Impaired Activity Research Articles

Microvascular insulin resistance with enhanced muscle glucose disposal in CD36 deficiency.

Microvascular dysfunction contributes to insulin resistance. CD36, a fatty acid transporter and modulator of insulin signalling, is abundant in microvascular endothelial cells. Humans carrying the minor allele (G) of CD36 coding variant rs3211938 have 50% reduced CD36 expression and show endothelial dysfunction. We aimed to determine whether G allele carriers have microvascular resistance to insulin and, if so, how this affects glucose disposal. Our multi-disciplinary approach included hyperinsulinaemic-euglycaemic clamps in Cd36-/- and wild-type mice, and in individuals with 50% CD36 deficiency, together with control counterparts, in addition to primary human-derived microvascular endothelial cells with/without CD36 depletion. Insulin clamps showed that Cd36-/- mice have enhanced insulin-stimulated glucose disposal but reduced vascular compliance and capillary perfusion. Intravital microscopy of the gastrocnemius showed unaltered transcapillary insulin flux. CD36-deficient humans had better insulin-stimulated glucose disposal but insulin-unresponsive microvascular blood volume (MBV). Human microvascular cells depleted of CD36 showed impaired insulin activation of Akt, endothelial NO synthase and NO generation. Thus, in CD36 deficiency, microvascular insulin resistance paradoxically associated with enhanced insulin sensitivity of glucose disposal. CD36 deficiency was previously shown to reduce muscle/heart fatty acid uptake, whereas here we showed that it reduced vascular compliance and the ability of insulin to increase MBV for optimising glucose and oxygen delivery. The muscle and heart respond to these energy challenges by transcriptional remodelling priming the tissue for insulin-stimulated glycolytic flux. Reduced oxygen delivery activating hypoxia-induced factors, endothelial release of growth factors or small intracellular vesicles might mediate this adaptation. Targeting NO bioavailability in CD36 deficiency could benefit the microvasculature and muscle/heart metabolism. Clinicaltrials.gov NCT03012386 DATA AVAILABILITY: The RNAseq data generated in this study have been deposited in the NCBI Gene Expression Omnibus ( www.ncbi.nlm.nih.gov/geo/ ) under accession code GSE235988 ( https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE235988 ).

StCDF1: A 'jack of all trades' clock output with a central role in regulating potato nitrate reduction activity.

Transcription factors of the CYCLING DOF FACTOR (CDF) family activate in potato the SP6A FT tuberization signal in leaves. In modern cultivars, truncated StCDF1.2 alleles override strict SD control by stabilizing the StCDF1 protein, which leads to StCOL1 suppression and impaired activation of the antagonic SP5G paralog. By using DAP-seq and RNA-seq studies, we here show that StCDF1 not only acts as an upstream regulator of the day length pathway but also directly regulates several N assimilation and transport genes. StCDF1 directly represses expression of NITRATE REDUCTASE (NR/NIA), which catalyses the first reduction step in nitrate assimilation, and is encoded by a single potato locus. StCDF1 knock-down lines performed better in N-limiting conditions, and this phenotype correlated with derepressed StNR expression. Also, deletion of the StNR DAP-seq region abolished repression by StCDF1, while it did not affect NLP7-dependent activation of the StNR promoter. We identified multiple nucleotide polymorphisms in the DAP-seq region in potato cultivars with early StCDF1 alleles, suggesting that this genetic variation was selected as compensatory mechanism to the negative impact of StCDF1 stabilization. Thereby, directed modification of the StCDF1-recognition elements emerges as a promising strategy to enhance limiting StNR activity in potato.

Delirium risk profiles in a population-based study of United States older adults undergoing common noncardiac surgeries.

Older adults often require surgical care and are at elevated risk of delirium. We explored delirium risk profiles across the population of U.S. older adults who underwent one of 10 common noncardiac surgeries. We analyzed Health and Retirement Study (HRS) participants linked with Medicare billing data who underwent the following 10 noncardiac surgeries from 2000 to 2018 at age 65 or more: total knee arthroplasty (TKA), total hip arthroplasty (THA), spine surgery, cholecystectomy, colorectal surgery, hernia repair (ventral, umbilical, or incisional), endarterectomy, prostatectomy, transurethral resection of the prostate (TURP), and hysterectomy. Demographic and health covariates were obtained from the HRS dataset. Latent cognitive ability was calculated from cognitive testing, proxy reports, and demographics at the preoperative HRS interview. We compared standardized differences for delirium risk factors across the 10 surgeries and qualitatively clustered them into phenotypical subgroups. We analyzed 7424 older adults (mean age 76 ± 6 years, 45% male). Endarterectomy patients presented with the highest burden of nearly all health and cognitive factors, implying higher delirium risk (e.g., stroke, 22%; depressive symptoms, 30%; high school or less education, 73%; frailty, 42%; lowest latent cognitive ability). A second "general surgery" phenotype, including cholecystectomy, colorectal, and hernia surgery patients, experienced more frailty (29%-32%) and depressive symptoms (24%-26%), with moderate comorbidity burden. A third "pain" phenotype, which included TKA, THA, and spine surgery patients, commonly reported moderate or severe pain (47%-53%) and impairment in activities of daily living (ADL, 23%-30%), but fewer comorbid medical conditions. The remaining surgery types (hysterectomy, prostatectomy, TURP) were not phenotypically grouped and generally had lower risk features for delirium. In an epidemiological cohort of US older adults, we identified clinically meaningful heterogeneity in delirium risk profiles across different surgical types, which may have implications for delirium risk stratification and delirium prevention or treatment.

