Long-term trajectories of peak expiratory flow rate in older men and women show linear decline mainly determined by baseline levels.

BACKGROUND: Peak expiratory flow rate (PEFR) predicts mortality and other negative health outcomes. However, little evidence exists on how PEFR changes with ageing and how trajectories of change differ among older people. AIMS: To identify trajectories of PEFR in older men and women, and to study characteristics associated with these trajectories. METHODS: Data from the Longitudinal Aging Study Amsterdam were used, an ongoing cohort study in a representative sample of Dutch older men and women. PEFR was assessed using the Mini-Wright peak flow meter across a 13-year follow-up in 991 men and 1107 women. Trajectories were analyzed using Latent Class Growth Analysis. RESULTS: Mean age was 72.5 (SD 8.4) in men and 72.4 (SD 8.4) in women. In men, three declining trajectories were identified, i.e. high, intermediate and low, with prevalences of 30%, 46% and 24%, respectively. In women, two declining trajectories were identified, i.e. high and low, with prevalences of 62 and 38%. All trajectories showed linear decline and differed mostly with regard to their intercept. Significant differences between trajectories with regard to baseline demographic, health and lifestyle characteristics were observed, e.g., men and women in the low PEFR trajectory were older, had more chronic diseases, and were more often smoker. DISCUSSION AND CONCLUSIONS: Trajectories in both men and women differ mainly in baseline level of PEFR and not in rate of decline over time. Therefore, one PEFR measurement might be sufficient to give an indication of the trajectory that an older adult is likely to follow.

Cognitively healthy centenarians are genetically protected against Alzheimer's disease.

BACKGROUND: Alzheimer's disease (AD) prevalence increases with age, yet a small fraction of the population reaches ages > 100 years without cognitive decline. We studied the genetic factors associated with such resilience against AD. METHODS: Genome-wide association studies identified 86 single nucleotide polymorphisms (SNPs) associated with AD risk. We estimated SNP frequency in 2281 AD cases, 3165 age-matched controls, and 346 cognitively healthy centenarians. We calculated a polygenic risk score (PRS) for each individual and investigated the functional properties of SNPs enriched/depleted in centenarians. RESULTS: Cognitively healthy centenarians were enriched with the protective alleles of the SNPs associated with AD risk. The protective effect concentrated on the alleles in/near ANKH, GRN, TMEM106B, SORT1, PLCG2, RIN3, and APOE genes. This translated to >5-fold lower PRS in centenarians compared to AD cases (P = 7.69 × 10-71), and 2-fold lower compared to age-matched controls (P = 5.83 × 10-17). DISCUSSION: Maintaining cognitive health until extreme ages requires complex genetic protection against AD, which concentrates on the genes associated with the endolysosomal and immune systems. HIGHLIGHTS: Cognitively healthy cent enarians are enriched with the protective alleles of genetic variants associated with Alzheimer's disease (AD). The protective effect is concentrated on variants involved in the immune and endolysosomal systems. Combining variants into a polygenic risk score (PRS) translated to > 5-fold lower PRS in centenarians compared to AD cases, and ≈ 2-fold lower compared to middle-aged healthy controls.

Combining user-centered design and behavioral theory to enhance health technologies: A personas-based approach for a primary-care based multifactorial falls risk assessment tool.

