Population-Based Evidence for the Use of Serum Neurofilaments as Individual Diagnostic and Prognostic Biomarkers in Amyotrophic Lateral Sclerosis.

OBJECTIVE: Neurofilament light chains (NfL) and phosphorylated neurofilament heavy chains (pNfH), established as diagnostic and prognostic biomarkers in hospital-based amyotrophic lateral sclerosis (ALS) cohorts, are now surrogate markers in clinical trials. This study extends their evaluation to a population level, with the aim of advancing their full establishment and assessing the transferability of biomarker findings from controlled cohorts to real-world ALS populations. METHODS: We measured serum NfL and pNfH levels in all ALS patients (n = 790) and general population controls (n = 570) with available baseline samples participating in the epidemiological ALS Registry Swabia, providing platform-specific (ELLA™) reference data and Z-scores for controls, as well as reference data, disease-specific Z-scores and longitudinal data in ALS. We evaluated the diagnostic and prognostic utility of neurofilaments and quantified the impact of ALS-related factors and non-ALS confounders. RESULTS: Neurofilaments showed high diagnostic and prognostic utility at the population level, with NfL superior to pNfH. The novel concept of a population-based ALS Z-score significantly improved the prognostic utility compared to absolute raw values. Both biomarkers increased more strongly with age in controls than in ALS, and age adjustment improved diagnostic accuracy. Our data show that disease progression rates, ALS phenotype, body mass index (BMI), and renal function need to be considered when interpreting neurofilament levels; longitudinal neurofilament levels were generally stable in individual patients, especially when adjusted for age and baseline levels. INTERPRETATION: Population-based assessment enhances the utility of particularly serum NfL as a diagnostic and prognostic biomarker in ALS and improves the translation of findings from controlled cohorts to real-world populations. ANN NEUROL 2024.

Pre-existing sleep problems as a predictor of post-acute sequelae of COVID-19.

Several months after COVID-19 many individuals still report persisting symptoms, the so-called 'post-COVID-19 syndrome'. An immunological dysfunction is one of the main pathophysiological hypotheses. As sleep is central to the functioning of the immune system, we investigated whether self-reported pre-existing sleep disturbance might be an independent risk factor for the development of post-COVID-19 syndrome. A total of 11,710 participants of a cross-sectional survey (all tested positive for severe acute respiratory syndrome coronavirus-2) were classified into probable post-COVID-19 syndrome, an intermediate group, and unaffected participants at an average of 8.5 months after infection. The case definition was based on newly occurring symptoms of at least moderate severity and ≥20% reduction in health status and/or working capacity. Unadjusted and adjusted odds ratios were calculated to investigate the association between pre-existing sleep disturbances and subsequent development of post-COVID-19 syndrome while controlling for a variety of demographic, lifestyle, and health factors. Pre-existing sleep disturbances were found to be an independent predictor of subsequent probable post-COVID-19 syndrome (adjusted odds ratio 2.7, 95% confidence interval 2.27-3.24). Sleep disturbances as part of the post-COVID-19 syndrome were reported by more than half of the participants and appeared to be a new symptom and to occur independent of a mood disorder in most cases. Recognition of disturbed sleep as an important risk factor for post-COVID-19 syndrome should promote improved clinical management of sleep disorders in the context of COVID-19. Further, it may stimulate further research on the effect of improving sleep on the prognosis of COVID-19 long-term sequelae and other post-viral conditions.

Effect of an osteoporotic fracture prevention program on fracture incidence in routine care: a cluster-randomized trial.

