Linear ubiquitin chains remodel the proteome and influence the levels of hundreds of regulators in Drosophila.

Ubiquitin controls many cellular processes via its post-translational conjugation onto substrates. Its use is highly variable due to its ability to form poly-ubiquitin with various topologies. Among them, linear chains have emerged as important regulators of immune responses and protein degradation. Previous studies in Drosophila melanogaster found that expression of linear poly-ubiquitin that cannot be dismantled into single moieties leads to their own ubiquitination and degradation or, alternatively, to their conjugation onto proteins. However, it remains largely unknown which proteins are sensitive to linear poly-ubiquitin. To address this question, here we expanded the toolkit to modulate linear chains and conducted ultra-deep coverage proteomics from flies that express non-cleavable, linear chains comprising 2, 4, or 6 moieties. We found that these chains regulate shared and distinct cellular processes in Drosophila by impacting hundreds of proteins. Our results provide key insight into the proteome subsets and cellular pathways that are influenced by linear poly-ubiquitin with distinct lengths and suggest that the ubiquitin system is exceedingly pliable.

The ubiquitin-conjugating enzyme UBE2D/eff maintains a youthful proteome and ensures protein quality control during aging.

Ubiquitin-conjugating enzymes (E2s) are key for regulating protein function and turnover via ubiquitination but it remains undetermined which E2s maintain proteostasis during aging. Here, we find that E2s have diverse roles in handling a model aggregation-prone protein (huntingtin-polyQ) in the Drosophila retina: while some E2s mediate aggregate assembly, UBE2D/effete (eff) and other E2s are required for huntingtin-polyQ degradation. UBE2D/eff is key for proteostasis also in skeletal muscle: eff protein levels decline with aging, and muscle-specific eff knockdown causes an accelerated buildup in insoluble poly-ubiquitinated proteins (which progressively accumulate with aging) and shortens lifespan. Transgenic expression of human UBE2D2, homologous to eff, partially rescues the lifespan and proteostasis deficits caused by muscle-specific effRNAi by re-establishing the physiological levels of effRNAi-regulated proteins, which include several regulators of proteostasis. Interestingly, UBE2D/eff knockdown in young age reproduces part of the proteomic changes that normally occur in old muscles, suggesting that the decrease in UBE2D/eff protein levels that occurs with aging contributes to reshaping the composition of the muscle proteome. Altogether, these findings indicate that UBE2D/eff is a key E2 ubiquitin-conjugating enzyme that ensures protein quality control and helps maintain a youthful proteome composition during aging.

An umbrella review of effectiveness and efficacy trials for app-based health interventions.

Health interventions based on mobile phone or tablet applications (apps) are promising tools to help patients manage their conditions more effectively. Evidence from randomized controlled trials (RCTs) on efficacy and effectiveness of such interventions is increasingly available. This umbrella review aimed at mapping and narratively summarizing published systematic reviews on efficacy and effectiveness of mobile app-based health interventions within patient populations. We followed a pre-specified publicly available protocol. Systematic reviews were searched in two databases from inception until August 28, 2023. Reviews that included RCTs evaluating integrated or stand-alone health app interventions in patient populations with regard to efficacy/effectiveness were considered eligible. Information on indications, outcomes, app characteristics, efficacy/effectiveness results and authors' conclusions was extracted. Methodological quality was assessed using the AMSTAR2 tool. We identified 48 systematic reviews published between 2013 and 2023 (35 with meta-analyses) that met our inclusion criteria. Eleven reviews included a broad spectrum of conditions, thirteen focused on diabetes, five on anxiety and/or depression, and others on various other indications. Reported outcomes ranged from medication adherence to laboratory, anthropometric and functional parameters, symptom scores and quality of life. Fourty-one reviews concluded that health apps may be effective in improving health outcomes. We rated one review as moderate quality. Here we report that the synthesized evidence on health app effectiveness varies largely between indications. Future RCTs should consider reporting behavioral (process) outcomes and measures of healthcare resource utilization to provide deeper insights on mechanisms that make health apps effective, and further elucidate their impact on healthcare systems.

An adaptive stress response that confers cellular resilience to decreased ubiquitination.