Immune system activation and cognitive impairment in arterial hypertension.

Chronic arterial hypertension disrupts the integrity of the cerebral microvasculature, doubling the risk of age-related dementia. Despite sufficient antihypertensive therapy, in still a significant proportion of individuals blood pressure lowering alone does not preserve cognitive health. Accumulating evidence highlights the role of inflammatory mechanisms in the pathogenesis of hypertension. In this review, we introduce a temporal framework to explore how early immune system activation and interactions at neurovascular-immune interfaces pave the way to cognitive impairment. The overall paradigm suggests that pro-hypertensive stimuli induce mechanical stress and systemic inflammatory responses that shift peripheral and meningeal immune effector mechanisms towards a pro-inflammatory state. Neurovascular-immune interfaces in the brain include a dysfunctional blood-brain barrier, crossed by peripheral immune cells; the perivascular space, in which macrophages respond to cerebrospinal fluid- and blood-derived immune regulators; and the meningeal immune reservoir, particularly T cells. Immune responses at these interfaces bridge peripheral and neurovascular unit inflammation, directly contributing to impaired brain perfusion, clearance of toxic metabolites and synaptic function. We propose that deep immunophenotyping in biofluids together with advanced neuroimaging could aid in the translational determination of sequential immune and brain endotypes specific to arterial hypertension. This could close knowledge gaps on how and when immune system activation transits into neurovascular dysfunction and cognitive impairment. In the future, targeting specific immune mechanisms could prevent and halt hypertension disease progression before clinical symptoms arise, addressing the need for new interventions against one of the leading threats to cognitive health.

Functional Evaluation of a Novel Homozygous ADCY3 Variant Causing Childhood Obesity

Adenylate cyclase 3 (ADCY3) is a transmembrane protein predominantly expressed in the primary cilia of neurons. It plays a vital role in converting ATP to cAMP, a secondary messenger that regulates various downstream signaling pathways such as carbohydrates and lipids metabolism. Homozygous loss-of-function variants in the ADCY3 gene lead to severe early-onset obesity and insulin resistance whereas gain-of-function variants protect against obesity. To describe a novel pathogenic ADCY3 variant implicated in early-onset obesity and functionally characterize this variant via in vitro and in silico validation, we identified a novel homozygous nonsense variant c.2520C>G, p.Thr840X in the ADCY3 gene using gene panel sequencing in a four-year-old girl. She was born to first-cousin consanguineous parents. The patient presented with severe obesity, and exhibited hepatomegaly and insulin resistance, with other biochemical and hormonal tests being normal. In vitro and in silico functional analyses showed downregulation and impaired activation of the ADCY3 protein. Our findings contribute to existing research that supports the role of ADCY3 in the genetic pathogenesis of early-onset obesity. In vitro and in silico functional characterization of the novel p.Thr840X variant showed impaired enzymatic activity leading to receptor loss of function, consistent with the patient’s phenotype. Genetic testing is essential in severe early-onset obesity and early diagnosis could benefit patients with personalized treatment strategies.

Non-activating ITGB3 mutation in β3 cytoplasmic region causes macrothrombocytopenia with impaired αIIbβ3/RhoA pathway

