults ≥ 65 years with a body mass index (BMI) ≥ 30 kg/m 2 . Weekly dietitian visits and twice-weekly physical therapist-led exercise classes were delivered using telemedicine. We conducted a secondary retrospective analysis of the parent study (n = 53 enrolled, n = 44 completers) that investigated the feasibility of a technology-based weight management intervention in rural older adults with obesity. Herein, we applied five definitions of sarcopenic obesity (outlined in the consensus) to ascertain whether the response to the intervention differed among those with and without sarcopenic obesity. Primary outcomes evaluated included weight loss and physical function (30-s sit-to-stand)., Results: In the parent study, mean weight loss was - 4.6 kg (95% CI - 3.6, - 5.6; p < 0.001). Physical function measures of 30-s sit-to-stand showed a mean increase of 3.1 in sit-to-stand repetitions (+ 1.9, + 4.3; p < 0.001). In this current analysis, there was a significant decrease in weight and an increase in repetitions between baseline and follow-up within each group of individuals with and without sarcopenia for each of the proposed definitions. However, we did not observe any significant differences in the changes between groups from baseline to follow-up., Conclusions: The potential lack of significant differences in weight loss or physical function between older adults with and without sarcopenic obesity participating in a weight loss intervention may suggest that well-designed, multicomponent interventions can lead to similar outcomes irrespective of sarcopenia status in persons with obesity. Fully powered randomized clinical trials are critically needed to confirm these preliminary results., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Rationale and Objectives: There is universal interest in increasing sustainability in health care, including in imaging. We studied and characterized energy consumption in a representative imaging department in Denmark to identify and quantify the effect of specific optimizations., Methods: Protocols and energy parameters for the three main scanner modalities along with supportive systems and workflows were monitored and scrutinized. Potential savings were measured and/or calculated., Results: Only few optimizations were identified at the protocol level. However, examination of usage patterns and cooling systems revealed numerous potential optimizations which fell into three categories. 1) Optimizations requiring minimal changes in installations or workflows, for example, reduction of bed-position time, 2) optimizations requiring altered work flows such as strict adherence to timed shut-down procedures and 3) optimizations requiring retro-fitting equipment, typically at considerable monetary expense, for example fitting variable flow control on pumps. The single biggest identified optimization was raising the temperature of the circulating cooling water., Conclusion: This study highlights the complexity of increasing sustainability in health care, specifically in imaging. We identified multiple potential optimizations but also technical, monetary and organizational barriers preventing immediate implementation., Competing Interests: Declaration of competing interest None of the authors have any conflicts of interest., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: The role of protein in glucose homeostasis has demonstrated conflicting results. However, little research exists on its impact following weight loss. This study examined the impact of protein supplementation on glucose homeostasis in older adults >65 years with obesity seeking to lose weight., Methods: A 12-week, nonrandomized, parallel group intervention of protein (PG) and nonprotein (NPG) arms for 28 older rural adults (body mass index (BMI) ≥ 30 kg/m 2 ) was conducted at a community aging center. Both groups received twice weekly physical therapist-led group strength training classes. The PG consumed a whey protein supplement three times per week, post-strength training. Primary outcomes included pre/post-fasting glucose, insulin, inflammatory markers, and homeostasis model assessment of insulin resistance (HOMA-IR)., Results: Mean age and baseline BMI were 72.9 ± 4.4 years and 37.6 ± 6.9 kg/m 2 in the PG and 73.0 ± 6.3 and 36.6 ± 5.5 kg/m 2 in the NPG, respectively. Mean weight loss was -3.45 ± 2.86 kg in the PG and -5.79 ± 3.08 kg in the NPG ( p < 0.001). There was a smaller decrease in pre- vs. post-fasting glucose levels (PG: -4 mg ± 13.9 vs. NPG: -12.2 ± 25.8 mg/dL; p = 0.10), insulin (-7.92 ± 28.08 vs. -46.7 ± 60.8 pmol/L; p = 0.01), and HOMA-IR (-0.18 ± 0.64 vs. -1.08 ± 1.50; p = 0.02) in the PG compared to the NPG., Conclusions: Protein supplementation during weight loss demonstrated a smaller decrease in insulin resistance compared to the NPG, suggesting protein may potentially mitigate beneficial effects of exercise on glucose homeostasis.

Purpose: Cervical artery dissection (CeAD), which includes both vertebral artery dissection (VAD) and carotid artery dissection (CAD), is the most serious safety concern associated with cervical spinal manipulation (CSM). We evaluated the association between CSM and CeAD among US adults., Methods: Through analysis of health claims data, we employed a case-control study with matched controls, a case-control design in which controls were diagnosed with ischemic stroke, and a case-crossover design in which recent exposures were compared to exposures in the same case that occurred 6-7 months earlier. We evaluated the association between CeAD and the 3-level exposure, CSM versus office visit for medical evaluation and management (E&M) versus neither, with E&M set as the referent group., Results: We identified 2337 VAD cases and 2916 CAD cases. Compared to population controls, VAD cases were 0.17 (95% CI 0.09 to 0.32) times as likely to have received CSM in the previous week as compared to E&M. In other words, E&M was about 5 times more likely than CSM in the previous week in cases, relative to controls. CSM was 2.53 (95% CI 1.71 to 3.68) times as likely as E&M in the previous week among individuals with VAD than among individuals experiencing a stroke without CeAD. In the case-crossover study, CSM was 0.38 (95% CI 0.15 to 0.91) times as likely as E&M in the week before a VAD, relative to 6 months earlier. In other words, E&M was approximately 3 times more likely than CSM in the previous week in cases, relative to controls. Results for the 14-day and 30-day timeframes were similar to those at one week., Conclusion: Among privately insured US adults, the overall risk of CeAD is very low. Prior receipt of CSM was more likely than E&M among VAD patients as compared to stroke patients. However, for CAD patients as compared to stroke patients, as well as for both VAD and CAD patients in comparison with population controls and in case-crossover analysis, prior receipt of E&M was more likely than CSM., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Antisense oligonucleotides (ASOs) dosed into cerebrospinal fluid (CSF) distribute broadly throughout the central nervous system (CNS). By modulating RNA, they hold the promise of targeting root molecular causes of disease and hold potential to treat myriad CNS disorders. Realization of this potential requires that ASOs must be active in the disease-relevant cells, and ideally, that monitorable biomarkers also reflect ASO activity in these cells. The biodistribution and activity of such centrally delivered ASOs have been deeply characterized in rodent and non-human primate (NHP) models, but usually only in bulk tissue, limiting our understanding of the distribution of ASO activity across individual cells and across diverse CNS cell types. Moreover, in human clinical trials, target engagement is usually monitorable only in a single compartment, CSF. We sought a deeper understanding of how individual cells and cell types contribute to bulk tissue signal in the CNS, and how these are linked to CSF biomarker outcomes. We employed single nucleus transcriptomics on tissue from mice treated with RNase H1 ASOs against Prnp and Malat1 and NHPs treated with an ASO against PRNP. Pharmacologic activity was observed in every cell type, though sometimes with substantial differences in magnitude. Single cell RNA count distributions implied target RNA suppression in every single sequenced cell, rather than intense knockdown in only some cells. Duration of action up to 12 weeks post-dose differed across cell types, being shorter in microglia than in neurons. Suppression in neurons was generally similar to, or more robust than, the bulk tissue. In macaques, PrP in CSF was lowered 40% in conjunction with PRNP knockdown across all cell types including neurons, arguing that a CSF biomarker readout is likely to reflect ASO pharmacodynamic effect in disease-relevant cells in a neuronal disorder. Our results provide a reference dataset for ASO activity distribution in the CNS and establish single nucleus sequencing as a method for evaluating cell type specificity of oligonucleotide therapeutics and other modalities., (© The Author(s) 2023. Published by Oxford University Press on behalf of Nucleic Acids Research.)