Ubiquitination is a post-translational modification initiated by the E1 enzyme UBA1, which transfers ubiquitin to ~35 E2 ubiquitin-conjugating enzymes. While UBA1 loss is cell lethal, it remains unknown how partial reduction in UBA1 activity is endured. Here, we utilize deep-coverage mass spectrometry to define the E1-E2 interactome and to determine the proteins that are modulated by knockdown of UBA1 and of each E2 in human cells. These analyses define the UBA1/E2-sensitive proteome and the E2 specificity in protein modulation. Interestingly, profound adaptations in peroxisomes and other organelles are triggered by decreased ubiquitination. While the cargo receptor PEX5 depends on its mono-ubiquitination for binding to peroxisomal proteins and importing them into peroxisomes, we find that UBA1/E2 knockdown induces the compensatory upregulation of other PEX proteins necessary for PEX5 docking to the peroxisomal membrane. Altogether, this study defines a homeostatic mechanism that sustains peroxisomal protein import in cells with decreased ubiquitination capacity.

Burden of sequelae and healthcare resource utilization in the first year of life in infants born with congenital cytomegalovirus (cCMV) infection in Germany: A retrospective statutory health insurance claims database analysis.

BACKGROUND: Congenital cytomegalovirus (cCMV) infection can have a broad range of manifestations. This study aimed to assess cCMV-associated sequelae and healthcare resource utilization (HCRU) in infants during the first year of life in Germany. METHODS: A retrospective, controlled cohort study using German claims data from the Institute for Applied Health Research Berlin (InGef) database was conducted. cCMV-associated sequelae and HCRU during the first year of life were assessed by matching (1:60) infants with at least one inpatient/outpatient cCMV diagnosis (ICD-10-GM: P35.1) ≤90 days after birth (cCMV90 cohort) and infants with at least one inpatient cCMV diagnosis plus specific sequelae ≤21 days after birth (cCMV21-S) to infants without cCMV or CMV (ICD-10-GM: B25) diagnosis (control group), respectively. Outcomes were analyzed during the first 365 days of life. RESULTS: Between 2014-2018, we identified 54 newborns for cCMV90 and 24 newborns for cCMV21-S cohort. Compared to the 3,240 and 1,440 controls, respectively, more cCMV90 infants (83.3% vs. 41.9%, p<0.01) presented with at least one sequela during the first year of life, including intrauterine growth retardation (42.6% vs. 5.3%, p<0.01), sensorineural hearing loss (SNHL) to deafness (38.9% vs. 2.2%, p<0.01), and motor development disorders (33.3% vs. 10.9%, p<0.01). Further, 13.0% of cCMV90 infants (vs. 2.3%, p<0.01) suffered from visual impairment. In cCMV21-S cohort, intrauterine growth retardation (79.2% vs. 6.0%, p<0.01), prematurity (54.2% vs. 7.3%, p<0.01), and motor development disorders (50.0% vs. 11.0%, p<0.01) were the most frequent sequelae. Infants in the cCMV90 and cCMV21-S cohort had, on average, 7.3 times and 9.5 times more hospitalizations and 2.0 times and 2.1 times more outpatient physician visits than their respective controls (p<0.01). Hospitalized infants with cCMV stayed, on average, significantly longer in hospital compared to their controls (cCMV90 cohort: 30.3 days vs. 9.0 days, p<0.01; cCMV21-S cohort: 46.5 days vs. 9.3 days, p<0.01). CONCLUSIONS: cCMV-infection shows a considerable disease and healthcare burden during the first year of life. More than 80% of the identified newborns with cCMV suffered from at least one associated sequela during the first year of life, including long-term sequelae such as SNHL (40%) and visual impairment (13%). Additional steps for prevention of cCMV infection and associated sequelae as well as a comprehensive monitoring of disease burden are needed.

Signaling roles of platelets in skeletal muscle regeneration.

Platelets have important hemostatic functions in repairing blood vessels upon tissue injury. Cytokines, growth factors, and metabolites stored in platelet α-granules and dense granules are released upon platelet activation and clotting. Emerging evidence indicates that such platelet-derived signaling factors are instrumental in guiding tissue regeneration. Here, we discuss the important roles of platelet-secreted signaling factors in skeletal muscle regeneration. Chemokines secreted by platelets in the early phase after injury are needed to recruit neutrophils to injured muscles, and impeding this early step of muscle regeneration exacerbates inflammation at later stages, compromises neo-angiogenesis and the growth of newly formed myofibers, and reduces post-injury muscle force production. Platelets also contribute to the recruitment of pro-regenerative stromal cells from the adipose tissue, and the platelet releasate may also regulate the metabolism and proliferation of muscle satellite cells, which sustain myogenesis. Therefore, harnessing the signaling functions of platelets and the platelet secretome may provide new avenues for promoting skeletal muscle regeneration in health and disease.