BACKGROUND: Fractures are a major health problem in aging societies. Preventive approaches combining bone health and fall prevention are rare. The osteoporotic fracture prevention program in rural areas (OFRA) is a health care fund-driven program for older people in randomly selected districts in Germany. The components of the program were falls prevention exercise classes, examination of bone health by a dual-energy X-ray absorptiometry (DXA) scan, and a consultation about "safety in the living environment." The aim of this study was to evaluate this complex preventive intervention in a routine health care setting. METHODS: This cluster-randomized trial was performed from October 2015 to October 2018 and took place in 186 administrative districts in five federal states, 47 districts served as intervention districts, and 139, as controls. Within these districts, we included (a) all community-living women and men aged 70-85 years with prior fragility fractures and (b) all community-living women aged 75-80 years. The analysis used routine data collected by a health insurance company. The primary endpoint was all fragility fractures combined. Fracture types, mortality, and nursing home admission were explorative endpoints. Cox frailty models were used for comparative analyses with a median follow-up time of 365 days (interquartile range: 0 days). RESULTS: Nine thousand four hundred eight individuals were approached to participate in one of the program components, 27,318 individuals served as controls. The mean age was 78.7 years. Of those approached to participate, nearly 30% joined the exercise classes. DXA measurement was reimbursed for 13.6%, and 51.8% received advice about measures to increase "safety in the living environment." The incidence of fragility fractures did not differ between the intervention and the control group (HR 0.94; 95% CI 0.80-1.11). However, femoral fractures, the most frequent fracture type, were reduced in the intervention group (HR 0.76; 95% CI 0.59-0.99). Mortality and nursing home admission did not differ between the intervention and the control group. CONCLUSIONS: A comprehensive fracture prevention program for older people living in rural areas was implemented. The program did not affect the primary endpoint of all fragility fractures combined. It has to be considered that we used a modified intention to treat approach based on geographic randomization and information about endpoints relied exclusively on routine data of the health care insurance. TRIAL REGISTRATION: German Clinical Trials Register DRKS-ID: 00009000.

Metabolic factors and the risk of small intestine cancers: Pooled study of 800 000 individuals in the metabolic syndrome and cancer project.

To explore the largely unknown etiology of small intestine cancer, we examined metabolic factors and risk of small intestine cancer overall and by subtypes. Among 404 220 women and 403 265 men in six European cohorts, we applied Cox regression with adjustment for smoking and body mass index (BMI), to calculate sex-specific hazard ratios (HRs) of small intestine cancer by levels of BMI, mean arterial pressure (MAP) and plasma total cholesterol, triglycerides and glucose. We also calculated HRs for these factors combined (metabolic score; MetS) and used Wald test statistics to investigate pairwise interactions between metabolic factors on risk. We also performed analyses separately per subtype (neuroendocrine tumors [NETs] and adenocarcinomas). During a median follow-up of 16.9 years, 144 women and 195 men were diagnosed with small intestine cancer, including 184 NETs and 99 adenocarcinomas. Among men, no main associations or interactions between metabolic factors were observed in relation to the risk of small intestine cancer. Among women, triglycerides were positively and linearly associated with risk (HR per standard deviation [SD]: 1.23, 95% confidence interval [CI]: 1.04-1.46), and a positive association was also observed for the MetS (HR per SD: 1.25, 95% CI: 1.02-1.52). Positive interactions were observed among women between triglycerides and cholesterol (P = .0005), and between MAP and glucose (P = .009), on risk. Glucose was positively associated with adenocarcinomas among women. This large, prospective study suggests that elevated triglycerides, and metabolic factors in interaction, confer an increased risk of small intestine cancer among women, but not among men.

Long-term exposure to air pollution and liver cancer incidence in six European cohorts.

Particulate matter air pollution and diesel engine exhaust have been classified as carcinogenic for lung cancer, yet few studies have explored associations with liver cancer. We used six European adult cohorts which were recruited between 1985 and 2005, pooled within the "Effects of low-level air pollution: A study in Europe" (ELAPSE) project, and followed for the incidence of liver cancer until 2011 to 2015. The annual average exposure to nitrogen dioxide (NO2 ), particulate matter with diameter <2.5 µm (PM2.5 ), black carbon (BC), warm-season ozone (O3 ), and eight elemental components of PM2.5 (copper, iron, zinc, sulfur, nickel, vanadium, silicon, and potassium) were estimated by European-wide hybrid land-use regression models at participants' residential addresses. We analyzed the association between air pollution and liver cancer incidence by Cox proportional hazards models adjusting for potential confounders. Of 330 064 cancer-free adults at baseline, 512 developed liver cancer during a mean follow-up of 18.1 years. We observed positive linear associations between NO2 (hazard ratio, 95% confidence interval: 1.17, 1.02-1.35 per 10 µg/m3 ), PM2.5 (1.12, 0.92-1.36 per 5 µg/m3 ), and BC (1.15, 1.00-1.33 per 0.5 10-5 /m) and liver cancer incidence. Associations with NO2 and BC persisted in two-pollutant models with PM2.5 . Most components of PM2.5 were associated with the risk of liver cancer, with the strongest associations for sulfur and vanadium, which were robust to adjustment for PM2.5 or NO2 . Our study suggests that ambient air pollution may increase the risk of liver cancer, even at concentrations below current EU standards.

