Clinical Utility of Thigh and Mid-Thigh Dual-Energy x-Ray Absorptiometry to Identify Bone and Muscle Loss.

Sarcopenia and osteoporosis are highly prevalent syndromes in older people, characterized by loss of muscle and bone tissue, and related to adverse outcomes. Previous reports indicate mid-thigh dual-energy X-ray absorptiometry (DXA) is well suited for the simultaneous assessment of bone, muscle, and fat mass in a single scan. Using cross-sectional clinical data and whole-body DXA images of 1322 community-dwelling adults from the Geelong Osteoporosis Study (57% women, median age 59 years), bone and lean mass were quantified in three unconventional regions of interest (ROIs): (i) a 2.6-cm-thick slice of mid-thigh, (ii) a 13-cm-thick slice of mid-thigh, and (iii) the whole thigh. Conventional indices of tissue mass were also calculated (appendicular lean mass [ALM] and bone mineral density [BMD] of lumbar spine, hip, and femoral neck). The performance of thigh ROIs in identifying osteoporosis, osteopenia, low lean mass and strength, past falls, and fractures was evaluated. All thigh regions (especially whole thigh) performed well in identifying osteoporosis (area under the receiver-operating characteristic [ROC] curve [AUC] > 0.8) and low lean mass (AUC >0.95), but they performed worse in the diagnosis of osteopenia (AUC 0.7-0.8). All thigh regions were equivalent to ALM in discrimination of poor handgrip strength, gait speed, past falls, and fractures. BMD in conventional regions was more strongly associated with past fractures than thigh ROIs. In addition to being faster and easier to quantify, mid-thigh tissue masses can be used for identifying osteoporosis and low lean mass. They are also equivalent to conventional ROIs in their associations with muscle performance, past falls, and fractures; however, further validation is required for the prediction of fractures. © 2022 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

Appendicular and mid-thigh lean mass are associated with muscle strength, physical performance, and dynamic balance in older persons at high risk of falls.

BACKGROUND: Falls in older persons are associated with muscle mass and strength alterations, which may also affect balance parameters. However, the most appropriate combined approach to assess muscle and balance components that predict falls in older persons is still lacking. RESEARCH QUESTION: We hypothesized that appendicular lean and/or mid-thigh mass and muscle strength and performance are positively associated with balance indices and fall risk in older persons. METHODS: Cross-sectional analyses of retrospective data from 260 participants with risk and/or history of falls examined at a Falls and Fracture Clinic. Assessments included a comprehensive clinical exam, bone densitometry and body composition by DXA, grip strength, gait speed, posturography, timed up and go (TUG) and four-square step (FSST) tests. Retrospective falls and fracture history was collected. Associations between appendicular and mid-thigh lean mass and muscle strength/performance vs balance indicators were determined before and after adjusting for age and gender. RESULTS: Mean age of participants was 78 ± 6.7 (65-96) years. Both appendicular and mid-thigh lean masses corrected for BMI (but not for height2), and muscle strength and performance measures are associated with better dynamic balance. Conversely, static balance indicators showed less consistent associations with lean mass. Only TUG and sit to stand time consistently showed significant associations with most static balance indicators. SIGNIFICANCE: Combined with strength and performance parameters, ALM and mid-thigh estimates adjusted by BMI strongly correlate with dynamic balance parameters and could become practical elements of falls risk assessment as well as markers of therapeutic response to falls prevention interventions.

Intermittent fasting and continuous energy restriction result in similar changes in body composition and muscle strength when combined with a 12 week resistance training program.

PURPOSE: The objective of this study was to compare the effects of 12 weeks of resistance training combined with either 5:2 intermittent fasting or continuous energy restriction on body composition, muscle size and quality, and upper and lower body strength. METHODS: Untrained individuals undertook 12 weeks of resistance training plus either continuous energy restriction [20% daily energy restriction (CERT)] or 5:2 intermittent fasting [~ 70% energy restriction 2 days/week, euenergetic consumption 5 days/week (IFT)], with both groups prescribed a mean of ≥ 1.4 g of protein per kilogram of body weight per day. Participants completed 2 supervised resistance and 1 unsupervised aerobic/resistance training combination session per week. Changes in lean body mass (LBM), thigh muscle size and quality, strength and dietary intake were assessed. RESULTS: Thirty-four participants completed the study (CERT = 17, IFT = 17). LBM was significantly increased (+ 3.7%, p < 0.001) and body weight (- 4.6%, p < 0.001) and fat (- 24.1%, p < 0.001) were significantly reduced with no significant difference between groups, though results differed by sex. Both groups showed improvements in thigh muscle size and quality, and reduced intramuscular and subcutaneous fat assessed by ultrasonography and peripheral quantitative computed tomography (pQCT), respectively. The CERT group demonstrated a significant increase in muscle surface area assessed by pQCT compared to the IFT group. Similar gains in upper and lower body strength and muscular endurance were observed between groups. CONCLUSION: When combined with resistance training and moderate protein intake, continuous energy restriction and 5:2 intermittent fasting resulted in similar improvements in body composition, muscle quality, and strength. ACTRN: ACTRN12620000920998, September 2020, retrospectively registered.