Health and economic impact of improved glucose, blood pressure and lipid control among German adults with type 2 diabetes: a modelling study.

AIMS/HYPOTHESIS: The aim of this study was to estimate the long-term health and economic consequences of improved risk factor control in German adults with type 2 diabetes. METHODS: We used the UK Prospective Diabetes Study Outcomes Model 2 to project the patient-level health outcomes and healthcare costs of people with type 2 diabetes in Germany over 5, 10 and 30 years. We parameterised the model using the best available data on population characteristics, healthcare costs and health-related quality of life from German studies. The modelled scenarios were: (1) a permanent reduction of HbA1c by 5.5 mmol/mol (0.5%), of systolic BP (SBP) by 10 mmHg, or of LDL-cholesterol by 0.26 mmol/l in all patients, and (2) achievement of guideline care recommendations for HbA1c (≤53 mmol/mol [7%]), SBP (≤140 mmHg) or LDL-cholesterol (≤2.6 mmol/l) in patients who do not meet the recommendations. We calculated nationwide estimates using age- and sex-specific quality-adjusted life year (QALY) and cost estimates, type 2 diabetes prevalence and population size. RESULTS: Over 10 years, a permanent reduction of HbA1c by 5.5 mmol/mol (0.5%), SBP by 10 mmHg or LDL-cholesterol by 0.26 mmol/l led to per-person savings in healthcare expenditures of €121, €238 and €34, and 0.01, 0.02 and 0.015 QALYs gained, respectively. Achieving guideline care recommendations for HbA1c, SBP or LDL-cholesterol could reduce healthcare expenditure by €451, €507 and €327 and gained 0.03, 0.05 and 0.06 additional QALYs in individuals who did not meet the recommendations. Nationally, achieving guideline care recommendations for HbA1c, SBP and LDL-cholesterol could reduce healthcare costs by over €1.9 billion. CONCLUSIONS/INTERPRETATION: Sustained improvements in HbA1c, SBP and LDL-cholesterol control among diabetes patients in Germany can lead to substantial health benefits and reduce healthcare expenditures.

Platelet-derived chemokines promote skeletal muscle regeneration by guiding neutrophil recruitment to injured muscles.

Skeletal muscle regeneration involves coordinated interactions between different cell types. Injection of platelet-rich plasma is circumstantially considered an aid to muscle repair but whether platelets promote regeneration beyond their role in hemostasis remains unexplored. Here, we find that signaling via platelet-released chemokines is an early event necessary for muscle repair in mice. Platelet depletion reduces the levels of the platelet-secreted neutrophil chemoattractants CXCL5 and CXCL7/PPBP. Consequently, early-phase neutrophil infiltration to injured muscles is impaired whereas later inflammation is exacerbated. Consistent with this model, neutrophil infiltration to injured muscles is compromised in male mice with Cxcl7-knockout platelets. Moreover, neo-angiogenesis and the re-establishment of myofiber size and muscle strength occurs optimally in control mice post-injury but not in Cxcl7ko mice and in neutrophil-depleted mice. Altogether, these findings indicate that platelet-secreted CXCL7 promotes regeneration by recruiting neutrophils to injured muscles, and that this signaling axis could be utilized therapeutically to boost muscle regeneration.

Progressive development of melanoma-induced cachexia differentially impacts organ systems in mice.

Cachexia is a systemic wasting syndrome that increases cancer-associated mortality. How cachexia progressively and differentially impacts distinct tissues is largely unknown. Here, we find that the heart and skeletal muscle undergo wasting at early stages and are the tissues transcriptionally most impacted by cachexia. We also identify general and organ-specific transcriptional changes that indicate functional derangement by cachexia even in tissues that do not undergo wasting, such as the brain. Secreted factors constitute a top category of cancer-regulated genes in host tissues, and these changes include upregulation of the angiotensin-converting enzyme (ACE). ACE inhibition with the drug lisinopril improves muscle force and partially impedes cachexia-induced transcriptional changes, although wasting is not prevented, suggesting that cancer-induced host-secreted factors can regulate tissue function during cachexia. Altogether, by defining prevalent and temporal and tissue-specific responses to cachexia, this resource highlights biomarkers and possible targets for general and tissue-tailored anti-cachexia therapies.