Prognostic value of long-term trajectories of depression for incident diabetes mellitus in patients with stable coronary heart disease.

BACKGROUND: Diabetes mellitus (DM) and depression are bidirectionally interrelated. We recently identified long-term trajectories of depression symptom severity in individuals with coronary heart disease (CHD), which were associated with the risk for subsequent cardiovascular events (CVE). We now investigated the prognostic value of these trajectories of symptoms of depression with the risk of incident DM in patients with stable coronary heart disease. METHODS: The KAROLA cohort included CHD patients participating in an in-patient rehabilitation program (years 1999/2000) and followed for up to 15 years. We included 1048 patients (mean age 59.4 years, 15% female) with information on prevalent DM at baseline and follow-up data. Cox proportional hazards models were used to model the risk for incident DM during follow-up by depression trajectory class adjusted for age, sex, education, smoking status, body mass index, and physical activity. In addition, we modeled the excess risk for subsequent CVE due to incident DM during follow-up for each of the depression trajectories. RESULTS: DM was prevalent in 20.7% of patients at baseline. Over follow-up, 296 (28.2%) of patients had a subsequent CVE. During follow-up, 157 (15.0%) patients developed incident DM before experiencing a subsequent CVE. Patients following a high-stable depression symptom trajectory were at substantially higher risk of developing incident DM than patients following a low-stable depression symptom trajectory (hazard ratio (HR) = 2.50; 95% confidence interval (CI) (1.35, 4.65)). A moderate-stable and an increasing depression trajectory were associated with HRs of 1.48 (95%-CI (1.10, 1.98)) and 1.77 (95%-CI (1.00, 3.15)) for incident DM. In addition, patients in the high-stable depression trajectory class who developed incident DM during follow-up were at 6.5-fold risk (HR = 6.51; 95%-CI (2.77, 15.3)) of experiencing a subsequent cardiovascular event. CONCLUSIONS: In patients with CHD, following a trajectory of high stable symptoms of depression was associated with an increased risk of incident DM. Furthermore, incident DM in these patients was associated with a substantially increased risk of subsequent CVE. Identifying depressive symptoms and pertinent treatment offers might be an important and promising approach to enhance outcomes in patients with CHD, which should be followed up in further research and practice.

Long-term trajectories of anxiety and depression in patients with stable coronary heart disease and risk of subsequent cardiovascular events.

BACKGROUND: Anxiety and depression seem to be under-recognized in their importance and are often not incorporated in subsequent prevention strategies in routine clinical care of coronary heart disease. METHODS: The KAROLA cohort included coronary heart disease patients participating in an in-patient rehabilitation program (years 1999/2000) and followed after 1, 3, 6, 8, 10, 13, and 15 years. We identified anxiety and depression trajectories based on the hospital anxiety and depression scale subdomains using joint latent class mixture time-to-event models. We included cardiovascular (CV) events and non-CV mortality as competing endpoints. RESULTS: We included 1,109 patients (15.4% female; mean age, 59.4 (standard deviation [SD] = 8.0) years) with baseline covariate data. Over a median follow-up of 14.8 years, participants experienced 324 subsequent CV events. We identified four anxiety and depression trajectory classes, a low-stable class (52.2% and 69.6% of patients for anxiety and depression, respectively), moderate-stable class (37.6% and 23.8%), increasing class (2.3% and 3.3%), and high-stable/high-decreasing class (7.9% and 3.3%). The hazard ratio (HR) for subsequent CV events for the increasing anxiety class was 2.13 (95% confidence interval [CI], 0.61; 7.45) compared with the low-stable class after covariate adjustment. Patients following the high-decreasing anxiety trajectory showed an HR of 1.72 (95% CI, 1.11; 2.68) and patients following the high-stable depression trajectory an HR of 2.47 (95% CI, 1.35; 4.54). CONCLUSIONS: Chronic high anxiety and depression trajectory classes were associated with increased risk of subsequent CV events. Assessments of both symptoms of anxiety and depression during long-term routine medical care are recommended to identify patients who would benefit from appropriate interventions.

