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Abstract Background Oxygen-rich breathing mixtures up to 100% are used in some underwater diving operations for several reasons. Breathing elevated oxygen partial pressures (PO2) increases the risk of developing central nervous system oxygen toxicity (CNS-OT) which could impair performance or result in a seizure and subsequent drowning. We aimed to study the dynamics of the electrodermal activity (EDA) and heart rate (HR) while breathing elevated PO2 in the hyperbaric environment (HBO2) as a possible means to predict impending CNS-OT. Methods EDA is recorded during 50 subject exposures (26 subjects) to evaluate CNS-OT in immersed (head out of water) exercising divers in a hyperbaric chamber breathing 100% O2 at 35 feet of seawater (FSW), (PO2 = 2.06 ATA) for up to 120 min. Results 32 subject exposures exhibit symptoms “definitely” or “probably” due to CNS-OT before the end of the exposure, whereas 18 do not. We obtain traditional and time-varying spectral indices (TVSymp) of EDA to determine its utility as predictive physio markers. Variations in EDA and heart rate (HR) for the last 5 min of the experiment are compared to baseline values prior to breathing O2. In the subset of experiments where “definite” CNS-OT symptoms developed, we find a significant elevation in the mean ± standard deviation TVSymp value 57 ± 79 s and median of 10 s, prior to symptoms. Conclusions In this retrospective analysis, TVSymp may have predictive value for CNS-OT with high sensitivity (1.0) but lower specificity (0.48). Additional work is being undertaken to improve the detection algorithm.

Abstract Background Maintenance of physical function, mobility, and independent living are important goals for older adults. However, concerns about falling (CaF) play a central role in the vicious cycle of CaF, inflammation, loss of muscle mass, and decreasing physical function ultimately resulting in negative health outcomes. CaF, like other states of chronic stress and anxiety, can be considered as enduring adverse stimuli affecting the stress systems and the inflammatory system. Therefore, the aim of this study is to investigate whether a reduction of CaF leads to a reduction of stress and therefore possibly reduces chronic low-grade inflammation. Understanding the role and directionality of the effects of inflammation on CaF increases our understanding of age-related loss of mobility and physical function. Methods In this study, community-dwelling older adults, aged 70 years and older, will be randomly assigned to either a 4-month, multi-component intervention with exercise training and cognitive-behavioral components or to a sham control group with light stretching exercises, cognitive training, and educational health lectures. For the operationalization of specific CaF, the Falls Efficacy Scale—International will be used. Stress and related psychological symptoms will be monitored using established self-reports and by measuring salivary cortisol. Concentrations of C-reactive protein, interleukin 6, interleukin 10, and tumor-necrosis-factor-alpha, as well as gene expression of selected inflammatory transcripts, will be used as surrogate parameters of the inflammatory status at baseline, after the 4-month intervention and 8-month follow-up. Discussion This study will be the first to test whether CaF are related with stress system activity or reactivity or with markers of inflammation in the context of a multi-component intervention with exercise training and cognitive-behavioral components addressing CaF. The reduction of specific CaF or general psychological symptoms should reverse alterations in stress systems, and / or slow down low-grade inflammation. Changes in activity, as well as psychological and biological pathways leading from CaF to muscle loss will be measured, to disentangle the individual contribution to sarcopenia, and to provide an additional pathway to break or slow-down the vicious cycle of CaF and sarcopenia. Trial registration German Clinical Trials Register (DRKS): DRKS00029171 . Registered 22 July 2022.

Background Aortic coarctation (CoA) is a congenital anomaly leading to upper-body hypertension and lower-body hypotension. Despite surgical or interventional treatment, arterial hypertension may develop and contribute to morbidity and mortality. Conventional blood pressure (BP) measurement methods lack precision for individual diagnoses and therapeutic decisions. This study evaluated the use of artificial intelligence-based pulse wave analysis (AI-PWA) to assess central aortic blood pressure (CABP) and related parameters in post-treatment CoA patients.Methods This exploratory, cross-sectional study enrolled 47 adults with CoA, between June 2023 and May 2024. Peripheral BP (PBP) was conventionally measured, and CABP was assessed using the VascAssist2 (inmediQ, Butzbach, Germany). Hypertension was defined by systolic BP≥140 mm Hg and/or diastolic BP≥90 mm Hg for PBP. Using AI-PWA, patients with systolic CABP≥130 mm Hg and/or diastolic BP≥90 mm Hg were classified as hypertensive.Results The study cohort’s age was 41.5±13.7 years, with all patients having undergone previous aortic surgery or intervention. PBP measurements showed a systolic BP of 135.4±14.4 mm Hg at the upper and 147.8±20.3 mm Hg at the lower extremities. CABP measurements were significantly lower, with a systolic BP of 114.3±15.8 mm Hg (p

Abstract Adenoid cystic carcinoma (AdCC) is a salivary gland neoplasm that infrequently appears in the sinonasal region. The aim of this study was to evaluate the outcome and clinicopathological parameters of sinonasal AdCC. A retrospective analysis was conducted on all cases of AdCC affecting the nasal cavity or paranasal sinuses between 2000 and 2018 at the University Hospital Zurich. Tumor material was examined for morphological features and analyzed for molecular alterations. A total of 14 patients were included. Mean age at presentation was 57.7 years. Sequencing revealed MYB::NFIB gene fusion in 11/12 analyzable cases. Poor prognostic factors were solid variant (p 30%), high-grade transformation, and sphenoid sinus involvement are negative prognostic factors for sinonasal AdCC. A high prevalence of MYB::NFIB gene fusion may help to correctly classify diagnostically challenging (e.g. metatypical) cases.

Background:. The stabilization of metastatic lesions in the periacetabular region can be successfully performed using percutaneous techniques. Photodynamic nails (PDNs) are among the available tools for stabilization. Data on postoperative complications and functional outcomes are, however, scarce. Methods:. Patients undergoing percutaneous stabilization using PDNs (IlluminOss Medical) for impending or actual minimally displaced pathological fractures of the pelvis from metastatic bone disease, multiple myeloma, or primary bone lymphoma were enrolled prospectively. Outcomes were assessed preoperatively and postoperatively at the 2-day, 2-week, 6-week, 3-month, 6-month, and 1-year time points. Functional outcomes assessed included the Patient-Reported Outcomes Measurement Information System (PROMIS) Physical Function, PROMIS Pain Interference, Combined Pain and Ambulatory Function (CPAF), EuroQol-Visual Analogue Scale (EQ-VAS), and Musculoskeletal Tumor Society (MSTS) scores. Pain was assessed using a VAS. Results:. A total of 30 patients treated with PDNs were included. The median VAS pain score dropped from 60 points preoperatively to 30 at 6 weeks postoperatively (p = 0.004). The median CPAF score improved from 6 preoperatively to 7 postoperatively at the 6-week mark. The median EQ-VAS score showed significant improvement at 6 weeks (70 versus 50; p = 0.006). The median 2-week PROMIS Pain Interference score was significantly lower than preoperatively (64.1 versus 66.9; p = 0.03). An improvement in the median PROMIS Physical Function score was seen at 6 weeks following surgery compared with preoperatively (37 versus 30.1; p = 0.001). A significant improvement in the MSTS score was seen as soon as 2 days after surgery (77% versus 40%; p < 0.0001). Conclusions:. Among patients with pelvic bone metastases, multiple myeloma, or primary bone lymphoma, we found that treatment using PDNs resulted in immediate return to ambulation and rapid functional outcome improvement, with low complication rates. In this population, this technique represents a safe alternative to open surgery. Level of Evidence:. Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence.