Healthcare costs of congenital cytomegalovirus (cCMV) disease in infants during the first two years of life: a retrospective German claims database analysis.

BACKGROUND: Congenital cytomegalovirus (cCMV) infection can cause severe neurological damage, growth retardation, hearing loss, and microcephaly in infants. We aimed at assessing healthcare costs of infants with recorded cCMV diagnosis in an administrative claims database in the first 2 years of life. METHODS: We conducted a retrospective, controlled cohort study using German claims data from the Institute for Applied Health Research Berlin (InGef) database. Incremental healthcare costs during the first and second year of life were assessed by matching (1:60) infants with cCMV diagnoses ≤ 90 days after birth (cCMV90 cohort) to infants without cCMV diagnosis ("representative" controls) and infants with cCMV diagnoses ≤ 21 days after birth plus specific symptoms (cCMV21-S) to infants without cCMV and any ICD-10-GM records (besides Z00-Z99) until 4th preventive health check-up ("healthy" controls). Due to missing data, mean imputation was applied for aids and remedies costs. RESULTS: We identified 54 and 24 infants born 2014-2018 for the cCMV90 and cCMV21-S cohorts, respectively. During the first year, mean (median) healthcare costs were significantly higher in cCMV90 cases vs. "representative" controls (€22,737 (€9759) vs. €3091 (€863), p < 0.001), with 87.2% inpatient costs. Healthcare costs for cCMV21-S cases compared to "healthy" controls were €34,498 (€20,924) vs. €680 (€569), p < 0.001. Differences decreased for both comparisons in the second year but remained statistically significant. CONCLUSIONS: cCMV comprises a considerable economic burden for the German healthcare system (€19,646 to €33,818 higher mean costs for infants with recorded cCMV diagnosis in the first year of life). Attempts should be made to reduce this burden.

The NPXXY Motif Regulates ß-Arrestin Recruitment by the CB1 Cannabinoid Receptor.

Background: Activation of signaling effectors by G-protein coupled receptors (GPCRs) depends on different molecular mechanisms triggered by conserved amino acid residues. Although studies have focused on the G-protein signaling state, the mechanism for ß-arrestin signaling by CB1 is not yet well defined. Studies have indicated that transmembrane helix 7 (TMH7) and the highly conserved NPXXY motif can be subject to different conformational changes in response to biased ligands and could therefore participate in a molecular mechanism to trigger ß-arrestin recruitment. Objective: To investigate the effect of mutations in the NPXXY motif on different signaling pathways activated by the CB1 receptor. Materials and Methods: Point mutations of the NPXXY motif and associated residues were generated in the CB1 receptor using site-directed mutagenesis and transfection into HEK-293 cells. Signaling by wild-type and mutant receptors was analyzed by quantifying inhibition of cAMP, and by ß-arrestin recruitment assays. Results: We found that N7.49 and Y7.53 are essential for ß-arrestin recruitment by CB1. N7.49A and Y7.53F impair ß-arrestin signaling, with no effect on G-protein signaling. We found a regulatory role for residue I2.43; I2.43 interacts with Y7.53, affecting its positioning. Reducing steric bulk at I2.43 (I2.43A) enhances ß-arrestin1 recruitment, while introducing a polar residue (I2.43T) reduces ß-arrestin recruitment. Conclusions: These findings point to a novel mechanism for ß-arrestin recruitment, implicating amino acids in the NPXXY motif as critical for the putative ß-arrestin biased conformational state of Class A GPCRs.

Electroporation of Small Interfering RNAs into Tibialis Anterior Muscles of Mice.

Aging and wasting of skeletal muscle reduce organismal fitness. Regrettably, only limited interventions are currently available to address this unmet medical need. Many methods have been developed to study this condition, including the intramuscular electroporation of DNA plasmids. However, this technique requires surgery and high electrical fields, which cause tissue damage. Here, we report an optimized protocol for the electroporation of small interfering RNAs (siRNAs) into the tibialis anterior muscle of mice. This protocol does not require surgery and, because of the small siRNA size, mild electroporation conditions are utilized. By inducing target mRNA knockdown, this method can be used to interrogate gene function in muscles of mice from different strains, genotypes, and ages. Moreover, a complementary method for siRNA transfection into differentiated myotubes can be used for testing siRNA efficacy before in vivo use. Altogether, this streamlined protocol is instrumental for basic science and translational studies in muscles of mice and other animal models.