A prospective assessment of cardiac biomarkers for hemodynamic stress and necrosis and the risk of falls among older people: the ActiFE study.

Falls are related to a complex interaction of risk factors. We examined if cardiac biomarkers for hemodynamic stress (N-terminal pro Brain Natriuretic Peptide-NT-proBNP), and for necrosis [high sensitive (hs) cardiac troponins T (cTnT) and I (cTnI)] are associated with falls in older people. Biomarkers were measured at baseline in a cohort of 1506 community-dwelling adults ≥65 years. Falls were assessed prospectively in a falls calendar (median 370 days). Cox-proportional hazards models evaluated the association of each biomarker with the incidence of the first fall accounting for established confounders. We observed 430 incident falls among 1327 participants and an effect modification by sex for all biomarkers. In multivariable analyses among men a one unit increment of log-transformed hs-cTnI was associated with a hazard ratio (HR) of 1.26 (95 % CI 1.04, 1.53). Men with hs-cTnT ≥ 14 ng/L had a HR of 1.74 (95 % CI 1.15, 2.61) compared to those with undetectable hs-cTnT levels. In women cTn were not associated with falls. We did not detect an association between NT-proBNP and the risk of fall. Our results suggest that cardiac troponins may not only identify subjects at risk for cardiovascular diseases, but also help to understand the underlying complex pathophysiology of falls.

Associations of pre-diagnostic body mass index with overall and cancer-specific mortality in a large Austrian cohort.

PURPOSE: Although obesity is a well-known risk factor for several cancers, its role on cancer survival is poorly understood. METHODS: Within the VHM&PP cohort, 8,673 cancer patients (42.2% women) were followed over a median time of 11.9 years. Cox proportional hazard models were used to estimate the association of pre-diagnostic overweight (BMI 25.0-29.9 kg/m(2)) and obesity (BMI ≥ 30.0 kg/m(2)) with all-cause and cancer-specific mortality. Cubic restricted splines were additionally modeled. RESULTS: During 71,126 person-years, 4,571 deaths were observed. Compared to normal weight, overweight was associated with statistically significantly decreased all-cause mortality (HR 0.93; 95% CI 0.87-0.997) and cancer-specific mortality (HR 0.91; 95% CI 0.84-0.99). Underweight was statistically significantly associated with 28% increased overall mortality, in particular in men [HR 2.02 (95% CI 1.43-2.83) vs. HR 0.96 (95% CI 0.71-1.30) in women]. J-shaped associations were found between BMI and mortality with the nadir around a BMI of 25 kg/m(2). Analysis by cancer site showed though not statistically significantly that overweight was associated with reduced mortality, while obesity was associated with increased cancer-specific mortality except cancers of the upper digestive tract. In patients with local stage colorectal cancers, obesity was associated with increased all-cause (vs. normal weight HR 1.90; 95% CI 1.03-3.52) and cancer-specific mortality (HR 3.17; 95% CI 1.29-7.81). CONCLUSION: Overweight patients have a better overall prognosis, while for obesity no association and for underweight worse prognosis were found. Our results on common cancers indicate that there are tumor- and stage-specific differences.

Sex differences in mobility recovery after hip fracture: a time series analysis.