Validation of a Semiautomatic Image Analysis Software for the Quantification of Musculoskeletal Tissues.

Accurate quantification of bone, muscle, and their components is still an unmet need in the musculoskeletal field. Current methods to quantify tissue volumes in 3D images are expensive, labor-intensive, and time-consuming; thus, a reliable, valid, and quick application is highly needed. Tissue Compass is a standalone software for semiautomatic segmentation and automatic quantification of musculoskeletal organs. To validate the software, cross-sectional micro-CT scans images of rat femur (n = 19), and CT images of hip and abdomen (n = 100) from the Osteoporotic Fractures in Men (MrOS) Study were used to quantify bone, hematopoietic marrow (HBM), and marrow adipose tissue (MAT) using commercial manual software as a comparator. Also, abdominal CT scans (n = 100) were used to quantify psoas muscle volumes and intermuscular adipose tissue (IMAT) using the same software. We calculated Pearson's correlation coefficients, individual intra-class correlation coefficients (ICC), and Bland-Altman limits of agreement together with Bland-Altman plots to show the inter- and intra-observer agreement between Tissue Compass and commercially available software. In the animal study, the agreement between Tissue Compass and commercial software was r > 0.93 and ICC > 0.93 for rat femur measurements. Bland-Altman limits of agreement was - 720.89 (- 1.5e+04, 13,074.00) for MAT, 4421.11 (- 1.8e+04, 27,149.73) for HBM and - 6073.32 (- 2.9e+04, 16,388.37) for bone. The inter-observer agreement for QCT human study between two observers was r > 0.99 and ICC > 0.99. Bland-Altman limits of agreement was 0.01 (- 0.07, 0.10) for MAT in hip, 0.02 (- 0.08, 0.12) for HBM in hip, 0.05 (- 0.15, 0.25) for bone in hip, 0.02 (- 0.18, 0.22) for MAT in L1, 0.00 (- 0.16, 0.16) for HBM in L1, and 0.02 (- 0.23, 0.27) for bone in L1. The intra-observer agreement for QCT human study between the two applications was r > 0.997 and ICC > 0.99. Bland-Altman limits of agreement was 0.03 (- 0.13, 0.20) for MAT in hip, 0.05 (- 0.08, 0.18) for HBM in hip, 0.05 (- 0.24, 0.34) for bone in hip, - 0.02 (- 0.34, 0.31) for MAT in L1, - 0.14 (- 0.44, 0.17) for HBM in L1, - 0.29 (- 0.62, 0.05) for bone in L1, 0.03 (- 0.08, 0.15) for IMAT in psoas, and 0.02 (- 0.35, 0.38) for muscle in psoas. Compared to a conventional application, Tissue Compass demonstrated high accuracy and non-inferiority while also facilitating easier analyses. Tissue Compass could become the tool of choice to diagnose tissue loss/gain syndromes in the future by requiring a small number of CT sections to detect tissue volumes and fat infiltration.

Muscle Volume and Intramuscular Fat of the Tongue Evaluated With MRI Predict Malnutrition in People Living With Dementia: A 5-Year Follow-up Study.

