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.

A systematic mapping of public health master's and structured doctoral programs in Germany.

BACKGROUND: Well-trained public health professionals are key to addressing both global and local public health challenges of the twenty-first century. Though availability of programs has increased, the population health science (PHS) and public health (PH) higher education landscape in Germany remains scattered. To date, no comprehensive overview of programs exists. OBJECTIVES: This study aimed to map PHS and PH master's and structured doctoral programs in Germany, including selected program characteristics, curricula and target competencies. METHODS: We conducted a systematic mapping of PHS and PH programs in Germany following a prospectively registered protocol ( https://doi.org/10.17605/OSF.IO/KTCBA ). Relevant master's and doctoral programs were identified by two study authors independently searching a comprehensive higher education database, which was, for doctoral programs, supplemented with a google search. For PHS programs, general characteristics were mapped and for the subset of PH programs, in-depth characteristics were extracted. RESULTS: Overall, 75 master's and 18 structured doctoral PHS programs were included. Of these, 23 master's and 8 doctoral programs focused specifically on PH. The majority of PHS master's programs awarded a Master of Science degree (55 out of 75 programs). The PH master's program curricula offered various courses, allowing for different specializations. Courses on topics like public health, epidemiology, health systems (research) and research methods were common for the majority of the master's programs, while courses on physical activity, behavioral science, nutrition, and mental health were offered less frequently. Structured PH doctoral programs were mainly offered by medical faculties (6 out of 8 programs) and awarded a doctorate of philosophy (Ph.D.) (6 out of 8 programs). PH doctoral programs were very heterogeneous regarding curricula, entry, and publication requirements. There was a broad geographical distribution of programs across Germany, with educational clusters in Munich, Berlin, Bielefeld and Düsseldorf. CONCLUSION: Germany offers a diverse landscape of PHS and PH master's programs, but only few structured doctoral programs. The variety of mandatory courses and competencies in these programs reflect Germany's higher education system's answer to the evolving demands of the PH sector. This review may aid in advancing PH education both in Germany and globally.

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.

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.

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.

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.

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.

Being born in the aftermath of World War II increases the risk for health deficit accumulation in older age: results from the KORA-Age study.

Morbidity trends may result from cohort experiences in critical developmental age. Our objective was to compare the health status of 65-71 year-olds who were in critical developmental age before (1937-June 1945), during (June 1945-June 1948) and after (June 1948-1950) the early reconstruction and food crisis (ERFC) period in Germany following World War II. Data originate from the KORA (Cooperative Health Research in the Region of Augsburg)-Age study in Southern Germany. We used the 2008 baseline sample born 1937-1943 and the 2015 enrichment sample born 1944-1950. Health status was assessed as the number of accumulated health deficits using a Frailty Index (FI). Cohorts were defined based on co-occurrence of critical developmental age (gestation and the first 2 years of life) and the ERFC period. Cohort, age and sex effects on older-age health status were analyzed using generalized linear models. We included 590 (53% male) pre-war and war (PWW), 475 (51% male) ERFC and 171 post-currency reform (PCR) cohort participants (46% male). Adjusted for covariates, FI levels were significantly higher for the ERFC (Ratio 1.14, CL [1.06, 1.23]) but not for the PCR (Ratio 1.06, CL [0.94, 1.20]) as compared to the PWW cohort. Being in critical developmental age during the ERFC period increased FI levels in adults aged 65-71 years. Covariates did not explain these effects, suggesting a direct detrimental effect from being in critical developmental age during the ERFC period on older-age health. This expansion of morbidity in Germany was not detected in the PCR cohort.

Systematic Review and Meta-analysis of the Effectiveness of Implementation Strategies for Non-communicable Disease Guidelines in Primary Health Care.