Almost all mutations of ITGA2B or ITGB3 identified in congenital macrothrombocytopenia induce constitutive activation of αIIbβ3. However, whether concomitant αIIbβ3 activation is essential for macrothrombocytopenia development remains unknown. Recently, we identified the β3(R760C) mutation that does not induce αIIbβ3 activation in a subject with macrothrombocytopenia. The family study showed that macrothrombocytopenia with reduced expression of αIIbβ3 and GPVI appeared to be associated with subjects heterozygous for β3(R760C). We generated β3(R760C) knock-in (KI) mice and investigated the effects of the mutation on platelet/Mgk biology. Macrothrombocytopenia was decreased to 76% and 40% of platelet counts in heterozygous (Hetero) and homozygous (Homo) KI mice, respectively, compared to the wild-type mice. Platelet αIIbβ3 and GPVI expression were decreased in KI mice, and αIIbβ3 activation was not detected on non-stimulated KI platelets. Thus, the Hetero KI mice reproduced the phenotype of the human subject, indicating that the β3(R760C) mutation is responsible for the macrothrombocytopenia. Platelet aggregation, agonist-induced JON/A binding and P-selectin expression were impaired in KI mice. Platelet spreading on fibrinogen was also impaired in Homo mice with ADP or thrombin stimulation. Filopodia and lamellipodia formation was impaired in fibrinogen-adhered megakaryocytes of Homo mice with significantly impaired RhoA activation. Proplatelet formation in Homo mice was impaired with abnormal morphology. In addition, platelet lifespan was shortened in Homo mice. These data indicate that β3(R760C) mutation impairs the inside-out and outside-in signaling of αIIbβ3, and abnormal actin rearrangement and impaired RhoA activation may play major roles in leading to macrothrombocytopenia.

Impact of chronic constipation symptoms on work productivity and daily activity: A large-scale internet survey.

Chronic constipation negatively impacts work productivity and patients' quality of life. This retrospective study assessed the correlation between symptoms of chronic constipation and work/activity impairment with and without the use of laxative treatment. This cross-sectional, observational, web-based survey was conducted using the Work Productivity and Activity Impairment-Chronic Constipation Questionnaire and included Japanese patients with chronic constipation receiving prescribed medication. Outcomes of interest included total work productivity and activity impairment and their correlation with constipation symptoms. Among the 2351 analyzed patients (mean [SD] age, 51.7 [13.8] years), 80.7% were females, 63.3% had a disease duration of ≥10 years, and 1424 were working. The averages of total activity impairment, total work productivity impairment, presenteeism, and absenteeism were 39.2%, 33.9%, 31.2%, and 5.0%, respectively. The annual work productivity loss per patient was estimated to be 1.343 million Japanese Yen. Symptoms that had a statistically significant positive correlation with total work impairment (P < 0.05) were abdominal discomfort/nausea, abdominal pain, abdominal bloating, and unpredictable defecation timing. Total activity impairment was significantly (P < 0.05) affected by abdominal discomfort/nausea, abdominal bloating, abdominal pain, incomplete defecation, unpredictable defecation timing, loss of defecation desire, and straining. Work productivity and daily activity had improved in 71.2% and 72.6% of patients, respectively, after they received treatment. Symptoms of constipation, particularly abdominal symptoms and unpredictable defecation timing, can have a negative impact on work productivity and daily activity. Treatment focused on these symptoms may reduce the socio-economic burden of chronic constipation in Japan.

Dietary Lactate Intake and Physical Exercise Synergistically Reverse Brown Adipose Tissue Whitening to Ameliorate Diet-Induced Obesity.

Physical exercise represents an effective strategy for combating obesity via brown adipose tissue (BAT) activation, but the mechanism remains unclear. In this study, we demonstrated that the cooperation between lactate and adrenoceptor signaling regulated BAT activity during exercise. The lactate receptor GPR81 was highly expressed in the BAT of lean mice, whereas its expression was markedly decreased in obese mice. Notably, the level of GPR81 in BAT could be upregulated by exercise. The blockade of lactate production or GPR81 significantly impaired exercise-induced BAT activation. In addition, dietary lactate intake enhanced the efficacy of physical exercise in alleviating BAT whitening in obese mice, as evidenced by the improved mitochondrial ultrastructure, reduced lipid droplets, increased UCP1 expression, and elevated mitochondrial DNA content. Further data indicated that norepinephrine triggered UCP1 activation through both the cAMP/PKA and Ca2+/CaMK pathways during exercise, while lactate mediated this process via the GPR81-Ca2+/CaMK cascade. Our findings unveil a novel mechanism in the regulation of BAT function by physical exercise, providing a promising lifestyle intervention to improve metabolic health.

Intercalated amygdala dysfunction drives avoidance extinction deficits in the Sapap3 mouse model of obsessive-compulsive disorder

The avoidance of aversive stimuli through negative reinforcement learning is critical for survival in real-world environments, which demand dynamic responding to both positive and negative stimuli that often conflict with each other. Individuals with obsessive-compulsive disorder (OCD) commonly exhibit impaired negative reinforcement and extinction, perhaps involving deficits in amygdala functioning. An amygdala subregion of particular interest is the intercalated nuclei of the amygdala (ITC) which has been linked to negative reinforcement and extinction, with distinct clusters mediating separate aspects of behavior. This study focuses on the dorsal ITC cluster (ITCd) and its role in negative reinforcement during a complex behavior that models real-world dynamic decision making. We investigated the impact of ITCd function on negative reinforcement and extinction by applying fiber photometry measurement of GCamp6f signals and optogenetic manipulations during a platform-mediated avoidance task in a mouse model of OCD-like behavior: the Sapap3-null mouse. We find impaired neural activity in the ITCd of male and female Sapap3-null mice to the encoding of negative stimuli during platform-mediated avoidance. Sapap3-null mice also exhibit deficits in extinction of avoidant behavior, which is modulated by ITCd neural activity. Sapap3-null mice fail to extinguish avoidant behavior in platform-mediated avoidance, due to heightened ITCd activity. This deficit can be rescued by optogenetically inhibiting ITCd during extinction. Together, our results provide insight into the neural mechanisms underpinning negative reinforcement deficits in the context of OCD, emphasizing the necessity of ITCd in responding to negative stimuli in complex environments.