Caloric restriction and aerobic and resistance exercise are safe and effective lifestyle interventions for achieving weight loss in the obese older population (>65 years) and may improve physical function and quality of life. However, individual responses are heterogeneous. Our goal was to explore the use of untargeted metabolomics to identify metabolic phenotypes associated with achieving weight loss after a multi-component weight loss intervention. Forty-two older adults with obesity (body mass index, BMI, ≥30 kg/m 2 ) participated in a six-month telehealth-based weight loss intervention. Each received weekly dietitian visits and twice-weekly physical therapist-led group strength training classes with a prescription for aerobic exercise. We categorized responders' weight loss using a 5% loss of initial body weight as a cutoff. Baseline serum samples were analyzed to determine the variable importance to the projection (VIP) of signals that differentiated the responder status of metabolic profiles. Pathway enrichment analysis was conducted in Metaboanalyst. Baseline data did not differ significantly. Weight loss was 7.2 ± 2.5 kg for the 22 responders, and 2.0 ± 2.0 kg for the 20 non-responders. Mummichog pathway enrichment analysis revealed that perturbations were most significant for caffeine and caffeine-related metabolism ( p = 0.00028). Caffeine and related metabolites, which were all increased in responders, included 1,3,7-trimethylxanthine (VIP = 2.0, p = 0.033, fold change (FC) = 1.9), theophylline (VIP = 2.0, p = 0.024, FC = 1.8), paraxanthine (VIP = 2.0, p = 0.028, FC = 1.8), 1-methylxanthine (VIP = 1.9, p = 0.023, FC = 2.2), 5-acetylamino-6-amino-3-methyluracil (VIP = 2.2, p = 0.025, FC = 2.2), 1,3-dimethyl uric acid (VIP = 2.1, p = 0.023, FC = 2.3), and 1,7-dimethyl uric acid (VIP = 2.0, p = 0.035, FC = 2.2). Increased levels of phytochemicals and microbiome-related metabolites were also found in responders compared to non-responders. In this pilot weight loss intervention, older adults with obesity and evidence of significant enrichment for caffeine metabolism were more likely to achieve ≥5% weight loss. Further studies are needed to examine these associations in prospective cohorts and larger randomized trials.

Intrauterine hormonal contraception devices are widely used among Danish women. Cases of breast cancer have been reported in women using the devices and studies have found evidence of an increased risk, but a new meta-analysis did not find an increased risk. The reported relative risks in some of the studies are numerically substantial as quoted in this review, but it is very important that physicians take absolute numbers into account when interpreting risk in order to provide the best guidance of patients with regard to contraception and associated risks.

Background: Older adults frequently participate in behavior change studies, yet it is not clear how to quantify a potential relationship between their perception of the intervention and its efficacy., Research Aim: We assessed the relationship between participant sentiment toward the intervention from follow-up interviews with physical activity and questionnaires for the perception of health., Methods: Sentiment was calculated using the transcripts of exit interviews through a bag of words approach defined as the sum of positive and negative words in 28 older adults with obesity (body mass index ≥30kg/m 2 )., Results: Mean age was 73 years (82% female), and 54% lost ≥5% weight loss. Through linear regression we describe a significant association between positive sentiment about the intervention and weight loss; positive sentiment on technology and change in PROMIS-10 physical health and reduced physical activity time, while controlling for sex and age., Conclusions: This analysis demonstrates that sentiment analysis and natural language processing in program review identified an association between perception and topics with clinical outcomes., Competing Interests: Conflicts of interest Drs. Batsis and Petersen have equity in SynchroHealth LLC.

Objectives: We aimed to investigate the quality of evidence and the expected added clinical value of treatments recommended by the Danish Medicines Council (DMC)., Study Design: This was an observational study., Methods: The DMC prepares reports on drugs considered for possible new standard treatments in Danish hospitals. These reports evaluate the available evidence on efficacy and safety. The quality of evidence is systematically rated by the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) criteria, and estimates of added clinical value are presented. The recommendations take into account expected economic implications of new treatments. The publicly available reports up until December 29, 2021, were downloaded from the DMC Web page. Reports on drugs marked "recommended" were included. Data on quality of evidence, expected clinical value, and economic implications were imputed in a Microsoft Excel spreadsheet., Results: Seventy-nine reports were included in the analysis. In 79% of these, the quality of evidence was rated low (24%) or very low (55%), whereas no recommendations were based on evidence rated as high quality. Three (5%) of recommended treatments were expected to add large clinical value., Conclusions: Most recommendations by the DMC are based on evidence formally rated as low or very low quality by GRADE, and no recommendations were based on evidence rated as high quality. The added clinical value of the treatments was often not documented and rarely large. Continued attention to improve the clinical evidence behind national recommendations is necessary., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: Cervical artery dissection and subsequent ischemic stroke is the most serious safety concern associated with cervical spinal manipulation., Methods: We evaluated the association between cervical spinal manipulation and cervical artery dissection among older Medicare beneficiaries in the United States. We employed case-control and case-crossover designs in the analysis of claims data for individuals aged 65+, continuously enrolled in Medicare Part A (covering hospitalizations) and Part B (covering outpatient encounters) for at least two consecutive years during 2007-2015. The primary exposure was cervical spinal manipulation; the secondary exposure was a clinical encounter for evaluation and management for neck pain or headache. We created a 3-level categorical variable, (1) any cervical spinal manipulation, 2) evaluation and management but no cervical spinal manipulation and (3) neither cervical spinal manipulation nor evaluation and management. The primary outcomes were occurrence of cervical artery dissection, either (1) vertebral artery dissection or (2) carotid artery dissection. The cases had a new primary diagnosis on at least one inpatient hospital claim or primary/secondary diagnosis for outpatient claims on at least two separate days. Cases were compared to 3 different control groups: (1) matched population controls having at least one claim in the same year as the case; (2) ischemic stroke controls without cervical artery dissection; and (3) case-crossover analysis comparing cases to themselves in the time period 6-7 months prior to their cervical artery dissection. We made each comparison across three different time frames: up to (1) 7 days; (2) 14 days; and (3) 30 days prior to index event., Results: The odds of cervical spinal manipulation versus evaluation and management did not significantly differ between vertebral artery dissection cases and any of the control groups at any of the timepoints (ORs 0.84 to 1.88; p > 0.05). Results for carotid artery dissection cases were similar., Conclusion: Among Medicare beneficiaries aged 65 and older who received cervical spinal manipulation, the risk of cervical artery dissection is no greater than that among control groups., (© 2022. The Author(s).)

Abstract: The aim of this study was to assess if an evidence-based educational program focused on vocation and calling could improve undergraduate nursing students' sense of meaning in life and sense of calling/vocation. Using a mixed-methods, quasi-experimental design, a statistically significant increase occurred in sense of meaning in life and calling/vocation. Qualitative responses revealed growth in self-knowledge, importance of individual pathways, and recognition of nursing as one's calling. Courses on calling may encourage nursing students to commit to nursing as a calling., (Copyright © 2022 InterVarsity Christian Fellowship.)