BACKGROUND: As clinical practice guidelines represent the most important evidence-based decision support tool, several strategies have been applied to improve their implementation into the primary health care system. This study aimed to evaluate the effect of intervention methods on the guideline adherence of primary care providers (PCPs). METHODS: The studies selected through a systematic search in Medline and Embase were categorised according to intervention schemes and outcome indicator categories. Harvest plots and forest plots were applied to integrate results. RESULTS: The 36 studies covered six intervention schemes, with single interventions being the most effective and distribution of materials the least. The harvest plot displayed 27 groups having no effect, 14 a moderate and 21 a strong effect on the outcome indicators in the categories of knowledge transfer, diagnostic behaviour, prescription, counselling and patient-level results. The forest plot revealed a moderate overall effect size of 0.22 [0.15, 0.29] where single interventions were more effective (0.27 [0.17, 0.38]) than multifaceted interventions (0.13 [0.06, 0.19]). DISCUSSION: Guideline implementation strategies are heterogeneous. Reducing the complexity of strategies and tailoring to the local conditions and PCPs' needs may improve implementation and clinical practice.

Development of a complex intervention to improve participation of nursing home residents with joint contractures: a mixed-method study.

BACKGROUND: Joint contractures in nursing home residents limit the capacity to perform daily activities and restrict social participation. The purpose of this study was to develop a complex intervention to improve participation in nursing home residents with joint contractures. METHODS: The development followed the UK Medical Research Council framework using a mixed-methods design with re-analysis of existing interview data using a graphic modelling approach, group discussions with nursing home residents, systematic review of intervention studies, structured 2-day workshop with experts in geriatric, nursing, and rehabilitation, and group discussion with professionals in nursing homes. RESULTS: Graphic modelling identified restrictions in the use of transportation, walking within buildings, memory functions, and using the hands and arms as the central target points for the intervention. Seven group discussions with 33 residents revealed various aspects related to functioning and disability according the International Classification of Functioning, Disability and Health domains body functions, body structures, activities and participation, environmental factors, and personal factors. The systematic review included 17 studies with 992 participants: 16 randomised controlled trials and one controlled trial. The findings could not demonstrate any evidence in favour of an intervention. The structured 2-day expert workshop resulted in a variety of potential intervention components and implementation strategies. The group discussion with the professionals in nursing homes verified the feasibility of the components and the overall concept. The resulting intervention, Participation Enabling CAre in Nursing (PECAN), will be implemented during a 1-day workshop for nurses, a mentoring approach, and supportive material. The intervention addresses nurses and other staff, residents, their informal caregivers, therapists, and general practitioners. CONCLUSIONS: In view of the absence of any robust evidence, the decision to use mixed methods and to closely involve both health professionals and residents proved to be an appropriate means to develop a complex intervention to improve participation of and quality of life in nursing home residents. We will now evaluate the PECAN intervention for its impact and feasibility in a pilot study in preparation for an evaluation of its effectiveness in a definitive trial. TRIAL REGISTRATION: German clinical trials register, reference number DRKS00010037 (12 February 2016).

Male sex and poverty predict abrupt health decline: Deficit accumulation patterns and trajectories in the KORA-Age cohort study.

Ageing individuals differ both in their deficit accumulation (DA) trajectories and resulting DA patterns (improvement, stability, gradual or abrupt decline). This heterogeneity is still incompletely understood. The objectives of this study were thus to identify determinants of DA trajectories and DA patterns in people aged 65 and older. Data originates from the 2009 baseline assessment and 2012 follow-up of the KORA (Cooperative Health Research in the Region of Augsburg)-Age study from Southern Germany. DA was measured with a Frailty Index (FI). The effects of socio-demographic, socio-economic and lifestyle factors were analyzed using generalized linear mixed models and multinomial regressions. FI scores were available for 1076 participants at baseline (mean age 76years, 50% female) and 808 participants at follow-up. Higher baseline FI levels were significantly associated with higher age, female sex, lower physical activity, moderate alcohol consumption and obesity. Longitudinal increase in FI levels over 3years was 31% (CL: [-3%; 77%]) independent of all examined predictors. The most frequent DA patterns were stability (59%) and gradual decline (30%). Compared to stability, higher age, male sex and low income predicted (mostly fatal) abrupt decline. In conclusion, several factors are associated with FI levels at baseline whereas the change in FI levels over time seems hardly modifiable. Thus, future research should investigate if the same factors predicting older-age FI levels constitute predictors of DA onset earlier in life. Towards the end of life, being male with low income may increase the risk for abrupt decline, indicating need for early detection.

Altered Regional Myocardial Mechanics in Transplanted Hearts: Influence of Time and Transplantation.