Abstract Background Preservation of mobility and fall prevention have a high priority in geriatric rehabilitation. Square-Stepping Exercise (SSE) as an evaluated and standardized program has been proven to be an effective training for older people in the community setting to reduce falls and improve subjectively perceived health status. This randomized controlled trial (RCT), for the first time, examines SSE in the context of inpatient early geriatric rehabilitation compared to conventional physiotherapy (cPT). Methods Data were collected in a general hospital in the department of acute geriatric care at admission and discharge. Fifty-eight inpatients were randomized to control (CG, n = 29) or intervention groups (IG, n = 29). CG received usual care with cPT five days per week during their hospital stay. For the IG SSE replaced cPT for at least six sessions, alternating with cPT. Physical function was measured with the Short Physical Performance Battery (SPPB) and Timed “Up & Go” (TUG). Gait speed was measured over a distance of 10 m. In a subgroup (n = 17) spatiotemporal gait parameters were analyzed via a GAITRite® system. Results Both the SPPB total score improved significantly (p =

Abstract Background Adults with congenital heart defects (ACHD) globally constitute a notably medically underserved patient population. Despite therapeutic advancements, these individuals often confront substantial physical and psychosocial residua or sequelae, requiring specialized, integrative cardiological care throughout their lifespan. Heart failure (HF) is a critical challenge in this population, markedly impacting morbidity and mortality. Aims The primary aim of this study is to establish a comprehensive, prospective registry to enhance understanding and management of HF in ACHD. Named PATHFINDER-CHD, this registry aims to establish foundational data for treatment strategies as well as the development of rehabilitative, prehabilitative, preventive, and health-promoting interventions, ultimately aiming to mitigate the elevated morbidity and mortality rates associated with congenital heart defects (CHD). Methods This multicenter survey will be conducted across various German university facilities with expertise in ACHD. Data collection will encompass real-world treatment scenarios and clinical trajectories in ACHD with manifest HF or at risk for its development, including those undergoing medical or interventional cardiac therapies, cardiac surgery, inclusive of pacemaker or ICD implantation, resynchronization therapy, assist devices, and those on solid organ transplantation. Design The study adopts an observational, exploratory design, prospectively gathering data from participating centers, with a focus on patient management and outcomes. The study is non-confirmatory, aiming to accumulate a broad spectrum of data to inform future hypotheses and studies. Processes Regular follow-ups will be conducted, systematically collecting data during routine clinical visits or hospital admissions, encompassing alterations in therapy or CHD-related complications, with visit schedules tailored to individual clinical needs. Assessments Baseline assessments and regular follow-ups will entail comprehensive assessments of medical history, ongoing treatments, and outcomes, with a focus on HF symptoms, cardiac function, and overall health status. Discussion of the design The design of the PATHFINDER-CHD Registry is tailored to capture a wide range of data, prioritizing real-world HF management in ACHD. Its prospective nature facilitates longitudinal data acquisition, pivotal for comprehending for disease progression and treatment impacts. Conclusion The PATHFINDER-CHD Registry is poised to offer valuable insights into HF management in ACHD, bridging current knowledge gaps, enhancing patient care, and shaping future research endeavors in this domain.

The Columbia Stellarator eXperiment (CSX), currently being designed at Columbia University, aims to test theoretical predictions related to QA plasma behavior, and to pioneer the construction of an optimized stellarator using three-dimensional, non-insulated high-temperature superconducting (NI-HTS) coils. The magnetic configuration is generated by a combination of two circular planar poloidal field (PF) coils and two 3D-shaped interlinked (IL) coils, with the possibility to add windowpane coils to enhance shaping and experimental flexibility. The PF coils and vacuum vessel are repurposed from the former Columbia Non-Neutral Torus experiment, while the IL coils will be custom-wound in-house using NI-HTS tapes. To obtain a plasma shape that meets the physics objectives with a limited number of coils, novel single-stage optimization techniques are employed, optimizing both the plasma and coils concurrently, in particular targeting a tight aspect ratio QA plasma and minimized strain on the HTS tape. Despite the increased complexity due to the expanded degrees of freedom, these methods successfully identify optimized plasma geometries that can be realized by coils meeting engineering specifications. This paper discusses the derivation of the constraints and objectives specific to CSX, and describe how two recently developed single-stage optimization methodologies are applied to the design of CSX. A set of selected configurations for CSX is then described in detail.

We examined data from Naval Sea Systems Command grant project N0463A-12-C-001, “Hypercapnia: cognitive effects and monitoring”, with the objective of validating or repudiating heart rate variability (HRV) as a warning sign of cognitive impairment from diving gas narcosis or oxygen toxicity. We compared HRV feature scores to their temporally corresponding cognitive outcomes under normal and narcotizing conditions to identify specific HRV features associated with cognitive changes. N0463A-12-C-001 was conducted between 17 September 2013 and 29 January 2016 and employed NASA’s multi-attribute task battery (MATB-II) flight simulator to examine the independent effects of CO2, N2, and O2 partial pressure on diver performance at simulated depths up to 61 msw (200 fsw). We assessed the association of 23 distinct HRV features scores from 432 of the study’s analyzable exposure stages in relation to MATB-II’s four performance subclasses (motor, memory, attention, strategy) while controlling for exercise and CO2, N2, and O2 gas partial pressure. Performance decrements were associated with normalized high-frequency HRVfeatures (HFnu, p = 0.0016) and the number of pairs of successive R-R intervals that differed by more than 50 ms (NN50count1, p = 0.04). Secondary analysis with stratification restricted to non-exercise stages showed that several HRV parameters, including root mean square of the successive difference (RMSSD, p = 0.0015), width of Poincaré plot (p = 0.0017), NN50count1 (p = 0.0019), and standard deviation of normal-to-normal R peaks (p = 0.0082), were associated with performance impairment. The RMSSD association retained statistical significance after Bonferroni correction for multiple tests. HRV features collected from divers tested under narcotizing conditions of breathing gas partial pressure and exercise were associated with performance impairment.

Abstract Background Large deletions and duplications within the low-density lipoprotein receptor (LDLR) gene make up approximately 10% of LDLR pathogenic variants found in Czech patients with familial hypercholesterolemia. The goal of this study was to test the hypothesis that all probands with each rearrangement share identical breakpoints inherited from a common ancestor and to determine the role of Alu repetitive elements in the generation of these rearrangements. Methods The breakpoint sequence was determined by PCR amplification and Sanger sequencing. To confirm the breakpoint position, an NGS analysis was performed. Haplotype analysis of common LDLR variants was performed using PCR and Sanger sequencing. Results The breakpoints of 8 rearrangements within the LDLR gene were analysed, including the four most common LDLR rearrangements in the Czech population (number of probands ranging from 8 to 28), and four less common rearrangements (1–4 probands). Probands with a specific rearrangement shared identical breakpoint positions and haplotypes associated with the rearrangement, suggesting a shared origin from a common ancestor. All breakpoints except for one were located inside an Alu element. In 6 out of 8 breakpoints, there was high homology (≥ 70%) between the two Alu repeats in which the break occurred. Conclusions The most common rearrangements of the LDLR gene in the Czech population likely arose from one mutational event. Alu elements likely played a role in the generation of the majority of rearrangements inside the LDLR gene.

Abstract Background Regular physical activity has multiple health benefits, especially in older people. Therefore, the World Health Organization recommends at least 2.5 h of moderate physical activity per week. The aim of the POWER Study was to investigate whether volunteer-assisted walking improves the physical performance and health of older people. Methods We approached people aged 65 years and older with restricted mobility due to physical limitations and asked them to participate in this multicentre randomised controlled trial. The recruitment took place in nursing homes and the community setting. Participants randomly assigned to the intervention group were accompanied by volunteer companions for a 30–50 min walk up to three times a week for 6 months. Participants in the control group received two lectures that included health-related topics. The primary endpoint was physical function as measured with the Short Physical Performance Battery (SPPB) at baseline and 6 and 12 months. The secondary and safety endpoints were quality of life (EQ-5D-5L), fear of falling (Falls Efficacy Scale), cognitive executive function (the Clock Drawing Test), falls, hospitalisations and death. Results The sample comprised 224 participants (79% female). We failed to show superiority of the intervention with regard to physical function (SPPB) or other health outcomes in the intention-to-treat analyses. However, additional exploratory analyses suggest benefits in those who undertook regular walks. The intervention appears to be safe regarding falls. Conclusions Regular physical activity is essential to preserve function and to improve health and quality of life. Against the background of a smaller-than-planned sample size, resulting in low power, and the interference of the COVID-19 pandemic, we suggest that community based low-threshold interventions deserve further exploration. Trial registration The trial was registered with the German Clinical Trials Register ( www.germanctr.de ), with number DRKS00015188 on 31/08/2018.

Abstract Energetic local frustration offers a biophysical perspective to interpret the effects of sequence variability on protein families. Here we present a methodology to analyze local frustration patterns within protein families and superfamilies that allows us to uncover constraints related to stability and function, and identify differential frustration patterns in families with a common ancestry. We analyze these signals in very well studied protein families such as PDZ, SH3, ɑ and β globins and RAS families. Recent advances in protein structure prediction make it possible to analyze a vast majority of the protein space. An automatic and unsupervised proteome-wide analysis on the SARS-CoV-2 virus demonstrates the potential of our approach to enhance our understanding of the natural phenotypic diversity of protein families beyond single protein instances. We apply our method to modify biophysical properties of natural proteins based on their family properties, as well as perform unsupervised analysis of large datasets to shed light on the physicochemical signatures of poorly characterized proteins such as the ones belonging to emergent pathogens.