INTRODUCTION: Multifactorial falls risk assessment tools (FRATs) can be an effective falls prevention method for older adults, but are often underutilized by health care professionals (HCPs). This study aims to enhance the use and implementation of multifactorial FRATs by combining behavioral theory with the user-centered design (UCD) method of personas construction. Specifically, the study aimed to (1) construct personas that are based on external (i.e., needs, preferences) and intrinsic user characteristics (i.e., behavioral determinants); and (2) use these insights to inform requirements for optimizing an existing Dutch multifactorial FRAT (i.e., the 'Valanalyse'). METHODS: Survey data from HCPs (n = 31) was used to construct personas of the 'Valanalyse.' To examine differences between clusters on 68 clustering variables, a multivariate cluster analysis technique with non-parametric analyses and computational methods was used. The aggregated external and intrinsic user characteristics of personas were used to inform key design and implementation requirements for the 'Valanalyse,' respectively, whereby intrinsic user characteristics were matched with appropriate behavior change techniques to guide implementation. RESULTS: Significant differences between clusters were observed in 20 clustering variables (e.g., behavioral beliefs, situations for use). These variables were used to construct six personas representing users of each cluster. Together, the six personas helped operationalize four key design requirements (e.g., guide treatment-related decision making) and 14 implementation strategies (e.g., planning coping responses) for optimizing the 'Valanalyse' in Dutch geriatric, primary care settings. CONCLUSION: The findings suggest that theory- and evidence-based personas that encompass both external and intrinsic user characteristics are a useful method for understanding how the use and implementation of multifactorial FRATs can be optimized with and for HCPs, providing important implications for developers and eHealth interventions with regards to encouraging technology adoption.

Comparison of the Effect of Daily Vitamin D2 and Vitamin D3 Supplementation on Serum 25-Hydroxyvitamin D Concentration (Total 25(OH)D, 25(OH)D2, and 25(OH)D3) and Importance of Body Mass Index: A Systematic Review and Meta-Analysis.

BACKGROUND: Two previous meta-analyses showed smaller differences between vitamin D3 and vitamin D2 in raising serum 25-hydroxyvitamin D [25(OH)D] and a consistently high heterogeneity when only including daily dosing studies. OBJECTIVE: This study aimed to compare more frequently dosed vitamin D2 and vitamin D3 in improving total 25(OH)D and determine the concomitant effect of response modifiers on heterogeneity, and secondly, to compare the vitamin D2-associated change in 25(OH)D2 with the vitamin D3-associated change in 25(OH)D3. METHODS: PubMed, EMBASE, Cochrane, and the Web of Science Core collection were searched for randomized controlled trials of vitamin D2 compared with vitamin D3, daily or once/twice weekly dosed. After screening for eligibility, relevant data were extracted for meta-analyses to determine the standardized mean difference when different methods of 25(OH)D analyses were used. Otherwise, the weighted mean difference (WMD) was determined. RESULTS: Overall, the results based on 20 comparative studies showed vitamin D3 to be superior to vitamin D2 in raising total 25(OH)D concentrations, but vitamin D2 and vitamin D3 had a similar positive impact on their corresponding 25(OH)D hydroxylated forms. The WMD in change in total 25(OH)D based on 12 daily dosed vitamin D2-vitamin D3 comparisons, analyzed using liquid chromatography-tandem mass spectrometry, was 10.39 nmol/L (40%) lower for the vitamin D2 group compared with the vitamin D3 group (95% confidence interval: -14.62, -6.16; I2 = 64%; P < 00001). Body mass index (BMI) appeared to be the strongest response modifier, reducing heterogeneity to 0% in both subgroups. The vitamin D2- and vitamin D3-induced change in total 25(OH)D lost significance predominantly in subjects with a BMI >25 kg/m2 (P = 0.99). However, information on BMI was only available in 13/17 daily dosed comparisons. CONCLUSIONS: Vitamin D3 leads to a greater increase of 25(OH)D than vitamin D2, even if limited to daily dose studies, but vitamin D2 and vitamin D3 had similar positive impacts on their corresponding 25(OH)D hydroxylated forms. Next to baseline 25(OH)D concentration, BMI should be considered when comparing the effect of daily vitamin D2 and vitamin D3 supplementation on total 25(OH)D concentration. This study was registered in PROSPERO as CRD42021272674.

The phenotypic and genotypic association of grip strength with frailty, physical performance and functional limitations over time in older adults.

