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To individualize nutritional interventions for the prevention and treatment of malnutrition and sarcopenia, it is required to understand the nutritional needs of older adults. This study explores the nutritional needs of geriatric outpatients. We hypothesized that inadequate energy and protein intake is common in geriatric outpatients. Data were retrieved from 2 cohort studies encompassing community-dwelling older adults referred to geriatric outpatient mobility clinics in Amsterdam, The Netherlands and Melbourne, Australia. Indirect calorimetry and a food diary, respectively, were used to assess resting metabolic rate (RMR) and energy and protein intake. Total energy expenditure (TEE) was calculated by the RMR multiplied by an activity factor of 1.4. An energy deficit was defined as a relative difference >10% between TEE and energy intake. A protein deficit was defined as protein intake

Background: Understanding the association between motor capacity (MC) (what people can do in a standardized environment), mobility performance (MP) (what people actually do in real-life) and falls is important for early detection of and counteracting on functional decline, particularly in the rapidly growing population of young seniors. Therefore, this study aims to 1) explore the association between MC and MP, and between MC and falls, and 2) investigate whether challenging MC measures are better associated with MP and falls than basic MC measures., Methods: Basic (habitual gait speed, Timed Up-and-Go) and challenging (fast gait speed, Community Balance & Mobility Scale) MC measures were performed in 169 young seniors (61-70 years). MP was assessed using one-week sensor-monitoring including time being sedentary, light active, and at least moderately active. Falls in the previous six months were reported. Associations and discriminative ability were calculated using correlation, regression and receiver operating curve analysis., Results: Mean age was 66.4 (SD 2.4) years (50.6 % women). Small to moderate associations (r = 0.06 - 0.31; p < .001-.461) were found between MC, MP and falls. Challenging MC measures showed closer associations with MP and falls (r = 0.10 - 0.31; p < .001-.461) compared to basic (r = 0.06 - 0.22; p = .012-.181), remained significant in three out of four regression models explaining 2.5-8.6 % of the variance, and showed highest discriminative ability (area under the curve = 0.59 - 0.70) in all analyses., Conclusions: Challenging MC measures are closer associated with mobility performance and falls as compared to basic MC measures in young seniors. This indicates the importance of applying challenging motor capacity assessments in young seniors. On the same note, small to moderate associations imply a need for an assessment of both MC and MP in order to capture the best possible MC and the actual daily-life MP in young seniors.

OBJECTIVE: Sarcopenia is highly prevalent in older adults. Knowledge among community-dwelling adults is important for effective prevention and treatment of sarcopenia. This study aims to assess current knowledge about sarcopenia, investigate willingness for treatment and prevention, and awareness of muscle health.METHOD: Participants who attended health educational events completed a questionnaire on knowledge about sarcopenia. Self-perceived muscle health was assessed by visual analog scale. Objective muscle measures included muscle mass, handgrip strength, and gait speed.RESULTS: Included participants were 197 (median aged 67.9 years [interquartile range = 57.0-75.1]). Eighteen participants (9%) reported to know what sarcopenia is. Participants' self-perceived muscle health showed a low correlation with all objective muscle measures. 76% were willing, in case of sarcopenia diagnosis, to start treatment and 71% were willing to prevent sarcopenia.DISCUSSION: Knowledge about sarcopenia is limited while participants were willing to start treatment and prevention. Strategies to increase knowledge among community-dwelling adults are needed.

Context Pretreatment with α-adrenergic receptor blockers is recommended to prevent hemodynamic instability during resection of a pheochromocytoma or sympathetic paraganglioma (PPGL). Objective To determine which type of α-adrenergic receptor blocker provides the best efficacy. Design Randomized controlled open-label trial (PRESCRIPT; ClinicalTrials.gov NCT01379898) Setting Multicenter study including 9 centers in The Netherlands. Patients 134 patients with nonmetastatic PPGL. Intervention Phenoxybenzamine or doxazosin starting 2 to 3 weeks before surgery using a blood pressure targeted titration schedule. Intraoperative hemodynamic management was standardized. Main Outcome Measures Primary efficacy endpoint was the cumulative intraoperative time outside the blood pressure target range (ie, SBP >160 mmHg or MAP Results Median cumulative time outside blood pressure targets was 11.1% (interquartile range [IQR]: 4.3–20.6] in the phenoxybenzamine group compared to 12.2% (5.3–20.2)] in the doxazosin group (P = .75, r = 0.03). The hemodynamic instability score was 38.0 (28.8–58.0) and 50.0 (35.3–63.8) in the phenoxybenzamine and doxazosin group, respectively (P = .02, r = 0.20). The 30-day cardiovascular complication rate was 8.8% and 6.9% in the phenoxybenzamine and doxazosin group, respectively (P = .68). There was no mortality after 30 days. Conclusions The duration of blood pressure outside the target range during resection of a PPGL was not different after preoperative treatment with either phenoxybenzamine or doxazosin. Phenoxybenzamine was more effective in preventing intraoperative hemodynamic instability, but it could not be established whether this was associated with a better clinical outcome.

Background: Patients with primary hypothyroidism are treated with levothyroxine (LT4) to normalize their serum thyrotropin (TSH). Finding the optimal dosage is a long-lasting process, and a small change can have major impact. Currently, limited data are available on the impact of dose-equivalent substitution between brands. This study aimed to determine the effect of the shortage of the LT4 brand Thyrax® in the Netherlands and the resulting dose-equivalent switch to another brand on plasma TSH concentrations in a large cohort of patients. Methods: Observational cohort study. Two registries representative for the Dutch population containing prescription and laboratory test data: the Nivel Primary Care Database and the PHARMO Database Network. Patients using at least 25 μg Thyrax daily for one year or longer were included. Two cohorts were formed: a switch cohort consisting of patients who switched from Thyrax to an alternative brand, and a Thyrax cohort including patients who continued to use Thyrax. Patients in the switch cohort did switch from Thyrax to a different brand of LT4 in 2016 and had two consecutive TSH measurements on the same dose of LT4, one before and one 6 weeks after the switch. Patients in the Thyrax cohort had two consecutive TSH measurements on the same dose of Thyrax that were 6 weeks apart. Results: In the Thyrax cohort, 19% of euthyroid patients using ≤100 μg had a TSH level outside the reference range at the subsequent measurement compared with 24% in the switch cohort (p < 0.0001). For patients using >100 μg Thyrax, these figures were 24% and 63%, respectively (p < 0.0001). Furthermore, patients using >50 μg Thyrax were four to five times more likely to become hyperthyroid after a dose-equivalent switch to a different brand compared with patients who stayed on Thyrax. Conclusions: In euthyroid patients continuing the LT4 product Thyrax at the same dose, TSH was out of range in 19-24% at least 6 weeks later. A dose-equivalent switch from Thyrax to other LT4 brands induced biochemical signs of overdosing in an even larger proportion (24-63%) of patients. The results indicate that a dose-equivalent LT4 brand switch may necessitate a dose adjustment in a large number of patients.

Purpose Higher folate and vitamin-B12 have been linked to lower risk of overweight. However, whether this is a causal effect of these B-vitamins on obesity risk remains unclear and evidence in older individuals is scarce. This study aimed to assess the role of B-vitamin supplementation and levels on body composition in older individuals. Methods A double-blind, randomized controlled trial in 2919 participants aged ≥ 65 years with elevated homocysteine levels. The intervention comprised a 2-year supplementation with a combination of folic acid (400 µg) and vitamin B12 (500 µg), or with placebo. Serum folate, vitamin-B12, active vitamin-B12 (HoloTC), methylmalonic acid (MMA), and anthropometrics were measured at baseline and after 2 years of follow-up. Dietary intake of folate and vitamin-B12 was measured at baseline in a subsample (n = 603) using a validated food-frequency questionnaire. Fat mass index (FMI) and fat-free mass index (FFMI) were assessed with Dual Energy X-ray absorptiometry (DXA). Results Cross-sectional analyses showed that a 1 nmol/L higher serum folate was associated with a 0.021 kg/m2 lower BMI (95% CI − 0.039; − 0.004). Higher HoloTC (per pmol/L log-transformed) was associated with a 0.955 kg/m2 higher FMI (95% CI 0.262; 1.647), and higher MMA (per μgmol/L) was associated with a 1.108 kg/m2 lower FMI (95% CI − 1.899; − 0.316). However, random allocation of B-vitamins did not have a significant effect on changes in BMI, FMI or FFMI during 2 years of intervention. Conclusions Although observational data suggested that folate and vitamin B12 status are associated with body composition, random allocation of a supplement with both B-vitamins combined versus placebo did not confirm an effect on BMI or body composition. Electronic supplementary material The online version of this article (10.1007/s00394-019-01985-8) contains supplementary material, which is available to authorized users.