There are five cloned muscarinic acetylcholine receptors (M1-M5). Of these, the muscarinic type 5 receptor (M5) is the only one localized to dopamine neurons in the ventral tegmental area and substantia nigra. Unlike M1-M4, the M5 receptor has relatively restricted expression in the brain, making it an attractive therapeutic target. Here, we performed an in-depth characterization of M5-dependent potentiation of dopamine transmission in the nucleus accumbens and accompanying exploratory behaviors in male and female mice. We show that M5 receptors potentiate dopamine transmission by acting directly on the terminals within the nucleus accumbens. Using the muscarinic agonist oxotremorine, we revealed a unique concentration-response curve and a sensitivity to repeated forced swim stress or restraint stress exposure. We found that constitutive deletion of M5 receptors reduced exploration of the center of an open field while at the same time impairing normal habituation only in male mice. In addition, M5 deletion reduced exploration of salient stimuli, especially under conditions of high novelty, yet had no effect on hedonia assayed using the sucrose preference test or on stress-coping strategy assayed using the forced swim test. We conclude that M5 receptors are critical for both engaging with the environment and updating behavioral output in response to environment cues, specifically in male mice. A cardinal feature of mood and anxiety disorders is withdrawal from the environment. These data indicate that boosting M5 receptor activity may be a useful therapeutic target for ameliorating these symptoms of depression and anxiety. SIGNIFICANCE STATEMENT The basic physiological and behavioral functions of the muscarinic M5 receptor remain understudied. Furthermore, its presence on dopamine neurons, relatively restricted expression in the brain, and recent crystallization make it an attractive target for therapeutic development. Yet, most preclinical studies of M5 receptor function have primarily focused on substance use disorders in male rodents. Here, we characterized the role of M5 receptors in potentiating dopamine transmission in the nucleus accumbens, finding impaired functioning after stress exposure. Furthermore, we show that M5 receptors can modulate exploratory behavior in a sex-specific manner, without affecting hedonic behavior. These findings further illustrate the therapeutic potential of the M5 receptor, warranting further research in the context of treating mood disorders., (Copyright © 2022 the authors.)

Background: Aging alters biological processes resulting in body fat redistribution, loss of lean muscle mass, and reduced muscle strength, termed sarcopenia. Nutrition is an important modifiable risk factor in the development of sarcopenia. Food insecurity refers to limited or uncertain access to enough food for an active, healthy life, and is prevalent among older adults. The objective of this study was to examine the relationship between food insecurity and probable sarcopenia in older adults., Methods: We examined 3632 adults ≥60 years old from the 2011-2014 National Health and Nutrition Examination Surveys (NHANES). For our analysis food insecurity was identified using the Food Security Survey Module (FSSM). The primary outcome was based on the Sarcopenia Definitions and Outcomes consortium (SDOC) definition. Secondary outcomes were based on three other different grip strength cut-offs as there is debate within the field as to the optimal definition of sarcopenia. Consistent with the revised European consensus on the definition and diagnosis of Sarcopenia (EWGSOP2) recommendations, we used the term probable sarcopenia throughout this text as definitions were based on muscle strength alone and did not include an evaluation of muscle quality. Sensitivity analyses were performed using the standard four category definition of food security. We used logistic regression to examine the association between food insecurity and sarcopenia., Results: Using the Sarcopenia Definitions and Outcomes Consortium definition, 24.7% were classified as having probable sarcopenia (low grip strength); 5.5% had food insecurity and food insecurity was associated with probable sarcopenia (OR 1.51, 95%CI 1.03-2.22). Using three other definitions of probable sarcopenia, food insecurity was significantly associated with probable sarcopenia using the Foundation for the National Institute of Health definition using grip strength alone (OR 1.71, 95%CI 1.08-2.71), but food insecurity was not associated with food insecurity using definitions related to grip strength/BMI (OR 1.16, 95%CI 0.76-1.78) or grip strength/weight (OR 1.14, 95%CI 0.85-1.54)., Conclusions: In this nationally representative cohort study, individuals classified as having food insecurity were more likely to have probable sarcopenia (low grip strength) compared to those with full food security. Future studies should examine whether food insecurity interventions may reduce probable sarcopenia and associated adverse outcomes., Competing Interests: Conflict of interest None., (Copyright © 2022 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.)

Background: Older adults who engage in physical activity can reduce their risk of mobility impairment and disability. Short amounts of walking can improve quality of life, physical function, and cardiovascular health. Various programs have been implemented to encourage older adults to engage in physical activity, but sustaining their motivation continues to be a challenge. Ubiquitous devices, such as mobile phones and smartwatches, coupled with machine-learning algorithms, can potentially encourage older adults to be more physically active. Current algorithms that are deployed in consumer devices (eg, Fitbit) are proprietary, often are not tailored to the movements of older adults, and have been shown to be inaccurate in clinical settings. Step-counting algorithms have been developed for smartwatches, but only using data from younger adults and, often, were only validated in controlled laboratory settings., Objective: We sought to develop and validate a smartwatch step-counting app for older adults and evaluate the algorithm in free-living settings over a long period of time., Methods: We developed and evaluated a step-counting app for older adults on an open-source wrist-worn device (Amulet). The app includes algorithms to infer the level of physical activity and to count steps. We validated the step-counting algorithm in the lab (counting steps from a video recording, n=20) and in free-living conditions-one 2-day field study (n=6) and two 12-week field studies (using the Fitbit as ground truth, n=16). During app system development, we evaluated 4 walking patterns: normal, fast, up and down a staircase, and intermittent speed. For the field studies, we evaluated 5 different cut-off values for the algorithm, using correlation and error rate as the evaluation metrics., Results: The step-counting algorithm performed well. In the lab study, for normal walking (R 2 =0.5), there was a stronger correlation between the Amulet steps and the video-validated steps; for all activities, the Amulet's count was on average 3.2 (2.1%) steps lower (SD 25.9) than the video-validated count. For the 2-day field study, the best parameter settings led to an association between Amulet and Fitbit (R 2 =0.989) and 3.1% (SD 25.1) steps lower than Fitbit, respectively. For the 12-week field study, the best parameter setting led to an R 2 value of 0.669., Conclusions: Our findings demonstrate the importance of an iterative process in algorithm development before field-based deployment. This work highlights various challenges and insights involved in developing and validating monitoring systems in real-world settings. Nonetheless, our step-counting app for older adults had good performance relative to the ground truth (a commercial Fitbit step counter). Our app could potentially be used to help improve physical activity among older adults., (©George Boateng, Curtis L Petersen, David Kotz, Karen L Fortuna, Rebecca Masutani, John A Batsis. Originally published in JMIR Aging (https://aging.jmir.org), 10.08.2022.)