Bone loss is a prevalent characteristic among people with HIV (PWH). We focused on mesenchymal stem cells (MSCs) and osteoblasts, examining their susceptibility to different HIV strains (R5- and X4-tropic) and the subsequent effects on bone tissue homeostasis. Our findings suggest that MSCs and osteoblasts are susceptible to R5- and X4-tropic HIV but do not support productive HIV replication. HIV exposure during the osteoblast differentiation process revealed that the virus could not alter mineral and organic matrix deposition. However, the reduction in runt-related transcription factor 2 (RUNX2) transcription, the increase in the transcription of nuclear receptor activator ligand kappa B (RANKL), and the augmentation of vitronectin deposition strongly suggested that X4- and R5-HIV could affect bone homeostasis. This study highlights the HIV ability to alter MSCs’ differentiation into osteoblasts, critical for maintaining bone and adipose tissue homeostasis and function.

Abstract The purpose of this retrospective study was to investigate response of sinonasal mucosal melanoma (SMM) patients to treatment with immune checkpoint inhibitors (ICI), using hybrid PET imaging. Fifteen SMM patients underwent hybrid PET imaging before and three months after initiation of ICI. The disease-specific survival (DSS) was calculated. Quantitative PET parameters of the primary tumor and their association with DSS and therapy response were investigated. Nine of the fifteen (60%) patients responded to ICI therapy. Patients with therapy response depicted on hybrid PET imaging had better DSS than those without (p = 0.0058). Quantitative PET parameters of the initial PET harbored no association with DSS or therapy response. However, these findings lack of sufficient statistical power and must be interpreted with caution. The first restaging PET-imaging after ICI initiation can help stratify patients with regard to DSS.

Background: Hereditary angioedema (HAE) is a rare autosomal dominant genetic disease characterised by acute episodes of non-pruritic skin and submucosal swelling caused by increase in vascular permeability. Objective: Here we present the first complex analysis of the National HAE Slovakian cohort with the detection of 12 previously un-published genetic variants in SERPING1 gene. Methods: In patients diagnosed with hereditary angioedema caused by deficiency or dysfunction of C1 inhibitor (C1–INH-HAE) based on clinical manifestation and complement measurements, SERPING1 gene was tested by DNA sequencing (Sanger sequencing/massive parallel sequencing) and/or multiplex ligation-dependent probe amplification for detection of large rearrangements. Results: The Slovakian national cohort consisted of 132 living patients with confirmed HAE. We identified 51 index cases (32 families, 19 sporadic patients/112 adults, 20 children). One hundred seventeen patients had HAE caused by deficiency of C1 inhibitor (C1–INH-HAE-1) and 15 patients had HAE caused by dysfunction of C1 inhibitor (C1–INH-HAE-2). The prevalence of HAE in Slovakia has recently been calculated to 1:41 280 which is higher than average calculated prevalence. The estimated incidence was 1:1360 000. Molecular-genetic testing of the SERPING1 gene found 22 unique causal variants in 26 index cases, including 12 previously undescribed and unreported. Conclusion: The first complex report about epidemiology and genetics of the Slovakian national HAE cohort expands the knowledge of the C1–INH-HAE genetics. Twelve novel causal variants were present in the half of the index cases. A higher percentage of inframe variants comparing to other studies was observed. Heterozygous deletion of exon 3 found in a large C1–INH-HAE-1 family probably causes the dysregulation of the splicing isoforms balance and leads to the decrease of full-length C1–INH level.

Abstract Immune checkpoint inhibitor treatment has the potential to prolong survival in non-small cell lung cancer (NSCLC), however, some of the patients develop resistance following initial response. Here, we analyze the immune phenotype of matching tumor samples from a cohort of NSCLC patients showing good initial response to immune checkpoint inhibitors, followed by acquired resistance at later time points. By using imaging mass cytometry and whole exome and RNA sequencing, we detect two patterns of resistance¨: One group of patients is characterized by reduced numbers of tumor-infiltrating CD8+ T cells and reduced expression of PD-L1 after development of resistance, whereas the other group shows high CD8+ T cell infiltration and high expression of PD-L1 in addition to markedly elevated expression of other immune-inhibitory molecules. In two cases, we detect downregulation of type I and II IFN pathways following progression to resistance, which could lead to an impaired anti-tumor immune response. This study thus captures the development of immune checkpoint inhibitor resistance as it progresses and deepens our mechanistic understanding of immunotherapy response in NSCLC.

Coronavirus disease 2019 (COVID-19) might impact disease progression in people living with HIV (PLWH), including those on effective combination antiretroviral therapy (cART). These individuals often experience chronic conditions characterized by proviral latency or low-level viral replication in CD4+ memory T cells and tissue macrophages. Pro-inflammatory cytokines, such as TNF-α, IL-1β, IL-6, and IFN-γ, can reactivate provirus expression in both primary cells and cell lines. These cytokines are often elevated in individuals infected with SARS-CoV-2, the virus causing COVID-19. However, it is still unknown whether SARS-CoV-2 can modulate HIV reactivation in infected cells. Here, we report that exposure of the chronically HIV-1-infected myeloid cell line U1 to two different SARS-CoV-2 viral isolates (ancestral and BA.5) reversed its latent state after 24 h. We also observed that SARS-CoV-2 exposure of human primary monocyte-derived macrophages (MDM) initially drove their polarization towards an M1 phenotype, which shifted towards M2 over time. This effect was associated with soluble factors released during the initial M1 polarization phase that reactivated HIV production in U1 cells, like MDM stimulated with the TLR agonist resiquimod. Our study suggests that SARS-CoV-2-induced systemic inflammation and interaction with macrophages could influence proviral HIV-1 latency in myeloid cells in PLWH.

This study aims to explore the influence of coinfection with HCV and HIV on hepatic fibrosis. A coculture system was set up to actively replicate both viruses, incorporating CD4 T lymphocytes (Jurkat), hepatic stellate cells (LX-2), and hepatocytes (Huh7.5). LX-2 cells’ susceptibility to HIV infection was assessed through measurements of HIV receptor expression, exposure to cell-free virus, and cell-to-cell contact with HIV-infected Jurkat cells. The study evaluated profibrotic parameters, including programed cell death, ROS imbalance, cytokines (IL-6, TGF-β, and TNF-α), and extracellular matrix components (collagen, α-SMA, and MMP-9). The impact of HCV infection on LX-2/HIV-Jurkat was examined using soluble factors released from HCV-infected hepatocytes. Despite LX-2 cells being nonsusceptible to direct HIV infection, bystander effects were observed, leading to increased oxidative stress and dysregulated profibrotic cytokine release. Coculture with HIV-infected Jurkat cells intensified hepatic fibrosis, redox imbalance, expression of profibrotic cytokines, and extracellular matrix production. Conversely, HCV-infected Huh7.5 cells exhibited elevated profibrotic gene transcriptions but without measurable effects on the LX-2/HIV-Jurkat coculture. This study highlights how HIV-infected lymphocytes worsen hepatic fibrosis during HCV/HIV coinfection. They increase oxidative stress, profibrotic cytokine levels, and extracellular matrix production in hepatic stellate cells through direct contact and soluble factors. These insights offer valuable potential therapies for coinfected individuals.

Despite evidence indicating that depression is prevalent in men, gender stereotypes persist that position the disorder as feminine. This misperception may contribute to men's underdiagnosis with and undertreatment for depression. We applied the shifting standards model (SSM) to advance predictions about gender differences in the evaluation of individuals described as experiencing depression. These predictions took the form of objective and subjective evaluations, as well as minimum and confirmatory standards. We randomly assigned participants (N = 430) in a 3 (target gender: man, woman, control) x 2 (judgment standards: minimum, confirmatory) between-subjects experiment. Participants read a vignette describing a woman, man, or individual of unspecified gender and provided the evidence they would need to suspect or confirm depression in the target individual consistent with minimum and confirmatory judgment standards. Results from the pilot and main studies indicate more gender similarities than differences. We discuss the findings with respect to the SSM and how the increase in mental health salience during the COVID-19 pandemic may have mitigated gender stereotypical views of depression.