TMED4 facilitates Treg suppressive function via ROS homeostasis in tumor and autoimmune mouse models.

Endoplasmic reticulum stress (ERS) plays crucial roles in maintaining regulatory T cells (Treg) stability and function, yet the underlying mechanism remains largely unexplored. Here we demonstrate that ERS-related protein transmembrane p24 trafficking protein 4 (TMED4) Treg-specific knockout (Tmed4ΔTreg) mice contain more Treg cells with impaired Foxp3 stability, Treg signature and suppressive activity, which leads to T cell hyperactivation, exacerbated inflammatory phenotype and boosted anti-tumor immunity in mice. Mechanistically, loss of Tmed4 causes defects in ERS and nuclear factor erythroid 2-related factor 2 (NRF2)-related antioxidant response, which results in excessive reactive oxygen species (ROS) that reduces Foxp3 stability and suppressive function of Treg cells in an IRE1α-XBP1 axis-dependent manner. The abnormalities can be effectively rescued by ROS scavenger, NRF2 inducer or forcible expression of IRE1α. Moreover, TMED4 suppresses IRE1α proteosome degradation via the ER-associated degradation (ERAD) system including BIP. Our study reveals that TMED4 maintains Treg cell stability and suppressive function through IRE1α-dependent ROS and the NRF2-related antioxidant response.

Comparative cross-sectional study of comorbid depression in patients with irritable bowel syndrome and chronic gastritis at an urban outpatient clinic

This comparative cross-sectional study evaluates the prevalence of comorbid depression in patients with Irritable Bowel Syndrome (IBS) and chronic gastritis (CG) at an urban outpatient clinic. A total of 178 patients—89 diagnosed with IBS and 89 with CG—were assessed for depressive symptoms using the Beck Depression Inventory-II (BDI-II) and the 21-item Hamilton Depression Rating Scale (HDRS-21). Our findings indicate a significantly higher prevalence of depression in IBS patients, with 71.9% meeting criteria for depression based on the BDI-II and 70.8% based on the HDRS-21, compared to 10.1% in CG patients. The study highlights that retardation symptoms, including depressed mood and loss of interest, are central to depression and contribute to substantial impairment in daily activities and quality of life. Additionally, anxiety and somatization were prominent in the IBS cohort. This study emphasizes the need for integrated care approaches that address both gastrointestinal and psychological symptoms, fostering improved patient management and outcomes. Our results underscore the importance of regular psychological assessments in IBS patients, particularly those without overt depressive symptoms, to enhance their overall well-being.

Exploring the Importance of Race and Gender Concordance Between Patients and Physical Therapists in Digital Rehabilitation for Musculoskeletal Conditions: Observational, Longitudinal Study.