Introduction: Arterial vasodilation and hyperdynamic circulation are considered hallmarks of the pathophysiological mechanisms of decompensation in cirrhosis. However, detailed characterization of peripheral, splanchnic, renal, and cardiac hemodynamic have not previously been published in a spectrum from healthy stage to advanced decompensated liver disease with hepatorenal syndrome-acute kidney injury (HRS-AKI)., Methods: We included 87 patients with cirrhosis and 27 healthy controls in this prospective cohort study. The population comprised patients with compensated cirrhosis (n = 27) and decompensated cirrhosis (n = 60); patients with decompensated cirrhosis were further separated into subsets of responsive ascites (33), refractory ascites (n = 16), and HRS-AKI (n = 11). We measured portal pressure and assessed regional blood flow by magnetic resonance imaging., Results: Patients with compensated cirrhosis experienced higher azygos venous flow and higher hepatic artery flow fraction of cardiac index than controls ( P &lt; 0.01), but other flow parameters were not significantly different. Patients with decompensated cirrhosis experienced significantly higher cardiac index ( P &lt; 0.01), higher superior mesenteric artery flow ( P = 0.01), and lower systemic vascular resistance ( P &lt; 0.001) compared with patients with compensated cirrhosis. Patients with HRS-AKI had the highest cardiac output and lowest renal flow of all groups ( P &lt; 0.01 and P = 0.02, respectively). Associations of single hemodynamic parameters were stronger with model for end-stage liver disease than with portal pressure., Discussion: The regional cardiocirculatory changes seem closely linked to clinical symptoms with 3 distinguished hemodynamic stages from compensated to decompensated cirrhosis and, finally, to HRS-AKI. The attenuated renal perfusion despite high cardiac output in patients with HRS-AKI challenges the prevailing pathophysiological hypothesis of cardiac dysfunction as a causal factor in HRS-AKI. Finally, magnetic resonance imaging seems an accurate and reliable noninvasive method to assess hemodynamics and has potential as a diagnostic tool in patients with cirrhosis., (Copyright © 2022 by The American College of Gastroenterology.)

Cytomegalovirus (CMV) is a highly prevalent human herpes virus that exerts a strong influence on immune repertoire which may influence cancer risk. We have tested whether CMV immunoglobulin G (IgG) serostatus is associated with immune cell proportions (n = 132 population controls), human papillomavirus (HPV) co-infection and head and neck cancer risk (n = 184 cancer cases and 188 controls) and patient survival. CMV status was not associated with the proportion of Natural Killer cells, B cells or the neutrophil-to-lymphocyte ratio. However, CD8+ T cells increased with increasing categories of IgG titers (P =1.7 × 10-10), and titers were inversely associated with the CD4:CD8 ratio (P = 5.6 × 10-5). Despite these differences in T cell proportions, CMV was not associated with HPV16 co-infection. CMV seropositivity was similar in cases (52%) and controls (47%) and was not associated with patient survival (hazard ratio [HR] 1.14, 95% confidence interval [CI]: 0.70 to 1.86). However, those patients with the highest titers had the worst survival (HR 1.91, 95% CI: 1.13 to 3.23). Tumor-based data from The Cancer Genome Atlas demonstrated that the presence of CMV transcripts was associated with worse patient survival (HR 1.79, 95% CI: 0.96 to 2.78). These findings confirm that a history of CMV infection alters T cell proportions, but this does not translate to HPV16 co-infection or head and neck cancer risk. Our data suggest that high titers and active CMV virus in the tumor environment may confer worse survival., (© The Author(s) 2022. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Background: Declining mortality rates and an aging population have contributed to increasing rates of multimorbidity (MM) in the United States. MM is strongly associated with a decline in physical function. Obesity is an important risk factor for the development of MM, and its prevalence continues to rise. Our study aimed to evaluate the associations between obesity, MM, and rates of functional limitations in older adults., Methods: We analyzed body mass index (BMI) and self-reported comorbidity data from 7261 individuals aged ≥60 years from the National Health and Nutrition Examination Surveys 2005-2014. Weight status was defined based on standard BMI categories. MM was defined as 2 or more comorbidities, while functional limitations were self-reported. Adjusted logistic regression quantified the association between standard BMI categories and MM. We also examined the difference in the prevalence of limitations between those with and without MM., Results: The overall proportion of individuals with concomitant MM and obesity was 27.0%. Compared to a normal BMI, older adults with obesity had higher odds of MM (Prevalence odds ratio 1.79, 95% CI 1.49, 2.12). Overall, 67.5% of patients with MM also reported a functional limitation, with rates of functional limitation increasing with increasing BMI. When evaluating functional limitations in those with MM by BMI class, 90% of patients classified as severely obese (BMI ≥40 kg/m 2 ) with MM also had a concomitant functional limitation., Conclusions: Compared to normal weight status, obesity is associated with an increased burden of MM and functional limitation among older adults. Our results underscore the importance of identifying and addressing obesity, MM, and functional limitation patterns and the need for evidence-based interventions that address all three conditions in this population., (© 2022 The American Geriatrics Society.)

It is unclear which energy expenditure prediction equation should guide weight loss interventions in older adults with obesity. We ascertained the validity of four equations commonly used in practice in a series of weight loss studies of adults aged ≥65 with a body mass index ≥30kg/m 2 using indirect calorimetry data. Diagnostic accuracy was defined as <10% discrepancy between predicted and measured resting metabolic rate (RMR). Mean was 73.4 years. RMR using the ReeVue was 1,643 kCal. With 59.0% accuracy, the WHO equation demonstrated the highest accuracy while the Harris-Benedict yielded 53.5% accuracy. The Owens equation demonstrated the least variability (21.5% overprediction, 27.8% underprediction) with 50.7% accuracy. A SECA bioimpedance analyzer noted the second lowest accuracy of 49.6%. Only 43.1% of measurements were within 10% of the gold-standard indirect calorimetry value using the Mifflin equation. All equations demonstrated <60% accuracy suggesting a great need for estimating energy needs.

We conducted a post-hoc analysis of a pre/post, single-arm, non-randomized, multicomponent weight loss intervention in older adults. Fifty-three older adults aged ≥65 with a body mass index ≥ 30 kg/m2 were recruited to participate in a six-month, remote monitoring and video-conferencing delivered, prescriptive intervention consisting of individual and group-led registered dietitian nutrition and physical therapy sessions. We assessed weight, height, and body composition using a SECA 514 bioelectrical impedance analyzer. Mean age was 72.9±3.9 years (70% female) and all had ≥2 chronic conditions. Of those with complete data (n=30), we observed a 4.6±3.5kg loss in weight, 6.1±14.3kg (1.9%) loss in fat mass, and 0.78±1.69L loss in visceral fat (all p<0.05). Fat-free mass (-3.4kg±6.8, p=0.19), appendicular lean mass (-0.25±1.83, p=0.22), and grip strength (+3.46±7.89, p=0.56) did not significantly change. These variables were preserved after stratifying by 5% weight loss. Our intervention led to significant body and visceral fat loss while maintaining fat-free and appendicular lean muscle mass., Competing Interests: None

Ketamine may affect the reliability of electroencephalographic (EEG) depth-of-hypnosis indices as it affects power in high-frequency EEG components. The purpose of this study was to compare the effects of ketamine on three commonly-used depth-of-hypnosis indices by extending our EEG simulator to allow replay of previously-recorded EEG. Secondary analysis of previously-collected data from a randomized controlled trial of intravenous anesthesia with ketamine: Group 0.5 [ketamine, 0.5 mg kg -1 bolus followed by a 10 mcg kg -1  min -1 infusion], Group 0.25 [ketamine, 0.25 mg kg -1  bolus, 5 mcg kg -1  min -1 infusion], and Control [no ketamine]. EEG data were replayed to three monitors: NeuroSENSE (WAV), Bispectral Index (BIS), and Entropy (SE). Differences in depth-of-hypnosis indices during the initial 15 min after induction of anesthesia were compared between monitors, and between groups. Monitor agreement was evaluated using Bland-Altman analysis. Available data included 45.6 h of EEG recordings from 27 cases. Ketamine was associated with higher depth-of-hypnosis index values measured at 10 min (BIS, χ 2  = 8.01, p = 0.018; SE, χ 2  = 11.44, p = 0.003; WAV, χ 2  = 9.19, p = 0.010), and a higher proportion of index values > 60 for both ketamine groups compared to the control group. Significant differences between monitors were not observed, except between BIS and SE in the control group. Ketamine did not change agreement between monitors. The ketamine-induced increase in depth-of-hypnosis indices was observed consistently across the three EEG monitoring algorithms evaluated. The observed increase was likely caused by a power increase in the beta and gamma bands. However, there were no lasting differences in depth-of-hypnosis reported between the three compared indices., (© 2020. Springer Nature B.V.)

