Deprescribing of antidepressants: development of indicators of high-risk and overprescribing using the RAND/UCLA Appropriateness Method.

BACKGROUND: Antidepressants are first-line medications for many psychiatric disorders. However, their widespread long-term use in some indications (e.g., mild depression and insomnia) is concerning. Particularly in older adults with comorbidities and polypharmacy, who are more susceptible to adverse drug reactions, the risks and benefits of treatment should be regularly reviewed. The aim of this consensus process was to identify explicit criteria of potentially inappropriate antidepressant use (indicators) in order to support primary care clinicians in identifying situations, where deprescribing of antidepressants should be considered. METHODS: We used the RAND/UCLA Appropriateness Method to identify the indicators of high-risk and overprescribing of antidepressants. We combined a structured literature review with a 3-round expert panel, with results discussed in moderated meetings in between rounds. Each of the 282 candidate indicators was scored on a 9-point Likert scale representing the necessity of a critical review of antidepressant continuation (1-3 = not necessary; 4-6 = uncertain; 7-9 = clearly necessary). Experts rated the indicators for the necessity of review, since decisions to deprescribe require considerations of patient risk/benefit balance and preferences. Indicators with a median necessity rating of ≥ 7 without disagreement after 3 rating rounds were accepted. RESULTS: The expert panel comprised 2 general practitioners, 2 clinical pharmacologists, 1 gerontopsychiatrist, 2 psychiatrists, and 3 internists/geriatricians (total N = 10). After 3 assessment rounds, there was consensus for 37 indicators of high-risk and 25 indicators of overprescribing, where critical reviews were felt to be necessary. High-risk prescribing indicators included settings posing risks of drug-drug, drug-disease, and drug-age interactions or the occurrence of adverse drug reactions. Indicators with the highest ratings included those suggesting the possibility of cardiovascular risks (QTc prolongation), delirium, gastrointestinal bleeding, and liver injury in specific patient subgroups with additional risk factors. Overprescribing indicators target patients with long treatment durations for depression, anxiety, and insomnia as well as high doses for pain and insomnia. CONCLUSIONS: Explicit indicators of antidepressant high-risk and overprescribing may be used directly by patients and health care providers, and integrated within clinical decision support tools, in order to improve the overall risk/benefit balance of this commonly prescribed class of prescription drugs.

Hypogonadism is frequent in very old men with multimorbidity and is associated with anemia and sarcopenia.

BACKGROUND: Clinical data regarding hypogonadism in very old men with multimorbidity are rare. Hypogonadism can contribute to osteoporosis, anemia and sarcopenia and is therefore a relevant problem for geriatric patients. METHODS: A total of 167 men aged 65-96 years (mean 81 ± 7 years) admitted to an acute geriatric ward were included in a cross-sectional study. Body composition derived from dual-energy X­ray absorptiometry, bone mineral density, handgrip strength, multimorbidity, polypharmacy and laboratory values were obtained from the routine electronic clinical patient file. RESULTS: Hypogonadism was present in 62% (n = 104) of the study participants, of whom 83% showed clinical manifestation of hypogonadism (hypogonadism in combination with anemia, sarcopenia and/or low T­score). The subgroups showed a distribution of 52% primary and 48% secondary hypogonadism. Compared to the eugonadal patients, hypogonadal patients had reduced handgrip strength (p = 0.031) and lower hemoglobin levels (p = 0.043), even after adjustment for age, body mass index and glomerular filtration rate. CONCLUSION: Hypogonadism is common in geriatric patients. If chronic anemia, sarcopenia, or osteoporosis are diagnosed, testosterone levels should be determined in geriatric settings.

Sarcopenic obesity using the ESPEN and EASO consensus statement criteria of 2022 - Results from the German KORA-Age study.