OBJECTIVES: To replicate the phenotypic associations of grip strength with frailty, physical performance and functional limitations in older adults for longer follow-up periods and to examine whether these associations are due to shared genetic factors. METHODS: In total 2,262 participants 55 years and older with follow-up data up to 23 years (Nobservations = 8,262) from the Longitudinal Aging Study Amsterdam were included. Weighted polygenic risk scores for grip strength (PRS-GS) were built using the genome-wide meta-analysis results from UK Biobank as reference. Grip strength was measured two times on each hand using a dynamometer. Frailty index (FI) and frailty phenotype were operationalised following standard procedures. Performance tests included a timed walk test, a repeated chair stands test and put on-take off cardigan test. Functional limitations were assessed using a questionnaire with six items. RESULTS: Higher grip strength was phenotypically associated with lower FI (b = -0.013, 95% CI (-0.016, -0.009)), better physical performance (b = 0.040, 95% CI (0.026, 0.054)) and less functional limitations (OR = 0.965, 95% CI (0.954, 0.977)) over time for follow-up periods up to 23 years. However, PRS-GS was not associated with any of the traits. CONCLUSION: The phenotypic associations between grip strength, frailty, physical performance and functional limitations were replicated for follow-up periods up to 23 years. However, the associations between the traits could not be explained by shared genetics potentially indicating a more relevant involvement of non-genetic factors.

Effects of a clinical decision support system and patient portal for preventing medication-related falls in older fallers: Protocol of a cluster randomized controlled trial with embedded process and economic evaluations (ADFICE_IT).

BACKGROUND: Falls are the leading cause of injury-related mortality and hospitalization among adults aged ≥ 65 years. An important modifiable fall-risk factor is use of fall-risk increasing drugs (FRIDs). However, deprescribing is not always attempted or performed successfully. The ADFICE_IT trial evaluates the combined use of a clinical decision support system (CDSS) and a patient portal for optimizing the deprescribing of FRIDs in older fallers. The intervention aims to optimize and enhance shared decision making (SDM) and consequently prevent injurious falls and reduce healthcare-related costs. METHODS: A multicenter, cluster-randomized controlled trial with process evaluation will be conducted among hospitals in the Netherlands. We aim to include 856 individuals aged ≥ 65 years that visit the falls clinic due to a fall. The intervention comprises the combined use of a CDSS and a patient portal. The CDSS provides guideline-based advice with regard to deprescribing and an individual fall-risk estimation, as calculated by an embedded prediction model. The patient portal provides educational information and a summary of the patient's consultation. Hospitals in the control arm will provide care-as-usual. Fall-calendars will be used for measuring the time to first injurious fall (primary outcome) and secondary fall outcomes during one year. Other measurements will be conducted at baseline, 3, 6, and 12 months and include quality of life, cost-effectiveness, feasibility, and shared decision-making measures. Data will be analyzed according to the intention-to-treat principle. Difference in time to injurious fall between the intervention and control group will be analyzed using multilevel Cox regression. DISCUSSION: The findings of this study will add valuable insights about how digital health informatics tools that target physicians and older adults can optimize deprescribing and support SDM. We expect the CDSS and patient portal to aid in deprescribing of FRIDs, resulting in a reduction in falls and related injuries. TRIAL REGISTRATION: ClinicalTrials.gov NCT05449470 (7-7-2022).

Bone mineral density loci specific to the skull portray potential pleiotropic effects on craniosynostosis.

Skull bone mineral density (SK-BMD) provides a suitable trait for the discovery of key genes in bone biology, particularly to intramembranous ossification, not captured at other skeletal sites. We perform a genome-wide association meta-analysis (n ~ 43,800) of SK-BMD, identifying 59 loci, collectively explaining 12.5% of the trait variance. Association signals cluster within gene-sets involved in skeletal development and osteoporosis. Among the four novel loci (ZIC1, PRKAR1A, AZIN1/ATP6V1C1, GLRX3), there are factors implicated in intramembranous ossification and as we show, inherent to craniosynostosis processes. Functional follow-up in zebrafish confirms the importance of ZIC1 on cranial suture patterning. Likewise, we observe abnormal cranial bone initiation that culminates in ectopic sutures and reduced BMD in mosaic atp6v1c1 knockouts. Mosaic prkar1a knockouts present asymmetric bone growth and, conversely, elevated BMD. In light of this evidence linking SK-BMD loci to craniofacial abnormalities, our study provides new insight into the pathophysiology, diagnosis and treatment of skeletal diseases.