Abstract Background The risk of older adults being injured or killed in a bicycle accident increases significantly due to the age-related decline of physical function. Therefore, targeted interventions for older adults to improve safe cycling competence (CC) are urgently needed. Methods The “Safer Cycling in Older Age” (SiFAr) randomized controlled trial investigated if a progressive multi-component training program related to cycling improves CC of older adults. Between June 2020 and May 2022, 127 community-dwelling persons living in the area Nürnberg-Fürth-Erlangen, Germany aged 65 years and older were recruited, who are either (1) beginners with the e-bike or (2) feeling self-reported unsteadiness when cycling or (3) uptaking cycling after a longer break. Participants were either randomized 1:1 to an intervention group (IG; cycling exercise program, 8 sessions within 3 months) or an active control group (aCG; health recommendations). The CC as primary outcome was tested not blinded in a standardized cycle course prior and after the intervention period and after 6–9 months, which consists of variant tasks requiring skills related to daily traffic situations. Regression analyses with difference of errors in the cycling course as dependent variable and group as independent variable adjusted for covariates (gender, number of errors at baseline, bicycle type, age and cycled distance) were performed. Results 96 participants (73.4 ± 5.1 years; 59.4% female) were analyzed for primary outcome. Compared to the aCG (n = 49), the IG (n = 47) made an average of 2.37 fewer errors in the cycle course after the 3 months intervention period (p = 0.004). People with more errors at baseline had higher potential for improvement (B=-0.38; p

Abstract Introduction Infective endocarditis (IE) has undergone important changes in its epidemiology worldwide. Methods The study aimed to compare IE epidemiological features and outcomes according to predefined European regions and between two different time periods in the twenty-first century. Results IE cases from 13 European countries were included. Two periods were considered: 2000–2006 and 2008–2012. Two European regions were considered, according to the United Nations geoscheme for Europe: Southern (SE) and Northern–Central Europe (NCE). Comparisons were performed between regions and periods. A total of 4195 episodes of IE were included, 2113 from SE and 2082 from NCE; 2787 cases were included between 2000 and 2006 and 1408 between 2008 and 2012. Median (IQR) age was 63.7 (49–74) years and 69.4% were males. Native valve IE (NVE), prosthetic valve IE (PVE), and device-related IE were diagnosed in 68.3%, 23.9%, and 7.8% of cases, respectively; 52% underwent surgery and 19.3% died during hospitalization. NVE was more prevalent in NCE, whereas device-related IE was more frequent in SE. Higher age, acute presentation, hemodialysis, cancer, and diabetes mellitus all were more prevalent in the second period. NVE decreased and PVE and device-related IE both increased in the second period. Surgical treatment also increased from 48.7% to 58.4% (p

Hereditary angioedema (HAE) is a rare genetic disorder with variable expressivity even in carriers of the same underlying genetic defect, suggesting other genetic and epigenetic factors participate in modifying HAE severity. Recent knowledge indicates the role of immune cells in several aspects of HAE pathogenesis, which makes monocytes and macrophages candidates to mediate these effects. Here we combined a search for HAE phenotype modifying gene variants with the characterization of selected genes’ mRNA levels in monocyte and macrophages in a symptom-free period. While no such gene variant was found to be associated with a more severe or milder disease, patients revealed a higher number of dysregulated genes and their expression profile was significantly altered, which was typically manifested by changes in individual gene expression or by strengthened or weakened relations in mutually co-expressed gene groups, depending on HAE severity. SERPING1 showed decreased expression in HAE-C1INH patients, but this effect was significant only in patients carrying mutations supposedly activating nonsense-mediated decay. Pro-inflammatory CXC chemokine superfamily members CXCL8, 10 and 11 were downregulated, while other genes such as FCGR1A, or long non-coding RNA NEAT1 were upregulated in patients. Co-expression within some gene groups (such as an NF-kappaB function related group) was strengthened in patients with a severe and/or mild course compared to controls. All these findings show that transcript levels in myeloid cells achieve different activation or depression levels in HAE-C1INH patients than in healthy controls and/or based on disease severity and could participate in determining the HAE phenotype.

IntroductionOsteoclasts play a crucial role in bone resorption, and impairment of their differentiation can have significant implications for bone density, especially in individuals with HIV who may be at risk of altered bone health. The present study aimed to investigate the effects of HIV infection on osteoclast differentiation using primary human monocyte-derived macrophages as precursors. The study focused on assessing the impact of HIV infection on cellular adhesion, cathepsin K expression, resorptive activity, cytokine production, expression of co-receptors, and transcriptional regulation of key factors involved in osteoclastogenesis.MethodsPrimary human monocyte-derived macrophages were utilized as precursors for osteoclast differentiation. These precursors were infected with HIV, and the effects of different inoculum sizes and kinetics of viral replication were analyzed. Subsequently, osteoclastogenesis was evaluated by measuring cellular adhesion, cathepsin K expression, and resorptive activity. Furthermore, cytokine production was assessed by monitoring the production of IL-1β, RANK-L, and osteoclasts. The expression levels of co-receptors CCR5, CD9, and CD81 were measured before and after infection with HIV. The transcriptional levels of key factors for osteoclastogenesis (RANK, NFATc1, and DC-STAMP) were examined following HIV infection.ResultsRapid, massive, and productive HIV infection severely impaired osteoclast differentiation, leading to compromised cellular adhesion, cathepsin K expression, and resorptive activity. HIV infection resulted in an earlier production of IL-1β concurrent with RANK-L, thereby suppressing osteoclast production. Infection with a high inoculum of HIV increased the expression of the co-receptor CCR5, as well as the tetraspanins CD9 and CD81, which correlated with deficient osteoclastogenesis. Massive HIV infection of osteoclast precursors affected the transcriptional levels of key factors involved in osteoclastogenesis, including RANK, NFATc1, and DC-STAMP.ConclusionsThe effects of HIV infection on osteoclast precursors were found to be dependent on the size of the inoculum and the kinetics of viral replication. These findings underscore the importance of understanding the underlying mechanisms to develop novel strategies for the prevention and treatment of bone disorders in individuals with HIV.

Abstract Background Fear of falling (FoF) is an important risk factor for falls among older people. The objectives of our investigations were: a.) to present characteristics of older community-dwelling (CD) fallers with persistent or transient FoF (P-FoF or T-FoF) over 12 months, and b.) to investigate clinical predictors of P-FoF and T-FoF and c.) to explore differences between P-FoF and T-FoF. Methods Our series consisted of 389 older people reporting a fall or injurious fall at baseline and during 24 months follow-up participating in a multicenter prospective study. T-FoF was defined as participants reported “not at all” at baseline and “somewhat/fairly/very concerned” at follow-up, or “not at all” at follow-up, and “somewhat/fairly/very concerned” at baseline, and P-FoF was defined as participants answered “somewhat/fairly/very concerned” in both assessments at baseline and at follow-up. The association between risk factors and T-FoF or P-FoF was investigated by logistic regression analysis. Results The mean age of fallers in our sample was 79.0 years (SD 6.0), and 54.2% were females. Out of 389 older adults with a fall history at baseline, 83 participants (21.3%) did not report any FoF over time, P-FoF and T-FoF were observed in 42.7% and 35.9% of participants, respectively. After adjusting for potential confounders (e.g. age, gender), osteoporosis (OR = 2.04, 95%CI = 1.03–4.05) and impaired physical performance (OR = 2.38, 95%CI = 1.12–5.03) were significant predictors of T-FoF vs No-FoF. Osteoporosis (OR = 2.68, 95%CI = 1.31–5.48), depressive symptoms (OR = 3.54, 95%CI = 1.23–10.1) and living alone (OR = 2.44, 95%CI = 1.17–5.06) were significantly associated with P-FoF vs No-FoF. When comparing T-FoF and P-FoF, female gender (OR = 1.95, 95%CI = 1.16–3.27), BMI (OR = 1.08, 95%CI = 1.02–1.14), overall comorbidity (OR = 1.07, 95%CI = 1.02–1.13) and depression (OR = 2.55, 95%CI = 1.33–4.88) were significant predictors of P-FoF. Conclusions T-FoF and P-FoF may be predicted by different sets of risk factors among older fallers. Thus, fallers should be screened for FoF especially when carrying specific risk factors, including female gender, osteoporosis, depression, living alone, impaired physical performance, BMI, comorbidity. These findings may be helpful in designing tailored intervention to blunt the risks related to consequence of FoF among older people experiencing falls. Trial registration The SCOPE study was registered prospectively at clinicaltrials.gov (NCT02691546; 25/02/2016).

Abstract Background Mobility is one major component of healthy ageing of older persons. It includes gait speed, nowadays valued as the sixth vital sign of ageing. Quantitative gait analysis can support clinical diagnostics, monitor progression of diseases and provide information about the efficacy of interventions. Fast gait speed is an additional marker in the area of functional ability. Our aim was to contribute reference values of gait parameters of older persons based on their functional ability. Methods We visualised and combined three different established frameworks that assess gait characteristics into a new framework based approach that comprises eight gait parameters: gait speed, stride length, walk ratio, single and double support time, step width, step width CV (coefficient of variance), stride length CV. Gait parameters were stratified by two instruments that indicate levels of functional ability: First, the LUCAS Functional Ability Index (FAI), a self-administered screening tool easy to apply to a public-health orientated approach and second the Short Physical Performance Battery (SPPB), an established performance test widely used in comprehensive geriatric assessments (CGA). Gait parameters of older community-dwelling persons were measured with an objective Gait system (GAITRite) across differing functional ability ranging from robust to transient (postrobust and prefrail) to frail physical status. Results Of 642 community-dwelling participants (age 78.5 ± 4.8; n = 233 male, n = 409 female) categorisations by SPPB were 27.1% for robust (11–12 points), 44.2% for transient (8–10 points), 28.7% for frail (0–7 points), and 16.2, 50.3, 33.5% for robust, transient, frail by LUCAS FAI. Overall, our results showed that distinction by functional level only uncovers a wide spectrum of functional decline for all investigated gait parameters. Stratification by functional ability (biological age) revealed a greater range of differentiation than chronological age. Conclusions Gait parameters, carefully selected by literature, showed clinically meaningful differences between the functional featuring a gradient declining from robust over transient to frail in most gait parameters. We found discriminative power of stratifications by SPPB to be the highest, closely followed by LUCAS FAI, age groups and dichotomous age making the application of the LUCAS FAI more cost and time effective than conducting SPPB.