OBJECTIVE: The recent consensus statement of ESPEN and EASO recommends reviewing existing datasets to assess the prevalence of sarcopenic obesity based on the new definition and diagnostic criteria. Therefore, this study aimed to determine the prevalence of sarcopenic obesity in a population-based study and to assess the association of this new definition with clinical traits. METHODS: The KORA (Cooperative Health Research in the Region of Augsburg)-Age baseline examination (2008/2009) comprised 1079 participants aged 65 years and older from southern Germany. Sarcopenic obesity was defined in 998 participants (mean age 75.6 years, 498 women) with complete data according to the 2022 ESPEN and EASO algorithm, which includes reduced handgrip strength, reduced skeletal muscle mass per weight, and elevated fat mass. Body composition was measured using bioelectrical impedance analysis. Associations between sarcopenic obesity and physical activity, disability, multimorbidity, and polypharmacy were assessed using logistic regression analysis. RESULTS: The overall prevalence of sarcopenic obesity was 4.5 % (5.0 % in men, 4.0 % in women). Sarcopenic obesity was associated with disability (2.87 [CI 1.84-4.48]), multimorbidity (≥ 2 comorbidities; 2.59 [CI 1.23-5.46]), polypharmacy (≥ 5 drugs; 1.96 [CI 1.05-3.63]), cognitive impairment (3.03 [CI 1.51-6.06]) and arthritis (2.66 [CI 1.39-5.07]) after adjusting for age, sex and marital status. CONCLUSION: Sarcopenic obesity is prevalent in the older German population and is associated with several clinical traits. Future longitudinal studies are needed to further elucidate whether the observed associations could be causal.

Sarcopenia: investigation of metabolic changes and its associated mechanisms.

BACKGROUND: Sarcopenia is one of the most predominant musculoskeletal diseases of the elderly, defined as age-related progressive and generalized loss of muscle mass with a simultaneous reduction in muscle strength and/or function. Using metabolomics, we aimed to examine the association between sarcopenia and the plasma metabolic profile of sarcopenic patients, measured using a targeted HPLC-MS/MS platform. METHODS: Plasma samples from 22 (17 men) hip fracture patients undergoing surgery (8 sarcopenic, age 81.4+6.3, and 14 non-sarcopenic, age 78.4±8.1) were analyzed. T test, fold change, orthogonal partial least squares discriminant analysis, and sparse partial least squares discriminant analysis were used for mining significant features. Metabolite set enrichment analysis and mediation analysis by PLSSEM were thereafter performed. RESULTS: Using a univariate analysis for sarcopenia z score, the amino acid citrulline was the only metabolite with a significant group difference after FDR correction. Positive trends were observed between the sarcopenia z score and very long-chain fatty acids as well as dicarboxylic acid carnitines. Multivariate analysis showed citrulline, non-esterified fatty acid 26:2, and decanedioyl carnitine as the top three metabolites according to the variable importance in projection using oPLS-DA and loadings weight by sPLS-DA. Metabolite set enrichment analysis showed carnitine palmitoyltransferase deficiency (II) as the highest condition related to the metabolome. CONCLUSIONS: We observed a difference in the plasma metabolic profile in association with different measures of sarcopenia, which identifies very long-chain fatty acids, Carn.DC and citrulline as key variables associated with the disease severity. These findings point to a potential link between sarcopenia and mitochondrial dysfunction and portraits a number of possible biochemical pathways which might be involved in the disease pathogenesis.

Oral health in patients with neurodegenerative and cerebrovascular disease: a retrospective study.