Malnutrition is highly prevalent in older persons with dementia. Therefore, strong predictors of malnutrition in this population are crucial to initiating early interventions. This study evaluates the association between the probability of having malnutrition with the muscle volume and intramuscular fat (iMAT) of the masseter and the tongue in magnetic resonance imaging (MRI) of community-dwelling older persons diagnosed with mild dementia followed up for 5 years. This is a longitudinal study conducted in the western part of Norway. Muscle volume and iMAT of the tongue and masseter were computed from structural head MRI obtained from 65 participants of the Dementia Study of Western Norway using Slice-O-Matic software for segmentation. Malnutrition was assessed using the Global Leadership Initiative on Malnutrition Index. Linear mixed models were conducted. Having malnutrition at baseline was associated with lower muscle volume (odds ratio [OR] 0.60, standard error [SE] 0.20; p = .010) and higher iMAT (OR 3.31, SE 0.46; p = .010) in the tongue. At 5 years follow-up, those with lower muscle volume (OR 0.55, SE 0.20; p = .002) and higher iMAT (OR 2.52, SE 0.40; p = .022) in the tongue had a higher probability of presenting malnutrition. The masseter iMAT and volume were not associated with malnutrition in any of the adjusted models. In people diagnosed with mild dementia, tongue muscle volume and iMAT were associated with baseline malnutrition and the probability of developing malnutrition in a 5-year trajectory. In the masseter, there were no significant associations after adjustments.

Characterization of Skeletal Phenotype and Associated Mechanisms With Chronic Intestinal Inflammation in the Winnie Mouse Model of Spontaneous Chronic Colitis.

BACKGROUND: Osteoporosis is a common extraintestinal manifestation of inflammatory bowel disease (IBD). However, studies have been scarce, mainly because of the lack of an appropriate animal model of colitis-associated bone loss. In this study, we aimed to decipher skeletal manifestations in the Winnie mouse model of spontaneous chronic colitis, which carries a MUC2 gene mutation and closely replicates ulcerative colitis. In our study, Winnie mice, prior to the colitis onset at 6 weeks old and progression at 14 and 24 weeks old, were compared with age-matched C57BL/6 controls. We studied several possible mechanisms involved in colitis-associated bone loss. METHODS: We assessed for bone quality (eg, microcomputed tomography [micro-CT], static and dynamic histomorphometry, 3-point bending, and ex vivo bone marrow analysis) and associated mechanisms (eg, electrochemical recordings for gut-derived serotonin levels, real-time polymerase chain reaction [qRT-PCR], double immunofluorescence microscopy, intestinal inflammation levels by lipocalin-2 assay, serum levels of calcium, phosphorus, and vitamin D) from Winnie (6-24 weeks) and age-matched C57BL6 mice. RESULTS: Deterioration in trabecular and cortical bone microarchitecture, reductions in bone formation, mineral apposition rate, bone volume/total volume, osteoid volume/bone surface, and bone strength were observed in Winnie mice compared with controls. Decreased osteoblast and increased osteoclast numbers were prominent in Winnie mice compared with controls. Upregulation of 5-HTR1B gene and increased association of FOXO1 with ATF4 complex were identified as associated mechanisms concomitant to overt inflammation and high levels of gut-derived serotonin in 14-week and 24-week Winnie mice. CONCLUSIONS: Skeletal phenotype of the Winnie mouse model of spontaneous chronic colitis closely represents manifestations of IBD-associated osteoporosis/osteopenia. The onset and progression of intestinal inflammation are associated with increased gut-derived serotonin level, increased bone resorption, and decreased bone formation.

Frailty in Stroke-A Narrated Review.

This narrative review provides a summary introduction to the relationship between stroke and physical and cognitive frailty syndromes and the neuro-inflammatory similarities (including inflammaging) between the two. The review argues the potential effects of Post COVID-19 Neurological Syndrome (PCNS, also known as Long COVID) with similar pathophysiology. Many patients who have suffered from acute stroke experience long-lasting symptoms affecting several organs including fatigue, brain fog, reduced physical activity, loss of energy, and loss of cognitive reserve, culminating in the loss of independence and poor quality of life. This is very similar to the emerging reports of PCNS from different parts of the world. Stroke, particularly in older adults with comorbidities appears to impact the health and welfare of patients by reducing central neuronal input and neuromuscular function, with muscular atrophy and neuropsychiatric complications. The cumulative effects can potentially lead to a range of physical and cognitive frailty syndromes, which, in many cases may be attributed to persistent, maladapted, low grade, chronic inflammation. Meanwhile, post-COVID-19 Neurological Syndrome (also known as Long COVID Syndrome) appears to share a similar trajectory, adding further urgency for investigations into the mechanisms underlying this constellation of symptoms.

Evaluating the toxicity of escalating dose of oral picolinic acid in Sprague-Dawley rats.