Race/ethnicity and gender concordance between patients and providers is a potential strategy to improve health care interventions. In digital health, where human interactions occur both synchronously and asynchronously, the effect of concordance between patients and providers is unknown. This study aimed to evaluate the impact of race/ethnicity or gender concordance between patients and physical therapists (PTs) in engagement and the clinical outcomes following a digital care program (DCP) in patients with musculoskeletal (MSK) conditions. This secondary analysis of 2 prospective longitudinal studies (originally focused on assessing the acceptance, engagement, and clinical outcomes after a remote DCP) examined the impact of both race/ethnicity concordance and gender concordance between patients and PTs on outcomes for a digital intervention for MSK conditions. Outcomes included engagement (measured by the completion rate and communication, assessed by text interactions), satisfaction, and clinical outcomes (response rate, ie, percentage of patients achieving at least a minimal clinically important change in pain, measured by the Numerical Pain Rating Scale [NPRS]; anxiety, measured by the Generalized Anxiety Disorder 7-item scale [GAD-7]; depression, measured by the Patient Health Questionnaire 9-item [PHQ-9]; and daily activity impairment, measured by the Work Productivity and Activity Impairment [WPAI] questionnaire). Of 71,201 patients, 63.9% (n=45,507) were matched with their PT in terms of race/ethnicity, while 61.2% (n=43,560) were matched for gender. Concordant dyads showed a higher completion rate among White (adjusted odds ratio [aOR] 1.11, 95% CI 1.05-1.19, P<.001) and Hispanic (aOR 1.27, 95% CI 1.08-1.54, P=.009) groups, as well as women (aOR 1.10, 95% CI 1.06-1.18, P<.001), when compared to discordant dyads. High and similar levels of interaction between patients and PTs were observed across race/ethnicity and gender dyads, except for Asian concordant dyads (adjusted β coefficient 5.32, 95% CI 3.28-7.36, P<.001). Concordance did not affect satisfaction, with high values (>8.52, 95% CI 8.27-8.77) reported across all dyads. Response rates for pain, anxiety, and daily activity impairment were unaffected by race/ethnicity concordance. An exception was observed for depression, with White patients reporting a higher response rate when matched with PTs from other races/ethnicities (aOR 1.20, 95% CI 1.02-1.39, P=.02). In terms of gender, men had a slightly higher pain response rate in discordant dyads (aOR 1.08, 95% CI 1.01-1.15, P=.03) and a higher depression response rate in concordant dyads (aOR 1.23, 95% CI 1.05-1.47, P=.01). Race/ethnicity and gender concordance between patients and PTs does not translate into higher satisfaction or improvement for most clinical outcomes, aside from a positive effect on treatment completion. These results highlight the importance of other PT characteristics, in addition to race/ethnicity or gender concordance, suggesting the potential benefit of experience, languages spoken, and cultural safety training as ways to optimize care. ClinicalTrials.gov NCT04092946, NCT05417685; https://clinicaltrials.gov/study/NCT05417685, https://clinicaltrials.gov/study/NCT04092946.

TRPV4—A Multifunctional Cellular Sensor Protein with Therapeutic Potential

Transient receptor potential vanilloid (TRPV) channel proteins belong to the superfamily of TRP proteins that form cationic channels in the animal cell membranes. These proteins have various subtype-specific functions, serving, for example, as sensors for pain, pressure, pH, and mechanical extracellular stimuli. The sensing of extracellular cues by TRPV4 triggers Ca2+-influx through the channel, subsequently coordinating numerous intracellular signaling cascades in a spatio-temporal manner. As TRPV channels play such a wide role in various cellular and physiological functions, loss or impaired TRPV protein activity naturally contributes to many pathophysiological processes. This review concentrates on the known functions of TRPV4 sensor proteins and their potential as a therapeutic target.

The endoplasmic reticulum protein HSPA5/BiP is essential for decidual transformation of human endometrial stromal cells

Decidualization denotes the process of inflammatory reprogramming of endometrial stromal cells (EnSC) into specialized decidual cells (DC). During this process, EnSC are subjected to endoplasmic reticulum (ER) stress as well as acute cellular senescence. Both processes contribute to the proinflammatory mid-luteal implantation window and their dysregulation has been implicated in reproductive failure. Here, we evaluated the link between ER stress, decidual differentiation and senescence. In-silico analysis identified HSPA5 gene, codifying the ER chaperone BiP, as a potentially critical regulator of cell fate divergence of decidualizing EnSC into anti-inflammatory DC and pro-inflammatory senescent decidual cells (snDC). Knockdown of HSPA5 in primary EnSC resulted both in decreased expression of DC marker genes and attenuated induction of senescence associated β-galactosidase activity, a marker of snDC. Stalling of the decidual reaction upon HSPA5 knockdown was apparent at 8 days of differentiation and was preceded by the upregulation of ER stress associated proteins IRE1α and PERK. Further, HSPA5 knockdown impaired colony-forming unit activity of primary EnSC, indicative of loss of cellular plasticity. Together, our results point to a key role for HSPA5/BiP in decidual transformation of EnSCs and highlight the importance of constraining ER stress levels during this process.

Multi-dimensional assessment of long-term outcomes in patients treated with extracorporeal cardiopulmonary resuscitation during refractory cardiac arrest