Purpose: 19F-MRI is gaining widespread interest for cell tracking and quantification of immune and inflammatory cells in vivo. Different fluorinated compounds can be discriminated based on their characteristic MR spectra, allowing in vivo imaging of multiple 19F compounds simultaneously, so-called multicolor 19F-MRI. We introduce a method for multicolor 19F-MRI using an iterative sparse deconvolution method to separate different 19F compounds and remove chemical shift artifacts arising from multiple resonances. Methods: The method employs cycling of the readout gradient direction to alternate the spatial orientation of the off-resonance chemical shift artifacts, which are subsequently removed by iterative sparse deconvolution. Noise robustness and separation was investigated by numerical simulations. Mixtures of fluorinated oils (PFCE and PFOB) were measured on a 7T MR scanner to identify the relation between 19F signal intensity and compound concentration. The method was validated in a mouse model after intramuscular injection of fluorine probes, as well as after intravascular injection. Results: Numerical simulations show efficient separation of 19F compounds, even at low signal-to-noise ratio. Reliable chemical shift artifact removal and separation of PFCE and PFOB signals was achieved in phantoms and in vivo. Signal intensities correlated excellently to the relative 19F compound concentrations (r−2 = 0.966/0.990 for PFOB/PFCE). Conclusions: The method requires minimal sequence adaptation and is therefore easily implemented on different MRI systems. Simulations, phantom experiments, and in-vivo measurements in mice showed effective separation and removal of chemical shift artifacts below noise level. We foresee applicability for simultaneous in-vivo imaging of 19F-containing fluorine probes or for detection of 19F-labeled cell populations.

To suggest candidate genes involved in periodontitis, we combined gene expression data of periodontal biopsies from Collaborative Cross (CC) mouse lines, with previous reported quantitative trait loci (QTL) in mouse and with human genome-wide association studies (GWAS) associated with periodontitis. Periodontal samples from two susceptible, two resistant and two lines that showed bone formation after periodontal infection were collected during infection and naïve status. Differential expressed genes (DEGs) were analyzed in a case-control and case-only design. After infection, eleven protein-coding genes were significantly stronger expressed in resistant CC lines compared to susceptible ones. Of these, the most upregulated genes were MMP20 (P = 0.001), RSPO4 (P = 0.032), CALB1 (P = 1.06×10−4), and AMTN (P = 0.05). In addition, human orthologous of candidate genes were tested for their association in a case-controls samples of aggressive (AgP) and chronic (CP) periodontitis (5,095 cases, 9,908 controls). In this analysis, variants at two loci, TTLL11/PTGS1 (rs9695213, P = 5.77×10−5) and RNASE2 (rs2771342, P = 2.84×10−5) suggested association with both AgP and CP. In the association analysis with AgP only, the most significant associations were located at the HLA loci HLA-DQH1 (rs9271850, P = 2.52×10−14) and HLA-DPA1 (rs17214512, P = 5.14×10−5). This study demonstrates the utility of the CC RIL populations as a suitable model to investigate the mechanism of periodontal disease.

Objective: The objective of this study was to examine correlates of discordance between 13-year trajectories of self-reported functional limitations and performance-based physical functioning in older adults. Method: We included 2,135 participants from the population-based Longitudinal Aging Study Amsterdam, the Netherlands, followed across 1995-2008. Self-reported functional limitations included six (instrumental) activities of daily living. Performance-based functioning was a composite of four tests. We used latent class growth analysis and multinomial logistic regression to examine discordance and its correlates. Results: Patterns of discordance and concordance (41% concordance, 46% “overestimation” of daily functioning, 13% “underestimation”) appeared to be persistent over 13 years. Older age, male sex, cognitive impairment, absence of pain, and light alcohol use were associated with overestimation. Younger age, female sex, and lower self-rated health were associated with underestimation. Discussion: Factors associated with overestimation partly differ from those associated with underestimation. Factors that are highly stable over time are particularly good indicators of persistent discordance.

Background and Purpose: The revised European Working Group on Sarcopenia in Older People (EWGSOP2, version 2019) definition of sarcopenia differs with respect to the EWGSOP (version 2010) definition in applied criteria and their cut-off values. We aimed to investigate the impact of the new definition on sarcopenia pre valence in various populations of older adults. Methods: Eight cohorts, including community-dwelling older adults, geriatric outpatients and patients admitted to acute and subacute inpatient wards were assessed on sarcopenia prevalence. Results: A total of 2256 participants (56.4 % female) were included with a median age of the cohorts of 71.7–83.3 years. In males, sarcopenia prevalence was 31.9 % according to EWGSOP compared to 12.0 % ac cording to EWGSOP2. In females, sarcopenia prevalence was 4.9 % and 6.1 % according to EWGSOP and EWGSOP2 respectively. Lower cut-off points for handgrip strength (27 kg versus 30 kg (males) and 16 kg versus 20 kg (females) for EWGSOP and EWGSOP2 respectively) resulted in the lower sarcopenia prevalence in males. Conclusions: According to the EWGSOP2 definition, the prevalence of sarcopenia in males is significantly lower compared to the EWGSOP definition, whereas the prevalence among women is slightly higher. The lower cut-off points for handgrip strength result in fewer adults being diagnosed with sarcopenia.

Purpose To investigate prevalence, independent associations, and variation over time of potentially inappropriate prescriptions in a population of older hospitalized patients. Methods A longitudinal study using a large dataset of hospital admissions of older patients (≥ 70 years) based on an electronic health records cohort including data from 2015 to 2019. Potentially inappropriate medication (PIM) and potential prescribing omission (PPO) prevalence during hospital stay were identified based on the Dutch STOPP/START criteria v2. Univariate and multivariate logistic regression were used for analyzing associations and trends over time. Results The data included 16,687 admissions. Of all admissions, 56% had ≥ 1 PIM and 58% had ≥ 1 PPO. Gender, age, number of medications, number of diagnoses, Charlson score, and length of stay were independently associated with both PIMs and PPOs. Additionally, number of departments and number of prescribing specialties were independently associated with PIMs. Over the years, the PIM prevalence did not change (OR = 1.00, p = .95), whereas PPO prevalence increased (OR = 1.08, p p Conclusion We found potentially inappropriate prescriptions in the majority of admissions of older patients. Prescribing relatively improved over time when considering complexity of the admissions. Nevertheless, the high prevalence shows a clear need to better address this issue in clinical practice. Studies seeking effective (re)prescribing interventions are warranted.

A maladaptive shift from fat to carbohydrate (CHO) oxidation during exercise is thought to underlie myopathy and exercise-induced rhabdomyolysis in patients with fatty acid oxidation (FAO) disorders. We hypothesised that ingestion of a ketone ester (KE) drink prior to exercise could serve as an alternative oxidative substrate supply to boost muscular ATP homeostasis. To establish a rational basis for therapeutic use of KE supplementation in FAO, we tested this hypothesis in patients deficient in Very Long-Chain acyl-CoA Dehydrogenase (VLCAD). Five patients (range 17-45 y; 4 M/1F) patients were included in an investigator-initiated, randomised, blinded, placebo-controlled, 2-way cross-over study. Patients drank either a KE + CHO mix or an isocaloric CHO equivalent and performed 35 minutes upright cycling followed by 10 minutes supine cycling inside a Magnetic Resonance scanner at individual maximal FAO work rate (fatmax; approximately 40% VO2max). The protocol was repeated after a 1-week interval with the alternate drink. Primary outcome measures were quadriceps phosphocreatine (PCr), Pi and pH dynamics during exercise and recovery assayed by in vivo 31P-MR spectroscopy. Secondary outcomes included plasma and muscle metabolites and respiratory gas exchange recordings. Ingestion of KE rapidly induced mild ketosis and increased muscle BHB content. During exercise at FATMAX, VLCADD-specific plasma acylcarnitine levels, quadriceps glycolytic intermediate levels and in vivo Pi/PCr ratio were all lower in KE + CHO than CHO. These results provide a rational basis for future clinical trials of synthetic ketone ester supplementation therapy in patients with FAO disorders. Trial registration: ClinicalTrials.gov. Protocol ID: NCT03531554; METC2014.492; ABR51222.042.14.