Picolinic acid (PIC) is a byproduct of tryptophan catabolism through the kynurenine pathway, with anabolic effects on bone in vivo and in vitro. Hence, PIC has been nominated as a possible candidate to treat and/or prevent osteoporosis. However, the effective dose and toxicity of PIC are not known yet. To test the effect of escalating and very high doses of oral PIC, male Sprague-Dawley rats were gavaged PIC: Group 1 (n = 3) received incremental doses of 125, 250 and 500 mg/kg/day PIC on days 1, 3 and 5. Group 2 (n = 3) received 500 mg/kg BID (8 h apart; i.e. 1000 mg/kg/day) PIC on Day 1. Group 3 (n = 3) received 125 mg/kg/day PIC for seven consecutive days. Group 4 (n = 3) received 250 mg/kg/day PIC for seven consecutive days. Groups 1, 3 and 4 rats were euthanized on Day 8. Group 5 (n = 6) received 500 mg/kg/day PIC for two consecutive days and then once a week dose (Days 9, 16 and 23) of 500 mg/kg/dose PIC, until euthanasia (Day 30). Blood and cerebrospinal fluid (CSF) were sampled at euthanasia, and tissues showing abnormalities at necropsy underwent histopathology evaluation. All rats displayed some degree of mild hypercalcemia and hyperkalemia. Rats receiving high doses (500 or 1000 mg/kg/day) of PIC died or were euthanized on humane grounds within the first week after showing clinical neurological signs, with animals later revealed to have brain necrosis and hemorrhage at histopathology. Rats receiving lower doses (125 or 250 mg/kg/day) of PIC completed treatment course without apparent clinical adverse events. In summary, very high doses of PIC (≥500 mg/kg/day) were vascular-neurotoxic. Possible future experiments must consider significantly lower doses.

Experimental Methods to Study the Pathogenesis of Human Enteric RNA Viruses.

Every year, millions of children are infected with viruses that target the gastrointestinal tract, causing acute gastroenteritis and diarrheal illness. Indeed, approximately 700 million episodes of diarrhea occur in children under five annually, with RNA viruses norovirus, rotavirus, and astrovirus serving as major causative pathogens. Numerous methodological advancements in recent years, including the establishment of novel cultivation systems using enteroids as well as the development of murine and other animal models of infection, have helped provide insight into many features of viral pathogenesis. However, many aspects of enteric viral infections remain elusive, demanding further study. Here, we describe the different in vitro and in vivo tools available to explore different pathophysiological attributes of human enteric RNA viruses, highlighting their advantages and limitations depending upon the question being explored. In addition, we discuss key areas and opportunities that would benefit from further methodological progress.

Body composition reference ranges in community-dwelling adults using dual-energy X-ray absorptiometry: the Australian Body Composition (ABC) Study.

BACKGROUND: Reference ranges for lean mass (LM) and fat mass (FM) are essential in identifying soft tissue disorders; however, no such reference ranges exist for the most commonly used Hologic dual-energy X-ray absorptiometry (DXA) machine in Australia. METHODS: Cross-sectional study of community-dwelling adults (aged 18-88 years) who underwent a Hologic DXA scan at one of three commercialized densitometry centres in Australia. Age-specific and sex-specific percentile curves were generated for LM [LM, appendicular lean mass (ALM), ALM adjusted for height squared (ALM/h2 ), and ALM adjusted for body mass index (ALM/BMI)] and FM [FM, FM adjusted for height squared (FM/h2 ), appendicular fat mass, and android and gynoid fat] parameters using the LMS statistical method. Cutpoints equivalent to T-scores of -1, -2, and -2.5 standard deviations below the young mean reference group (20-29 years) were also generated for LM parameters. RESULTS: A total of 15 479 community-dwelling adults (54% men) with a median age of 33 years (interquartile range: 28, 42) were included. LM, ALM, and ALM/h2 remained stable until age 50, after which these parameters started to decline in both sexes. Compared with age 50, median percentiles of LM, ALM, and ALM/h2 declined by -5.9 kg, -3.7 kg, and -0.86 kg/m2 in men and by -2.5 kg, -1.8 kg, and -0.10 kg/m2 in women at age 70, respectively. Adjusting ALM for BMI (rather than height squared) resulted in different trends, with ALM/BMI decreasing from as early as age 20. Compared with age 20, median percentiles of ALM/BMI at age 40 declined by -0.10 kg/kg/m2 in men and by -0.06 kg/kg/m2 in women; and at age 70, ALM/BMI declined by -0.25 kg/kg/m2 in men and by -0.20 kg/kg/m2 in women. Cutpoints equivalent to T-scores of -1, -2, and -2.5 standard deviations for ALM/BMI were 1.01, 0.86, and 0.77 kg/kg/m2 in men and 0.70, 0.59, and 0.53 kg/kg/m2 in women, respectively. All FM parameters progressively increased from age 20 and continued up until age 70. CONCLUSIONS: We developed reference ranges for LM and FM parameters from Hologic DXA machines in a large cohort of Australian adults, which will assist researchers and clinicians in identifying soft tissue disorders such as obesity, sarcopenia, and cachexia.