Methodological aspects of in vivo axial loading in rodents: a systematic review.

Axial loading in rodents provides a controlled setting for mechanical loading, because load and subsequent strain, frequency, number of cycles and rest insertion between cycles, are precisely defined. These methodological aspects as well as factors, such as ovariectomy, aging, and disuse may affect the outcome of the loading test, including bone mass, structure, and bone mineral density. This review aims to overview methodological aspects and modifying factors in axial loading on bone outcomes. A systematic literature search was performed in bibliographic databases until December 2021, which resulted in 2183 articles. A total of 144 articles were selected for this review: 23 rat studies, 74 mouse studies, and 47 knock out (KO) mouse studies. Results indicated that peak load, frequency, and number of loading cycles mainly affected the outcomes of bone mass, structure, and density in both rat and mouse studies. It is crucial to consider methodological parameters and modifying factors such as age, sex-steroid deficiency, and disuse in loading protocols for the prediction of loading-related bone outcomes.

Validation of the ADFICE_IT Models for Predicting Falls and Recurrent Falls in Geriatric Outpatients.

OBJECTIVES: Before being used in clinical practice, a prediction model should be tested in patients whose data were not used in model development. Previously, we developed the ADFICE_IT models for predicting any fall and recurrent falls, referred as Any_fall and Recur_fall. In this study, we externally validated the models and compared their clinical value to a practical screening strategy where patients are screened for falls history alone. DESIGN: Retrospective, combined analysis of 2 prospective cohorts. SETTING AND PARTICIPANTS: Data were included of 1125 patients (aged ≥65 years) who visited the geriatrics department or the emergency department. METHODS: We evaluated the models' discrimination using the C-statistic. Models were updated using logistic regression if calibration intercept or slope values deviated significantly from their ideal values. Decision curve analysis was applied to compare the models' clinical value (ie, net benefit) against that of falls history for different decision thresholds. RESULTS: During the 1-year follow-up, 428 participants (42.7%) endured 1 or more falls, and 224 participants (23.1%) endured a recurrent fall (≥2 falls). C-statistic values were 0.66 (95% CI 0.63-0.69) and 0.69 (95% CI 0.65-0.72) for the Any_fall and Recur_fall models, respectively. Any_fall overestimated the fall risk and we therefore updated only its intercept whereas Recur_fall showed good calibration and required no update. Compared with falls history, Any_fall and Recur_fall showed greater net benefit for decision thresholds of 35% to 60% and 15% to 45%, respectively. CONCLUSIONS AND IMPLICATIONS: The models performed similarly in this data set of geriatric outpatients as in the development sample. This suggests that fall-risk assessment tools that were developed in community-dwelling older adults may perform well in geriatric outpatients. We found that in geriatric outpatients the models have greater clinical value across a wide range of decision thresholds compared with screening for falls history alone.

Changes in physical performance according to job demands across three cohorts of older workers in the Longitudinal Aging Study Amsterdam.

This study set out to evaluate the association between job demands at baseline and physical performance over a six-year period across three cohorts of older Dutch workers examined 10 years apart. Data were drawn from three cohorts (1992-1999, 2002-2009 and 2012-2019) of the Longitudinal Aging Study Amsterdam. Individuals aged 55-65 years from each cohort who worked for pay were included (n = 274, n = 416, n = 618, respectively). Physical performance was measured using gait speed and chair stand performance. A population-based job exposure matrix was used to indicate levels of exposure probability of physical (use of force and repetitive movements) and psychosocial (cognitive demands and time pressure) job demands. We found that psychosocial job demands increased and physical demands decreased across the three cohorts. No between cohort differences were found for how job demands affected changes in physical performance over follow-up. For men, faster decline in gait speed was observed when comparing higher and lower use of force at baseline (ß -0.012, 95% CI -0.021, -0.004). Greater use of force and repetitive movements were associated with faster decline in chair stand performance (ß -0.012, 95% CI -0.020, -0.004 and ß -0.009, 95% CI -0.017, -0.001, respectively). In women, no association of job demands on change in physical performance was observed. The study concluded that higher physical job demands were associated with stronger decline in physical performance across six years for men in all cohorts, while no associations were found among women.