Introduction: Sex differences are commonly reported for hip fracture incidence rates and recovery. Current knowledge about mobility recovery after hip fracture involves clinical assessments of physical capacity or patient-reported outcomes. Information on mobility performance during daily life is missing but relevant to evaluate patients' recovery. Hence, it remains unclear whether sex differences exist in the longitudinal progression of mobility performance in hip fracture patients. To investigate this, we pooled data from four studies in Germany and Norway. Methods: In all studies, real-world mobility was assessed continuously over 1 to 7 days using a sensor fixed to the unaffected frontal thigh. All studies assessed mobility at different time points that were allocated to three distinct phases: Acute and post-acute phase (week 1-6), extended recovery (7-26), and long-term recovery (27-52). Sex-specific continuous trajectories of the median (50th percentile) as well as the 1st (25th percentile) and 3rd quartile (75th percentile) were estimated using quantile regression models with splines for daily walking and standing duration; number of sit-to-stand-to-walk transfers and walking bouts; mean walking bout duration; maximum number of steps per walking bout. Results: There were 5,900 valid observation days from n = 717 participants (mean age = 83.4 years, SD 6.1). The majority was female (75.3%), with similar sex distribution across all studies. Demographics of both sexes were comparable, but a higher percentage of women was living alone (69.0% compared to 40.9% in men) and had experienced an indoor fall leading to the fracture (74.3% compared to 67.4% in men). There were clear sex differences in mobility recovery. Women improved their mobility faster than men, but men showed larger increases later in the year after surgery. At the end of the first year, both sexes reached comparable levels in almost all mobility parameters. Conclusion: We identified varying aspects of mobility recovery between men and women, i.e., timely development of mobility recovery shows different patterns. Our findings support the consideration of sex differences in planning and implementing rehabilitation measures for hip fracture patients and highlight the need to provide adapted support at different time points. The underlying mechanisms of these sex differences need further investigation.

Coping as a resource to allow for psychosocial adjustment in fatal disease: results from patients with amyotrophic lateral sclerosis.

Background: Amyotrophic lateral sclerosis (ALS) is a fatal disorder, which imposes a severe emotional burden on patients. Appropriate coping mechanisms may alleviate this burden and facilitate wellbeing, with social support known to be a successful coping strategy. This observational study aimed to determine the interplay of general coping traits of hope for success and fear of failure, coping behavior of social activity, and patients' wellbeing. Methods: In this cross-sectional study, patients with ALS from a clinical-epidemiological registry in Southwestern Germany were interviewed regarding coping traits (achievement-motivated behavior: hope for success and fear of failure), coping behavior of social activity, and psychosocial adjustment, determined using measures of depressiveness, anxiety [both measured by Hospital Anxiety and Depression Scale (HADS)], and quality of life [Anamnestic Comparative Self-Assessment (ACSA)]. Demographics, clinical [ALS Functional Rating Scale revised version (ALSFRS-R)], and survival data were recorded. Results: A total of 868 patients [60.70% male patients, mean age: 64.70 (±10.83) years, mean ALSFRS-R: 37.36 ± 7.07] were interviewed. Anxiety in patients was found to be associated with a high fear of failure. In contrast, a generally positive attitude in patients exemplified in high hopes for success was associated with better wellbeing. Finally, coping behavior of social activity explained up to 65% of the variance of depressiveness among the patients with ALS. Conclusion: In this study, we present evidence that the wellbeing of patients with ALS is not an immediate fatalistic consequence of physical degradation but rather determined by coping traits and behavior, which may be trained to substantially increase the wellbeing of patients with ALS.

Post-COVID syndrome and work ability 9-12 months after a SARS-CoV-2 infection among over 9000 employees from the general population.

