Mice lacking MBNL1 and MBNL2 exhibit sudden cardiac death and molecular signatures recapitulating myotonic dystrophy.

Myotonic dystrophy (DM) is caused by expansions of C(C)TG repeats in the non-coding regions of the DMPK and CNBP genes, and DM patients often suffer from sudden cardiac death due to lethal conduction block or arrhythmia. Specific molecular changes that underlie DM cardiac pathology have been linked to repeat-associated depletion of Muscleblind-like (MBNL) 1 and 2 proteins and upregulation of CUGBP, Elav-like family member 1 (CELF1). Hypothesis solely targeting MBNL1 or CELF1 pathways that could address all the consequences of repeat expansion in heart remained inconclusive, particularly when the direct cause of mortality and results of transcriptome analyses remained undetermined in Mbnl compound knockout (KO) mice with cardiac phenotypes. Here, we develop Myh6-Cre double KO (DKO) (Mbnl1-/-; Mbnl2cond/cond; Myh6-Cre+/-) mice to eliminate Mbnl1/2 in cardiomyocytes and observe spontaneous lethal cardiac events under no anesthesia. RNA sequencing recapitulates DM heart spliceopathy and shows gene expression changes that were previously undescribed in DM heart studies. Notably, immunoblotting reveals a nearly 6-fold increase of Calsequestrin 1 and 50% reduction of epidermal growth factor proteins. Our findings demonstrate that complete ablation of MBNL1/2 in cardiomyocytes is essential for generating sudden death due to lethal cardiac rhythms and reveal potential mechanisms for DM heart pathogenesis.

Treating heart failure by targeting the vagus nerve.

Increased sympathetic and reduced parasympathetic nerve activity is associated with disease progression and poor outcomes in patients with chronic heart failure. The demonstration that markers of autonomic imbalance and vagal dysfunction, such as reduced heart rate variability and baroreflex sensitivity, hold prognostic value in patients with chronic heart failure despite modern therapies encourages the research for neuromodulation strategies targeting the vagus nerve. However, the approaches tested so far have yielded inconclusive results. This review aims to summarize the current knowledge about the role of the parasympathetic nervous system in chronic heart failure, describing the pathophysiological background, the methods of assessment, and the rationale, limits, and future perspectives of parasympathetic stimulation either by drugs or bioelectronic devices.

Ovulation-induced frozen embryo transfer regimens in women with polycystic ovary syndrome: a systematic review and meta-analysis.

PURPOSE: To evaluate whether the type of frozen embryo transfer (FET) regimen - ovulation-induced regimens vs. hormone replacement therapy regimens (HRT) - is associated with live birth rates and the risk of hypertensive diseases of pregnancy (HDP) in women with polycystic ovary syndrome (PCOS). METHODS: All studies in PubMed, Embase, Web of Science, Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov were searched using a combination of MeSH terms and keywords. Inclusion criteria included studies on women with a diagnosis of PCOS, utilization of FET, and reporting of pregnancy and/or obstetric outcomes. Studies were excluded if they were case series or conference abstracts or used other FET regimens. A random effects meta-analysis was performed. Primary outcomes include relative risk (RR) of live birth and HDP. RESULTS: Eleven studies were included in the meta-analysis for the final review. Ovulation-induced regimens were associated with a higher live birth rate (8 studies, RR 1.14 [95% CI 1.08, 1.21]) compared to HRT regimens. The risk of HDP (3 studies RR 0.78 [95% CI 0.53, 1.15]) was not significantly different. Ovulation-induced regimens were associated with a lower miscarriage rate (9 studies, RR 0.67 [95% CI 0.59-0.76]). Rates of clinical pregnancy (10 studies, RR 1.05 [95% CI 0.99, 1.11]) and ectopic pregnancy (7 studies, RR 1.40 [95% CI 0.84, 2.33]), were not significantly different. CONCLUSION: This SR/MA demonstrates that for women with PCOS, ovulation-induced FET regimens are associated with higher rates of live birth and lower rates of miscarriage compared to HRT regimens.

Muscleblind-like 2 knockout shifts adducin 1 isoform expression and alters dendritic spine dynamics of cortical neurons during brain development.