Development and validation of an intrinsic capacity composite score in the Longitudinal Aging Study Amsterdam: a formative approach.

BACKGROUND: Intrinsic capacity (IC) defined by the WHO refers to the composite of five domains of capacities. So far, developing and validating a standardized overall score of the concept have been challenging partly because its conceptual framework has been unclear. We consider that a person's IC is determined by its domain-specific indicators suggesting a formative measurement model. AIMS: To develop an IC score applying a formative approach and assess its validity. METHODS: The study sample (n = 1908) consisted of 57-88-year-old participants from the Longitudinal Aging Study Amsterdam (LASA). We used logistic regression models to select the indicators to the IC score with 6-year functional decline as an outcome. An IC score (range 0-100) was constructed for each participant. We examined the known-groups' validity of the IC score by comparing groups based on age and number of chronic diseases. The criterion validity of the IC score was assessed with 6-year functional decline and 10-year mortality as outcomes. RESULTS: The constructed IC score included seven indicators covering all five domains of the construct. The mean IC score was 66.7 (SD 10.3). The scores were higher among younger participants and those who had lower number of chronic diseases. After adjustment for sociodemographic indicators, chronic diseases, and BMI, a one-point higher IC score was associated with a 7% decreased risk for 6-year functional decline and a 2% decreased risk for 10-year mortality. CONCLUSIONS: The developed IC score demonstrated discriminative ability according to age and health status and is associated with subsequent functional decline and mortality.

External validation of the Johns Hopkins Fall Risk Assessment Tool in older Dutch hospitalized patients.

PURPOSE: Fall prevention is a safety goal in many hospitals. The performance of the Johns Hopkins Fall Risk Assessment Tool (JHFRAT) in older inpatients is largely unknown. We aimed to assess the JHFRAT performance in a large sample of Dutch older inpatients, including its trend over time. METHODS: We used an Electronic Health Records (EHR) dataset with hospitalized patients (≥ 70), admitted for ≥ 24 h between 2016 and 2021. Inpatient falls were extracted from structured and free-text data. We assessed the association between JHFRAT and falls using logistic regression. For test accuracy, we calculated sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV). Discrimination was measured by the AUC. For calibration, we plotted the predicted fall probability with the actual probability of falls. For time-related effects, we calculated the AUC per 6 months (using data of patients admitted during the 6 months' time interval) and plotted these different AUC values over time. Furthermore, we compared the model (JHFRAT and falls) with and without adjusting for seasonal influenza, COVID-19, spring, summer, fall or winter periods. RESULTS: Data included 17,263 admissions with at least 1 JHFRAT measurement, a median age of 76 and a percentage female of 47%. The in-hospital fall prevalence was 2.5%. JHFRAT [OR = 1.11 (1.03-1.20)] and its subcategories were significantly associated with falls. For medium/high risk of falls (JHFRAT > 5), sensitivity was 73%, specificity 51%, PPV 4% and NPV 99%. The overall AUC was 0.67, varying over time between 0.62 and 0.71 (for 6 months' time intervals). Seasonal influenza did affect the association between JHFRAT and falls. COVID-19, spring, summer, fall or winter did not affect the association. CONCLUSIONS: Our results show an association between JHFRAT and falls, a low discrimination by JHFRAT for older inpatients and over-prediction in the calibration. Improvements in the fall-risk assessment are warranted to improve efficiency.

Longitudinal Aging Study Amsterdam COVID-19 exposure index: a cross-sectional analysis of the impact of the pandemic on daily functioning of older adults.