Abstract Background To review the validated instruments that assess gait, balance, and functional mobility to predict falls in older adults across different settings. Methods Umbrella review of narrative- and systematic reviews with or without meta-analyses of all study types. Reviews that focused on older adults in any settings and included validated instruments assessing gait, balance, and functional mobility were included. Medical and allied health professional databases (MEDLINE, PsychINFO, Embase, and Cochrane) were searched from inception to April 2022. Two reviewers undertook title, abstract, and full text screening independently. Review quality was assessed through the Risk of Bias Assessment Tool for Systematic Reviews (ROBIS). Data extraction was completed in duplicate using a standardised spreadsheet and a narrative synthesis presented for each assessment tool. Results Among 2736 articles initially identified, 31 reviews were included; 11 were meta-analyses. Reviews were primarily of low quality, thus at high risk of potential bias. The most frequently reported assessments were: Timed Up and Go, Berg Balance Scale, gait speed, dual task assessments, single leg stance, functional Reach Test, tandem gait and stance and the chair stand test. Findings on the predictive ability of these tests were inconsistent across the reviews. Conclusions In conclusion, we found that no single gait, balance or functional mobility assessment in isolation can be used to predict fall risk in older adults with high certainty. Moderate evidence suggests gait speed can be useful in predicting falls and might be included as part of a comprehensive evaluation for older adults.

Due to a common mode of transmission through infected human blood, hepatitis C virus (HCV) and human immunodeficiency virus (HIV) co-infection is relatively prevalent. In alignment with this, HCV co-infection is associated with an increased size of the HIV reservoir in highly active antiretroviral therapy (HAART)-treated individuals. Hence, it is crucial to comprehend the physiological mechanisms governing the latency and reactivation of HIV in reservoirs. Consequently, our study delves into the interplay between HCV/HIV co-infection in liver cells and its impact on the modulation of HIV latency. We utilized the latently infected monocytic cell line (U1) and the latently infected T-cell line (J-Lat) and found that mediators produced by the infection of hepatic stellate cells and hepatocytes with HIV and HCV, respectively, were incapable of inducing latency reversal under the studied conditions. This may favor the maintenance of the HIV reservoir size among latently infected mononuclear cells in the liver. Further investigations are essential to elucidate the role of the interaction between liver cells in regulating HIV latency and/or reactivation, providing a physiologically relevant model for comprehending reservoir microenvironments in vivo.

The DIII-D tokamak has elucidated crucial physics and developed projectable solutions for ITER and fusion power plants in the key areas of core performance, boundary heat and particle transport, and integrated scenario operation, with closing the core-edge integration knowledge gap being the overarching mission. New experimental validation of high-fidelity, multi-channel, non-linear gyrokinetic turbulent transport models for ITER provides strong confidence it will achieve Q ⩾ 10 operation. Experiments identify options for easing H-mode access in hydrogen, and give new insight into the isotopic dependence of transport and confinement. Analysis of 2,1 islands in unoptimized low-torque IBS demonstration discharges suggests their onset time occurs randomly in the constant β phase, most often triggered by non-linear 3-wave coupling, thus identifying an NTM seeding mechanism to avoid. Pure deuterium SPI for disruption mitigation is shown to provide favorable slow cooling, but poor core assimilation, suggesting paths for improved SPI on ITER. At the boundary, measured neutral density and ionization source fluxes are strongly poloidally asymmetric, implying a 2D treatment is needed to model pedestal fuelling. Detailed measurements of pedestal and SOL quantities and impurity charge state radiation in detached divertors has validated edge fluid modelling and new self-consistent ‘pedestal-to-divertor’ integrated modeling that can be used to optimize reactors. New feedback adaptive ELM control minimizes confinement reduction, and RMP ELM suppression with sustained high core performance was obtained for the first time with the outer strike point in a W-coated, compact and unpumped small-angle slot divertor. Advances have been made in integrated operational scenarios for ITER and power plants. Wide pedestal intrinsically ELM-free QH-modes are produced with more reactor-relevant conditions, Low torque IBS with W-equivalent radiators can exhibit predator-prey oscillations in T _e and radiation which need control. High- β _P scenarios with q _min > 2, q _95 –7.9, β _N > 4, β _T –3.3% and H _98y2 > 1.5 are sustained with high density ( $\bar n$ = 7E19 m ^−3 , f _G –1) for 6 τ _E , improving confidence in steady-state tokamak reactors. Diverted NT plasmas achieve high core performance with a non-ELMing edge, offering a possible highly attractive core-edge integration solution for reactors.

A plasma scenario with negative triangularity (NT) shaping is achieved on MAST-U for the first time. While edge localized modes (ELMs) are eventually suppressed as the triangularity is decreased below $\delta\lesssim-0.06$ , an extended period of H-mode operation with Type-III ELMs is sustained at less negative δ even through access to the second stability region for ideal ballooning modes is closed. This documents a qualitative difference from the ELM-free access conditions documented in NT scenarios on conventional aspect ratio machines. The electron temperature at the pedestal top drops across the transition to ELM-free operation, but a steady rise in core temperature as δ is decreased allows for similar normalized β in the ELM-free NT and H-mode positive triangularity shapes.

Abstract Within the growing family of strained carbon nanohoops and nanobelts, [10]CPP arguably offers the best compromise between synthetic accessibility and strong binding affinity for C60. In this work, we report the synthesis of two nitrogen-containing analogues of [10]CPP and we systematically compare the structure, optoelectronic properties and C60 binding affinities of this small set of structurally similar macrocycles. While Aza[10]CPP outcompetes the parent compound by approximately one order of magnitude with respect to C60 binding, we found that the reverse was true for the methylaza analogue. Transient absorption studies showed that photo-induced electron transfer occurred readily from [10]CPP and its aza-analogue to an encapsulated C60 guest. Formation of a charge-separated complex was not observed however for the N-methylated derivative. These insights will prove useful for further applications of strained nanohoops in supramolecular chemistry and organic electronics.

IntroductionPulmonary and extrapulmonary manifestations have been described after infection with SARS-CoV-2, the causative agent of coronavirus disease 2019 (COVID-19). The virus is known to persist in multiple organs due to its tropism for several tissues. However, previous reports were unable to provide definitive information about whether the virus is viable and transmissible. It has been hypothesized that the persisting reservoirs of SARS-CoV-2 in tissues could be one of the multiple potentially overlapping causes of long COVID.MethodsIn the present study, we investigated autopsy materials obtained from 21 cadaveric donors with documented first infection or reinfection at the time of death. The cases studied included recipients of different formulations of COVID-19 vaccines. The aim was to find the presence of SARS-CoV-2 in the lungs, heart, liver, kidneys, and intestines. We used two technical approaches: the detection and quantification of viral genomic RNA using RT-qPCR, and virus infectivity using permissive in vitro Vero E6 culture.ResultsAll tissues analyzed showed the presence of SARS-CoV-2 genomic RNA but at dissimilar levels ranging from 1.01 × 102 copies/mL to 1.14 × 108 copies/mL, even among those cases who had been COVID-19 vaccinated. Importantly, different amounts of replication-competent virus were detected in the culture media from the studied tissues. The highest viral load were measured in the lung (≈1.4 × 106 copies/mL) and heart (≈1.9 × 106 copies/mL) samples. Additionally, based on partial Spike gene sequences, SARS-CoV-2 characterization revealed the presence of multiple Omicron sub-variants exhibiting a high level of nucleotide and amino acid identity among them.DiscussionThese findings highlight that SARS-CoV-2 can spread to multiple tissue locations such as the lungs, heart, liver, kidneys, and intestines, both after primary infection and after reinfections with the Omicron variant, contributing to extending knowledge about the pathogenesis of acute infection and understanding the sequelae of clinical manifestations that are observed during post-acute COVID-19.