Background Early mobilization has been proven effective for patients in intensive care units (ICUs) to improve functional recovery. However, early mobilization of critically ill, often mechanically ventilated, patients is cumbersome because of the attachment to tubes, drains, monitoring devices and muscle weakness. A mobile treadmill with bodyweight support may help to initiate mobilization earlier and more effectively. The aim of this study is to assess the effectiveness of weight-supported treadmill training in critically ill patients during and after ICU stay on time to independent functional ambulation. Methods In this randomized controlled trial, a custom-built bedside body weight-supported treadmill will be used and evaluated. Patients are included if they have been mechanically ventilated for at least 48 hours, are able to follow instructions, have quadriceps muscle strength of Medical Research Council sum-score 2 (MRC 2) or higher, can sit unsupported and meet the safety criteria for physical exercise. Exclusion criteria are language barriers, no prior walking ability, contraindications for physiotherapy or a neurological condition as reason for ICU admission. We aim to include 88 patients and randomize them into either the intervention or the control group. The intervention group will receive usual care plus bodyweight-supported treadmill training (BWSTT) daily. The BWSSTT consists of walking on a mobile treadmill while supported by a harness. The control group will receive usual care physiotherapy treatment daily consisting of progressive activities such as bed-cycling and active functional training exercises. In both groups, we will aim for a total of 40 minutes of physiotherapy treatment time every day in one or two sessions, as tolerated by the patient. The primary outcome is time to functional ambulation as measured in days, secondary outcomes include walking distance, muscle strength, status of functional mobility and symptoms of post-traumatic stress. All measurements will be done by assessors who are blinded to the intervention on the regular wards until hospital discharge. Discussion This will be the first study comparing the effects of BWSTT and conventional physiotherapy for critically ill patients during and after ICU stay. The results of this study contribute to a better understanding of the effectiveness of early physiotherapy interventions for critically ill patients. Trial registration Dutch Trial Register (NTR) ID: NL6766. Registered at 1 December 2017.

Background Intensive Care Units (ICUs) are daunting environments for physiotherapy (PT) students performing clinical rotations. To prepare students for this environment, a newly developed, evidence-based e-learning module was designed and implemented in the undergraduate curriculum. The aim of this study was to investigate whether e-learning is a feasible method in preparing PT students for clinical work in complex ICU environments, as perceived by students and experts. Methods A mixed methods proof of concept study was undertaken. Participants were final-year students of an international curriculum, and experts from didactic and clinical fields. An e-learning module consisting of 7 separate chapters based on the latest scientific evidence and clinical expertise was developed, piloted and incorporated into the undergraduate curriculum as a compulsory course to be completed prior to clinical ICU rotations. Data were collected through 3 focus group meetings and 5 semi-structured interviews; these meetings and interviews were audio recorded, transcribed verbatim and analyzed. Results The study sample comprised of 14 students and 5 experts. Thematic analysis revealed three themes: expected competencies of PT students in ICU, feeling prepared for ICU clinical work and dealing with local variety. The e-learning module enabled students to anticipate clinical situations and PT tasks in the ICU. Higher level clinical reasoning skills, handling of lines and wires and dealing with out-of-textbook situations could not be achieved with the e-learning module alone. Conclusions An e-learning module can sufficiently prepare PT students for their clinical tasks in the ICU, as long as it is integrated with, or closely connected to, the students’ clinical placement.

Background The relationship between orthostatic hypotension and clinical outcome in older adults is poorly understood. Blood pressure drop rate (ie, speed of blood pressure drop) may particularly reflect the imposed challenge to the baroreflex and the associated clinical outcome (ie, frailty and number of falls). This study aimed to compare orthostatic blood pressure drop rate and drop magnitude with regard to their association with frailty and number of falls. Methods and Results Blood pressure was measured continuously during a standardized active stand task in 168 patients (mean age 81.4±7.0; 55.4% female) who visited a geriatric outpatient clinic for cognitive or mobility problems. The association of orthostatic blood pressure drop rate, blood pressure drop magnitude, and baroreflex sensitivity (ie, increase in heart rate divided by systolic blood pressure drop magnitude) with frailty (Fried criteria and 4 frailty markers) and self‐reported number of falls was assessed using linear regression models, adjusting for age and sex. Systolic blood pressure drop rate had the strongest association with frailty according to the 4 frailty markers (β 0.30; 95% CI , 0.11–0.49; P =0.003) and number of falls (β 1.09; 95% CI , 0.19–1.20; P =0.018); diastolic blood pressure drop magnitude was most strongly associated with frailty according to the Fried criteria (β 0.37; 95% CI , 0.15–0.60; P Conclusions Orthostatic blood pressure drop rate was associated with frailty and falls and may reflect the challenge to the baroreflex rather than drop magnitude.

OBJECTIVES: Knee osteoarthritis (OA) is characterized by its heterogeneity, with large differences in clinical characteristics between patients. Therefore, a stratified approach to exercise therapy, whereby patients are allocated to homogeneous subgroups and receive a stratified, subgroup-specific intervention, can be expected to optimize current clinical effects. Recently, we developed and pilot tested a model of stratified exercise therapy based on clinically relevant subgroups of knee OA patients that we previously identified. Based on the promising results, it is timely to evaluate the (cost-)effectiveness of stratified exercise therapy compared with usual, "nonstratified" exercise therapy.METHODS: A pragmatic cluster randomized controlled trial including economic and process evaluation, comparing stratified exercise therapy with usual care by physical therapists (PTs) in primary care, in a total of 408 patients with clinically diagnosed knee OA. Eligible physical therapy practices are randomized in a 1:2 ratio to provide the experimental (in 204 patients) or control intervention (in 204 patients), respectively. The experimental intervention is a model of stratified exercise therapy consisting of (a) a stratification algorithm that allocates patients to a "high muscle strength subgroup," "low muscle strength subgroup," or "obesity subgroup" and (b) subgroup-specific, protocolized exercise therapy (with an additional dietary intervention from a dietician for the obesity subgroup only). The control intervention will be usual best practice by PTs (i.e., nonstratified exercise therapy). Our primary outcome measures are knee pain severity (Numeric Rating Scale) and physical functioning (Knee Injury and Osteoarthritis Outcome Score subscale daily living). Measurements will be performed at baseline, 3-month (primary endpoint), 6-month (questionnaires only), and 12-month follow-up, with an additional cost questionnaire at 9 months. Intention-to-treat, multilevel, regression analysis comparing stratified versus usual care will be performed.CONCLUSION: This study will demonstrate whether stratified care provided by primary care PTs is effective and cost-effective compared with usual best practice from PTs.

AIM: Calcium ions play a pivotal role in matching energy supply and demand in cardiac muscle. Mitochondrial calcium concentration is lower in animal models of heart failure with reduced ejection fraction (HFrEF), but limited information is available about mitochondrial calcium handling in heart failure with preserved ejection fraction (HFpEF).METHODS: We assessed mitochondrial Ca2+ handling in intact cardiomyocytes from Zucker/fatty Spontaneously hypertensive F1 hybrid (ZSF1)-lean (control) and ZSF1-obese rats, a metabolic risk-related model of HFpEF. A mitochondrially targeted Ca2+ indicator (MitoCam) was expressed in cultured adult rat cardiomyocytes. Cytosolic and mitochondrial Ca2+ transients were measured at different stimulation frequencies. Mitochondrial respiration and swelling, and expression of key proteins were determined ex vivo.RESULTS: At rest, mitochondrial Ca2+ concentration in ZSF1-obese was larger than in ZSF1-lean. The diastolic and systolic mitochondrial Ca2+ concentrations increased with stimulation frequency, but the steady-state levels were larger in ZSF1-obese. The half-widths of the contractile responses, the resting cytosolic Ca2+ concentration and the decay half-times of the cytosolic Ca2+ transients were higher in ZSF1-obese, likely because of a lower SERCA2a/phospholamban ratio. Mitochondrial respiration was lower, particularly with nicotinamide adenine dinucleotide (NADH) (complex I) substrates, and mitochondrial swelling was larger in ZSF1-obese.CONCLUSION: The free mitochondrial calcium concentration is higher in HFpEF owing to alterations in mitochondrial and cytosolic Ca2+ handling. This coupling between cytosolic and mitochondrial Ca2+ levels may compensate for myocardial ATP supply in vivo under conditions of mild mitochondrial dysfunction. However, if mitochondrial Ca2+ concentration is sustainedly increased, it might trigger mitochondrial permeability transition pore opening.

While many health-care issues and technological solutions are viewed locally, developing new technological solutions might benefit from lessons learned globally. The aim of this study was to develop a shared international research agenda of health-care ICT, applied to rehabilitation and daily living support. This study was focused on sensor technology and social robots used for supporting older persons in the Netherlands (Amsterdam) and Japan (Tokyo). Three researchers from Amsterdam University of Applied Sciences visited Japan and four researchers from Tokyo Metropolitan University visited the Netherlands and conducted field-visits and mutual presentations. Using a nominal group technique (NGT) facilitated the expert panel deliberations. Research priorities were identified qualitatively through in-action critical reflection on emerging ideas, and quantitatively by ranking of identified knowledge gaps (using the Mentimeter© app). The resulting joint research agenda identified topics around the utility of sensor monitoring and processes of acceptance of health-care ICT among older persons and occupational therapists. The agenda was complemented by formulating underlying assumptions prescribing such research to be embedded in real-life situations with the participation of stakeholders.