Background & Aims: Weight loss in older adults enhances physical function, but may lead to sarcopenia and osteoporosis. Whey protein is a low cost rich source of essential amino acids, may improve physical function. We evaluated the feasibility and acceptability of consuming whey protein in the context of a weight-loss intervention in older adults with obesity., Methods: A 12-week pilot feasibility, non-randomized weight loss study of 28 older adults was conducted, consisting of individualized, weekly dietitian visits with twice weekly physical therapist-led group strengthening classes. Half consumed whey protein, three times weekly, following exercise. Preliminary efficacy measures of body composition, sit-to-stand, 6-min walk and grip strength and subjective measures of self-reported health and function were also evaluated., Results: Of the 37 enrolled, 28 completed the study (50 % in the protein group). Attendance rates for protein vs. non-protein groups were 89.9 ± 11.1 % vs. 95.6 ± 3.4 % (p = 0.08). Protein consumption was high in those attending classes (90.3 %) as was compliance at home (82.6 %). Whey was pleasant (67.3 ± 22.1, range 30-100, above average), had little aftertaste, and was neither salty or sticky. All were compliant (0.64 ± 0.84, range 0-5, low = higher compliance). Both groups lost significant weight (protein vs. no protein, -3.45 ± 2.86 vs. -5.79 ± 3.08, p = 0.47); Sit-to-stand, 6-min walk, and gait speed were no different, grip strength was improved in the protein compared to the non-protein group (-2.63 kg vs. 4.29 kg; p < 0.001)., Conclusions: Our results suggest that whey protein is a low-cost and readily available nutritional supplement that can be integrated into a weight loss intervention., Competing Interests: Declaration of Competing interest There are no conflicts of interest pertaining to this manuscript., (Copyright © 2021 European Society for Clinical Nutrition and Metabolism. Published by Elsevier Ltd. All rights reserved.)

Background: Nucleotide-specific 5-hydroxymethylcytosine (5hmC) remains understudied in pediatric central nervous system (CNS) tumors. 5hmC is abundant in the brain, and alterations to 5hmC in adult CNS tumors have been reported. However, traditional approaches to measure DNA methylation do not distinguish between 5-methylcytosine (5mC) and its oxidized counterpart 5hmC, including those used to build CNS tumor DNA methylation classification systems. We measured 5hmC and 5mC epigenome-wide at nucleotide resolution in glioma, ependymoma, and embryonal tumors from children, as well as control pediatric brain tissues using tandem bisulfite and oxidative bisulfite treatments followed by hybridization to the Illumina Methylation EPIC Array that interrogates over 860,000 CpG loci., Results: Linear mixed effects models adjusted for age and sex tested the CpG-specific differences in 5hmC between tumor and non-tumor samples, as well as between tumor subtypes. Results from model-based clustering of tumors was used to test the relation of cluster membership with patient survival through multivariable Cox proportional hazards regression. We also assessed the robustness of multiple epigenetic CNS tumor classification methods to 5mC-specific data in both pediatric and adult CNS tumors. Compared to non-tumor samples, tumors were hypohydroxymethylated across the epigenome and tumor 5hmC localized to regulatory elements crucial to cell identity, including transcription factor binding sites and super-enhancers. Differentially hydroxymethylated loci among tumor subtypes tended to be hypermethylated and disproportionally found in CTCF binding sites and genes related to posttranscriptional RNA regulation, such as DICER1. Model-based clustering results indicated that patients with low 5hmC patterns have poorer overall survival and increased risk of recurrence. Our results suggest 5mC-specific data from OxBS-treated samples impacts methylation-based tumor classification systems giving new opportunities for further refinement of classifiers for both pediatric and adult tumors., Conclusions: We identified that 5hmC localizes to super-enhancers, and genes commonly implicated in pediatric CNS tumors were differentially hypohydroxymethylated. We demonstrated that distinguishing methylation and hydroxymethylation is critical in identifying tumor-related epigenetic changes. These results have implications for patient prognostication, considerations of epigenetic therapy in CNS tumors, and for emerging molecular neuropathology classification approaches., (© 2021. The Author(s).)

DNA methylation (DNAm) alterations have been heavily implicated in carcinogenesis and the pathophysiology of diseases through upstream regulation of gene expression. DNAm deep-learning approaches are able to capture features associated with aging, cell type, and disease progression, but lack incorporation of prior biological knowledge. Here, we present modular, user-friendly deep-learning methodology and software, MethylCapsNet and MethylSPWNet, that group CpGs into biologically relevant capsules-such as gene promoter context, CpG island relationship, or user-defined groupings-and relate them to diagnostic and prognostic outcomes. We demonstrate these models' utility on 3,897 individuals in the classification of central nervous system (CNS) tumors. MethylCapsNet and MethylSPWNet provide an opportunity to increase DNAm deep-learning analyses' interpretability by enabling a flexible organization of DNAm data into biologically relevant capsules., (© 2021. The Author(s).)

As the United States population ages, managing pathologies that largely affect older adults, including sarcopenia (i.e., loss of muscle mass and strength) represents a significant and growing clinical challenge. In addition to increased rates of sarcopenia with age, its incidence and impact increase after acute illness, increasing the risk of functional decline, institutionalization, or death. Resistance-based exercises promote muscle regeneration and strength and are an advised therapy for such patients. Yet, such therapeutic exercises are normally conducted either under direct clinical oversight or unsupervised by patients at home, where compliance rates are low. The presented device, BandPass , aims to create an integrated force data detection and acquisition system for monitoring and transmitting at-home exercise force data to patients and clinicians. A potentiometer-based sensor was integrated to a resistance exercise band through the use of custom designed electronics, which incorporated Bluetooth Low Energy (BLE) for wireless transmission to a mobile 'app'. A protocol for calibrating the device was developed using a range of loads and validated in static benchtop and dynamic testing. Data from a pilot study with 7 older adults was also collected and analyzed to test the device. BandPass is 94% accurate with a coefficient of variation (CoV) of 4.9% and sensitivity of 150g. The pilot study recorded 147 exercises, allowing for analysis on patients' exercise performances. BandPass was successfully able to measure force continuously over time during exercises, measure longitudinal compliance with exercises, and quantify force continuously over time. A mobile health (mHealth) force-sensing system allows for the remote monitoring of prescribed in-home resistance exercise band programs for at-risk older adults, bridging the gap between clinicians and patients.