OBJECTIVES: The aim of this study was to develop an index to measure older adults' exposure to the COVID-19 pandemic and to study its association with various domains of functioning. DESIGN: Cross-sectional study. SETTING: The Longitudinal Aging Study Amsterdam (LASA), a cohort study in the Netherlands. PARTICIPANTS: Community-dwelling older adults aged 62-102 years (n=1089) who participated in the LASA COVID-19 study (June-September 2020), just after the first wave of the pandemic. PRIMARY OUTCOME MEASURES: A 35-item COVID-19 exposure index with a score ranging between 0 and 1 was developed, including items that assess the extent to which the COVID-19 situation affected daily lives of older adults. Descriptive characteristics of the index were studied, stratified by several sociodemographic factors. Logistic regression analyses were performed to study associations between the exposure index and several indicators of functioning (functional limitations, anxiety, depression and loneliness). RESULTS: The mean COVID-19 exposure index score was 0.20 (SD 0.10). Scores were relatively high among women and in the southern region of the Netherlands. In models adjusted for sociodemographic factors and prepandemic functioning (2018-2019), those with scores in the highest tertile of the exposure index were more likely to report functional limitations (OR: 2.24; 95% CI: 1.48 to 3.38), anxiety symptoms (OR: 3.14; 95% CI: 1.82 to 5.44), depressive symptoms (OR: 2.49; 95% CI: 1.55 to 4.00) and loneliness (OR: 2.97; 95% CI: 2.08 to 4.26) than those in the lowest tertile. CONCLUSIONS: Among older adults in the Netherlands, higher exposure to the COVID-19 pandemic was associated with worse functioning in the physical, mental and social domain. The newly developed exposure index may be used to identify persons for whom targeted interventions are needed to maintain or improve functioning during the pandemic or postpandemic.

Delay or postponement of medical care among older adults in the Netherlands at earlier and later stages of the COVID-19 pandemic.

AIMS: The aim of the current study was to compare cancellations or postponement of medical care among older adults during the COVID-19 pandemic between 2021 and 2020. METHODS: Data of respondents aged ≥ 62 years were used from the longitudinal aging study Amsterdam (LASA), collected in 2020 and 2021, directly after the main COVID-19 waves in the Netherlands. A questionnaire assessed cancellations of medical care and postponed help-seeking behavior. Descriptive analyses were performed. RESULTS: Overall, cancellations declined from 35% in 2020 (sample n = 1128) to 17% in 2021 (sample n = 1020). Healthcare-initiated cancellations declined from 29 to 8%. Respondent-initiated cancellations declined from 12 to 7%. Postponed help-seeking remained around 8%. CONCLUSIONS: In 2021, less cancellations were reported compared to just after the first wave of the pandemic in 2020, while postponed help-seeking remained the same. It is important to investigate how cancellations and postponed help-seeking can be prevented in future pandemics.

Comparing cardiovascular disease incidence and prevalence between depressed and non-depressed older persons over time: Cohort differences in the Longitudinal Aging Study Amsterdam.

OBJECTIVE: Previous studies suggest that prevention of cardiovascular disease (CVD) is more difficult in depressed persons. Although the prevalence and incidence of CVD decreased over the past decades, it is uncertain whether this is also true for depressed persons. This study examined whether changes in the prevalence and incidence of CVD differ between depressed and non-depressed older persons. METHODS: Longitudinal data from three community-based representative birth cohorts aged 55-65 years of the Longitudinal Aging Study Amsterdam were used; N = 1070 born in 1926-1937, N = 995 born in 1938-1947, N = 1019 born in 1948-1957. The outcome included fatal and non-fatal CVD. Depression was defined as ≥16 points on the Center for Epidemiological Studies Depression Scale or a general practitioner's diagnosis of depression. Data were analysed with for age and sex adjusted logistic regression and cox regression models. RESULTS: Comparing cohort 2 and 3 with cohort 1 in the complete sample, the prevalence of CVD decreased by 2% (OR = 0.98, 95%CI = 0.76-1.26) and 32% (OR = 0.68, 95%CI = 0.52-0.89), respectively, and the three-year incidence of CVD decreased by 6% (OR = 0.94, 95%CI = 0.63-1.41) and 26% (OR = 0.74, 95%CI = 0.48-1.15), respectively. The 13-year incidence of CVD decreased by 19% (HR = 0.81, 95%CI = 0.67-0.99) in cohort 2 compared to cohort 1. These decreases did not differ statistically significantly between depressed and non-depressed respondents (p-values of interaction terms: 0.35-0.98). CONCLUSION: Substantial decreases in the prevalence and incidence of CVD were observed in depressed and non-depressed older persons. Although this is encouraging, cardiovascular risk remained higher in depressed persons over time, warranting tailored prevention programs for depressed older persons.