Loop diuretics (LD) may affect bone health by inhibiting renal calcium reuptake. However, whether vitamin D status and dietary calcium intake modify the association between LD and bone outcome is unclear. Therefore, this study aimed to evaluate whether vitamin D level or calcium intake modify the association between LD and various indices of bone health including bone mineral density (BMD) and Trabecular Bone Score (TBS). From The Rotterdam Study, a prospective population-based cohort study, we used data from 6990 participants aged > 45 year with a DXA scan (2002–2008), 6908 participants with femoral neck (FN)-BMD, 6677 participants with lumbar spine (LS)-BMD and 6476 participants with LS-TBS measurements. Use of LD was available from pharmacy dispensing records. Vitamin D (25(OH)D) level was measured in serum, and dietary calcium intake was measured with a validated food frequency questionnaire. Almost eight percent of the participants used LD. The association between LD (past-users compared to never-users) and LS-TBS was significantly different by 25(OH)D concentrations (P for interaction = 0.04). A significantly lower LS-TBS among LD past-users was observed for 25(OH)D ≥ 50 nmol/l compared to ≤ 20 and 20–50 nmol/l (β = − 0.036, 95% CI − 0.060; − 0.013 vs. β = − 0.012, 95% CI − 0.036; 0.013 and β = − 0.031, 95% CI − 0.096; 0.034, respectively). However, no other significant effect modification by 25(OH)D and dietary calcium intake was found in the associations between LD use and bone health outcomes (P-interaction > 0.13). This study suggests that the association between LD use and indices of bone health is not consistently modified by vitamin D or dietary calcium intake.

OBJECTIVES: To explore the feasibility of a newly developed model of stratified exercise therapy in primary care for patients with knee osteoarthritis (OA).DESIGN: Mixed method design (process, outcome and qualitative evaluation).SETTING: Six physical therapy practices in primary care around Amsterdam.PARTICIPANTS: Fifty eligible patients with knee OA, visiting one of the participating physical therapists (PTs).INTERVENTION: Patients were allocated to a subgroup based on a simple stratification tool and received subgroup-specific, protocolized, 4-month, exercise therapy.MAIN OUTCOME MEASURES: Feasibility of this model of stratified exercise therapy was explored by multiple process parameters, outcome measures (physical functioning and knee pain; at baseline and 4-months follow-up) and experiences from patients and PTs.RESULTS: From 97 potentially eligible patients, fifty patients were included and allocated to the 'high muscle strength subgroup' (n=17), 'depression subgroup' (n=4), 'obesity subgroup' (n=6) or 'low muscle strength subgroup' (n=23). Three patients dropped out during the study period. PTs provided relatively low numbers of sessions (on average 10 sessions), although exceedance of the recommended maximum number of sessions did occur frequently. We found clinically relevant improvements on physical functioning and knee pain (PCONCLUSIONS: Our model of stratified exercise therapy seems to be feasible in primary care, although a number of limitations were reported. Future research should determine the (cost-)effectiveness of an adapted model, compared to usual, non-stratified exercise therapy.

Context Multiple endocrine neoplasia type 1 (MEN1) is a rare autosomal dominant hereditary disease caused by the loss of function of the MEN1 gene, a tumor-suppressor gene that encodes the protein menin. It is characterized by the occurrence of primary hyperparathyroidism (pHPT), duodenopancreatic neuroendocrine tumors (dpNET), pituitary tumors (PIT), adrenal adenomas, and bronchopulmonary (bp-NET), thymic, and gastric neuroendocrine tumors. More insight into factors influencing the age-related penetrance of MEN1 manifestations could provide clues for more personalized screening programs. Objective To investigate whether genetic anticipation plays a role in the largest known MEN1 families in the Netherlands. Methods All Dutch MEN1 families with ≥ 10 affected members in ≥ 2 successive generations were identified. Age at detection of the different MEN1-related manifestations were compared among generations using regression analyses adjusted for competing risks. To correct for the beneficial effect of being under surveillance, manifestations occurring during surveillance were also separately compared. Results A total of 152 MEN1 patients from 10 families were included. A significantly decreased age at detection of pHPT, dpNET, PIT, and bp-NET was found in successive generations (P Conclusions These results suggest the presence of genetic anticipation. However, due to a risk of residual bias, the results must be interpreted with caution. After independent validation in other cohorts and further translational research investigating the molecular mechanisms explaining this phenomenon in MEN1, the results might add to future, more personalized, screening protocols and earlier screening for future generations of MEN1 patients.

Atrial fibrillation (AF), the most common progressive tachyarrhythmia, results in structural remodeling which impairs electrical activation of the atria, rendering them increasingly permissive to the arrhythmia. Previously, we reported on endoplasmic reticulum stress and NAD+ depletion in AF, suggesting a role for mitochondrial dysfunction in AF progression. Here, we examined mitochondrial function in experimental model systems for AF (tachypaced HL-1 atrial cardiomyocytes and Drosophila melanogaster) and validated findings in clinical AF. Tachypacing of HL-1 cardiomyocytes progressively induces mitochondrial dysfunction, evidenced by impairment of mitochondrial Ca2+-handling, upregulation of mitochondrial stress chaperones and a decrease in the mitochondrial membrane potential, respiration and ATP production. Atrial biopsies from AF patients display mitochondrial dysfunction, evidenced by aberrant ATP levels, upregulation of a mitochondrial stress chaperone and fragmentation of the mitochondrial network. The pathophysiological role of mitochondrial dysfunction is substantiated by the attenuation of AF remodeling by preventing an increased mitochondrial Ca2+-influx through partial blocking or downregulation of the mitochondrial calcium uniporter, and by SS31, a compound that improves bioenergetics in mitochondria. Together, these results show that conservation of the mitochondrial function protects against tachypacing-induced cardiomyocyte remodeling and identify this organelle as a potential novel therapeutic target.

PURPOSE: To assess the association of clinical variables and the development of specified chronic conditions in ICU survivors.MATERIALS AND METHODS: A retrospective cohort study, combining a national health insurance claims database and a national quality registry for ICUs. Claims data from 2012 to 2014 were combined with clinical data of patients admitted to an ICU during 2013. To assess the association of clinical variables (ICU length of stay, mechanical ventilation, acute physiology score, reason for ICU admission, mean arterial pressure score and glucose score) and the development of chronic conditions (i.e. heart diseases, COPD or asthma, Diabetes mellitus type II, depression and kidney diseases), logistic regression was used.RESULTS: 49,004 ICU patients were included. ICU length of stay was associated with the development of heart diseases, asthma or COPD and depression. The reason for ICU admission was an important risk factor for the development of all chronic conditions with adjusted ORs ranging from 2.05 (CI 1.56; 2.69) for kidney diseases to 5.14 (CI 3.99; 6.62) for depression.CONCLUSIONS: Clinical variables, especially the reason for ICU admission, are associated with the development of chronic conditions after ICU discharge. Therefore, these clinical variables should be considered when organizing follow-up care for ICU survivors.

The objective of the study was to gain an insight into the perceptions and experiences of patients with rheumatoid arthritis and a high cardiovascular disease risk (CVD-RA) when undergoing an exercise intervention aimed at improving their cardiorespiratory fitness. This qualitative study was part of a pilot study, which investigated the effects of an exercise intervention on cardiorespiratory fitness in patients with CVD-RA. Six patients were invited to participate in face-to-face semi-structured interviews. We invited patients who completed the exercise intervention as well as patients who withdrew from the exercise intervention. The interviews were analyzed according to the method of thematic analysis. Six patients were interviewed, of whom four patients completed and two patients discontinued the exercise intervention. The mean (SD) age was 58 (9.7) years, the median disease duration was 10 years, and five patients were female. The analyses revealed seven themes that provided insight into perceptions and experiences: (1) ability to understand reasons for actions; (2) the need to be seen; (3) reaching their maximum effort; (4) experiencing their limits; (5) wanting personalized exercise therapy; (6) happy to be physically active; (7) benefits of exercise. Patients perceived that they were able to perform a cardiopulmonary exercise test with maximum effort and achieved the prescribed intensity of the exercise intervention. They also experienced an improvement in their physical activity by incorporating physical activity in their daily live. Overarching principles that re-occurred in the themes were: the need to be viewed as a person and the importance of feeling safe.