Objectives: Evidence on the work-related societal impact of long-term health-related consequences following SARS-CoV-2 is emerging. We characterize the modified work ability index (mWAI) of employees 6 to 12 months after an acute infection compared to pre-infection. Methods: Analyses were based on a population-based, multi-center cross-sectional study including employees aged 18-65 years with positive SARS-CoV-2 polymerase chain reaction (tested between October 2020-April 2021 in defined geographic regions in Germany). Prevalences and results of adjusted logistic regression analyses were given. Results: In 9752 employees (mean age 45.6 years, 58% females, response 24%), n = 1217 (13.1%) participants were regarded as having low mWAI compared to pre-infection. Outpatient medical treatment, inpatient treatment, and admission to intensive care during infection were associated with mWAI <15th percentile (P15, each odds ratio [OR] >3.0). Post-COVID symptom clusters most strongly linked to mWAI

Association of BMI with general health, working capacity recovered, and post-acute sequelae of COVID-19.

OBJECTIVE: The aim of this study was to determine the risk of post-acute sequelae of COVID-19 associated with the continuous spectrum of BMI. METHODS: Epidemiology of Long COVID (EPILOC) is a population-based study conducted in Baden-Württemberg (Germany), including subjects aged 18 to 65 years who tested positive for SARS-CoV-2 between October 2020 and April 2021. Eligible subjects answered a standardized questionnaire, including sociodemographic characteristics, lifestyle factors, and the presence of specific symptoms. Participants assessed their current general health recovery and working capacity compared with the pre-infection situation and provided their body height and weight. Generalized additive models were used to assess the association of BMI with general health recovered, working capacity recovered, and prevalence of fatigue, cognitive impairment, and chest symptoms. RESULTS: The analyses included 11,296 individuals (41% male), with a mean age of 44.0 (SD 13.7) years. Best general health recovery was observed at BMI of 22.1 (95% CI: 21.0-27.0) kg/m2 in men and BMI of 21.6 (95% CI: 20.3-23.1) kg/m2 in women. In addition, we found that increasing BMI was consistently associated with post-COVID fatigue, neurocognitive impairment, and chest symptoms. CONCLUSIONS: High BMI contributes to impaired recovery after SARS-CoV-2 infection; however, a low BMI is associated with impaired recovery as well.

Diversity and trends of human milk banking: a scoping review from 1946 to 2021.

BACKGROUND: The provision of donor human milk (DHM) through human milk banks is now widely practised globally. The study aimed to describe the current state, identify major topics and map out the emerging trends in human milk banking. METHODS: PubMed was systematically searched for publications related to DHM, with the last update on 14 May 2021, for papers published between 1946 and 2021. Titles and abstracts were screened and indexed into 8 main and 39 subcategories. A top-up search was done in April 2022, but these results have not been incorporated. RESULTS: A total of 1083 publications were identified, and more than a third (41%) were either observational or interventional studies. Predominant topics were milk type and milk composition. Almost half (49%) of the publications in the last decade were funded through government/research councils, and industry funding started shortly after links between formula and necrotising enterocolitis were published. Literature from high-income countries was six times more than publications from low-income or middle-income countries (LMICs). CONCLUSION: The diversity and trends of publications included in this scoping review ranged from descriptive studies comparing biological and compositional differences of mother's own milk, DHM and/or formula. Very few studies have investigated associations of different milk types with infant outcomes. Evidence on breastfeeding and recipient psychological health outcomes is limited. Further research should identify the appropriateness of different funding sources. Future collaborations between academics, clinicians and milk banks in LMICs should be fostered to bridge the gap that exists between DHM and access.

Association of blood lipids with onset and prognosis of amyotrophic lateral sclerosis: results from the ALS Swabia registry.