Physical activity as a risk or protective factor for falls and fall-related fractures in non-frail and frail older adults: a longitudinal study.

BACKGROUND: Physical activity may be both a risk and protective factor for falls and fall-related fractures. Despite its positive effects on muscle and bone health, physical activity also increases exposure to situations where falls and fractures occur. This paradox could possibly be explained by frailty status. Therefore, the aim of this study was to investigate the associations between physical activity and both falls and fractures, and to determine whether frailty modifies the association of physical activity with falls, and fractures. METHODS: Data of 311 community-dwelling participants aged 75 years or older from the Longitudinal Aging Study Amsterdam, who participated in a three-year longitudinal study with five nine-monthly measurements between 2015/2016 and 2018/2019. Their mean age was 81.1 (SD 4.8) years and frailty was present in 30.9% of the participants. Physical activity in minutes per day was objectively assessed with an inertial sensor (Actigraph) for seven consecutive days. Falls and fractures were assessed every nine months using self-report during an interview over a follow-up period of three years. Frailty was determined at baseline using the frailty index. Associations were estimated using longitudinal logistic regression analyses based on generalized estimating equations. RESULTS: No association between physical activity and falls was found (OR = 1.00, 95% CI: 0.99-1.00). Fall risk was higher in frail compared to non-frail adults (OR = 2.21, 95% CI: 1.33-3.68), but no effect modification was seen of frailty on the association between physical activity and falls. Also no relation between physical activity and fractures was found (OR = 1.00, 95% CI: 0.99-1.01). Fracture risk was higher in frail compared to non-frail adults (OR = 2.81, 95% CI: 1.02-7.75), but also no effect modification of frailty was present in the association between physical activity and fractures. CONCLUSIONS: No association between physical activity and neither falls nor fractures was found, and frailty appeared not to be an effect modifier. However, frailty was a risk factor for falls and fractures in this population of older adults. Our findings suggest that physical activity can be safely recommended in non-frail and frail populations for general health benefits, without increasing the risk of falls.

The Association Between the Kyphosis Angle and Physical Performance in Community-Dwelling Older Adults.

BACKGROUND: We investigated prospectively among community-dwelling older adults aged 65 years and older whether a larger kyphosis angle is associated with poorer physical performance (balance, muscle strength, or both), and whether this association is unidirectional. METHODS: Male and female participants performed a multicomponent physical performance test with subscores for gait, muscle strength, and balance at baseline and after 2 years. Hand grip strength was also measured at baseline and at follow-up. The Cobb angle was measured on DXA-based Vertebral Fracture Assessments, made at the baseline and follow-up visit. Through linear and logistic regression analysis, we investigated the association between the kyphosis angle and physical performance and vice versa. We stratified for sex, and tested for effect modification by age and study center. RESULTS: The mean kyphosis angle was 37° and 15% of the participants (n = 1 220, mean age 72.9 ± 5.7 years) had hyperkyphosis (Cobb angle ≥50°). A larger kyphosis angle at baseline was independently associated with a poorer total physical performance score in women of the oldest quartile (≥77 years) in both the cross-sectional and longitudinal analyses (baseline B -0.32, 95% confidence interval [CI] -0.56-0.08; follow-up B 0.32, 95% CI -0.55-0.10). There was no association between physical performance at baseline and kyphosis progression. CONCLUSION: A larger kyphosis angle is independently associated with a poorer physical performance at baseline and over time, and the direction of this association is unidirectional. These results emphasize the importance of early detection and treatment of hyperkyphosis to prevent further worsening of the kyphosis angle, thereby potentially preserving physical performance.