Purpose Evidence for a hospital volume–outcome relationship in hip fracture surgery is inconclusive. This study aimed to analyze the association between hospital volume as a continuous parameter and several processes and outcomes of hip fracture care. Methods Adult patients registered in the nationwide Dutch Hip Fracture Audit (DHFA) between 2018 and 2020 were included. The association between annual hospital volume and turnaround times (time on the emergency ward, surgery Results In total, 43,258 patients from 68 hospitals were included. The median annual hospital volume was 202 patients [range 1–546]. Baseline characteristics did not differ with hospital volume. Provision of orthogeriatric co-treatment improved with higher volumes but decreased at > 367 patients per year (p Conclusion This is the first study analyzing the effect of hospital volume on hip fracture care, treating volume as a continuous parameter. Mortality and turnaround times showed no clinically relevant association with hospital volume. The provision of orthogeriatric co-treatment, however, increased with increasing volumes up to 367 patients per year, but decreased above this threshold. Future research on the effect of volume on complications and functional outcomes is indicated.

Stretching is applied to lengthen shortened muscles in pathological conditions such as joint contractures. We investigated (i) the acute effects of different types of stretching, i.e. constant length (CL) and constant force (CF) stretching, on acute deformations and changes in passive mechanical properties of medial gastrocnemius muscle (MG) and (ii) the association of acute muscle–tendon deformations or changes in mechanical properties with the impulse or maximal strain of stretching. Forty-eight hindlimbs from 13 male and 12 female Wistar rats (13 weeks old, respectively 424.6 ± 35.5 and 261.8 ± 15.6 g) were divided into six groups (n = 8 each). The MG was initially stretched to a length at which the force was 75%, 95%, or 115% of the force corresponding to estimated maximal dorsiflexion and held at either CF or CL for 30 min. Before and after the stretching protocol, the MG peak force and peak stiffness were assessed by lengthening the passive muscle to the length corresponding to maximal ankle dorsiflexion. Also, the muscle belly length and tendon length were measured. CF stretching affected peak force, peak stiffness, muscle belly length, and tendon length more than CL stretching (p < 0.01). Impulse was associated only with the decrease in peak force, while maximal strain was associated with the decrease in peak force, peak stiffness, and the increase in muscle belly length. We conclude that CF stretching results in greater acute deformations and changes in mechanical properties than CL stretching, which appears to be dependent predominantly on the differences in imposed maximal strain.

Background Physical activity (PA) levels might be a simple overall physical function indicator of recovery in acutely hospitalized older adults; however it is unknown which amount and level of PA is associated with recovery. Our objective was to evaluate the amount and level of post discharge PA and its optimum cut-off values associated with recovery among acutely hospitalized older adults and stratified for frailty. Methods We performed a prospective observational cohort study including acutely hospitalized older adults (≥ 70 years). Frailty was assessed using Fried’s criteria. PA was assessed using Fitbit up to one week post discharge and quantified in steps and minutes light, moderate or higher intensity. The primary outcome was recovery at 3-months post discharge. ROC-curve analyses were used to determine cut-off values and area under the curve (AUC), and logistic regression analyses to calculate odds ratios (ORs). Results The analytic sample included 174 participants with a mean (standard deviation) age of 79.2 (6.7) years of whom 84/174 (48%) were frail. At 3-months, 109/174 participants (63%) had recovered of whom 48 were frail. In all participants, determined cut-off values were 1369 steps/day (OR: 2.7, 95% confidence interval [CI]: 1.3–5.9, AUC 0.7) and 76 min/day of light intensity PA (OR: 3.9, 95% CI: 1.8–8.5, AUC 0.73). In frail participants, cut-off values were 1043 steps/day (OR: 5.0, 95% CI: 1.7–14.8, AUC 0.72) and 72 min/day of light intensity PA (OR: 7.2, 95% CI: 2.2–23.1, AUC 0,74). Determined cut-off values were not significantly associated with recovery in non-frail participants. Conclusions Post-discharge PA cut-offs indicate the odds of recovery in older adults, especially in frail individuals, however are not equipped for use as a diagnostic test in daily practice. This is a first step in providing a direction for setting rehabilitation goals in older adults after hospitalization.

Although various neurodegenerative disorders have been associated with coeliac disease (CD), the underlying neuropathological link between these brain and gut diseases remains unclear. We postulated that the neuronal damage sporadically observed in CD patients is immune-mediated. Our aim was to determine if the loss of neurons, especially Purkinje cells, coincides with microglia activation and T- and B-cell infiltration in the cerebellum of patients with CD and a concomitant idiopathic neurological disease affecting the cerebellum (NeuroCD). Post-mortem cerebellar tissue was collected of validated NeuroCD cases. Gender- and age-matched genetic spinocerebellar ataxia (SCA) controls and non-neurological controls (NNC) were selected based on clinical reports and pathological findings. Cerebellar tissue of seventeen patients was included (6 NeuroCD, 5 SCA, 6 NNC). In SCA cases we found that the Purkinje cell layer was 58.6% reduced in comparison with NNC. In NeuroCD cases this reduction was even more prominent with a median reduction of 81.3% compared to NNC. Marked increased numbers of both CD3+ and CD8+ cells were observed in the NeuroCD but not in SCA patients. This coincided with significantly more microglial reactivity in NeuroCD patients. These findings demonstrate that the massive loss of Purkinje cells in the cerebellum of neuro CD patients is accompanied by local innate and T-cell mediated immune responses.

Objectives To investigate cartilage tissue turnover in response to a supervised 12-week exercise-related joint loading training program followed by a 6-month period of unsupervised training in patients with knee osteoarthritis (OA). To study the difference in cartilage tissue turnover between high- and low-resistance training. Method Patients with knee OA were randomized into either high-intensity or low-intensity resistance supervised training (two sessions per week) for 3 months and unsupervised training for 6 months. Blood samples were collected before and after the supervised training period and after the follow-up period. Biomarkers huARGS, C2M, and PRO-C2, quantifying cartilage tissue turnover, were measured by ELISA. Changes in biomarker levels over time within and between groups were analyzed using linear mixed models with baseline values as covariates. Results huARGS and C2M levels increased after training and at follow-up in both low- and high-intensity exercise groups. No changes were found in PRO-C2. The huARGS level in the high-intensity resistance training group increased significantly compared to the low-intensity resistance training group after resistance training (p = 0.029) and at follow-up (p = 0.003). Conclusion Cartilage tissue turnover and cartilage degradation appear to increase in response to a 3-month exercise-related joint loading training program and at 6-month follow-up, with no evident difference in type II collagen formation. Aggrecan remodeling increased more with high-intensity resistance training than with low-intensity exercise. These exploratory biomarker results, indicating more cartilage degeneration in the high-intensity group, in combination with no clinical outcome differences of the VIDEX study, may argue against high-intensity training.

Background Mobility is a key determinant and outcome of healthy ageing but its definition, conceptual framework and underlying constructs within the physical domain may need clarification for data comparison and sharing in ageing research. This study aimed to (1) review definitions and conceptual frameworks of mobility, (2) explore agreement on the definition of mobility, conceptual frameworks, constructs and measures of mobility, and (3) define, classify and identify constructs. Methods A three-step approach was adopted: a literature review and two rounds of expert questionnaires (n = 64, n = 31, respectively). Agreement on statements was assessed using a five-point Likert scale; the answer options ‘strongly agree’ or ‘agree’ were combined. The percentage of respondents was subsequently used to classify agreements for each statement as: strong (≥ 80%), moderate (≥ 70% and Results A variety of definitions of mobility, conceptual frameworks and constructs were found in the literature and among respondents. Strong agreement was found on defining mobility as the ability to move, including the use of assistive devices. Multiple constructs and measures were identified, but low agreements and variability were found on definitions, classifications and identification of constructs. Strong agreements were found on defining physical capacity (what a person is maximally capable of, ‘can do’) and performance (what a person actually does in their daily life, ‘do’) as key constructs of mobility. Conclusion Agreements on definitions of mobility, physical capacity and performance were found, but constructs of mobility need to be further identified, defined and classified appropriately. Clear terminology and definitions are essential to facilitate communication and interpretation in operationalising the physical domain of mobility as a prerequisite for standardisation of mobility measures.