Uncovering the Bone-Muscle Interaction and Its Implications for the Health and Function of Older Adults (the Wellderly Project): Protocol for a Randomized Controlled Crossover Trial.

BACKGROUND: Bone and muscle are closely linked anatomically, biochemically, and metabolically. Acute exercise affects both bone and muscle, implying a crosstalk between the two systems. However, how these two systems communicate is still largely unknown. We will explore the role of undercarboxylated osteocalcin (ucOC) in this crosstalk. ucOC is involved in glucose metabolism and has a potential role in muscle maintenance and metabolism. OBJECTIVE: The proposed trial will determine if circulating ucOC levels in older adults at baseline and following acute exercise are associated with parameters of muscle function and if the ucOC response to exercise varies between older adults with low muscle quality and those with normal or high muscle quality. METHODS: A total of 54 men and women aged 60 years or older with no history of diabetes and warfarin and vitamin K use will be recruited. Screening tests will be performed, including those for functional, anthropometric, and clinical presentation. On the basis of muscle quality, a combined equation of lean mass (leg appendicular skeletal muscle mass in kg) and strength (leg press; one-repetition maximum), participants will be stratified into a high or low muscle function group and randomized into the controlled crossover acute intervention. Three visits will be performed approximately 7 days apart, and acute aerobic exercise, acute resistance exercise, and a control session (rest) will be completed in any order. Our primary outcome for this study is the effect of acute exercise on ucOC in older adults with low muscle function and those with high muscle function. RESULTS: The trial is active and ongoing. Recruitment began in February 2018, and 38 participants have completed the study as of May 26, 2019. CONCLUSIONS: This study will provide novel insights into bone and muscle crosstalk in older adults, potentially identifying new clinical biomarkers and mechanistic targets for drug treatments for sarcopenia and other related musculoskeletal conditions. TRIAL REGISTRATION: Australia New Zealand Clinical Trials Registry ACTRN12618001756213; https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=375925. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/18777.

Norovirus evolution in immunodeficient mice reveals potentiated pathogenicity via a single nucleotide change in the viral capsid.

Interferons (IFNs) are key controllers of viral replication, with intact IFN responses suppressing virus growth and spread. Using the murine norovirus (MNoV) system, we show that IFNs exert selective pressure to limit the pathogenic evolutionary potential of this enteric virus. In animals lacking type I IFN signaling, the nonlethal MNoV strain CR6 rapidly acquired enhanced virulence via conversion of a single nucleotide. This nucleotide change resulted in amino acid substitution F514I in the viral capsid, which led to >10,000-fold higher replication in systemic organs including the brain. Pathogenicity was mediated by enhanced recruitment and infection of intestinal myeloid cells and increased extraintestinal dissemination of virus. Interestingly, the trade-off for this mutation was reduced fitness in an IFN-competent host, in which CR6 bearing F514I exhibited decreased intestinal replication and shedding. In an immunodeficient context, a spontaneous amino acid change can thus convert a relatively avirulent viral strain into a lethal pathogen.

Murine astrovirus tropism for goblet cells and enterocytes facilitates an IFN-λ response in vivo and in enteroid cultures.

Although they globally cause viral gastroenteritis in children, astroviruses are understudied due to the lack of well-defined animal models. While murine astroviruses (muAstVs) chronically infect immunodeficient mice, a culture system and understanding of their pathogenesis is lacking. Here, we describe a platform to cultivate muAstV using air-liquid interface (ALI) cultures derived from mouse enteroids, which support apical infection and release. Chronic muAstV infection occurs predominantly in the small intestine and correlates with higher interferon-lambda (IFN-λ) expression. MuAstV stimulates IFN-λ production in ALI, recapitulating our in vivo findings. We demonstrate that goblet cells and enterocytes are targets for chronic muAstV infection in vivo, and that infection is enhanced by parasite co-infection or type 2 cytokine signaling. Depletion of goblet cells from ALI limits muAstV infection in vitro. During chronic infection, muAstV stimulates IFN-λ production in infected cells and induces ISGs throughout the intestinal epithelium in an IFN-λ-receptor-dependent manner. Collectively, our study provides insights into the cellular tropism and innate immune responses to muAstV and establishes an enteroid-based culture system to propagate muAstV in vitro.