Abstract Background Stereotypes and false assumptions about chronic and visible skin diseases can determine the behaviour towards affected individuals and result in stigmatization or discrimination. Objective The aim of this study was to analyze the perceived disease‐related stigmatization of individuals with psoriasis, atopic dermatitis (AD) or mastocytosis. The study also aims to broaden people‐centred knowledge of the effects of stigmatization in different areas of life, namely in everyday life, at work, in sports and in relationships. Methods Qualitative in‐depth semi‐structured interviews were conducted among individuals with either psoriasis, AD or mastocytosis. Participants were recruited via self‐help networks and were asked to express their experience of stigmatization in different areas of life. All interviews were audio recorded, transcribed verbatim and evaluated based on Mayring's content analysis. Results In total, 24 individuals aged 19–79 years and living in Germany were included in the study—eight for each disease. Stigmatization was experienced in all three diseases in all mentioned areas of life as well as in interaction with medical professionals. Self‐exclusion, negative self‐perception and negative behaviour of others were the most frequent experiences with stigmatization. Conclusion Stigmatization, both internal and external, is an important factor contributing to the mental burden of people with chronic skin diseases. More research is needed to gain deeper insight into stigmatization and its psychological burden in various contexts to enhance people‐centred care in chronic skin diseases.

Abstract Background Cycling has positive effects on health and the proportion of older cyclists is rising. However, the risk for older adults to be injured or killed by a bicycle accident increases. The aim of the ongoing project “Safer Cycling in Older Age (SiFAr)” is to promote safer cycling in community-dwelling older adults with a structured, multi-component exercise training. Methods SiFAr is a randomized, controlled trial with a duration of 3 months for the intervention and a 6–9 months follow-up. We address community-dwelling persons aged 65 years and older living in the area Nürnberg-Fürth-Erlangen (Germany) who are either 1) beginners with the e-bike or 2) feeling self-reported unsteadiness when cycling or 3) uptaking cycling after a longer break. Long-term, experienced cyclists without subjectively reported limitations or worries when cycling are excluded. Participants are either randomized 1:1 to an intervention group (IG; receiving multi-component exercise program related to cycling, MEPC) or an active control group (aCG; receiving health and bicycle-related presentations, HRP). The purpose of this study is to investigate if the cycling competence of the IG will improve compared to the aCG. The cycling competence as primary outcome is tested not blinded in a standardized cycle course prior and after the intervention period, which consists of variant tasks requiring motor and cognitive skills related to traffic situations in daily life. Additional assessments such as physical functioning, quality of life, fear of falling, questionnaires regarding cycling behavior are obtained. To investigate the primary objective, regression analyses with difference of errors in the cycling course as independent variable and group as dichotomous dependent variable adjusted for covariates (sex, bicycle type) will be performed. The trial design is described in the present manuscript, using the extended CONSORT checklist for reporting pragmatic trials. Discussion Since there is a lack of cycling-related interventions for older people, SiFAr aims to evaluate a standardized intervention to enhance cycling safety. The results of the SiFAr trial could contribute to the implementation of an evaluated cycling course concept promoting mobility and independence of older adults. Trial registration This study was registered with clinicaltrials.gov : NCT04362514 on April 27, 2020

Abstract Background An increasing number of older people in Germany receive care at home from family members, particularly from spouses. Family care has been associated not only with subjective burden but also with negative effects on caregivers’ health. A heterogeneous group, caregivers are confronted with individual situational demands and use different available coping strategies. To date, little is known about the relationship between burden and coping by spousal caregivers, particularly in the context of geriatric patients without dementia. Objectives The aim of this study is to explore the burden and coping strategies of caregiving spouses of geriatric patients without dementia and with a hospitalization within the last year. To help explore this population, a typology is presented that has been based on reported perceptions of home care burden and individual coping strategies. Furthermore, a case study is presented for each type of spousal caregiver. Methods The study used a concurrent mixed method design with a sample of nine spousal caregivers (mean age: 78.9 years). Four women and five men were recruited in an acute hospital setting during the TIGER study. Quantitative data were collected using a self-questionnaire and qualitative data were gathered through nine problem-centered interviews with spousal caregivers. The latter were subsequently analyzed utilizing the structured content analysis method. The data were then summarized to nine individual cases. Finally, the results were clustered using the empirically grounded construction of types and typologies. Each type of spousal caregiver is presented by a case study. Results Three types of caregiving spouses were identified: “The Caring Partner”, “The Worried Manager” and “The Desperate Overburdened”. These types differ primarily in the level of subjective burden and caregiving stress, the coping strategies, the motivation for caregiving, and expressed emotions. Conclusions The development of this new typology of caregiving spouses could help health care professionals better understand caregiving arrangements and thus provide more targeted advice. Trial registration The TIGER study was registered with clinicaltrials.gov: NCT03513159 . Registered on April 17, 2018.

Abstract Background SiFAr-Stress investigates the impact of cycling on stress levels in older adults. Uncertainty due to change to motorized bicycle or fear of falling can be perceived as stressors for cyclists. Stress activates different physiological signal cascades and stimulates the hypothalamic-pituitary-adrenal (HPA) axis, which leads to the release of the stress hormone cortisol and further effects such as the development of low-grade inflammation. Both can—in the long term—be associated with negative health outcomes. The aim of the study SiFAr-Stress is to analyze inflammatory processes as well as the activity of stress systems before and after a cycling intervention for older adults. Methods In this study, community-dwelling older adults aged 65 years and older will be randomly assigned to either a cycling or a control intervention in a parallel-group design. Objective HPA axis–related measures (saliva cortisol and hair cortisol) will be assessed before, after, and 6–9 months after the cycling and control intervention (T0, T1, and T2). Furthermore, changes in cortisol reactivity in response to the cycling intervention will be investigated at the second and seventh training lessons. Furthermore, secondary outcomes (fear of falling, perceived stress, salivary alpha amylase, and C-reactive protein) will be assessed at T0, T1, and T2. Discussion The study will be the first, in which stress- and health-related bio-physiological outcomes will be assessed in the context of a multicomponent exercise intervention, addressing cycling in older adults. It will enable us to better understand the underlying patho-physiological and psychological mechanisms and will help to improve interventions for this target group. Trial registration ClinicalTrials.gov NCT04362514 . Prospectively registered on 27 April 2020

Abstract Background Previous studies have pointed to the impact of self-perceptions of aging (SPA) on self-reported physical function in later life. However, less is known about associations of SPA with objectively measured physical function, especially gait. Research that examined other psychological variables and objectively measured gait has focused on single gait parameters such as gait speed, which seems to fall short for the complexity of this movement. Some approaches have proposed ways to identify gait patterns in specific patient groups, but not in community samples. Our goal was (a) to identify gait patterns based on a combination of important gait parameters in a community sample, and (b) to investigate differential associations of gain- and loss-related SPA with these gait patterns. Methods The study used an electronic walkway to assess gait parameters of 150 community dwelling adults aged 71–93 years (61.0% women) at their usual and maximum gait speed. SPA were assessed with a questionnaire. We used latent profile analysis (LPA) to identify groups exhibiting distinct gait patterns and binary logistic regression to investigate associations of SPA with these groups, controlling for personality traits, number of illnesses, age, gender, and education. To compare overall function between groups, a t-test for scores in the Short Physical Performance Battery was used. Results LPA revealed two distinct groups in both gait speed conditions. The fit group exhibited a stable, well-coordinated and faster gait pattern, while the functionally limited group’s gait pattern was less stable, less coordinated and slower. The odds of belonging to the functionally limited group were increased by loss-related SPA at usual gait speed, while the odds of belonging to the fit group were increased by gain-related SPA at individual maximum speed. Conclusions The findings (a) suggest LPA as a useful approach to investigate complex gait patterns considering several gait parameters simultaneously, and (b) provide first evidence for differential associations of gain- and loss-related SPA with gait patterns at usual and maximum gait speed. Intervention studies addressing gait in older adults should additionally address gain-related views on aging.