Protocol paper: a multi-center, double-blinded, randomized, 6-month, placebo-controlled study followed by 12-month open label extension to evaluate the safety and efficacy of Saracatinib in Fibrodysplasia Ossificans Progressiva (STOPFOP).

BACKGROUND: Fibrodysplasia Ossificans Progressiva (FOP) is a genetic, progressive and devastating disease characterized by severe heterotopic ossification (HO), loss of mobility and early death. There are no FDA approved medications. The STOPFOP team identified AZD0530 (saracatinib) as a potent inhibitor of the ALK2/ACVR1-kinase which is the causative gene for this rare bone disease. AZD0530 was proven to prevent HO formation in FOP mouse models. The STOPFOP trial investigates the repositioning of AZD0530, originally developed for ovarian cancer treatment, to treat patients with FOP. METHODS: The STOPFOP trial is a phase 2a study. It is designed as a European, multicentre, 6-month double blind randomized controlled trial of AZD0530 versus placebo, followed by a 12-month trial comparing open-label extended AZD0530 treatment with natural history data as a control. Enrollment will include 20 FOP patients, aged 18-65 years, with the classic FOP mutation (ALK2 R206H). The primary endpoint is objective change in heterotopic bone volume measured by low-dose whole-body computer tomography (CT) in the RCT phase. Secondary endpoints include 18F NaF PET activity and patient reported outcome measures. DISCUSSION: Clinical trials in rare diseases with limited study populations pose unique challenges. An ideal solution for limiting risks in early clinical studies is drug repositioning - using existing clinical molecules for new disease indications. Using existing assets may also allow a more fluid transition into clinical practice. With positive study outcome, AZD0530 may provide a therapy for FOP that can be rapidly progressed due to the availability of existing safety data from 28 registered clinical trials with AZD0530 involving over 600 patients. TRIAL REGISTRATION: EudraCT, 2019-003324-20. Registered 16 October 2019, https://www.clinicaltrialsregister.eu/ctr-search/trial/2019-003324-20/NL . CLINICALTRIALS: gov , NCT04307953 . Registered 13 March 2020.

High-intensity versus low-intensity resistance training in patients with knee osteoarthritis: A randomized controlled trial.

OBJECTIVES: To assess whether (i) high-intensity resistance training (RT) leads to increased muscle strength compared to low-intensity RT in patients with knee osteoarthritis (OA); and (ii) RT with vitamin D supplementation leads to increased muscle strength compared to placebo in a subgroup with vitamin D deficiency. DESIGN: Randomized controlled trial. SETTING: Outpatient rehabilitation centre. SUBJECTS: Patients with knee OA. INTERVENTIONS: 12 weeks of RT at high-intensity RT (70-80% of 1-repetition maximum (1-RM)) or low-intensity RT (40-50% of 1-RM) and 24 weeks of vitamin D (1200 International units vitamin D3 per day) or placebo supplementation. MAIN MEASURES: Primary outcome measure was isokinetic muscle strength. Other outcome measure for muscle strength was the estimated 1-RM. Secondary outcome measures were knee pain and physical functioning. RESULTS: 177 participants with a mean age of 67.6 ± 5.8 years were included, of whom 50 had vitamin D deficiency. Isokinetic muscle strength (in Newton metre per kilogram bodyweight) at start, end and 24 weeks after the RT was 0.98 ± 0.40, 1.11 ± 0.40, 1.09 ± 0.42 in the high-intensity group and 1.02 ± 0.41, 1.15 ± 0.42, 1.12 ± 0.40 in the low-intensity group, respectively. No differences were found between the groups, except for the estimated 1-RM in favour of the high-intensity group. In the subgroup with vitamin D deficiency, no difference on isokinetic muscle strength was found between the vitamin D and placebo group. CONCLUSIONS: High-intensity RT did not result in greater improvements in isokinetic muscle strength, pain and physical functioning compared to low-intensity RT in knee OA, but was well tolerated. Therefore these results suggest that either intensity of resistance training could be utilised in exercise programmes for patients with knee osteoarthritis. No synergistic effect of vitamin D supplementation and RT was found, but this finding was based on underpowered data.