Long-term outcomes of warfarin versus aspirin after Fontan surgery.

OBJECTIVES: Because of the nature of the Fontan physiology, patients are at an increased risk of thromboembolic complications. As such, warfarin or aspirin is generally prescribed lifelong for thromboprophylaxis. This study aimed to compare long-term rates of cerebrovascular injury, thrombosis, bleeding, bone mineral density, and quality of life in people living with Fontan circulation receiving warfarin compared with aspirin. METHODS: This was a multicenter study of a selected cohort from the Australia and New Zealand Fontan population. Participants underwent cerebral magnetic resonance imaging to detect the presence of cerebrovascular injury (n = 84) and dual-energy X-ray absorptiometry to assess bone mineral density (n = 120). Bleeding (n = 100) and quality of life (n = 90) were assessed using validated questionnaires: Warfarin and Aspirin Bleeding assessment tool and Pediatric Quality of Life Inventory, respectively. RESULTS: Stroke was detected in 33 participants (39%), with only 7 (6%) being clinically symptomatic. There was no association between stroke and Fontan type or thromboprophylaxis type. Microhemorrhage and white matter injury were detected in most participants (96% and 86%, respectively), regardless of thromboprophylaxis type. Bleeding rates were high in both groups; however, bleeding was more frequent in the warfarin group. Bone mineral density was reduced in our cohort compared with the general population; however, this was further attenuated in the warfarin group. Quality of life was similar between the warfarin and aspirin groups. Home international normalized ratio monitoring was associated with better quality of life scores in the warfarin group. CONCLUSIONS: Cerebrovascular injury is a frequent occurrence in the Australia and New Zealand Fontan population regardless of thromboprophylaxis type. No benefit of long-term warfarin prophylaxis could be demonstrated over aspirin; however, consideration must be given to important clinical features such as cardiac function and lung function. Furthermore, the association of reduced bone health in children receiving warfarin warrants further mechanistic studies.

Impact of adiposity on clinical outcomes in people living with a Fontan circulation.

BACKGROUND: To assess the association between body composition and the risk of adverse outcomes in Fontan patients. METHODS: Participants from the Australian and New Zealand Fontan Registry with dual-energy X-ray absorptiometry scans were included. Appendicular lean mass (ALM), appendicular lean mass index (ALM divided by height squared; ALMI) and total body fat mass percentage (%BF) were calculated. ALMI and %BF z-scores were derived using age- and sex-matched reference ranges. The primary outcome was Fontan failure (death, transplantation, New York Heart Association functional class III/IV, protein-losing enteropathy, and plastic bronchitis) or moderate-or-severe ventricular dysfunction. RESULTS: 144 patients were included. Mean %BF was 29% (SD 10) with 50% having increased adiposity. Mean ALMI z-score was -1.4 (SD 1.1); one third of patients had skeletal muscle deficiency (ALMI z-score < -1 and -2) and another third had Fontan-associated myopaenia (ALMI z-score < -2). Age and %BF were associated with the risk of the endpoint in univariable regression (age: HR 1.09 per year, 95% CI 1.02-1.17, p = 0.01; %BF: HR 1.08, 95% CI 1.01-1.17, p = 0.03). On multivariable regression, every 1% increase in %BF was associated with a 10% increased risk of reaching the clinical endpoint (HR 1.10, 95% CI 1.01-1.19; p = 0.03). ALM was not associated with the endpoint (HR 1.02 per kg, 95% CI 0.88-1.20, p = 0.77). CONCLUSIONS: Increased adiposity is associated with higher risk for adverse outcomes. Prospective studies to assess lifestyle interventions to optimise body composition should be prioritised.

Sarcopenia Definitions and Outcomes Consortium (SDOC) Criteria are Strongly Associated With Malnutrition, Depression, Falls, and Fractures in High-Risk Older Persons.