Abstract Background Recent randomised controlled trials showed short-term survival benefits with extracorporeal cardiopulmonary resuscitation (ECPR) compared to standard cardiac arrest treatment in selected patients with refractory cardiac arrest. Only limited data exist on multi-dimensional long-term outcomes after ECPR. Purpose To investigate multi-dimensional long-term outcomes of ECPR survivors, that is general health status, as well as cardiac, cognitive and psychological functions. Methods This is a multicenter, mixed-method clinical study conducted by cardiologists, neurologists and psychologists between May 2021 and December 2023. Adult patients who survived ECPR with veno-arterial extracorporeal membrane oxygenation (VA-ECMO) or "ECMELLA" (i.e., VA-ECMO plus percutaneous left-ventricular assist device) in two German tertiary care centers were included. A comprehensive set of functional outcomes across multiple dimensions were assessed at approximately 18 months after the index cardiac arrest event (see Figure for stations A to E and explanation of abbreviations). Results Long-term outcomes were assessed in 32 ECPR survivors, out of whom 15 patients (46%) had received VA-ECMO and 18 (54%) ECMELLA treatment. 23 patients (70%) were male and the average age was 55 years (±13). Vital signs and laboratory markers were unremarkable. Most patients denied heart failure symptoms although the average EQ-5D-5L score was 52 (±8). The left-ventricular ejection fraction was 51% (±9), which improved by 14% (±11) in the ECMO group and 31% (±15) in the ECMELLA group since the index cardiac arrest event. Bicycle exercise (on average 6 minutes duration with a power of up to 100 Watts) and 6-minute walk test (average distance of 394 meters ±145) revealed physical impairments. 29 patients (88%) had a good cerebral performance (i.e., Cerebral Performance Category scale of 1) and the average mental status was good (mini–mental state examination score 29 ±1). 22 patients (56%) perceived (partial) impairments in activities of daily living although the average Barthel index was 100 (±5) and modified Rankin scale was 1 (±1). 12 patients (36%) were unable to return to their jobs. Remarkably, 17 (51%) and 4 (12%) patients reported depressive symptoms and suicidal thoughts, respectively. Conclusion Although ECPR remains a highly complex procedure, cardiac and neurologic functions in survivors have almost recovered, while physical and psychological impairments still persisted at 18 months after cardiac arrest. Physical rehabilitation and psychological care appear to be important measures for ECPR survivors.

Association of Workplace Toilet Access with Urinary Tract Symptoms and Productivity Loss among Female

Abstract Purpose Lower urinary tract symptoms (LUTS) are prevalent among women, affecting not only their physical well-being but also their quality of working life. We investigate workplace toilet access related to LUTS among women in the Korean workforce. Materials and methods An online survey was conducted to determine the demographic characteristics, occupational risk factors, and urinary tract symptoms among employed Korean women. Occupational risk factors included three survey questions on access to toilets at work: A) enduring urinary symptoms at work; B) capability to use the toilet at will during work, and C) needing to use the toilet during work but were unable to. The LUTS were assessed using the overactive bladder symptom score (OABSS) and international consultation on incontinence questionnaire-urinary incontinence short form (ICIQ-SF). Health-related productivity losses (HRPL) were estimated using the work productivity and activity impairment (WPAI) questionnaire for urinary symptoms. Multiple logistic regression was used to determined the association between workplace toilet access and LUTS. In addition, generalised linear regression analysis was performed to assess HRPL according to workplace toilet access. Results Of the 1057 participants, 260 (24.6%) and 294 (27.81%) had overactive bladder and urinary incontinence, respectively. More than 50% reported poor access to toilet. Multiple logistic regression analysis showed that the lower the access to toilets in the workplace, the higher the incidence of LUTS and the higher HRPL. Conclusions Restricted access to toilets at work are associated with poor urinary health and loss of productivity. The results highlight the need for interventions to improve the workplace environment. Key messages • Restricted access to toilets at work are associated with poor urinary health and loss of productivity. • The results highlight the need for interventions to improve the workplace environment.

The clinical characteristics and prognosis of patients with acute non-ST-segment elevation myocardial infarction complicated with impaired activity daily living

Abstract Background Impaired activities of daily living (ADL) have been identified as an independent risk factor for cardiovascular diseases. This study aims to describe the clinical characteristics, treatment modalities, and prognosis of acute non-ST-segment elevation myocardial infarction (NSTEMI) patients with impaired ADL. Methods The data for this study were derived from a Health and Medical Big Data Superplatform, comprising a retrospective cohort of patients admitted to and discharged from 72 secondary and tertiary hospitals from 2010 to 2023. The inclusion criteria encompassed patients with a discharge diagnosis of NSTEMI.ADL prior to NSTEMI was evaluated using the Barthel index(BI),a widely used assessment tool for evaluating ADL.The patients' BI were obtained from patients’ resident health records, and patients were categorized into two groups: ADL normal and ADL impaired group. A comparative analysis was conducted between the two groups regarding clinical characteristics, treatment regimens, and prognosis. Results The study included 28,227 NSTEMI patients with normal ADL and 1,576 NSTEMI patients with impaired ADL. Baseline data revealed that the ADL impaired group had a higher proportion of females (49.4% vs. 43.2%, p &amp;lt; 0.001), older age (77.0 [69.0, 83.0] vs. 71.0 [66.0, 78.0], p &amp;lt; 0.001), and a higher proportion of patients with KILLIP III and above (25.86% vs. 17.44%, p &amp;lt; 0.001). Additionally, the ADL impaired group had a greater number of pre-existing comorbidities. Regarding treatment, the proportion of patients undergoing percutaneous coronary intervention (PCI) was significantly lower in the ADL impaired group (16.5% vs. 65.3%, p &amp;lt; 0.001). Moreover, the ADL impaired group showed lower utilization rates of antiplatelet agents, ACEI/ARBs, beta-blockers, ARNI, statins, and nitrates, while the utilization rates of diuretics and cardiac glycosides were higher. In terms of prognosis, the ADL impaired group exhibited a higher in-hospital mortality rate (6.03% vs. 3.35%, p &amp;lt; 0.001). During a median follow-up period of 876 days, the ADL impaired group had significantly higher rates of all-cause mortality (61.2% vs. 35.9%, p &amp;lt; 0.001) and cardiovascular mortality (41.8% vs. 24.8%, p &amp;lt; 0.001), while the rate of revascularization (6.69% vs. 9.20%, p = 0.008) was lower. There were no significant differences in the risks of recurrent non-fatal myocardial infarction (10.7% vs. 10.8%, p = 0.935), recurrent stroke (10.90% vs. 9.48%, p = 0.08), and hemorrhagic stroke (0.82% vs. 0.74%, p = 0.806). Following adjustment for age, gender, KILLIP classification, medical history, and treatment strategies in a multivariable Cox regression analysis, impaired ADL remained an independent risk factor for increased all-cause mortality (aHR 1.167, 95%CI: 1.091-1.249, p &amp;lt; 0.001). Conclusions The decline in ADL is significantly associated with adverse clinical outcomes among NSTEMI patients.Baseline characteristics of patientsMedications of patients