Background: Shared decision-making in cardiology is increasingly recommended to improve patient-centeredness of care. Decision aids can improve patient knowledge and decisional quality but are infrequently used in real-world practice. This mixed-methods study tests the efficacy and acceptability of a decision aid integrated into the electronic health record (Integrated Decision Aid [IDeA]) and delivered by clinicians for patients with atrial fibrillation considering options to reduce stroke risk. We aimed to determine whether the IDeA improves patient knowledge, reduces decisional conflict, and is seen as acceptable by clinicians and patients., Methods: A small cluster randomized trial included 6 cardiovascular clinicians and 66 patients randomized either to the IDeA (HealthDecision) or usual care (clinician discretion) during a clinical encounter when stroke prevention treatment options were discussed. The primary outcome was patient knowledge of personalized stroke risk. Exploratory outcomes included decisional conflict, values concordance, trust, the presence of a shared decision-making process, and patient knowledge related to time spent using the IDeA. Additionally, we conducted semistructured interviews with clinicians and patients who used the IDeA were conducted to assess acceptability and predictions of future use., Results: The IDeA significantly increased patients' knowledge of their stroke risk (odds ratio, 3.88 [95% CI, 1.39-10.78]; P <0.01]). Patients had less uncertainty about their final decision ( P =0.04). There were no significant differences in values concordance, trust in clinician or shared decision-making. Despite training, each clinician used the IDeA differently. Qualitative analysis revealed patients prefer using the IDeA earlier in their diagnosis. Clinicians were satisfied with the IDeA, yet varied in the contexts in which they planned to use it in the future., Conclusions: Using an Integrated Decision Aid, or IDeA, increases patient knowledge and lessens uncertainty for decision-making around stroke prevention in atrial fibrillation. Qualitative data provide insight into potential implementation strategies in real-world practice.

Type 2 diabetes mellitus represents a multi-dimensional challenge for European and global societies alike. Building on an iterative six-step disease management process that leverages feedback loops and utilizes commodity digital tools, the PDM-ProValue study program demonstrated that integrated personalized diabetes management, or iPDM, can improve the standard of care for persons living with diabetes in a sustainable way. The novel "iPDM Goes Europe" consortium strives to advance iPDM adoption by (1) implementing the concept in a value-based healthcare setting for the treatment of persons living with type 2 diabetes, (2) providing tools to assess the patient's physical and mental health status, and (3) exploring new avenues to take advantage of emerging big data resources., (Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Resistance-based exercises effectively enhance muscle strength, which is especially important in older populations as it reduces the risk of disability. Our group developed a Bluetooth-enabled handle for resistance exercise bands that wirelessly transmits relative force data through low-energy Bluetooth to a local smartphone or similar device. We present a usability assessment that evaluates an exercise system featuring a novel Bluetooth-enabled resistance exercise band, ultimately intended to expand the accessibility of resistance training through technology-enhanced home-based exercise programs for older adults. Although our target population is older adults, we assess the user experience among younger adults as a convenient and meaningful starting point in the testing and development of our device., Methods: There were 32 young adults participating in three exercise sessions with the exercise band, after which each completed an adapted version of the Usefulness, Satisfaction, and Ease (USE) questionnaire to characterize the exercise system's strengths and weaknesses in usability., Results: Questionnaire data reflected a positive and consistent user experience, with all 20 items receiving mean scores greater than 5.0 on a seven-point Likert scale. There were no specific areas of significant weakness in the device's user experience., Conclusions: The positive reception among young adults is a promising indication that the device can be successfully incorporated into exercise interventions and that the system can be further developed and tested for the target population of older adults., Competing Interests: Declaration of Interest The authors report no conflicts of interest.

Past social experience affects the circuitry responsible for producing and interpreting current behaviors. The social behavior network (SBN) is a candidate neural ensemble to investigate the consequences of early-life social isolation. The SBN interprets and produces social behaviors, such as vocalizations, through coordinated patterns of activity (functional connectivity) between its multiple nuclei. However, the SBN is relatively unexplored with respect to murine vocal processing. The serotonergic system is sensitive to past experience and innervates many nodes of the SBN; therefore, we tested whether serotonin signaling interacts with social experience to affect patterns of immediate early gene (IEG; cFos) induction in the male SBN following playback of social vocalizations. Male mice were separated into either social housing of three mice per cage or into isolated housing at 18-24 d postnatal. After 28-30 d in housing treatment, mice were parsed into one of three drug treatment groups: control, fenfluramine (FEN; increases available serotonin), or pCPA (depletes available serotonin) and exposed to a 60-min playback of female broadband vocalizations (BBVs). FEN generally increased the number of cFos-immunoreactive (-ir) neurons within the SBN, but effects were more pronounced in socially isolated mice. Despite a generalized increase in cFos immunoreactivity, isolated mice had reduced functional connectivity, clustering, and modularity compared with socially reared mice. These results are analogous to observations of functional dysconnectivity in persons with psychopathologies and suggests that early-life social isolation modulates serotonergic regulation of social networks., (Copyright © 2021 Petersen et al.)

Background: Assessing functional ability is an important component of understanding healthy aging. Objective measures of functional ability include grip strength, gait speed, sit-to-stand time, and 6-min walk distance. Using samples from a weight loss clinical trial in older adults with obesity, we examined the association between changes in physical function and DNA-methylation-based biological age at baseline and 12 weeks in 16 individuals. Peripheral blood DNA methylation was measured (pre/post) with the Illumina HumanMethylationEPIC array and the Hannum, Horvath, and PhenoAge DNA methylation age clocks were used. Linear regression models adjusted for chronological age and sex tested the relationship between DNA methylation age and grip strength, gait speed, sit-to-stand, and 6-min walk., Results: Participant mean weight loss was 4.6 kg, and DNA methylation age decreased 0.8, 1.1, and 0.5 years using the Hannum, Horvath, and PhenoAge DNA methylation clocks respectively. Mean grip strength increased 3.2 kg. Decreased Hannum methylation age was significantly associated with increased grip strength (β = -0.30, p = 0.04), and increased gait speed (β = 0.02, p = 0.05), in adjusted models. Similarly, decreased methylation age using the PhenoAge clock was associated with significantly increased gait speed (β = 0.02, p = 0.04). A decrease in Horvath DNA methylation age and increase in physical functional ability did not demonstrate a significant association., Conclusions: The observed relationship between increased physical functional ability and decreased biological age using DNA methylation clocks demonstrate the potential utility of DNA methylation clocks to assess interventional approaches to improve health in older obese adults., Trial Registration: National Institute on Aging (NIA), NCT03104192. Posted April 7, 2017, https://clinicaltrials.gov/ct2/show/NCT03104192.

Objective: Spinal manipulation (SM) is recommended for first-line treatment of patients with low back pain. Inadequate access to SM may result in inequitable spine care for older US adults, but the supply of clinicians who provide SM under Medicare is uncertain. The purpose of this study was to measure temporal trends and geographic variations in the supply of clinicians who provide SM to Medicare beneficiaries., Methods: Medicare is a US government-administered health insurance program that provides coverage primarily for older adults and people with disabilities. We used a serial cross-sectional design to examine Medicare administrative data from 2007 to 2015 for SM services identified by procedure code. We identified unique providers by National Provider Identifier and distinguished between chiropractors and other specialties by Physician Specialty Code. We calculated supply as the number of providers per 100 000 beneficiaries, stratified by geographic location and year., Results: Of all clinicians who provide SM to Medicare beneficiaries, 97% to 98% are doctors of chiropractic. The geographic supply of doctors of chiropractic providing SM services in 2015 ranged from 20/100 000 in the District of Columbia to 260/100 000 in North Dakota. The supply of other specialists performing the same services ranged from fewer than 1/100 000 in 11 states to 8/100 000 in Colorado. Nationally, the number of Medicare-active chiropractors declined from 47 102 in 2007 to 45 543 in 2015. The count of other clinicians providing SM rose from 700 in 2007 to 1441 in 2015., Conclusion: Chiropractors constitute the vast majority of clinicians who bill for SM services to Medicare beneficiaries. The supply of Medicare-active SM providers varies widely by state. The overall supply of SM providers under Medicare is declining, while the supply of nonchiropractors who provide SM is growing., (Copyright © 2021. Published by Elsevier Inc.)