AIMS: Muscleblind-like 2 (MBNL2) plays a crucial role in regulating alternative splicing during development and mouse loss of MBNL2 recapitulates brain phenotypes in myotonic dystrophy (DM). However, the mechanisms underlying DM neuropathogenesis during brain development remain unclear. In this study, we aim to investigate the impact of MBNL2 elimination on neuronal development by Mbnl2 conditional knockout (CKO) mouse models. METHODS: To create Mbnl2 knockout neurons, cDNA encoding Cre-recombinase was delivered into neural progenitors of Mbnl2flox/flox mouse brains by in utero electroporation. The morphologies and dynamics of dendritic spines were monitored by confocal and two-photon microscopy in brain slices and live animals from the neonatal period into adulthood. To investigate the underlying molecular mechanism, we further detected the changes in the splicing and molecular interactions of proteins associated with spinogenesis. RESULTS: We found that Mbnl2 knockout in cortical neurons decreased dendritic spine density and dynamics in adolescent mice. Mbnl2 ablation caused the adducin 1 (ADD1) isoform to switch from adult to fetal with a frameshift, and the truncated ADD1 failed to interact with alpha-II spectrin (SPTAN1), a critical protein for spinogenesis. In addition, expression of ADD1 adult isoform compensated for the reduced dendritic spine density in cortical neurons deprived of MBNL2. CONCLUSION: MBNL2 plays a critical role in maintaining the dynamics and homeostasis of dendritic spines in the developing brain. Mis-splicing of downstream ADD1 may account for the alterations and contribute to the DM brain pathogenesis.

Shortened neural conduction time in young adults with tinnitus as revealed by chirp-evoked auditory brainstem response.

Tinnitus is generally considered to be caused by neuroplastic changes in the central nervous system, triggered by a loss of input from the damaged peripheral system; however, conflicting results on auditory brainstem responses (ABRs) to clicks have been reported previously in humans with tinnitus. This study aimed to compare the effect of tinnitus on ABRs to chirps with those to clicks in normal-hearing young adults with tinnitus. The results showed that the tinnitus group had no significantly poorer hearing thresholds (0.25-16 kHz), click-evoked otoacoustic emissions (1-16 kHz), and speech perception in noise (SPIN) than the control group. Although chirps evoked significantly larger wave I and V amplitudes than clicks, people with tinnitus had no significantly smaller wave I amplitudes for either stimulus. Nevertheless, adults with tinnitus exhibited significantly smaller interpeak interval (IPI) between waves I and V for chirps (IPI-chirp) but not for clicks. In addition, the IPI-chirp correlated significantly with the SPIN for individuals with tinnitus when the signal-to-noise ratio was low. The present results suggest that the chirp-evoked ABR may be a valuable clinical tool for objectively assessing the SPIN in individuals with tinnitus. Further studies should be conducted to investigate possible etiologies of tinnitus.

Evaluating auditory brainstem response to a level-dependent chirp designed based on derived-band latencies.

The best cochlear-neural delay model for designing a chirp that can produce the largest auditory brainstem response (ABR) has not been established. This study comprised two experiments. Experiment I aimed to estimate the delay model by measuring derived-band ABR latencies at different levels. The results demonstrated that, as the level decreased, the delay between the center frequencies of 0.7 and 5.7 kHz increased. The aim of experiment II was to compare ABRs generated by three stimuli: (1) a level-dependent derived-band (DB)-Chirp, designed based on the model in experiment I; (2) a level-dependent level specific (LS)-Chirp from Kristensen and Elberling [(2012). J. Am. Acad. Audiol. 23, 712-721]; and (3) a click. The results demonstrated that the DB-Chirp produced significantly larger wave V than the LS-Chirp at 45 dB normal hearing level (nHL); however, no differences were observed at other levels. The wave I generated by the DB-Chirp and LS-Chirp were significantly larger than those evoked by the click at 45 and 60 dB nHL and at 30 and 45 dB nHL, respectively; however, at all levels, no differences between these two chirps were observed. The DB-Chirp may be a valuable stimulus for producing ABRs for clinical applications such as assessing cochlear synaptopathy and estimating hearing sensitivity.

DEAD-Box RNA Helicase 42 Plays a Critical Role in Pre-mRNA Splicing under Cold Stress.

Low temperature is an important environmental stress that adversely affects rice (Oryza sativa) growth and productivity. Splicing of pre-mRNA is a crucial posttranscriptional regulatory step in gene expression in plants and is sensitive to temperature. DEAD-box RNA helicases belong to an RNA helicase family involved in the rearrangement of ribonucleoprotein complexes and the modification of RNA structure and are therefore involved in all aspects of RNA metabolism. In this study, we demonstrate that the rate of pre-mRNA splicing is reduced in rice at low temperatures and that the DEAD-box RNA Helicase42 (OsRH42) is necessary to support effective splicing of pre-mRNA during mRNA maturation at low temperatures. OsRH42 expression is tightly coupled to temperature fluctuation, and OsRH42 is localized in the splicing speckles and interacts directly with U2 small nuclear RNA. Retarded pre-mRNA splicing and plant growth defects were exhibited by OsRH42-knockdown transgenic lines at low temperatures, thus indicating that OsRH42 performs an essential role in ensuring accurate pre-mRNA splicing and normal plant growth under low ambient temperature. Unexpectedly, our results show that OsRH42 overexpression significantly disrupts the pre-mRNA splicing pathway, causing retarded plant growth and reducing plant cold tolerance. Combined, these results indicate that accurate control of OsRH42 homeostasis is essential for rice plants to respond to changes in ambient temperature. In addition, our study presents the molecular mechanism of DEAD-box RNA helicase function in pre-mRNA splicing, which is required for adaptation to cold stress in rice.