OBJECTIVES: Sarcopenia Definitions and Outcomes Consortium (SDOC) provides cut-points based on muscle weakness (low grip strength) and slowness (poor gait speed) for low-risk populations; however, it is unknown if these criteria apply to high-risk populations. We examined the association between SDOC criteria and important health status indicators in high-risk older persons. DESIGN: Cross-sectional study. SETTING AND PARTICIPANTS: 356 community-dwelling older persons (median age: 79 years, interquartile range: 73, 83; 75.2% women) attending a falls and fractures clinic in Melbourne, Australia. METHODS: Grip strength (hydraulic dynamometer) and gait speed (over 4 m) were used to define sarcopenia using SDOC cut-points. Health measures included falls (past 1 year) and fractures (past 5 years) by self-report, and malnutrition, depression, balance confidence, fear of falling, static balance (limits of stability), dynamic balance (Four-Square Step Test), and body composition [body mass index and lean mass, fat mass, and bone density (via dual-energy x-ray absorptiometry)] were assessed using validated procedures. Fasting vitamin D and parathyroid hormone concentrations were measured by immunoassays. Participants were categorized as nonsarcopenic or sarcopenic based on the SDOC cut-points, and multivariate models were used to examine the association between sarcopenia and health status indicators while adjusting for confounding factors. RESULTS: After adjusting for covariates, sarcopenic older persons (n = 162, 45.5%) were positively associated with malnutrition [odds ratio (OR) 3.21, 95% confidence interval (CI) 1.63, 6.32], depression (OR 4.11, 95% CI 2.31, 7.29), fear of falling (OR 1.08, 95% CI 1.06, 1.10) as well as recurrent (2 or more) falls (OR 1.62, 95% CI 1.01, 2.59) and fractures (OR 2.26, 95% CI 1.17, 4.36), and negatively associated with poor balance confidence (OR 0.96, 95% CI 0.95, 0.97) (P < .05 vs nonsarcopenic). CONCLUSIONS AND IMPLICATIONS: SDOC criteria are strongly associated with important health status indicators in high-risk older persons, which strengthens the clinical utility of the SDOC in these populations.

The diagnostic value of the Short Physical Performance Battery for sarcopenia.

BACKGROUND: Sarcopenia is defined as the age-related loss of muscle mass, strength, and physical performance. The original European Working Group on Sarcopenia in Older Persons (EWGSOP1) definition, and its revision (EWGSOP2), provide new cut-points and alternate measures for sarcopenia diagnosis. However, sarcopenia is rarely diagnosed in clinical settings owing to its labor-intensive diagnostic process. Given the Short Physical Performance Battery (SPPB) is a quick, easily administrable, and objective measure of muscle strength and physical performance, both of which are key components of sarcopenia, this study examined the diagnostic value of the SPPB for this muscle disease. METHODS: A cross-sectional analysis of 294 community-dwelling older persons (≥65 years) was conducted. Appendicular lean body mass [(ALM) divided by height squared (ALM/h2)], muscle strength (handgrip/sit to stand), and physical performance [gait speed, timed up and go (TUG) and SPPB] were assessed using validated procedures, while participants were diagnosed with sarcopenia following the EWGSOP1 and EWGSOP2 criteria. Diagnostic ability of the SPPB independently and combined with ALM/h2 for sarcopenia was determined using area under the curve (AUC). Potential cut-points were identified, and sensitivity and specificity calculated. RESULTS: Prevalence of sarcopenia ranged from 4 to 16% depending on the definition. The SPPB demonstrated moderate (AUC = 0.644-0.770) value in diagnosing sarcopenia, and a cut-point of ≤8points in SPPB performance resulted in high sensitivity (82-100%) but low specificity (36-41%) for diagnosing those with severe sarcopenia. CONCLUSIONS: The SPPB displayed acceptable value in diagnosing older adults with severe sarcopenia. Moreover, the high sensitivity of the SPPB when using the cut-point of ≤8 suggests it may be a favorable screening tool for sarcopenia in clinical settings where ALM measurements are not available.

Hemoglobin Levels are Low in Sarcopenic and Osteosarcopenic Older Persons.