The myokine Fibcd1 is an endogenous determinant of myofiber size and mitigates cancer-induced myofiber atrophy.

Decline in skeletal muscle cell size (myofiber atrophy) is a key feature of cancer-induced wasting (cachexia). In particular, atrophy of the diaphragm, the major muscle responsible for breathing, is an important determinant of cancer-associated mortality. However, therapeutic options are limited. Here, we have used Drosophila transgenic screening to identify muscle-secreted factors (myokines) that act as paracrine regulators of myofiber growth. Subsequent testing in mouse myotubes revealed that mouse Fibcd1 is an evolutionary-conserved myokine that preserves myofiber size via ERK signaling. Local administration of recombinant Fibcd1 (rFibcd1) ameliorates cachexia-induced myofiber atrophy in the diaphragm of mice bearing patient-derived melanoma xenografts and LLC carcinomas. Moreover, rFibcd1 impedes cachexia-associated transcriptional changes in the diaphragm. Fibcd1-induced signaling appears to be muscle selective because rFibcd1 increases ERK activity in myotubes but not in several cancer cell lines tested. We propose that rFibcd1 may help reinstate myofiber size in the diaphragm of patients with cancer cachexia.

Burden of CIN2+ diagnoses and conizations in women aged 18-45 years-a retrospective secondary data analysis of German statutory health insurance claims data.

PURPOSE: High grade cervical intraepithelial neoplasia (CIN2+) may progress to cervical cancer. They may be detected by screening and are usually treated by conization. This study aimed at assessing annual proportions of screening, prevalent and incident CIN2+ diagnoses, as well as proportions of (re-)conizations during 24 months follow-up after conization in Germany. METHODS: A descriptive retrospective claims data analysis of the years 2013-2018 was conducted using the InGef Research Database. Women aged 18-45 years with CIN2+ diagnoses were identified by ICD-10-GM codes (N87.1, N87.2, D06.-, and C53.-). Cervical conizations were identified by OPS codes (5-671.0* or 5-671.1*). Screening participation was identified by EBM codes (01730, 01733, 32819 or 32820). Annual proportions were calculated as women with the respective documented codes divided by all women in the respective age group per calendar year. RESULTS: Overall annual proportions of screened women spanned from 60.01 to 61.33% between 2013 and 2018. The overall annual prevalence of CIN2+ diagnoses (regardless of screening participation) ranged from 0.72 to 0.84% between 2013 and 2018, with highest proportions observed in women aged 27-45 years. Also, CIN2+ incidence was highest in women 27-45 years. Annual proportion of women undergoing conization was 0.24% in 2013 and 0.21% in 2018. During a 24-month follow-up period after conization, 2.91% of women underwent a re-conization 3 months or later after the initial conization. CONCLUSION: This analysis demonstrates a considerable burden of CIN2+, conizations and re-conizations in Germany, especially in women aged 27-45 years. This highlights the need for intensified prevention efforts such as expanding human papillomavirus (HPV) vaccination.

Healthcare Costs and Resource Use Associated With Cervical Intraepithelial Neoplasia and Cervical Conization: A Retrospective Study of German Statutory Health Insurance Claims Data.