PURPOSE: This retrospective study investigates oral health and oral care in patients with neurodegenerative and cerebrovascular diseases (CVDs) treated in a dental facility for people with disabilities. METHODS: Oral health indices decayed, missing, and filled teeth (DMFT), periodontal screening index (PSI), treatment spectrum, and oral hygiene were evaluated in 152 patients with multiple sclerosis, Parkinson's disease, dementia, and CVD and 30 controls. Regression analyses identified group differences and influencing factors on DMFT. RESULTS: Patients with neurodegenerative or CVD had a significantly higher DMFT (21.2 ± 5.8 vs. 18.3 ± 5.9), more decayed teeth (4.3 ± 4.8 vs. 1 ± 1.9), fewer filled teeth (7.9 ± 5.5 vs. 11 ± 5.6), and a higher number of surgical (39.5% vs. 20%) treatments but significantly less conservative (49.3% vs. 73.3%) and prosthetic (15.1% vs. 56.7%) treatments than the control group (p< 0.05). The frequency of toothbrushing and the use of an electric toothbrush were related to lower DMFT in patients with neurodegenerative and CVD. Smoking was associated with higher DMFT. CONCLUSIONS: Poor oral health was found in all individuals with disabilities, suggesting that limitations in oral care attributed to aging and neurological disorders negatively affect oral health. Oral rehabilitation of patients with disabilities requires awareness of oral health limitations and early intervention through dental care. Implications for rehabilitationPoor oral health and oral hygiene is common among older people with disabilities.To optimize oral rehabilitation of patients with disabilities, early intervention, individualized treatment plans and an adapted time frame for dental treatment are required.Education of dentists, caregivers, and family members is essential for oral rehabilitation and improvement of oral hygiene in patients with disabilities.

Increased Geriatric Treatment Frequency Improves Mobility and Secondary Fracture Prevention in Older Adult Hip Fracture Patients-An Observational Cohort Study of 23,828 Patients from the Registry for Geriatric Trauma (ATR-DGU).

Interdisciplinary orthogeriatric care of older adult hip fracture patients is of growing importance due to an ageing population, yet there is ongoing disagreement about the most effective model of care. This study aimed to compare different forms of orthogeriatric treatment, with focus on their impact on postoperative mobilization, mobility and secondary fracture prevention. In this observational cohort study, patients aged 70 years and older with a proximal femur fracture requiring surgery, were included from 1 January 2016 to 31 December 2019. Data were recorded from hospital stay to 120-day follow-up in the Registry for Geriatric Trauma (ATR-DGU), a specific designed registry for older adult hip fracture patients. Of 23,828 included patients from 95 different hospitals, 72% were female, median age was 85 (IQR 80-89) years. Increased involvement of geriatricians had a significant impact on mobilization on the first day (OR 1.1, CI 1.1-1.2) and mobility seven days after surgery (OR 1.1, CI 1.1-1.2), initiation of an osteoporosis treatment during in-hospital stay (OR 2.5, CI 2.4-2.7) and of an early complex geriatric rehabilitation treatment (OR 1.3, CI 1.2-1.4). These findings were persistent after 120 days of follow-up. Interdisciplinary treatment of orthogeriatric patients is beneficial and especially during in-patient stay increased involvement of geriatricians is decisive for early mobilization, mobility and initiation of osteoporosis treatment. Standardized treatment pathways in certified geriatric trauma departments with structured data collection in specific registries improve outcome monitoring and interpretation.

Influence of IGF-I serum concentration on muscular regeneration capacity in patients with sarcopenia.

BACKGROUND: Previous research has described a neuroprotective effect of IGF-I, supporting neuronal survival, axon growth and proliferation of muscle cells. Therefore, the association between IGF-I concentration, muscle histology and electrophysiological markers in a cohort of patients with sarcopenia dares investigation. METHODS: Measurement of serum concentrations of IGF-I and binding partners, electromyographic measurements with the MUNIX (Motor Unit Number Index) method and muscle biopsies were performed in 31 patients with acute hip fracture older age 60 years. Molecular markers for denervation (neural cell adhesion molecule NCAM) and proliferation markers (Ki67) were assessed by immunofluorescence staining of muscle biopsy tissue. Skeletal muscle mass by bioelectrical impedance analysis and hand-grip strength were measured to assess sarcopenia status according to EWGSOP2 criteria. RESULTS: Thirty-one patients (20 women) with a mean age of 80.6 ± 7.4 years were included. Concentrations of IGF-I and its binding partners were significantly associated with sarcopenia (ß = - 0.360; p = 0.047) and MUNIX (ß = 0.512; p = 0.005). Further, expression of NCAM (ß = 0.380; p = 0.039) and Ki67 (ß = 0.424; p = 0.022) showed significant associations to IGF-I concentrations. CONCLUSIONS: The findings suggest a pathogenetic role of IGF-I in sarcopenia based on muscle denervation.