Anemia is commonly associated with osteoporosis and sarcopenia in older persons. However, there is a common subset of patients identified as osteosarcopenic at a higher risk of adverse outcomes. Whether these patients are also at a higher risk of anemia remains unknown. In this study, we aimed to compare hemoglobin (Hb) levels in osteosarcopenic older subjects versus those with sarcopenia, osteopenia/osteoporosis alone and controls. Cross-sectional study in 558 community-dwelling participants older than 65 (mean age 79 ± 7.5 years) from Western Sydney, Australia. Associations of anemia with sarcopenia, osteopenia/osteoporosis and osteosarcopenia were assessed. Participants were able to mobilize independently, reported a risk/history of falls and were not cognitively impaired. We used the original (EWGOP) and revised (EWGSOP2) European consensus on definition of sarcopenia, and WHO definitions of osteoporosis and osteopenia. Based on both European definitions of sarcopenia prevalence of anemia was the highest among sarcopenic patients (39%), followed by osteosarcopenic (34%), osteoporotic/penic (26%), and controls (24%). Anemia prevalence in total was 176/553 (31.5%). Osteosarcopenic patients on average had 6.3 g/L lower Hb levels compared to controls (p = 0.001), and 3.7 g/L lower Hb than patients with osteoporosis/penia (p < 0.026). Interestingly, levels of Hb did not differ between sarcopenic vs osteosarcopenic patients (p = 0.817) and between osteoporotic/osteopenic patients vs controls (p > 0.259). The higher prevalence of anemia and lower hemoglobin in sarcopenic and osteosarcopenic subjects compared to osteoporotic/penic participants and controls was established. However, the previously reported associations between osteoporosis and anemia were not confirmed. A likely explanation can be inclusion of osteosarcopenic subjects as osteoporotic in previous studies.

Associations between osteoporosis, the severity of sarcopenia and fragility fractures in community-dwelling older adults.

PURPOSE: To investigate the association between bone mineral density (BMD) and the severity of sarcopenia using the revised European Working Group on Sarcopenia in Older People (EWGSOP2) definition. METHODS: BMD [dual energy X-ray absorptiometry (DXA)], appendicular lean mass (DXA), handgrip strength (hydraulic dynamometer) and gait speed (over 4-m) were used to screen for osteoporosis and sarcopenia. Participants were categorized as osteoporotic according to the World Health Organization definition (T score ≤ - 2.5), and classified with probable sarcopenia or confirmed sarcopenia according to the EWGSOP2 criteria. Fasting biochemistry profile, fragility fractures, malnutrition index, geriatric depression scale and fear of falling, were also measured using validated procedures. RESULTS: A total of 484 community-dwelling older adults (69.6% women) with a median age of 76 years [Interquartile range (IQR) 70-81] were included in this study. Osteoporosis prevalence increased from 47.6% in non-sarcopenia to 65.5% in probable sarcopenia and 78.1% in those with confirmed sarcopenia (p < 0.05). After adjusting for age, sex and vitamin D in multivariate models, osteoporosis was associated with a greater risk of confirmed sarcopenia [odds ratio (OR) 2.885, 95% CI 1.155, 7.204, p = 0.023]. The number of fragility fractures was also higher in those with confirmed sarcopenia versus those without (p = 0.013), but this finding did not remain significant in adjusted models (p = 0.078). CONCLUSION: Prevalence of osteoporosis increased across the severity of sarcopenia, and osteoporosis was associated with a greater risk of sarcopenia. As such, health care professionals should screen for sarcopenia in those with low BMD.

CD300lf is the primary physiologic receptor of murine norovirus but not human norovirus.

Murine norovirus (MNoV) is an important model of human norovirus (HNoV) and mucosal virus infection more broadly. Viral receptor utilization is a major determinant of cell tropism, host range, and pathogenesis. The bona fide receptor for HNoV is unknown. Recently, we identified CD300lf as a proteinaceous receptor for MNoV. Interestingly, its paralogue CD300ld was also sufficient for MNoV infection in vitro. Here we explored whether CD300lf is the sole physiologic receptor in vivo and whether HNoV can use a CD300 ortholog as an entry receptor. We report that both CD300ld and CD300lf are sufficient for infection by diverse MNoV strains in vitro. We further demonstrate that CD300lf is essential for both oral and parenteral MNoV infection and to elicit anti-MNoV humoral responses in vivo. In mice deficient in STAT1 signaling, CD300lf is required for MNoV-induced lethality. Finally, we demonstrate that human CD300lf (huCD300lf) is not essential for HNoV infection, nor does huCD300lf inhibit binding of HNoV virus-like particles to glycans. Thus, we report huCD300lf is not a receptor for HNoV.