Background: Cervical intraepithelial neoplasia (CIN) can be a consequence of human papillomavirus (HPV) infection. High-grade CIN (CIN2/CIN3) may develop from persistent HPV infection and progress to cervical cancer if left untreated. Management of CIN includes conservative surveillance or ablation and excision by conization. Internationally, CIN and its treatment generate a considerable economic burden, but no current data regarding costs and resource use from the perspective of the German statutory health insurance exist. Objectives: The aim of this study was to explore the health economic burden in women with CIN diagnoses who either underwent cervical conization or were managed conservatively. Methods: We conducted a retrospective claims data analysis using the InGef Research Database from 2013 to 2018. Healthcare costs and resource utilization in a 24-month observation period (1:1:1 matching) were compared in 18- to 45-year-old women with CIN (1-3) who underwent a conization procedure (study cohort 1) and in women with CIN (1-3) who did not undergo conization (study cohort 2) to women with neither CIN nor conization (control group). Results: For each group, 2749 women were identified. Mean total healthcare costs after 24 months were higher in study cohort 1 (€4446, P<.01) and study cohort 2 (€3754, P=.09) compared with the control group (€3426). Comparing study cohort 1 and 2 to controls, mean differences were highest in age groups 41-45 years (cohort 1: €5115 vs €3354, P<.01; cohort 2: €4152 vs €3354, P=.14). Significantly more women were hospitalized at least once in study cohort 1 (57.46%, P<.01) and study cohort 2 (38.74%, P<.01) compared with the control group (31.14%). Frequency of outpatient physician visits was significantly higher in both study cohorts (43.23 visits, P<.01 and 38.60 visits, P<.01) compared with the control group (32.07 visits). Conclusion: Our results revealed 30% and 10% increased total healthcare costs in women with CIN undergoing invasive treatment (study cohort 1) and conservative management (study cohort 2), respectively, compared with a control group of women with no CIN in a 2-year follow-up period.

Does preoperative antibiotic prophylaxis affect sonication-based diagnosis in implant-associated infection?

As culture-negative implant-associated infection denote a diagnostic challenge, sonicate fluid cultures of the explanted endoprosthesis and osteosynthesis components are frequently used. However, the effect of antibiotic treatment on pathogen detection by sonication fluid cultures in implant-associated infection has not been investigated. Thus, the aim of this study was to evaluate the influence of preoperative antibiotic prophylaxis (PAP) and antibiotic therapy (AT) on sonicate fluid cultures in patients with implant-associated infection. In this retrospective study three groups were compared: (i) standard PAP, (ii) AT for at least one day, and (iii) no antibiotics before surgery. For the inclusion criteria, an established diagnostic protocol for implant-associated infection was used. Sonicate fluid cultures were validated by corresponding microbiological and histopathological samples. In 90 patients with single and multiple infections, 114 pathogens were detected. The detection rate by sonicate fluid cultures in patients receiving PAP (n = 27, 29 pathogens), AT before surgery (n = 33, 48 pathogens) and no antibiotics before surgery (n = 30, 37 pathogens) were 86.2%, 81.3%, and 86.5% (p = .778), respectively. Eleven of 114 infectious agents were detected exclusively by sonicate fluid cultures, while conventional tissue culture failed in these cases. PAP and AT do not affect intraoperative cultures in implant-associated infection. It is therefore not recommended to omit antibiotic prophylaxis in patients with implant-associated infection. Algorithms including both sonicate fluid cultures and tissue samples should be used for appropriate microbiological diagnosis of implant-associated infections.

Living longer but less healthy: The female disadvantage in health expectancy. Results from the KORA-Age study.

OBJECTIVES: We explored the male-female health-survival paradox in the context of health expectancy (HE) at age 65 and thereafter, using three different morbidity measures and different severity cut-offs with and without adjustments for the share of nursing home residents. METHODS: HE at ages 65, 70, 75, 80, and 85 was estimated with the Sullivan method, linking morbidity prevalence from the KORA (Cooperative Health Research in the Region of Augsburg)-Age study to 2016 Bavarian mortality data. Morbidity measures comprised deficit accumulation (Frailty Index, FI, cut-offs 0.08 and 0.25), disability (Health Assessment Questionnaire-Disability Index, HAQ-DI, cut-off >0) and participation (Global Activity Limitation Indicator, GALI, "limited" vs "not limited"). RESULTS: Morbidity data were available for 4083 participants (52.7% female). HE was lower in women than in men at all ages. Differences in morbidity prevalence, absolute HE, and health proportions of life expectancy (relative HE) increased with age for FI ≥ 0.25 and GALI, but not for HAQ-DI > 0 and FI > 0.08. Accounting for the share of nursing home residents resulted in a slight reduction of HE estimates but had no impact on estimated sex differences. CONCLUSIONS: In HE at age 65 and thereafter, women's health disadvantage was larger than their life expectancy advantage over men.

The times we are born into and our lifestyle choices determine our health trajectories in older age - Results from the KORA-Age study.