BACKGROUND: To date, the role of blood lipid levels and their association with the onset and prognosis of ALS is controversial. We explored these associations in a large, population-based case-control study. METHODS: Between October 2010 and June 2014, 336 ALS patients (mean age 65.7 ± 10.7; 57.7% male) and 487 sex- and age-matched controls from the same geographic region were recruited within the ALS registry in Southwest Germany. Triglycerides and cholesterol (high-density lipoprotein (HDL), low-density lipoprotein (LDL), total) were measured. The ALS cohort was followed up for vital status. Conditional logistic regression models were applied to calculate odds ratio (OR) for risk of ALS associated with serum lipid concentrations. In ALS patients only, survival models were used to appraise the prognostic value. RESULTS: High concentration of total cholesterol (OR 1.60, 95% confidence interval (CI) 1.03-2.49, top vs. bottom quartile), but not HDL, LDL, LDL-HDL ratio, or triglycerides, was positively associated with the risk of ALS. During the median follow-up time of 88.9 months, 291 deaths occurred among 336 ALS patients. In the adjusted survival analysis, higher HDL (HR 1.72, 95% CI 1.19-2.50) and LDL cholesterol levels (HR 1.58, 95% CI 1.11-2.26) were associated with higher mortality in ALS patients. In contrast, higher triglyceride levels were associated with lower mortality (HR 0.68, 95% CI 0.48-0.96). CONCLUSION: The results highlight the importance to distinguish cholesterol from triglycerides when considering the prognostic role of lipid metabolism in ALS. It further strengthens the rationale for a triglyceride-rich diet, while the negative impact of cholesterol must be further explored.

Cystatin C based estimation of chronic kidney disease and amyotrophic lateral sclerosis in the ALS registry Swabia: associated risk and prognostic value.

Kidney function as part of metabolic changes could be associated with amyotrophic lateral-sclerosis (ALS). We investigated the associations between estimated chronic kidney disease (CKD), based on the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) cystatin C equation, and the risk at onset and prognostic value of CKD for ALS. Between October 2010 and June 2014, 362 ALS cases (59.4% men, mean age 65.7 years) and 681 controls (59.5% men, means age 66.3 years) were included in a population-based case-control study based on the ALS registry Swabia in Southern Germany. All ALS cases were followed-up (median 89.7 months), 317 died. Serum samples were measured for cystatin C to estimate the glomerular filtration rate (eGFR) according to the CKD-EPI equation. Information on covariates were assessed by an interview-based standardized questionnaire. Conditional logistic regression models were applied to calculate odds ratios (OR) for risk of ALS associated with eGFR/CKD stages. Time-to-death associated with renal parameters at baseline was assessed in ALS cases only. ALS cases were characterized by lower body mass index, slightly lower smoking prevalence, more intense occupational work and lower education than controls. Median serum cystatin-C based eGFR concentrations were lower in ALS cases than in controls (54.0 vs. 59.5 mL/min pro 1.73 m2). The prevalence of CKD stage ≥ 3 was slightly higher in ALS cases than in controls (14.1 vs. 11.0%). In the adjusted models, CKD stage 2 (OR 1.82, 95% CI 1.32, 2.52) and stage 3 (OR 2.34, 95% CI 1.38, 3.96) were associated with increased ALS risk. In this cohort of ALS cases, eGFR and CKD stage ≥ 3 (HR 0.94; 95% CI 0.64, 1.38) were not associated with prognosis. In this case-control study, higher CKD stages were associated with increased ALS risk, while in the prospective cohort of ALS cases, no indication of an association of CysC-based CKD on mortality was seen. In addition, our work strengthens the importance to evaluate renal function using a marker independent of muscle mass in ALS patients.

Post-acute sequelae of covid-19 six to 12 months after infection: population based study.

OBJECTIVES: To describe symptoms and symptom clusters of post-covid syndrome six to 12 months after acute infection, describe risk factors, and examine the association of symptom clusters with general health and working capacity. DESIGN: Population based, cross sectional study SETTING: Adults aged 18-65 years with confirmed SARS-CoV-2 infection between October 2020 and March 2021 notified to health authorities in four geographically defined regions in southern Germany. PARTICIPANTS: 50 457 patients were invited to participate in the study, of whom 12 053 (24%) responded and 11 710 (58.8% (n=6881) female; mean age 44.1 years; 3.6% (412/11 602) previously admitted with covid-19; mean follow-up time 8.5 months) could be included in the analyses. MAIN OUTCOME MEASURES: Symptom frequencies (six to 12 months after versus before acute infection), symptom severity and clustering, risk factors, and associations with general health recovery and working capacity. RESULTS: The symptom clusters fatigue (37.2% (4213/11 312), 95% confidence interval 36.4% to 38.1%) and neurocognitive impairment (31.3% (3561/11 361), 30.5% to 32.2%) contributed most to reduced health recovery and working capacity, but chest symptoms, anxiety/depression, headache/dizziness, and pain syndromes were also prevalent and relevant for working capacity, with some differences according to sex and age. Considering new symptoms with at least moderate impairment of daily life and ≤80% recovered general health or working capacity, the overall estimate for post-covid syndrome was 28.5% (3289/11 536, 27.7% to 29.3%) among participants or at least 6.5% (3289/50 457) in the infected adult population (assuming that all non-responders had completely recovered). The true value is likely to be between these estimates. CONCLUSIONS: Despite the limitation of a low response rate and possible selection and recall biases, this study suggests a considerable burden of self-reported post-acute symptom clusters and possible sequelae, notably fatigue and neurocognitive impairment, six to 12 months after acute SARS-CoV-2 infection, even among young and middle aged adults after mild infection, with a substantial impact on general health and working capacity. TRIAL REGISTRATION: German registry of clinical studies DRKS 00027012.