Substantial morbidity and mortality due to cardiovascular diseases in hospitalized vaccinated and un-vaccinated patients with COVID-19 from 16 countries: the WHF COVID-19 Long-term study

Abstract Background Long-term adverse consequences of the COVID-19 affect many organ systems, and this requires the identification and appropriate care of diverse symptoms. Purpose The World Heart Federation (WHF) international study describes the burden of clinical sequelae of COVID-19 up to 1 year after hospitalization, including patients from low- middle-and high-income countries. Methods We prospectively recruited patients hospitalized due to COVID-19 from 16 countries between January 2022 and June 2023. Patients were followed up at 1, 3, 6, and 9-12 months after hospital discharge. A standardized questionnaire administered by telephone collected data on long COVID symptoms, quality of life using the EuroQol 5 Dimension scale (EQ-5D), and disease outcomes including new onset diabetes and hypertension, major adverse cardiovascular events (MACE), and mortality. We report a descriptive analysis including demographic characteristics and outcomes up to one year after initial hospitalization. Results Of 2504 patients, the majority were Asian (78%), and male (56%). Mean age was 59.2 years (SD 19.9). Low- and lower-middle-income country participants constituted 65% of the cohort, with upper middle-income and high-income representing 20% and 15%, respectively. Follow-up rate was complete for 86%. 55% had received at least two doses of COVID-19 vaccination. At 1 month, 63% reported at least one persistent symptom, which decreased to 28% at 9-12 months. Fatigue was reported by 45% at 1-month and 17% at final follow-up. Anxiety occurred in 20% and 9% at these respective timepoints, and breathlessness in 12% and 6%. At 9-12 months, moderate to severe impairment of usual activities as measured by EQ-5D occurred in 19%, anxiety/depression in 10%, and mobility problems in 10%. The most frequent post-discharge new-onset illnesses were pulmonary embolism (7%), kidney problems (4%), and hypertension (3%). In-hospital mortality was 4% (n=102), and a further 12% (265 patients) died by one-year. The most common cause was sudden cardiac death (59%), respiratory disease including pulmonary embolism (13%), and stroke (6%). Conclusions We observed a significant burden of post-COVID-19 complications with one fifth of patients with persistent difficulties in usual activities at one year. This underscores the urgent need to understand the underlying mechanisms for organ damage and death, and for targeted preventive strategies and proactive management approaches to reduce them.

The H222P-Lamin mutation induces heart failure via impaired mitochondrial calcium uptake in human cardiac laminopathy