Background: Older adults with obesity residing in rural areas have reduced access to weight management programs. We determined the feasibility, acceptability and preliminary outcomes of an integrated technology-based health promotion intervention in rural-living, older adults using remote monitoring and synchronous video-based technology., Methods: A 6-month, non-randomized, non-blinded, single-arm study was conducted from October 2018 to May 2020 at a community-based aging center of adults aged ≥65 years with a body mass index (BMI) ≥30 kg/m 2 . Weekly dietitian visits focusing on behavior therapy and caloric restriction and twice-weekly physical therapist-led group strength, flexibility and balance training classes were delivered using video-conferencing to participants in their homes. Participants used a Fitbit Alta HR for remote monitoring with data feedback provided by the interventionists. An aerobic activity prescription was provided and monitored., Results: Mean age was 72.9±3.9 years (82% female). Baseline anthropometric measures of weight, BMI, and waist circumference were 97.8±16.3 kg, 36.5±5.2 kg/m 2 , and 115.5±13.0 cm, respectively. A total of 142 participants were screened (n=27 ineligible), and 53 consented. There were nine dropouts (17%). Overall satisfaction with the trial (4.7+ 0.6, scale: 1 (low) to 5 (high)) and with Fitbit (4.2+ 0.9) were high. Fitbit was worn an average of 81.7±19.3% of intervention days. In completers, mean weight loss was 4.6±3.5 kg or 4.7±3.5% (p< 0.001). Physical function measures of 30-s sit-to-stand repetitions increased from 13.5±5.7 to 16.7±5.9 (p< 0.001), 6-min walk improved by 42.0±77.3 m (p=0.005) but no differences were observed in gait speed or grip strength. Subjective measures of late-life function improved (3.4±4.7 points, p< 0.001)., Conclusions: A technology-based obesity intervention is feasible and acceptable to older adults with obesity and may lead to weight loss and improved physical function., Clinical Trial Registration: Registered on Clinicaltrials.gov # NCT03104205 . Registered on April 7, 2017. First participant enrolled on October 1st, 2018.

Background: Older persons with obesity aged 65+ residing in rural areas have reduced access to weight management programs due to geographic isolation. The ability to integrate technology into health promotion interventions shows a potential to reach this underserved population., Methods: A 12-week pilot in 28 older rural adults with obesity (body mass index [BMI] ≥ 30 kg/m2) was conducted at a community aging center. The intervention consisted of individualized, weekly dietitian visits focusing on behavior therapy and caloric restriction with twice weekly physical therapist-led group strengthening training classes in a community-based aging center. All participants were provided a Fitbit Flex 2. An aerobic activity prescription outside the strength training classes was provided., Results: Mean age was 72.9 ± 5.3 years (82% female). Baseline BMI was 37.1 kg/m2, and waist circumference was 120.0 ± 33.0 cm. Mean weight loss (pre/post) was 4.6 ± 3.2 kg (4.9 ± 3.4%; p < .001). Of the 40 eligible participants, 33 (75%) enrolled, and the completion rate was high (84.8%). Objective measures of physical function improved at follow-up: 6-minute walk test improved: 35.7 ± 41.2 m (p < .001); gait speed improved: 0.10 ± 0.24 m/s (p = .04); and five-times sit-to-stand improved by 2.1 seconds (p < .001). Subjective measures of late-life function improved (5.2 ± 7.1 points, p = .003), as did Patient-Reported Outcome Measurement Information Systems mental and physical health scores (5.0 ± 5.7 and 4.4 ± 5.0, both p < .001). Participants wore their Fitbit 93.9% of all intervention days, and were overall satisfied with the trial (4.5/5.0, 1-5 low-high) and with Fitbit (4.0/5.0)., Conclusions: A multicomponent obesity intervention incorporating a wearable device is feasible and acceptable to older adults with obesity, and potentially holds promise in enhancing health., (© The Author(s) 2020. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background and Aims: Obesity significantly impacts older adults. Intensive nutrition counseling can aid in weight reduction and improve diet quality, but data are sparse in this population. The objective of this intervention is to determine how intensive nutrition counseling affects diet quality and anthropometric measures during a multi-component weight loss intervention in rural older adults with obesity., Methods: A series of 12-week, single-arm feasibility pilots were conducted in fall 2017 and winter/spring 2018 in a community aging center in rural Northern New England. Adults were eligible if ≥ 65 years old with a Body Mass Index (BMI) ≥30 kg/m 2 . Exclusion criteria included dementia/cognitive impairment, uncontrolled psychiatric illness, weight-loss surgery, weight loss >5% in previous 6-months, life-threatening illness, palliative/hospice services, current participation in another weight-loss study/program, obesogenic medications, or presence of major chronic conditions. Participants received once-weekly nutrition counseling by a registered dietitian nutritionist (RDN), and twice-weekly exercise sessions by a physical therapist (PT). Primary outcomes were diet quality changes measured by total Rapid Eating and Activity Assessment for Patients-Short Version (REAP-S) and Automated Self-Administered 24-h dietary recall (ASA-24). Secondary outcome measures were changes in weight (kilograms) and waist circumference (centimeters). McNemar test was conducted for all paired categorical data while paired t-tests were conducted for all paired continuous data. All analyses were conducted in R; p-value<0.05 was significant., Results: Total n = 23. Mean age was 72.2 (5.8) years (73.9% female); mean BMI was 35.9 ± 5.0 kg/m 2 . At 12 weeks, diet quality significantly improved. REAP-S scores increased by 3.53 ± 3.13 points (p < 0.001). Kilocalories, grams fat, grams saturated fat, milligrams sodium, grams added sugar, and grams alcohol via ASA-24 significantly decreased (all p < 0.05). Significant reductions in weight (-5.22 ± 3.13 kg) and waist circumference (-6.88 ± 5.67 cm) were observed (both p < 0.001)., Conclusion: Intensive nutrition counseling significantly enhances diet quality and reduces weight and waist circumference in rural older adults with obesity., Competing Interests: Conflict of interest Dr. Batsis has consulted for Dinse, Knapp McAndrew LLC, legal firm for expert testimony, and received honoraria for grant review activities from the National Institute of Health, the European Research Foundation, and the Irish Medical Council. He has received honoraria for speaking at the Endocrine Society annual meeting and holds a preliminary patent #62/672,827 for a Bluetooth-enabled resistance exercise band., (Copyright © 2020 European Society for Clinical Nutrition and Metabolism. Published by Elsevier Ltd. All rights reserved.)

Sarcopenia is the age-related loss of muscle mass and strength that is associated with adverse health outcomes. Resistance-based exercises are effective for mitigation and enhancement of strength; however, adherence is low and challenging to measure when patients are at home. In a single-arm, pilot study of seven older adults, we conducted a field-based usability study evaluating the feasibility and acceptability of using a system consisting of a Bluetooth-connected resistance exercise band and tablet-based app which together we call BandPass in completing four different home-based exercises. The system measured a total of 147 exercises by participants with a mean duration of 94±66 seconds, completing an average of 30±20 repetitions. Though not all patients completed each exercise type, patients were positive about use: patient activation measure: 80.7±14; system usability scale: 6.9±2.9; and confidence in use: 7.7±2.7. The BandPass system demonstrated its ability to collect data on exercise type, force during an exercise, and duration of exercise when older adults use it for monitoring exercise at home.