Late-onset neuromuscular disorders in the differential diagnosis of sarcopenia.

BACKGROUND: Sarcopenia is the age-related loss of muscle mass and strength. Undiagnosed late-onset neuromuscular disorders need to be considered in the differential diagnosis of sarcopenia. AIM: Based on emblematic case reports and current neuromuscular diagnostic guidelines for three common late-onset neuromuscular disorders, a differential diagnostic approach for geriatric patients presenting with a sarcopenic phenotype is given. METHODS: Patients over 65 years of age with sarcopenia, amyotrophic lateral sclerosis, inclusion body myositis and myotonic dystrophy type 2 were recruited. All patients were assessed for sarcopenia based on the revised European consensus definition. Patients with neuromuscular diseases were diagnosed according to the revised El Escorial criteria and the European neuromuscular centre criteria. Phenotypes and diagnostic criteria for all patients were summarized including their specific histopathological findings. RESULTS: All patients with neuromuscular diseases were positively screened for sarcopenia and classified as severe sarcopenic by means of assessment. The clinical phenotype, the evolution pattern of weakness and muscle atrophy combined with laboratory finding including electromyography could unquestionably distinguish the diseases. DISCUSSION: Neuromuscular disorders can manifest beyond the age of 65 years and misdiagnosed as sarcopenia. The most common diseases are inclusion body myositis, amyotrophic lateral sclerosis and myotonic dystrophy type 2. A diagnostic work-up for neuromuscular diseases ensures their correct diagnosis by clinical-, electrophysiological, histopathological, and genetic work-up. CONCLUSIONS: In geriatric patients with a focal or asymmetrical muscular weakness and atrophy, sarcopenia assessment should be extended with patient's history of disease course. Furthermore, concomitant diseases, analysis of serum creatine kinase, electrophysiological examination, and in selected patients muscle biopsy and gene analysis is needed to rule out a late-onset neuromuscular disorder.

Proteomic profiling of low muscle and high fat mass: a machine learning approach in the KORA S4/FF4 study.

BACKGROUND: The coexistence of low muscle mass and high fat mass, two interrelated conditions strongly associated with declining health status, has been characterized by only a few protein biomarkers. High-throughput proteomics enable concurrent measurement of numerous proteins, facilitating the discovery of potentially new biomarkers. METHODS: Data derived from the prospective population-based Cooperative Health Research in the Region of Augsburg S4/FF4 cohort study (median follow-up time: 13.5 years) included 1478 participants (756 men and 722 women) aged 55-74 years in the cross-sectional and 608 participants (315 men and 293 women) in the longitudinal analysis. Appendicular skeletal muscle mass (ASMM) and body fat mass index (BFMI) were determined through bioelectrical impedance analysis at baseline and follow-up. At baseline, 233 plasma proteins were measured using proximity extension assay. We implemented boosting with stability selection to enable false positives-controlled variable selection to identify new protein biomarkers of low muscle mass, high fat mass, and their combination. We evaluated prediction models developed based on group least absolute shrinkage and selection operator (lasso) with 100× bootstrapping by cross-validated area under the curve (AUC) to investigate if proteins increase the prediction accuracy on top of classical risk factors. RESULTS: In the cross-sectional analysis, we identified kallikrein-6, C-C motif chemokine 28 (CCL28), and tissue factor pathway inhibitor as previously unknown biomarkers for muscle mass [association with low ASMM: odds ratio (OR) per 1-SD increase in log2 normalized protein expression values (95% confidence interval (CI)): 1.63 (1.37-1.95), 1.31 (1.14-1.51), 1.24 (1.06-1.45), respectively] and serine protease 27 for fat mass [association with high BFMI: OR (95% CI): 0.73 (0.61-0.86)]. CCL28 and metalloproteinase inhibitor 4 (TIMP4) constituted new biomarkers for the combination of low muscle and high fat mass [association with low ASMM combined with high BFMI: OR (95% CI): 1.32 (1.08-1.61), 1.28 (1.03-1.59), respectively]. Including protein biomarkers selected in ≥90% of group lasso bootstrap iterations on top of classical risk factors improved the performance of models predicting low ASMM, high BFMI, and their combination [delta AUC (95% CI): 0.16 (0.13-0.20), 0.22 (0.18-0.25), 0.12 (0.08-0.17), respectively]. In the longitudinal analysis, N-terminal prohormone brain natriuretic peptide (NT-proBNP) was the only protein selected for loss in ASMM and loss in ASMM combined with gain in BFMI over 14 years [OR (95% CI): 1.40 (1.10-1.77), 1.60 (1.15-2.24), respectively]. CONCLUSIONS: Proteomic profiling revealed CCL28 and TIMP4 as new biomarkers of low muscle mass combined with high fat mass and NT-proBNP as a key biomarker of loss in muscle mass combined with gain in fat mass. Proteomics enable us to accelerate biomarker discoveries in muscle research.