Background Improvement of functional status with physiotherapy is an important goal for patients with postoperative complications and an increased length of hospital stay (LoS) after esophagectomy. Supervised physiotherapy with telerehabilitation instead of conventional face-to-face care could be an alternative to treat these patients in their home environment after hospital discharge (T0), but its feasibility has not yet been investigated in detail. Objective The aim of this study was to investigate the feasibility of a 12-week supervised postoperative physiotherapy intervention with telerehabilitation for patients with esophageal cancer who underwent esophagectomy and had postoperative complications or who had an increased LoS. The secondary objective was to investigate the preliminary effectiveness of telerehabilitation on functional recovery compared with usual care. Methods A prospective feasibility study with a matched historical comparison group was performed. Feasibility outcomes included willingness and adherence to participate, refusal rate, treatment duration, occurrence of adverse events, and patient satisfaction. Secondary outcome measures were measurements of musculoskeletal and cardiovascular functions and activities according to the domains of the International Classification of Functioning, Disability and Health. Results A total of 22 patients with esophageal cancer who underwent esophagectomy and had postoperative complications or an increased LoS were included. The mean age at surgery was 64.55 (SD 6.72) years, and 77% (17/22) of patients were male. Moreover, 15 patients completed the intervention. Patient adherence was 99.8% in the first 6 weeks and dropped to 75.6% in the following 6 weeks, with a mean difference of −24.3% (95% CI 1.3 to 47.2; P=.04). At 3 months post operation, no differences in functional status were found between the intervention group and the matched historical comparison group. Conclusions This study showed that a postoperative physiotherapeutic intervention with telerehabilitation is feasible for patients with postoperative complications or an increased LoS after esophageal cancer surgery up to 6 weeks after T0.

Background and Purpose: Decreased muscle mass and muscle strength are independent predictors of poor postoperative recovery in patients with esophageal cancer. If there is an association between muscle mass and muscle strength, physiotherapists are able to measure muscle strength as an early predictor for poor postoperative recovery due to decreased muscle mass. Therefore, in this cross-sectional study, we aimed to investigate the association between muscle mass and muscle strength in predominantly older patients with esophageal cancer awaiting esophagectomy prior to neoadjuvant chemoradiation. Methods: In patients with resectable esophageal cancer eligible for surgery between March 2012 and October 2015, we used computed tomographic scans to assess muscle mass and compared them with muscle strength measures (handgrip strength, inspiratory and expiratory muscle strength, 30 seconds chair stands test). We calculated Pearson correlation coefficients and determined associations by multivariate linear regression analysis. Results and Discussion: A tertiary referral center referred 125 individuals to physiotherapy who were eligible for the study; we finally included 93 individuals for statistical analysis. Multiple backward regression analysis showed that gender (95% confidence interval [CI], 2.05-33.82), weight (95% CI, 0.39-1.02), age (95% CI, -0.91 to -0.04), left handgrip strength (95% CI, 0.14-1.44), and inspiratory muscle strength (95% CI, 0.08-0.38) were all independently associated with muscle surface area at L3. All these variables together explained 66% of the variability (R2) in muscle surface area at L3 (P

Purpose To describe the long-term clinical results of arthroscopic fragment fixation for chronic primary osteochondral lesions of the talus (OLT), using the Lift-Drill-Fill-Fix (LDFF) technique. Methods Eighteen patients (20 ankles) underwent fixation for a primary OLT with an osteochondral fragment using arthroscopic LDFF and were evaluated at a minimum of 5-year follow-up. Pre- and postoperative clinical assessment was prospectively performed by measuring the Numeric Rating Scale (NRS) of pain at rest, during walking and when running. Additionally, the change in Foot and Ankle Outcome Score (FAOS) and the procedure survival (i.e., no reoperation for the OLT) at final follow-up was assessed. Results At a mean follow-up of 7 years, the median NRS during walking significantly improved from 7 (IQR 5–8) pre-operatively to 0 (IQR 0–1.5) at final follow-up (p = p p = Conclusion Arthroscopic LDFF for fixable chronic primary OLTs results in excellent pain reduction and improved patient-reported outcomes, with sustained results at long-term follow-up. These results indicate that surgeons may consider arthroscopic LDFF as treatment of choice for fragmentous OLT. Level of evidence Level IV, prospective case series.

Background: Fibrinogen plays an essential role in blood coagulation and inflammation. Circulating fibrinogen levels may be determined based on interindividual differences in DNA methylation at cytosine-phosphate-guanine (CpG) sites and vice versa. Objectives: To perform an EWAS to examine an association between blood DNA methylation levels and circulating fibrinogen levels to better understand its biological and pathophysiological actions. Methods: We performed an epigenome-wide association study of circulating fibrinogen levels in 18 037 White, Black, American Indian, and Hispanic participants, representing 14 studies from the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium. Circulating leukocyte DNA methylation was measured using the Illumina 450K array in 12 904 participants and using the EPIC array in 5133 participants. In each study, an epigenome-wide association study of fibrinogen was performed using linear mixed models adjusted for potential confounders. Study-specific results were combined using array-specific meta-analysis, followed by cross-replication of epigenome-wide significant associations. We compared models with and without CRP adjustment to examine the role of inflammation. Results: We identified 208 and 87 significant CpG sites associated with fibrinogen levels from the 450K (p < 1.03 × 10−7) and EPIC arrays (p < 5.78 × 10−8), respectively. There were 78 associations from the 450K array that replicated in the EPIC array and 26 vice versa. After accounting for overlapping sites, there were 83 replicated CpG sites located in 61 loci, of which only 4 have been previously reported for fibrinogen. The examples of genes located near these CpG sites were SOCS3 and AIM2, which are involved in inflammatory pathways. The associations of all 83 replicated CpG sites were attenuated after CRP adjustment, although many remained significant. Conclusion: We identified 83 CpG sites associated with circulating fibrinogen levels. These associations are partially driven by inflammatory pathways shared by both fibrinogen and CRP.

Biological aging of human organ systems reflects the interplay of age, chronic disease, lifestyle and genetic risk. Using longitudinal brain imaging and physiological phenotypes from the UK Biobank, we establish normative models of biological age for three brain and seven body systems. Here we find that an organ’s biological age selectively influences the aging of other organ systems, revealing a multiorgan aging network. We report organ age profiles for 16 chronic diseases, where advanced biological aging extends from the organ of primary disease to multiple systems. Advanced body age associates with several lifestyle and environmental factors, leukocyte telomere lengths and mortality risk, and predicts survival time (area under the curve of 0.77) and premature death (area under the curve of 0.86). Our work reveals the multisystem nature of human aging in health and chronic disease. It may enable early identification of individuals at increased risk of aging-related morbidity and inform new strategies to potentially limit organ-specific aging in such individuals.

Purpose: Older patients with COVID-19 can present with atypical complaints, such as falls or delirium. In other diseases, such an atypical presentation is associated with worse clinical outcomes. However, it is not known whether this extends to COVID-19. We aimed to study the association between atypical presentation of COVID-19, frailty and adverse outcomes, as well as the incidence of atypical presentation. Methods: We conducted a retrospective observational multi-center cohort study in eight hospitals in the Netherlands. We included patients aged ≥ 70 years hospitalized with COVID-19 between February 2020 until May 2020. Atypical presentation of COVID-19 was defined as presentation without fever, cough and/or dyspnea. We collected data concerning symptoms on admission, demographics and frailty parameters [e.g., Charlson Comorbidity Index (CCI) and Clinical Frailty Scale (CFS)]. Outcome data included Intensive Care Unit (ICU) admission, discharge destination and 30-day mortality. Results: We included 780 patients, 9.5% (n = 74) of those patients had an atypical presentation. Patients with an atypical presentation were older (80 years, IQR 76–86 years; versus 79 years, IQR 74–84, p = 0.044) and were more often classified as severely frail (CFS 6–9) compared to patients with a typical presentation (47.6% vs 28.7%, p = 0.004). Overall, there was no significant difference in 30-day mortality between the two groups in univariate analysis (32.4% vs 41.5%; p = 0.173) or in multivariate analysis [OR 0.59 (95% CI 0.34–1.0); p = 0.058]. Conclusions: In this study, patients with an atypical presentation of COVID-19 were more frail compared to patients with a typical presentation. Contrary to our expectations, an atypical presentation was not associated with worse outcomes.

Objective The primary aim was to determine and compare the complication rate of different surgical treatment options for osteochondral lesions of the talus (OLTs). The secondary aim was to analyze and compare the severity and types of complications. Design A literature search was performed in MEDLINE (PubMed), EMBASE (Ovid), and the Cochrane Library. Methodological quality was assessed using the Methodological Index for Non-Randomized Studies (MINORS). Primary outcome was the complication rate per surgical treatment option. Secondary outcomes included the severity (using the Modified Clavien-Dindo-Sink Complication Classification System for Orthopedic Surgery) and types of complications. The primary outcome, the severity, and the sub-analyses were analyzed using a random effects model. A moderator test for subgroup-analysis was used to determine differences. The types of complications were presented as rates. Results In all, 178 articles from the literature search were included for analysis, comprising 6,962 OLTs with a pooled mean age of 35.5 years and follow-up of 46.3 months. Methodological quality was fair. The overall complication rate was 5% (4%-6%; treatment group effect, P = 0.0015). Analysis resulted in rates from 3% (2%-4%) for matrix-assisted bone marrow stimulation to 15% (5%-35%) for metal implants. Nerve injury was the most observed complication. Conclusions In 1 out of 20 patients treated surgically for an OLT, a complication occurs. Metal implants have a significantly higher complication rate compared with other treatment modalities. No life-threatening complications were reported.