Background Global longitudinal strain is reduced in heart transplant recipients, but little is known about regional contractility of the transplanted heart. Moreover, it is unclear if factors such as time after transplant and ischemic time have an influence on regional contractility. To test for regional changes in myocardial deformation, we assessed regional myocardial deformation using three-dimensional speckle tracking echocardiography in heart transplant recipients and controls. Methods Global and regional longitudinal, circumferential, and radial strain was assessed in 51 heart transplant recipients and a control group of healthy individuals (n = 26). Moreover, we correlated regional contractility with clinical characteristics and compared subgroups of heart transplant recipients with normal (n = 32) and reduced left ventricular ejection fraction (n = 32). Results Global longitudinal and circumferential strain was significantly reduced in all heart transplant recipients, as well as in the transplant group with normal ejection fraction compared with the control group (p < 0.001). Global radial strain (GRS) was elevated in both transplant groups, but was significantly higher in transplant recipients with normal ejection fraction compared with the control group (p < 0.01). Both transplant groups revealed lower longitudinal and circumferential strain values in the mid- and apical regions (p < 0.001), whereas longitudinal and circumferential strain was higher in the basal region (p < 0.01). In both groups, transplanted hearts showed increased radial strain in the basal (p < 0.05, p < 0.01) and midregions (p = 0.22; p < 0.01) and did not differ in the apical regions. Cold ischemic time (150 ± 12.6 minutes) was independently associated with reduction in circumferential strain. Time since transplantation ranging from 18 days to 21 years had no effect on myocardial deformation parameters. Conclusion Left ventricular mechanics in transplanted hearts display significantly different systolic deformation patterns than native hearts. Strain capability forms a regional gradient from the base toward the apex. The presence of a time-independent deformation pattern and the correlation with cold ischemic time suggest damage induced by the transplantation itself. These findings might be important for understanding pseudo-abnormal echocardiograms in heart transplant patients.

A high level of household physical activity compensates for lack of leisure time physical activity with regard to deficit accumulation: Results from the KORA-Age study.

INTRODUCTION: Aging is associated with increasing loss of physiological resilience and successive accumulation of physiological deficits. This can be measured through a frailty index which sums up symptoms, health conditions and impairments. One possible factor in preventing or delaying deficit accumulation is physical activity. The effect of leisure time physical activity on health is well investigated; however, the effect of household physical activity is less clear. The objective of this cross-sectional study was to examine the association of household physical activity with deficit accumulation while controlling for level of leisure time physical activity. METHODS: Data originates from the 2008 baseline assessment of the KORA (Cooperative Health Research in the Region of Augsburg)-Age study from Southern Germany. A frailty index of deficit accumulation (Deficit Accumulation Index, DAI) was constructed from 31 age-related health deficits. Physical activity was measured with the Physical Activity Scale for the Elderly (PASE). The association of deficit accumulation and physical activity was analyzed using negative binomial regression analysis. RESULTS: The participants' (n=960, mean age 76years, 49.0% female) DAI ranged from 0.00 to 0.68. Higher levels of both types of physical activity were statistically significantly associated with less deficit accumulation. Participants in the highest household (leisure time) physical activity quartile had 29% (30%) less deficits than participants in the respective lowest quartiles. CONCLUSION: High levels of household physical activity might compensate for low levels of leisure time physical activity in the prevention of deficit accumulation. Further research efforts investigating the temporal sequence of this association are needed.

Aortic Dissection Presenting as "Hysteria".

BACKGROUND: Patients with medical conditions may present with psychiatric symptoms, which may lead to worse physical health care. Here we present the case of a patient with acute aortic dissection masked by psychiatric symptoms after a stressful event. CASE REPORT: A 29-year-old female medical student presented to the Emergency Department (ED) complaining about the feeling of "hysteria" after an argument with her boyfriend earlier the same day. She did not report other symptoms or pain. Careful physical examination, initially impeded by the patient's agitation, revealed pulseless extremities. Blood gas analysis showed metabolic acidosis. Transthoracic echocardiography and computed tomography ultimately led to the correct diagnosis: Stanford Type-A aortic dissection. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: Medical conditions requiring acute diagnostic work-up and therapy may present with psychiatric symptoms. Increased awareness and the use of standardized operating procedures in the ED may prevent fatal misdiagnoses in these patients.

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.

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.

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.

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.

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.