Background: Multiple studies have related psychiatric disorders and immune alterations. Panic disorder (PD) has been linked with changes in leukocytes distributions in several small studies using different methods for immune characterization. Additionally, alterations in the methylation of repetitive DNA elements, such as LINE-1, have been associated with mental disorders. Here, we use peripheral blood DNA methylation data from two studies and an updated DNA methylation deconvolution library to investigate the relation of leukocyte proportions and methylation status of repetitive elements in 133 patients with panic disorder compared with 118 controls., Methods and Results: We used DNA methylation data to deconvolute leukocyte cell-type proportions and to infer LINE-1 element methylation comparing PD cases and controls. We also identified differentially methylated CpGs associated with PD using an epigenome-wide association study approach (EWAS), with models adjusting for sex, age, and cell-type proportions. Individuals with PD had a lower proportion of CD8T cells (OR: 0.86, 95% CI: 0.78-0.96, P-adj = 0.030) when adjusting for age, sex, and study compared with controls. Also, PD cases had significantly lower LINE-1 repetitive element methylation than controls (P < 0.001). The EWAS identified 61 differentially methylated CpGs (58 hypo- and 3 hypermethylated) in PD (Bonferroni adjusted P < 1.33 × 10 -7 )., Conclusions: These results suggest that those with panic disorder have changes to their immune system and dysregulation of repeat elements relative to controls.

Background: Deep diaphragmatic breathing, also called belly breathing, is a popular behavioral intervention that helps children cope with anxiety, stress, and their experience of pain. Combining physiological monitoring with accessible mobile technology can motivate children to comply with this intervention through biofeedback and gaming. These innovative technologies have the potential to improve patient experience and compliance with strategies that reduce anxiety, change the experience of pain, and enhance self-regulation during distressing medical procedures., Objective: The aim of this paper was to describe a simple biofeedback method for quantifying breathing compliance in a mobile smartphone app., Methods: A smartphone app was developed that combined pulse oximetry with an animated protocol for paced deep breathing. We collected photoplethysmogram data during spontaneous and subsequently paced deep breathing in children. Two measures, synchronized respiratory sinus arrhythmia (RSA sync ) and the corresponding relative synchronized inspiration/expiration heart rate ratio (HR-I:E sync ), were extracted from the photoplethysmogram., Results: Data collected from 80 children aged 5-17 years showed a positive RSA sync effect in all participants during paced deep breathing, with a median (IQR; range) HR-I:E sync ratio of 1.26 (1.16-1.35; 1.01-1.60) during paced deep breathing compared to 0.98 (0.96-1.02; 0.82-1.18) during spontaneous breathing (median difference 0.25, 95% CI 0.23-0.30; P<.001). The measured HR-I:E sync values appeared to be independent of age., Conclusions: An HR-I:E sync level of 1.1 was identified as an age-independent threshold for programming the breathing pattern for optimal compliance in biofeedback., (©Christian L Petersen, Matthias Görges, Evgenia Todorova, Nicholas C West, Theresa Newlove, J Mark Ansermino. Originally published in JMIR Perioperative Medicine (http://periop.jmir.org), 23.09.2020.)

Background: Sarcopenia, defined as the age-associated loss of muscle mass and strength, can be effectively mitigated through resistance-based physical activity. With compliance at approximately 40% for home-based exercise prescriptions, implementing a remote sensing system would help patients and clinicians to better understand treatment progress and increase compliance. The inclusion of end users in the development of mobile apps for remote-sensing systems can ensure that they are both user friendly and facilitate compliance. With advancements in natural language processing (NLP), there is potential for these methods to be used with data collected through the user-centered design process., Objective: This study aims to develop a mobile app for a novel device through a user-centered design process with both older adults and clinicians while exploring whether data collected through this process can be used in NLP and sentiment analysis., Methods: Through a user-centered design process, we conducted semistructured interviews during the development of a geriatric-friendly Bluetooth-connected resistance exercise band app. We interviewed patients and clinicians at weeks 0, 5, and 10 of the app development. Each semistructured interview consisted of heuristic evaluations, cognitive walkthroughs, and observations. We used the Bing sentiment library for a sentiment analysis of interview transcripts and then applied NLP-based latent Dirichlet allocation (LDA) topic modeling to identify differences and similarities in patient and clinician participant interviews. Sentiment was defined as the sum of positive and negative words (each word with a +1 or -1 value). To assess utility, we used quantitative assessment questionnaires-System Usability Scale (SUS) and Usefulness, Satisfaction, and Ease of use (USE). Finally, we used multivariate linear models-adjusting for age, sex, subject group (clinician vs patient), and development-to explore the association between sentiment analysis and SUS and USE outcomes., Results: The mean age of the 22 participants was 68 (SD 14) years, and 17 (77%) were female. The overall mean SUS and USE scores were 66.4 (SD 13.6) and 41.3 (SD 15.2), respectively. Both patients and clinicians provided valuable insights into the needs of older adults when designing and building an app. The mean positive-negative sentiment per sentence was 0.19 (SD 0.21) and 0.47 (SD 0.21) for patient and clinician interviews, respectively. We found a positive association with positive sentiment in an interview and SUS score (ß=1.38; 95% CI 0.37 to 2.39; P=.01). There was no significant association between sentiment and the USE score. The LDA analysis found no overlap between patients and clinicians in the 8 identified topics., Conclusions: Involving patients and clinicians allowed us to design and build an app that is user friendly for older adults while supporting compliance. This is the first analysis using NLP and usability questionnaires in the quantification of user-centered design of technology for older adults., (©Curtis Lee Petersen, Ryan Halter, David Kotz, Lorie Loeb, Summer Cook, Dawna Pidgeon, Brock C Christensen, John A Batsis. Originally published in JMIR mHealth and uHealth (http://mhealth.jmir.org), 07.08.2020.)

Background: Self-reported weight change may lead to adverse outcomes. We evaluated weight change with cutpoints of low lean mass (LLM) in older adults., Methods: Of 4984 subjects ≥60 years from NHANES 1999-2004, we applied LLM cutoffs of appendicular lean mass (ALM):body mass index (BMI) males<0.789, females<0.512. Self-reported weight was assessed at time of survey, and questions asked participants their weight one and 10 years earlier, and at age 25. Weight changes were categorized as greater/less/none than 5%. Logistic regression assessed weight change (gain, loss, no change) on LLM, after adjustment., Results: Of 4984 participants (56.5% female), mean age and BMI were 71.1 years and 28.2 kg/m 2 . Mean ALM was 19.7 kg. In those with LLM, 13.5% and 16.3% gained/lost weight in the past year, while 48.9% and 19.4% gained/lost weight in the past decade. Compared to weight at age 25, 85.2 and 6.1% of LLM participants gained and lost ≥5% of their weight, respectively. Weight gain over the past year was associated with a higher risk of LLM (OR 1.35 [0.99,1.87]) compared to weight loss ≥5% over the past year (0.89 [0.70,1.12]). Weight gain (≥5%) over 10-years was associated with a higher risk of LLM (OR 2.03 [1.66, 2.49]) while weight loss (≥5%) was associated with a lower risk (OR 0.98 [0.76,1.28]). Results were robust compared to weight at 25 years (gain OR 2.37 [1.76,3.20]; loss OR 0.95 [0.65,1.39])., Conclusion: Self-reported weight gain suggests an increased risk of LLM. Future studies need to verify the relationship with physical function., Competing Interests: Conflicts of interest There are no conflicts of interest pertaining to this manuscript., (Copyright © 2019 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.)