Health-economic evaluation of collaborative orthogeriatric care for patients with a hip fracture in Germany: a retrospective cohort study using health and long-term care insurance claims data.

BACKGROUND: Evidence suggests benefits of orthogeriatric co-management (OGCM) for hip fracture patients. Yet, evidence on cost-effectiveness is limited and based on small datasets. The aim of our study was to conduct an economic evaluation of the German OGCM for geriatric hip fracture patients. METHODS: This retrospective cohort study was based on German health and long-term care insurance data. Individuals were 80 years and older, sustained a hip fracture in 2014, and were treated in hospitals providing OGCM (OGCM group) or standard care (control group). Health care costs from payer and societal perspective, life years gained (LYG) and cost-effectiveness were investigated within 1 year. We applied weighted gamma and two-part models, and entropy balancing to account for the lack of randomisation. We calculated incremental cost-effectiveness ratios (ICER) and employed the net-benefit approach to construct cost-effectiveness acceptability curves. RESULTS: 14,005 patients were treated in OGCM, and 10,512 in standard care hospitals. Total average health care costs per patient were higher in the OGCM group: €1181.53 (p < 0.001) from payer perspective, and €1408.21 (p < 0.001) from societal perspective. The ICER equalled €52,378.12/ LYG from payer and €75,703.44/ LYG from societal perspective. The probability for cost-effectiveness would be 95% if the willingness-to-pay was higher than €82,000/ LYG from payer, and €95,000/ LYG from societal perspective. CONCLUSION: Survival improved in hospitals providing OGCM. Costs were found to increase, driven by inpatient and long-term care. The cost-effectiveness depends on the willingness-to-pay. The ICER is likely to improve with a longer follow-up.

Association of Insulin-like Growth Factor 1 Concentrations with Risk for and Prognosis of Amyotrophic Lateral Sclerosis - Results from the ALS Registry Swabia.

We investigated the associations of serum concentration of insulin-like growth factor 1 (IGF1) with risk and prognosis of ALS in the ALS registry (October 2010-June 2014, median follow-up 67.6 months) in a case-control and cohort study, respectively. Serum samples were measured for IGF-1. Information on covariates was collected by standardized questionnaire. We applied conditional logistic regression to appraise the risk and Cox proportional hazards models to appraise the prognostic value of IGF-1. Data of 294 ALS patients (mean age 65.4 (SD 11.0) years, 60.2% men) and 504 controls were included in the case-control study. Median serum IGF-1 concentrations were slightly higher in ALS cases than in controls (101 vs. 99.5 ng/ml). IGF-1 concentrations were not associated with ALS risk in the fully adjusted model (top vs. bottom quartile: OR 1.16; 95%-CI 0.73-1.84, p for trend = 0.44). Among 293 ALS cases (mean age 65.5 (SD 10.5) years, 56.8% men) 243 died during follow-up. We found a statistically significant inverse association between continuous IGF-1 concentrations and survival (p = 0.01). Very high values IGF-1 were associated with a better prognosis of ALS suggesting that functions related to IGF-1 could be involved in survival.