The Effect of Biochemical Remission on Bone Metabolism in Cushing's Syndrome: A 2-Year Follow-Up Study.

Endogenous Cushing's syndrome (CS) is a rare cause of secondary osteoporosis. The long-term consequences for bone metabolism after successful surgical treatment remain largely unknown. We assessed bone mineral density and fracture rates in 89 patients with confirmed Cushing's syndrome at the time of diagnosis and 2 years after successful tumor resection. We determined five bone turnover markers at the time of diagnosis, 1 and 2 years postoperatively. The bone turnover markers osteocalcin, intact procollagen-IN-propeptide (PINP), alkaline bone phosphatase, CTX-I, and TrAcP 5b were measured in plasma or serum by chemiluminescent immunoassays. For comparison, 71 sex-, age-, and body mass index (BMI)-matched patients in whom Cushing's syndrome had been excluded were studied. None of the patients received specific osteoanabolic treatment. At time of diagnosis, 69% of the patients had low bone mass (mean T-score = -1.4 ± 1.1). Two years after successful surgery, the T-score had improved in 78% of patients (mean T-score 2 years postoperatively -1.0 ± 0.9). The bone formation markers osteocalcin and intact PINP were significantly decreased at time of diagnosis (p ≤ 0.001 and p = 0.03, respectively), and the bone resorption marker CTX-I and TrAcP 5b increased. Postoperatively, the bone formation markers showed a three- to fourfold increase 1 year postoperatively, with a moderate decline thereafter. The bone resorption markers showed a similar but less pronounced course. This study shows that the phase immediately after surgical remission from endogenous CS is characterized by a high rate of bone turnover resulting in a striking net increase in bone mineral density in the majority of patients. © 2020 The Authors. Journal of Bone and Mineral Research published by American Society for Bone and Mineral Research.

Longitudinal association of type 2 diabetes and insulin therapy with muscle parameters in the KORA-Age study.

AIMS: The aim of the current study was to investigate the association of type 2 diabetes (T2D) and insulin treatment with changes in muscle mass, muscle strength, and physical performance in older adults. METHODS: In 731 participants of the population-based KORA-Age study aged 74.6 ± 6.2 years (T2D: n = 118; insulin treatment: n = 20), skeletal muscle index (SMI [kg/m2]), hand grip strength (GS [kg]), and a timed up and go test (TUG [s]) were performed at baseline and after a follow-up time of 3 years. The association of T2D and insulin therapy with changes in muscle parameters was analyzed using linear regression models. RESULTS: After adjustment for sex, age, BMI, physical activity, smoking, and multimorbidity, T2D was associated with the change in SMI during follow-up (ß - 0.1 (95% CI - 0.3 to - 0.02) kg/m2; p = 0.02), but not with a change in GS (ß - 0.9 (95% CI - 1.9 to 0.04) kg) or TUG (ß - 0.1 (95% CI - 0.7 to 0.5) s). Insulin therapy was positively associated with change in SMI (ß 0.6 (95% CI 0.3-0.9) kg/m2; p = 0.001), but not in GS (ß - 1.6 (95% CI - 4.1 to 0.8) kg) or TUG (ß 1.6 (95% CI - 0.2-3.4) s) in comparison with treatment with oral anti-diabetic medication alone. CONCLUSIONS: Participants with T2D showed an accelerated decline in muscle mass compared to non-diabetic participants. Insulin therapy was associated with preserved muscle mass, but not muscle function parameters, indicating a discrepancy between muscle mass and function in this high-risk population.