Summary: Hip fractures are associated with significant healthcare costs. In frail institutionalized patients, the costs of nonoperative management are less than operative management with comparable short-term quality of life. Nonoperative management of hip fractures in patients at the end of life should be openly discussed with SDM. Purpose: The aim was to describe healthcare use with associated costs and to determine cost-utility of nonoperative management (NOM) versus operative management (OM) of frail institutionalized older patients with a proximal femoral fracture. Methods: This study included institutionalized patients with a limited life expectancy aged ≥ 70 years who sustained a proximal femoral fracture in the Netherlands. Costs of hospital- and nursing home care were calculated. Quality adjusted life years (QALY) were calculated based on EuroQol-5D-5L utility scores at day 7, 14, and 30 and at 3 and 6 months. The incremental cost-effectiveness ratio (ICER) was calculated from a societal perspective. Results: Of the 172 enrolled patients, 88 (51%) patients opted for NOM and 84 (49%) for OM. NOM was associated with lower healthcare costs at 6 months (NOM; €2425 (SD 1.030), OM; €9325 (SD 4242), p < 0.001). The main cost driver was hospital stay (NOM; €738 (SD 841) and OM; €3140 (SD 2636)). The ICER per QALY gained in the OM versus NOM was €76,912 and exceeded the threshold of €20,000 per QALY. The gained QALY were minimal in the OM group in patients who died within 14- and 30-day post-injury, but OM resulted in more than triple the costs. Conclusion: OM results in significant higher healthcare costs, mainly due to the length of hospital stay. For frail patients at the end of life, NOM of proximal femoral fractures should be openly discussed in SDM conversations due to the limited gain in QoL. Trial registration. Netherlands Trial Register (NTR7245; date 10–06-2018).

Muscle injury classification systems for hamstring injuries have evolved to use anatomy and imaging information to aid management and prognosis. However, classification systems lack reliability and validity data and are not specific to individual hamstring muscles, potentially missing parameters vital for sport-specific and activity-specific decision making. A narrative evidence review was conducted followed by a modified Delphi study to build an international consensus on best-practice decision-making for the classification of hamstring injuries. This comprised a digital information gathering survey to a cohort of 46 international hamstring experts (sports medicine physicians, physiotherapists, surgeons, trainers and sports scientists) who were also invited to a face-to-face consensus group meeting in London . Fifteen of these expert clinicians attended to synthesise and refine statements around the management of hamstring injury. A second digital survey was sent to a wider group of 112 international experts. Acceptance was set at 70% agreement. Rounds 1 and 2 survey response rates were 35/46 (76%) and 99/112 (88.4%) of experts responding. Most commonly, experts used the British Athletics Muscle Injury Classification (BAMIC) (58%), Munich (12%) and Barcelona (6%) classification systems for hamstring injury. Issues identified to advance imaging classifications systems include: detailing individual hamstring muscles, establishing optimal use of imaging in diagnosis and classification, and testing the validity and reliability of classification systems. The most used hamstring injury classification system is the BAMIC. This consensus panel recommends hamstring injury classification systems evolve to integrate imaging and clinical parameters around: individual muscles, injury mechanism, sporting demand, functional criteria and patient-reported outcome measures. More research is needed on surgical referral and effectiveness criteria, and validity and reliability of classification systems to guide management.

Introduction Negative pain-related cognitions are associated with persistence of low-back pain (LBP), but the mechanism underlying this association is not well understood. We propose that negative pain-related cognitions determine how threatening a motor task will be perceived, which in turn will affect how lumbar movements are performed, possibly with negative long-term effects on pain. Objective To assess the effect of postural threat on lumbar movement patterns in people with and without LBP, and to investigate whether this effect is associated with task-specific pain-related cognitions. Methods 30 back-healthy participants and 30 participants with LBP performed consecutive two trials of a seated repetitive reaching movement (45 times). During the first trial participants were threatened with mechanical perturbations, during the second trial participants were informed that the trial would be unperturbed. Movement patterns were characterized by temporal variability (CyclSD), local dynamic stability (LDE) and spatial variability (meanSD) of the relative lumbar Euler angles. Pain-related cognition was assessed with the task-specific ‘Expected Back Strain’-scale (EBS). A three-way mixed Manova was used to assess the effect of Threat, Group (LBP vs control) and EBS (above vs below median) on lumbar movement patterns. Results We found a main effect of threat on lumbar movement patterns. In the threat-condition, participants showed increased variability (MeanSDflexion-extension, p2 = 0.26; CyclSD, p = 0.003, η2 = 0.14) and decreased stability (LDE, p = 0.004, η2 = 0.14), indicating large effects of postural threat. Conclusion Postural threat increased variability and decreased stability of lumbar movements, regardless of group or EBS. These results suggest that perceived postural threat may underlie changes in motor behavior in patients with LBP. Since LBP is likely to impose such a threat, this could be a driver of changes in motor behavior in patients with LBP, as also supported by the higher spatial variability in the group with LBP and higher EBS in the reference condition.

Introduction: The association between obesity and outcome in critical illness is unclear. Since the amount of visceral adipose tissue(VAT) rather than BMI mediates the health effects of obesity we aimed to investigate the association between visceral obesity, BMI and 90-day mortality in critically ill patients. Method: In 555 critically ill patients (68% male), the VAT Index(VATI) was measured using Computed Tomography scans on the level of vertebra L3. The association between visceral obesity, BMI and 90-day mortality was investigated using univariable and multivariable analyses, correcting for age, sex, APACHE II score, sarcopenia and muscle quality. Results: Visceral obesity was present in 48.1% of the patients and its prevalence was similar in males and females. Mortality was similar amongst patients with and without visceral obesity (27.7% vs 24.0%, p = 0.31). The corrected odds ratio of 90-day mortality for visceral obesity was 0.667 (95%CI 0.424–1.049, p = 0.080). Using normal BMI as reference, the corrected odds ratio for overweight was 0.721 (95%CI 0.447–1.164 p = 0.181) and for obesity 0.462 (95%CI 0.208–1.027, p = 0.058). Conclusion: No significant association of visceral obesity and BMI with 90-day mortality was observed in critically ill patients, although obesity and visceral obesity tended to be associated with improved 90-day mortality.

Background: Physiotherapy (PT) is important to optimize functional recovery in geriatric rehabilitation. The dose of PT received by inpatients during geriatric rehabilitation and the determinants of dose are unknown. Objectives: Describe PT dose in terms of total number of sessions, frequency, duration and type of sessions, and inpatient characteristics determining the frequency of PT in geriatric rehabilitation. Methods: The observational, longitudinal REStORing health of acutely unwell adulTs (RESORT) cohort consists of geriatric inpatients undergoing rehabilitation including PT (Melbourne, Australia). Ordinal regression was used to assess the determinants of PT frequency (total number of sessions divided by length of stay in weeks). Malnutrition, frailty and sarcopenia were diagnosed according to the Global Leadership Initiative on Malnutrition criteria, Clinical Frailty Scale and revised definition of the European Working Group on Sarcopenia in Older People respectively. Results: Of the 1890 participants, 1799, median (quartile 1; quartile 3) age 83.4 (77.6; 88.4) years, 56% females received PT and were admitted for at least 5 days. Median total number of PT sessions was 15 (8; 24); median frequency was 5.2 sessions per week (3.0; 7.7); and duration was 27 (22; 34) minutes per session. Higher disease burden, cognitive impairment, delirium, higher anxiety and depression scores, malnutrition, frailty and sarcopenia were associated with a lower PT frequency. Older age, female sex, musculoskeletal reason for admission, greater independence in (instrumental) activities of daily living and handgrip strength were associated with a higher PT frequency. Conclusions: PT frequency varied widely with a median of 1 session per working day. PT frequency was lowest in participants with poorest health characteristics.

Purpose Antidepressants are well-established fall-risk increasing drugs (FRIDs) and therefore falls should be considered an important adverse drug event (ADE) of antidepressants. However, not all antidepressant users experience fall incidents and factors associated with increased fall risk among antidepressant users are incompletely understood. Our objective was to explore whether antidepressant plasma concentrations are associated with falls in older antidepressant users. Methods For this study, we included antidepressant users of the multicenter B-PROOF study. Fall incidents were recorded prospectively using fall calendars. Antidepressant plasma concentrations were analyzed by Liquid chromatography-mass spectrometry (LC–MS) at baseline and at 2 years follow-up. The associations between the observed antidepressant concentration and fall risk were assessed using Cox proportional hazard and logistic regression models and adjusted for potential confounders. Results In total 93 selective serotonin reuptake inhibitor (SSRI) and 41 antidepressant (TCA) users were identified. There was a significant association between baseline TCA plasma concentration and fall risk within users (HR 2.50, 95% CI 1.07–5.87, crude model). In the adjusted model, there were no significant associations between concentrations of SSRIs and fall risk. Conclusion There might be an association between plasma concentrations of TCAs and the risk of falling in older users. However, these results needs to be interpreted with caution considering the small sample size and accompanying limitation of confinement to crude analyses. Therefore, these novel findings need to replicated in a larger cohort, preferably including adjustment for potential confounders and more frequent measures of plasma concentrations is needed.