Abstract Background Mutations in LMNA gene, which encodes lamins A/C, cause a variety of diseases, called laminopathies. Some mutations are particularly associated with the occurrence of dilated cardiomyopathy. The pathological mechanisms are still unclear limiting the development of specific therapies. Purpose Here, we focused on a mutation in the LMNA gene (c.665A&amp;gt;C, p.His222Pro), associated with the Emery-Dreyfuss Muscular dystrophy. We used LMNA H222P mutant human induced pluripotent stem cells (hiPSCs) and CRISPR/Cas9 corrected isogenic control hiPSCs to better characterize the cardiac phenotype associated with the mutation. Methods LMNA H222P mutant and the isogenic control hiPSCs clones were differentiated into cardiomyocytes (CMs). Immunofluorescence staining was performed on hiPSC-CMs to quantify their sarcomere organization (SarcOrgScore) using a Matlab code. Ring-shaped cardiac organoids were generated to compare the contractile properties of the two clones. Calcium transients in mutant and corrected hiPSC-CMs were measured by live confocal imaging. Mitochondrial respiration was measured by Seahorse. Results hiPSC-CMs were generated from the LMNA H222P mutant and the corrected hiPSCs with no difference in the differentiation yield (proportion of troponin-positive cells: 92.74% for LMNA H222P vs. 89.38% for Ctrl-iso1, p=0.1038). The nuclei of LMNA H222P mutant hiPSC-CMs showed morphological abnormalities, typically observed with Lamin A/C mutations. hiPSC-CMs displayed well-formed sarcomeres and their organization was similar between the two cell lines. However, 3D cardiac organoids generated with LMNA H222P hiPSC-CMs showed an impaired contractility compared to control organoids. Calcium transient recordings in LMNA H222P mutant hiPSC-CMs showed a significantly higher calcium transient amplitude with a significantly slower calcium re-uptake. Transcriptomic analyses suggested a global mitochondrial dysfunction and in particular an impaired mitochondrial calcium uptake with a significantly decreased expression of the mitochondrial calcium uniporter (MCU). This decrease in MCU expression was confirmed by Western blot and was accompanied by an increased MICU1 : MCU ratio, as well as an increased PDH Ser232 and Ser300 phosphorylation, indicating a decreased mitochondrial calcium uptake in the LMNA H222P mutant hiPSC-CMs. Finally, measurement of mitochondrial respiration using Seahorse showed lower basal and maximal respiration in LMNA H222P hiPSC-CMs. Conclusions LMNA H222P mutant hiPSC-CMs exhibit contractile dysfunction associated with mitochondrial dysfunction with impaired MCU complex activity, decreased mitochondrial calcium homeostasis, and reduced mitochondrial energy production.

Perfusion metabolism mismatch predicts short-term complications in Takotsubo syndrome

Abstract Background Takotsubo syndrome (TTS) is a transient cardiac condition triggered by sudden emotional or physical stress characterized by LV dysfunction in the absence of obstructive epicardial coronary artery disease. 123I-BMIPP, an iodinated fatty acid analogue, can identify impaired myocardial metabolic activity. With the use of dual SPECT protocol, reduced uptake of 123I-BMIPP compared to perfusion which is called perfusion-metabolic mismatch is observed in apical regions in TTS. The mismatch may indicate jeopardized but viable myocardium, reflecting transient ischemic damage or metabolically stunned myocardium. However, the association between the perfusion metabolism mismatch in TTS and its complications remains underexplored. Purpose Our study aimed to analyze the degree of perfusion metabolism mismatch at the acute phase in TTS and investigate its association with short-term complications. Methods This retrospective study conducted between 2012 and 2024 at a single center included 82 patients diagnosed with TTS. Patients underwent dual SPECT imaging using 99mTc or 201 Tl and 123I-BMIPP within two weeks of admission. We applied quantitative analysis using QGS/QPS software from Cedars-Sinai. Total perfusion deficit ("TPD") was calculated based on sex-matched normal limits providing the extent of perfusion abnormality. Meanwhile, perfusion-metabolism mismatch scores ("worsen") were determined by comparing the total BMIPP counts to the total counts of perfusion. We then assessed the correlation of these imaging findings with biomarkers, regional wall motion abnormalities, and the occurrence of short-term complications. Short-term complications included heart failure, left ventricular outflow (LVOT) obstruction, mitral regurgitation, cardiac arrhythmia, cardiogenic shock, left ventricle (LV) rupture, and cardiac death during the hospitalization period. Results All study patients exhibited wall motion abnormalities seen in apical segments. The count of myocardial segments with regional wall motion abnormality was correlated with both TPD (r=0.34, p=0.002) and perfusion metabolic mismatch score (r=0.40, p&amp;lt;0.001). TPD had a moderate correlation coefficient with max CK-MB (r=0.44, p&amp;lt;0.001) and troponin T (r=0.40, p&amp;lt;0.001) levels. However, perfusion metabolic mismatch did not display correlations with max CK-MB (r=0.05, p=0.65), and Troponin T (r=0.12, p=0.28) levels. Among 82 patients, 37 patients experienced any short-term complications. Importantly, patients with short-term complications had elevated perfusion mismatch scores compared to those without short-term complications (14.0 [6.0-22.5] vs. 5.0 [3.0-10.0], p&amp;lt;0.001). However, no significant difference was observed in TPD between the two groups (9.0 [4.5-20.0] vs. 7.0 [3.0-12.0], p=0.130). Conclusions Our research highlights a significant association between perfusion-metabolism mismatch and an increased risk for short-term complications in patients with Takotsubo syndrome.