Cushing's syndrome: a model for sarcopenic obesity.

PURPOSE: Obesity and its metabolic impairments are discussed as major risk factors for sarcopenia leading to sarcopenic obesity. Cushing's syndrome is known to be associated with obesity and muscle atrophy. We compared Cushing's syndrome with matched obese controls regarding body composition, physical performance, and biochemical markers to test the hypothesis that Cushing's syndrome could be a model for sarcopenic obesity. METHODS: By propensity score matching, 47 controls were selected by body mass index and gender as obese controls. Fat mass and muscle mass were measured by bioelectrical impedance analysis. Muscle function was assessed by chair rising test and hand grip strength. Biochemical markers of glucose and lipid metabolism and inflammation (hsCRP) were measured in peripheral blood. RESULTS: Muscle mass did not differ between Cushing's syndrome and obese controls. However, Cushing's syndrome patients showed significantly greater chair rising time (9.5 s vs. 7.3 s, p = 0.008) and significantly lower hand grip strength (32.1 kg vs. 36.8 kg, p = 0.003). Cushing's syndrome patients with impaired fasting glucose have shown the highest limitations in hand grip strength and chair rising time. CONCLUSIONS: Similar to published data in ageing medicine, Cushing's syndrome patients show loss of muscle function that cannot be explained by loss of muscle mass. Impaired muscle quality due to fat infiltration may be the reason. This is supported by the observation that Cushing's syndrome patients with impaired glucose metabolism show strongest deterioration of muscle function. Research in sarcopenic obesity in elderly is hampered by confounding comorbidities and polypharmacy. As Cushing's syndrome patients are frequently free of comorbidities and as Cushing's syndrome is potentially curable we suggest Cushing's syndrome as a clinical model for further research in sarcopenic obesity.

C-terminal agrin fragment (CAF) reflects renal function in patients suffering from severe sepsis or septic shock.

BACKGROUND: One of the main causes of acute kidney injury (AKI) in patients treated on an intensive care unit (ICU) is sepsis. The identification of new biomarkers indicating the early development and future course of AKI are of utmost medical interest. The C-terminal agrin fragment (CAF) is measurable in blood serum and might reflect kidney function. Therefore, this study evaluates CAF in patients presenting to an internal ICU with severe sepsis or septic shock. Serum levels of CAF are correlated with biomarkers of kidney function, markers of systemic inflammation, and the presence of AKI and renal replacement therapy (RRT). METHODS: 61 patients suffering from severe sepsis or septic shock were included during the first 24 hours of ICU treatment and blood samples for biomarker measurements, i.e., CAF, creatinine, cystatin C, procalcitonin (PCT), interleukin 6, C reactive protein (CRP), and white blood cells (WBC) were collected on the first day of intensive care treatment. The number of RRT days and the incidence of AKI were documented. RESULTS: 13% of the patients (8/61) suffered from SIRS/sepsis, 20% (12/61) from severe sepsis, and 67% (41/61) from septic shock. Serum levels of CAF significantly correlated with creatinine (r = 0.623, p < 0.001) and cystatin C (r = 0.578, p < 0.001). Multiple linear regression analyses adjusting CAF for inflammatory parameters (i.e., WBC, CRP, interleukin 6, PCT), age, and gender showed a strong correlation between CAF and creatinine (r = 0.643, p < 0.001). Serum levels of CAF were significantly associated with the need of RRT (area under the curve (AUC) = 0.772, 95% CI: 0.641-0.903, p = 0.002) and the incidence of AKI (AUC = 0.721, 95% CI: 591-0.850, p = 0.004) as indicated by ROC analysis. CONCLUSIONS: In patients suffering from severe sepsis and septic shock, serum levels of CAF were significantly associated with kidney function and RRT and were not influenced by severe septic conditions.