Purpose: To assess the influence of demographic risk factors, anatomic risk factors, and injury mechanisms on anterior cruciate ligament (ACL) tear patterns. Methods: All patients undergoing knee magnetic resonance imaging at our institution for acute ACL tears (within 1 month of injury) in 2019 were retrospectively analyzed. Patients with partial ACL tears and full-thickness posterior cruciate ligament injuries were excluded. On sagittal magnetic resonance images, the proximal and distal remnant lengths were measured, and the tear location was calculated as the distal remnant length divided by the total remnant length. Previously reported demographic and anatomic risk factors associated with ACL injury were then reviewed, including the notch width index, notch angle, intercondylar notch stenosis, alpha angle, posterior tibial slope, meniscal slope, and lateral femoral condyle index. In addition, the presence and severity of bone bruises were recorded. Finally, risk factors associated with ACL tear location were further analyzed using multivariate logistic regression. Results: A total of 254 patients (44% male patients; mean age, 34 years; age range, 9-74 years) were included, of whom 60 (24%) had a proximal ACL tear (tear at the proximal quarter). Multivariate enter logistic regression analysis showed that older age (P = .008) was predictive of a more proximal tear location whereas open physes (P = .025), bone bruises in both compartments (P = .005), and posterolateral corner injury (P = .017) decreased the likelihood of a proximal tear (R2 = 0.121, P < .001). Conclusions: No anatomic risk factors were identified to play a role in tear location. Although most patients have midsubstance tears, proximal ACL tears were more commonly found in older patients. Bone contusions involving the medial compartment are associated with midsubstance tears; these findings may indicate that different injury mechanisms play a role in the location at which the ACL tears. Level of Evidence: Level III, prognostic, retrospective cohort study.

The analysis of single motor unit (SMU) activity provides the foundation from which information about the neural strategies underlying the control of muscle force can be identified, due to the one-to-one association between the action potentials generated by an alpha motor neuron and those received by the innervated muscle fibers. Such a powerful assessment has been conventionally performed with invasive electrodes (i.e., intramuscular electromyography (EMG)), however, recent advances in signal processing techniques have enabled the identification of single motor unit (SMU) activity in high-density surface electromyography (HDsEMG) recordings. This matrix, developed by the Consensus for Experimental Design in Electromyography (CEDE) project, provides recommendations for the recording and analysis of SMU activity with both invasive (needle and fine-wire EMG) and non-invasive (HDsEMG) SMU identification methods, summarizing their advantages and disadvantages when used during different testing conditions. Recommendations for the analysis and reporting of discharge rate and peripheral (i.e., muscle fiber conduction velocity) SMU properties are also provided. The results of the Delphi process to reach consensus are contained in an appendix. This matrix is intended to help researchers to collect, report, and interpret SMU data in the context of both research and clinical applications.

Background: Recently, common genetic risk factors for intracranial aneurysm (IA) and aneurysmal subarachnoid hemorrhage (ASAH) were found to explain a large amount of disease heritability and therefore have potential to be used for genetic risk prediction. We constructed a genetic risk score to (1) predict ASAH incidence and IA presence (combined set of unruptured IA and ASAH) and (2) assess its association with patient characteristics. Methods: A genetic risk score incorporating genetic association data for IA and 17 traits related to IA (so-called metaGRS) was created using 1161 IA cases and 407 392 controls from the UK Biobank population study. The metaGRS was validated in combination with risk factors blood pressure, sex, and smoking in 828 IA cases and 68 568 controls from the Nordic HUNT population study. Furthermore, we assessed association between the metaGRS and patient characteristics in a cohort of 5560 IA patients. Results: Per SD increase of metaGRS, the hazard ratio for ASAH incidence was 1.34 (95% CI, 1.20–1.51) and the odds ratio for IA presence 1.09 (95% CI, 1.01–1.18). Upon including the metaGRS on top of clinical risk factors, the concordance index to predict ASAH hazard increased from 0.63 (95% CI, 0.59–0.67) to 0.65 (95% CI, 0.62–0.69), while prediction of IA presence did not improve. The metaGRS was statistically significantly associated with age at ASAH (β=−4.82×10 −3 per year [95% CI, −6.49×10 −3 to −3.14×10 −3 ]; P =1.82×10 −8 ), and location of IA at the internal carotid artery (odds ratio=0.92 [95% CI, 0.86–0.98]; P =0.0041). Conclusions: The metaGRS was predictive of ASAH incidence, although with limited added value over clinical risk factors. The metaGRS was not predictive of IA presence. Therefore, we do not recommend using this metaGRS in daily clinical care. Genetic risk does partly explain the clinical heterogeneity of IA warranting prioritization of clinical heterogeneity in future genetic prediction studies of IA and ASAH.

The key indications for surgical repair of hamstring injuries (HSIs) remain unclear in the literature due to a lack of high-level evidence and expert knowledge. The 2020 London International Hamstring Consensus meeting aimed to highlight clear surgical indications and to create a foundation for future research. A literature review was conducted followed by a modified Delphi process, with an international expert panel. Purposive sampling was used with two rounds of online questionnaires and an intermediate round involving a consensus meeting. The initial information gathering (round 1) questionnaire was sent to 46 international experts, which comprised open-ended questions covering decision-making domains in HSI. Thematic analysis of responses outlined key domains, which were evaluated by a smaller international subgroup (n=15) comprising clinical academic sports medicine physicians, physiotherapists and orthopaedic surgeons in a consensus meeting. After group discussion of each domain, a series of consensus statements were prepared, debated and refined. A round 2 questionnaire was sent to 112 international hamstring experts to vote on these statements and determine level of agreement. The consensus threshold was set a priori at 70% agreement. Rounds 1 and 2 survey respondents were 35/46 (76%) and 99/112 (88.4%), respectively. The consensus group agreed that the indications for operative intervention included: gapping at the zone of tendinous injury (87.2% agreement) and loss of tension (70.7%); symptomatic displaced bony avulsions (72.8%); and proximal free tendon injuries with functional compromise refractory to non-operative treatment (72.2%). Other important considerations for operative intervention included: the demands of the athlete/patient and the expected functional outcome (87.1%) based on the anatomy of the injury; the risk of functional loss/performance deficit with non-operative management (72.2%); and the capacity to restore anatomy and function (87.1%). Further research is needed to determine whether surgery can reduce the risk of reinjury as consensus was not reached within the whole group (48.2%) but was agreed by surgeons (70%) in the cohort. The consensus group did not support the use of corticosteroids or endoscopic surgery without further evidence. These guidelines will help standardise treatment of HSIs, specifically the indications and decision-making for surgical intervention.

Postoperative neurocognitive disorders occur frequently in older adult patients. Neuropsychological assessment is the gold standard for diagnosis, but the resources required for routine use are significant. Instead, it is common for simplified and unvalidated tests to be used for trials and in clinical practice. We undertook a single-centre prospective observational study in elective surgical patients aged ? 65 years recruited between September 2019 and January 2021. Patients underwent neuropsychological assessment, the Modified Telephone Interview for Cognitive Status and Montreal Cognitive Assessment before surgery. Tests were repeated at approximately four to eight postoperative weeks. We included 105 patients and 28 (27%) were lost to follow-up. Pre-operative Modified Telephone Interview for Cognitive Status and cognitive domain scores were very weakly to moderately correlated (r?=?0.09?0.41). Pre-operative Montreal Cognitive Assessment and cognitive domain scores were very weakly to weakly correlated (r?=?0.17?0.37) Postoperative Modified Telephone Interview for Cognitive Status and cognitive domain scores were very weakly to weakly correlated (r?=?0.09?0.36). Postoperative Montreal Cognitive Assessment score and cognitive domain scores were very weakly to weakly correlated (r?=?0.07?0.36). Overall, there was limited agreement between tests. We conclude that the Modified Telephone Interview for Cognitive Status and Montreal Cognitive Assessment should not be used in isolation to diagnose postoperative neurocognitive disorders. There seems to be little to no pre-operative, postoperative or pre- to postoperative correlation between these tests and the neuropsychological assessment in older adults without pre-operative cognitive impairment.