Diagnosis of salivary gland neoplasms is often challenging due to their high morphological diversity and overlaps. Several recurrent molecular alterations have been described recently, which can serve as powerful diagnostic tools and potential therapeutic targets (e.g. NTRK or RET fusions). However, current sequential molecular testing can be expensive and time consuming. In order to facilitate the diagnosis of salivary gland neoplasms, we designed an all-in-one RNA-based next generation sequencing panel suitable for the detection of mutations, fusions and gene expression levels (including NR4A3) of 27 genes involved in salivary gland neoplasms. Here we present the validation of the “SalvGlandDx” panel on FFPE histological specimen including fine needle aspiration (FNA) cell block material, against the standard methods currently used at our institution. In a second part we describe selected unique cases in which the SalvGlandDx panel allowed proper diagnosis and new insights into special molecular characteristics of selected salivary gland tumors. We characterize a unique salivary gland adenocarcinoma harboring a ZCCHC7-NTRK2 fusion, a highly uncommon spindle cell and pseudoangiomatoid adenoid-cystic carcinoma with MYBL1-NFIB fusion, and a purely oncocytic mucoepidermoid carcinoma, whereas diagnosis could be made by detection of a CRTC3-MAML2 rearrangement on the cell block specimen of the FNA. Further, a rare case of a SS18-ZBTB7A rearranged low-grade adenocarcinoma previously described as potential spectrum of microsecretory adenocarcinoma, is reported. In addition, features of six cases within the spectrum of polymorphous adenocarcinoma / cribriform adenocarcinoma of salivary gland including PRKD1 p.E710D mutations and novel fusions involving PRKAR2A-PRKD1, SNX9-PRKD1 and ATL2-PRKD3, are described.

Total knee arthroplasty is a common procedure performed to improve pain and dysfunction attributed to arthritis, yet postoperative patient dissatisfaction rates remain relatively high. Patient satisfaction and outcomes have been linked to successful joint gap balancing in the coronal and sagittal planes intraoperatively. In previously described balancing techniques, the fulcrum used for alignment changes is customarily centered on the intramedullary axis generating symmetric changes in medial and lateral gaps. We propose a novel technique in the literature that, with the use of robotic-arm assisted technology or similar systems, allows manipulation of the fulcrum center of rotation during pre-resection planning and intraoperative gap establishment before bony cuts to asymmetrically influence medial and lateral, flexion and extension gaps to aid in balancing during total knee arthroplasty.

Abstract Background Currently 21% of the German population is older than 65 years. Above this age, the risk of suffering from chronic disease and mental disorders increases rapidly. Therefore, physical inactivity is one of the most important public health concerns among older people. To address this issue, we have conceptualised and evaluated a simple and low-threshold intervention, which requires only minimal demand on the participants, targeting older people with inadequate activity levels. The aim of the POWER Study is to investigate whether volunteer-supported outdoor-walking improves physical function and quality of life in older people. Methods/design In a randomised, controlled interventional superiority-trial, individuals older than 65 years of age living in the community or nursing homes will be randomised into two groups. The study will be conducted in two study centres with assessments at baseline, 6 and 12 months. The intervention group will participate in a supported physical activity intervention for 6 months. An assigned volunteer will visit them three times a week for an outdoor walk between 30 and 50 min, or equivalent indoor activity. Persons in the control group will be invited to two lectures covering topics related to health. Primary endpoint is the physical function measured by the Short Physical Performance Battery (SPPB) at baseline, after 6 and 12 months. Secondary and safety endpoints will be quality of life (EQ. 5D), fear of falling (Falls Efficacy Scale), physical activity (activity diary), cognitive executive function (clock drawing test), falls requiring medical attention, hospitalisation and death. Primary analysis will be carried out by intention to treat. Discussion We expect the intervention to improve the overall health status of the participants in a wide range of health-related outcomes. If effectiveness can be shown, the intervention will close an important gap in current services for older people. We will disseminate our experiences and results in the form of informational documents (training manual) to allow municipalities and health care organisations to implement a similar intervention. Trial registration The trial was registered on 31 Aug 2018; German Clinical Trials Register (www.germanctr.de), Deutsches Register Klinischer Studien: DRKS00015188 .

Abstract Background Chronic kidney disease (CKD), cognitive impairment and depression share common risk factors. Previous studies did not investigate the possible association between kidney function and cognitive and mood disorders in older persons in a broad range of kidney function. The present study explored associations between kidney function, cognition and mood in outpatients of 75 years and over. Methods Baseline data of 2252 participants of the SCOPE study, an international multicenter cohort observational study,were used in which community-dwelling persons of 75 years and over were enrolled to screen for CKD Kidney function was estimated with the BIS1-eGFR equation, cognition was assessed with the Mini-Mental State Examination (MMSE) and mood with the Geriatric Depression Scale 15 items (GDS-15). Characteristics were compared across stages of CKD. Mean eGFR values were also compared across categories of MMSE ( 5/≤5). Results In total, 63% of the population had an eGFR

Abstract Aims Danon disease (DD) is a rare X‐linked disorder caused by mutations in the lysosomal‐associated membrane protein type 2 gene (LAMP2). DD is difficult to distinguish from other causes of dilated or hypertrophic cardiomyopathy (HCM) in female patients. As DD female patients regularly progress into advanced heart failure (AHF) aged 20–40 years, their early identification is critical to improve patient survival and facilitate genetic counselling. In this study, we evaluated the prevalence of DD among female patients with non‐ischemic cardiomyopathy, who reached AHF and were younger than 40 years. Methods and results The study cohort comprised 60 female patients: 47 (78%) heart transplant recipients, 2 (3%) patients treated with ventricular assist device, and 11 (18%) patients undergoing pre‐transplant assessment. Aetiology of the cardiomyopathy was known in 15 patients (including two DD patients). LAMP2 expression in peripheral white blood cells (WBC) was tested by flow cytometry (FC) in the remaining 45 female patients. Whole exome sequencing was used as an alternative independent testing method to FC. Five additional female DD patients (two with different novel LAMP2 mutations) were identified by FC. The total prevalence of DD in this cohort was 12%. HCM phenotype (57% vs. 9%, *P = 0.022) and delta waves identified by electrocardiography (43% vs. 0%, **P = 0.002) were significantly more frequent in DD female patients. Conclusions Danon disease is an underdiagnosed cause of AHF in young female patients. LAMP2 expression testing in peripheral WBCs by FC can be used as an effective screening/diagnostic tool to identify DD in this patient population.

Abstract Background Loss of muscle mass and function may be more pronounced in older adults with chronic kidney disease (CKD) and with albuminuria. Thus, we investigated the prevalence of sarcopenia among community-dwelling older adults according to kidney function and grade of albuminuria. We also explored differences in the prevalence of sarcopenia according to three different equations for the estimation of glomerular filtration rate (eGFR). Methods A cross-sectional analysis of 1420 community-dwelling older adults (≥75 years old) included in the SCOPE study, a multicenter prospective cohort study, was conducted. Comprehensive geriatric assessment including short physical performance battery (SPPB), handgrip strength test and bioelectrical impedance analysis (BIA) was performed. Sarcopenia was defined using the updated criteria of the European Working Group on Sarcopenia in Older People (EWGSOP2). eGFR was calculated using Berlin Initiative Study (BIS), Chronic Kidney Disease Epidemiological Collaboration (CKD-EPI) and Full Age Spectrum (FAS) equations, and urinary albumin-to-creatinine ratio (ACR) was collected to categorize CKD according to Kidney Disease Improving Global Outcomes guidelines. Results Median age was 79.5 years (77.0–83.0), 804 (56.6%) were women. Using EWGSOP2 definition, 150 (10.6%) participants met diagnostic criteria for sarcopenia. Moreover, 85 (6%) participants had severe sarcopenia. Sarcopenia was more prevalent in participants with more advanced stages of CKD according to BIS eq. (9.6% in stages 1 and 2 and 13.9% in stages 3a, 3b and 4, p = 0.042), and also according to CKD-EPI (9.8% vs. 14.2%, p = 0.042) and FAS although not reaching statistical signification (9.8% vs. 12.7%, p = 0.119). Thus, differences in prevalence are observed among CKD categories as estimated by different equations. Prevalence of sarcopenia was also higher with increasing albuminuria categories: 9.3% in normoalbuminuric, 13.2% in microalbuminuric and 16.8% in macroalbuminuric participants, (p = 0.019). Conclusions Sarcopenia is common among community-dwelling older adults, especially among those with more advanced CKD categories, with prevalence estimates differing slightly depending on the equation used for the estimation of eGFR; as well as among those with higher albuminuria categories.