Health projections often extrapolate from observations in current ageing cohorts, but health in older age may depend not only on individual characteristics but also on a person's historical context. Our objective was to investigate how health deficit accumulation trajectories after age 65 differed in five adjacent birth cohorts and according to individual life course characteristics. Data originate from the 2008/09 KORA (Cooperative Health Research in the Region of Augsburg)-Age cohort study from Southern Germany and their 2012 and 2016 follow-ups. Deficit accumulation was assessed using a Frailty Index. The effects of birth cohort membership and individual life course characteristics on deficit accumulation trajectories were analyzed using generalized linear mixed models. Out of 2701 participants (49% male) from five birth cohorts (1919-23, 1924-28, 1929-33, 1934-38, 1939-43), we included 2512 individuals with 5560 observations. Frailty Index levels were higher for women, smokers, alcohol abstainers, obese participants and persons with a sedentary lifestyle or living below the poverty threshold. We found higher age-specific Frailty Index levels for the two most recent birth cohorts (e.g. 61%, CI: [13%; 130%] for the 1934-38 as compared to the 1919-23 cohort), but the rate of deficit accumulation with age (7% per life year, (CI: [5%, 9%]) was cohort-independent. Results indicate that the historical context (birth cohort membership) may influence the number of accumulated health deficits after age 65 in addition to poverty and other individual life course characteristics, but BMI, physical activity and smoking remain the modifiable risk factors offering the highest prevention potential.

Improved survival after resection of colorectal liver metastases in patients with unresectable lung metastases.

BACKGROUND: Modern systemic therapies considerably improve tumour control and thus open the possibility of new surgical approaches in metastatic colorectal cancer. In this retrospective clinical cohort with a comparison group, we investigated whether liver resection in a combined liver-lung-metastasised stage is justified if pulmonary disease is not resected. METHODS: From 283 patients treated in our institution between 2000 and 2014 for combined colorectal liver- and lung metastases, 35 patients had their pulmonary metastases left in situ while they were eligible for both treatment options: resection versus non-resection of liver metastases. Effectively, 15 of these patients received whereas 20 did not receive a liver resection. In these patients, we compared overall survival and determined risk factors that are associated with poor survival, applying a Cox-Proportional Hazards model. RESULTS: Patients whose liver metastases were resected showed significantly longer median survival compared to patients who did not undergo hepatic surgery (median 2.6 vs 1.5 years, P = 0.0182). The Cox-Proportional Hazards model revealed hepatic metastasectomy to be the strongest determinant of patient survival (HR 5.27; CI: (1.89, 14.65)). CONCLUSION: Our results suggest that surgical removal of liver metastases may be beneficial in selected patients even if concomitant lung metastases cannot be resected.

Prevalence of a First-Degree Relative With Colorectal Cancer and Uptake of Screening Among Persons 40 to 54 Years Old.

BACKGROUND & AIMS: People with a first-degree relative with colorectal cancer (CRC) are recommended to start CRC screening at age 40. However, there is limited information on how many people in different age groups have a known family history of CRC and how many of them have had a colonoscopy. METHODS: We set up a multicenter, cross-sectional, population-based study in Germany to determine what proportions of persons in age groups from 40 to 54 years old have a known family history of CRC. We invited 160,000 persons to participate in an online survey from 2015 through 2016. We investigated what proportions of persons in each age group reported a family history of CRC and what proportions of persons underwent a colonoscopy examination using descriptive statistics and multiple logistic regression models. RESULTS: Of 28,711 responders to the online questionnaire (8428 were age 40-44 years, 9879 were age 45-49 years, and 10,404 were age 50-54 years), 2705 stated that they had a first-degree relative with CRC (9.4%). The prevalence of a first-degree relative with CRC increased with age: 7.5%, 9.6%, and 10.9% for people 40 to 44 years old, 45 to 49 years old, and 50 to 54 years old, respectively. The prevalence of a first-degree relative who received a diagnosis of CRC at age 70 years or older increased steadily with each age group. Although a greater proportion of people with a family history of CRC had undergone a colonoscopy examination (54.5%) than people without a family history of CRC (25.7%; P < .0001), large proportions of people within this risk group were not in compliance with the guidelines (54.8%, 47.6%, and 38.6% for ages 40-44 y, 45-49 y, and 50-54 y, respectively). CONCLUSIONS: One in 10 persons in Germany age 40 to 54 years old has a first-degree relative with CRC. Guidelines recommend initiation of screening at ages 40 to 45 years for people with a family history, yet at this age many people do not have a family history of CRC yet, and almost half of persons 40 to 54 years old with a family history of CRC have not yet received a screening colonoscopy.