Abstract Background Chronic kidney disease (CKD) is known to be associated with several co-occurring conditions. We aimed at exploring multimorbidity patterns associated with CKD, as well as the impact of physical performance and CKD severity on them in a population of older outpatients. Methods Our series consisted of 2252 patients enrolled in the Screening of CKD among Older People across Europe multicenter observational study. Hypertension, stroke, transient ischemic attack, cancer, hip fracture, osteoporosis, Parkinson’s disease, asthma, chronic obstructive pulmonary disease, congestive heart failure, angina, myocardial infarction, atrial fibrillation, anemia, CKD (defined as GFR

Abstract Background Different mechanisms connect the nutritional status with the occurrence and the course of chronic kidney disease (CKD). The end-stage renal disease is complicated by catabolic inflammatory reactions and cachexia which leads to malnutrition (undernutrition). On the other hand, obesity is an important risk factor for the development and acceleration of CKD. Methods In the SCOPE study, community-dwelling persons aged 75 years and over, from 6 European countries and Israel were examined at the baseline phase. We assessed the relationship between anthropometric measures (Body Mass Index (BMI), circumferences of arm (AC), waist (WC), hip (HC), and calf (CC), waist-to-hip ratio - WHR, waist-to-height ratio - WHtR, risk of malnutrition (Mini Nutritional Assessment - MNA), serum albumin) and estimated glomerular filtration rate (eGFR) calculated by Berlin Initiative Study (BIS) equation. Results We studied 2151 subjects (932 men and 1219 women) with a mean age of 79.5 ± 5.9 years. A total of 1333 (62%) participants had CKD (GRF 60 (OR = 2.95, 95%CI = 1.77–4.94 for MNA

Abstract Background Reduced kidney function has become a major public health concern, especially among older people, as Chronic Kidney Disease (CKD) is associated with increased risk of end stage renal disease and mortality. Falls are a serious negative health outcome in older persons with one third of people aged 65 years experiencing a fall per year and increasing fall rates with increasing age. The impact of CKD on falls in older community-dwelling persons is not well investigated. Additionally, lower urinary tract symptoms (LUTS) may also increase the risk of falls. Therefore, our aim was to investigate the impact of CKD and LUTS on falls as well as on injurious falls. Methods The SCOPE study is an observational, multinational, multicenter, prospective cohort study involving community-dwelling older persons aged 75 years and more recruited from August 2016 to March 2018 in seven European countries. The main outcomes of the present study were any falls and any injurious falls during the 12 months before enrolment. The cross-sectional association of estimated glomerular filtration rate (eGFR) and LUTS with study outcomes was investigated by logistic regression analysis adjusted for baseline characteristics of enrolled subjects. Results Our series consisted of 2256 SCOPE participants (median age = 79.5 years, 55.7% female). Of them, 746 participants experienced a fall and 484 reported an injurious fall in the 12 months prior to baseline assessment. CKD was not significantly associated with falls (OR = 0.95, 95%CI = 0.79–1.14 for eGFR

Abstract Background Quality of life (QoL) refers to the physical, psychological, social and medical aspects of life that are influenced by health status and function. The purpose of this study was to measure the self-perceived health status among the elderly population across Europe in different stages of Chronic Kidney Disease (CKD). Methods Our series consisted of 2255 community-dwelling older adults enrolled in the Screening for Chronic Kidney Disease (CKD) among Older People across Europe (SCOPE) study. All patients underwent a comprehensive geriatric assessment (CGA), including included demographics, clinical and physical assessment, number of medications taken, family arrangement, Geriatric Depression Scale (GDS), Cumulative Illness Rating Scale, History of falls, Lower urinary tract symptoms, and Short Physical Performance Battery (SPPB). Estimated glomerular filtration rate (eGFR) was calculated by Berlin Initiative Study (BIS) equation. Quality of life was assessed by Euro Qol questionnaire (Euro-Qol 5D) and EQ-Visual Analogue Scale (EQ-VAS). The association between CKD (eGFR

Maxime Billot,1,2 Riccardo Calvani,3,4 Annele Urtamo,5 Juan Luis Sánchez-Sánchez,6 Cecilia Ciccolari-Micaldi,1 Milan Chang,7,8 Regina Roller-Wirnsberger,9 Gerhard Wirnsberger,10 Alan Sinclair,11 Nieves Vaquero-Pinto,12 Satu Jyväkorpi,5 Hanna Öhman,5 Timo Strandberg,13,14 Jos MGA Schols,15 Annemie MWJ Schols,16 Nick Smeets,17 Eva Topinkova,18 Helena Michalkova,19 Anna Rita Bonfigli,20 Fabrizia Lattanzio,20 Leocadio Rodríguez-Mañas,21 Hélio Coelho-Júnior,4 Marianna Broccatelli,4 Maria Elena D’Elia,4 Damiano Biscotti,4 Emanuele Marzetti,3,4 Ellen Freiberger22 1Clinical Gerontology, University Hospital of Limoges, Limoges, France; 2PRISMATICS (Predictive Research in Spine/Neurostimulation Management and Thoracic Innovation in Cardiac Surgery), Poitiers University Hospital, Poitiers, France; 3Università Cattolica del Sacro Cuore, Rome, Italy; 4Fondazione Policlinico Universitario "Agostino Gemelli" IRCCS, Rome, Italy; 5University of Helsinki, Department of General Practice and Primary Health Care, Helsinki University Central Hospital, Unit of Primary Health Care, Helsinki, Finland; 6Foundation for Biomedical Research Getafe University Hospital, Madrid, Spain; 7Faculty of Health Promotion, Sports and Leisure Studies, School of Education, University of Iceland, Reykjavik, Iceland; 8The Icelandic Gerontological Research Center, Landspitali University Hospital and University of Iceland, Reykjavik, Iceland; 9Medical University of Graz, Department of Internal Medicine, Graz, Austria; 10Medical University of Graz, Division of Nephrology, Department of Internal Medicine, Graz, Austria; 11Foundation for Diabetes Research in Older People, Diabetes Frail Ltd., Luton, UK; 12University Hospital of Ramon Cajal IRYCIS, Madrid, Spain; 13University of Helsinki, Clinicum, Helsinki, Finland; Helsinki University Hospital, Medicine and Rehabilitation, Helsinki, Finland; 14University of Oulu, Center for Life Course Health Research, Oulu, Finland; 15Department of Health Services Research, Maastricht University Medical Center, Maastricht, The Netherlands; 16Department of Respiratory Medicine, School of Nutrition and Translational Research in Metabolism (NUTRIM), Maastricht University Medical Center, Maastricht, The Netherlands; 17Department of Health & Fitness, Maastricht University Medical Center, Maastricht, The Netherlands; 18 First Faculty of Medicine, Charles University, Prague, Czech Republic; 19Faculty of Social and Health Sciences, South Bohemian University, Ceske Budejovice, Czech Republic; 20Scientific Direction, IRCCS INRCA, Ancona, Italy; 21Geriatrics Service, University Hospital of Getafe, Madrid, Spain; 22Institute for Biomedicine of Aging, FAU Erlangen-Nürnberg, Nürnberg, GermanyCorrespondence: Maxime Billot CHU De Poitiers, PRISMATICS (Predictive Research in Spine/Neurostimulation Management and Thoracic Innovation in Cardiac Surgery)Poitiers University Hospital, 2 Rue De La Miléterie, Poitiers 86021, FranceTel +33 549 443 224Email maxime.billot2@gmail.comAbstract: One of the most widely conserved hallmarks of aging is a decline in functional capabilities. Mobility loss is particularly burdensome due to its association with negative health outcomes, loss of independence and disability, and the heavy impact on quality of life. Recently, a new condition, physical frailty and sarcopenia, has been proposed to define a critical stage in the disabling cascade. Physical frailty and sarcopenia are characterized by weakness, slowness, and reduced muscle mass, yet with preserved ability to move independently. One of the strategies that have shown some benefits in combatting mobility loss and its consequences for older adults is physical activity. Here, we describe the opportunities and challenges for the development of physical activity interventions in people with physical frailty and sarcopenia. The aim of this article is to review age-related physio(patho)logical changes that impact mobility in old age and to provide recommendations and procedures in accordance with the available literature.Keywords: physical exercise, muscle mass, strength, walking, balance, better aging

Abstract Background Demographic changes are taking place in most industrialized countries. Geriatric patients are defined by the European Union of Medical Specialists as aged over 65 years and suffering from frailty and multi-morbidity, whose complexity puts a major burden on these patients, their family caregivers and the public health care system. To counteract negative outcomes and to maintain consistency in care between hospital and community dwelling, the transitional of care has emerged over the last several decades. Our objectives were to identify and summarize the components of the Transitional Care Model implemented with geriatric patients (aged over 65 years, with multi-morbidity) for the reduction of all-cause readmission. Another objective was to recognize the Transitional Care Model components’ role and impact on readmission rate reduction on the transition of care from hospital to community dwelling (not nursing homes). Methods Randomized controlled trials (sample size ≥50 participants per group; intervention period ≥30 days), with geriatric patients were included. Electronic databases (MEDLINE, CINAHL, PsycINFO and The Cochrane Central Register of Controlled Trials) were searched from January 1994 to December 2019 published in English or German. A qualitative synthesis of the findings as well as a systematic assessment of the interventions intensities was performed. Results Three articles met the inclusion criteria. One of the included trials applied all of the nine Transitional Care Model components described by Hirschman and colleagues and obtained a high-intensity level of intervention in the intensities assessment. This and another trial reported reductions in the readmission rate (p