Deficiency of lrp4 in zebrafish and human LRP4 mutation induce aberrant activation of Jagged-Notch signaling in fin and limb development.

Low-density lipoprotein receptor-related protein 4 (LRP4) is a multi-functional protein implicated in bone, kidney and neurological diseases including Cenani-Lenz syndactyly (CLS), sclerosteosis, osteoporosis, congenital myasthenic syndrome and myasthenia gravis. Why different LRP4 mutation alleles cause distinct and even contrasting disease phenotypes remain unclear. Herein, we utilized the zebrafish model to search for pathways affected by a deficiency of LRP4. The lrp4 knockdown in zebrafish embryos exhibits cyst formations at fin structures and the caudal vein plexus, malformed pectoral fins, defective bone formation and compromised kidney morphogenesis; which partially phenocopied the human LRP4 mutations and were reminiscent of phenotypes resulting form a perturbed Notch signaling pathway. We discovered that the Lrp4-deficient zebrafish manifested increased Notch outputs in addition to enhanced Wnt signaling, with the expression of Notch ligand jagged1b being significantly elevated at the fin structures. To examine conservatism of signaling mechanisms, the effect of LRP4 missense mutations and siRNA knockdowns, including a novel missense mutation c.1117C > T (p.R373W) of LRP4, were tested in mammalian kidney and osteoblast cells. The results showed that LRP4 suppressed both Wnt/ß-Catenin and Notch signaling pathways, and these activities were perturbed either by LRP4 missense mutations or by a knockdown of LRP4. Our finding underscore that LRP4 is required for limiting Jagged-Notch signaling throughout the fin/limb and kidney development, whose perturbation representing a novel mechanism for LRP4-related diseases. Moreover, our study reveals an evolutionarily conserved relationship between LRP4 and Jagged-Notch signaling, which may shed light on how the Notch signaling is fine-tuned during fin/limb development.

Effect of referral systems on costs and outcomes after hip fracture surgery in Taiwan.

OBJECTIVE: To explore the economic burdens of hip fracture surgery in patients referred to lower-level medical institutions and to evaluate how referral systems affect costs and outcomes of hip fracture surgery. DESIGN: A nationwide population-based retrospective cohort study. SETTING: All hospitals in Taiwan. PARTICIPANTS: A total of 7500 patients who had received hip fracture surgery (International Classification of Disease, 9th Revision, Clinical Modification (ICD-9-CM) diagnostic codes 820.0 ∼ 820.9 and procedure codes 79.15, 79.35, 81.52, 81.53) performed in 1997 to 2013. MAIN OUTCOME MEASURES: Total costs including outpatient costs, inpatient costs and total medical costs and medical outcomes including 30-day readmission, 90-day readmission, infection, dislocation, revision and mortality. RESULTS: The patients were referred to a lower medical institution after hip fracture surgery (downward referral group) and 3034 patients continued treatment at the same medical institution (non-referral group). Demographic characteristics, clinical characteristics and institutional characteristics were significantly associated with postoperative costs and outcomes (P < 0.05). On average, the annual healthcare cost was New Taiwan Dollars (NT$)2262 per patient lower in the downward referral group compared with the non-referral group. The annual economic burdens of the downward referral group approximated NT$241 million (2019 exchange rate, NT$30.5 = US$1). CONCLUSIONS: Postoperative costs and outcomes of hip fracture surgery are related not only to demographic and clinical characteristics, but also to institutional characteristics. The advantages of downward referral after hip fracture surgery can save huge medical costs and provide a useful reference for healthcare authorities when drafting policies for the referral system.

Artificial Neural Network and Cox Regression Models for Predicting Mortality after Hip Fracture Surgery: A Population-Based Comparison.

This study purposed to validate the accuracy of an artificial neural network (ANN) model for predicting the mortality after hip fracture surgery during the study period, and to compare performance indices between the ANN model and a Cox regression model. A total of 10,534 hip fracture surgery patients during 1996-2010 were recruited in the study. Three datasets were used: a training dataset (n = 7,374) was used for model development, a testing dataset (n = 1,580) was used for internal validation, and a validation dataset (1580) was used for external validation. Global sensitivity analysis also was performed to evaluate the relative importances of input predictors in the ANN model. Mortality after hip fracture surgery was significantly associated with referral system, age, gender, urbanization of residence area, socioeconomic status, Charlson comorbidity index (CCI) score, intracapsular fracture, hospital volume, and surgeon volume (p < 0.05). For predicting mortality after hip fracture surgery, the ANN model had higher prediction accuracy and overall performance indices compared to the Cox model. Global sensitivity analysis of the ANN model showed that the referral to lower-level medical institutions was the most important variable affecting mortality, followed by surgeon volume, hospital volume, and CCI score. Compared with the Cox regression model, the ANN model was more accurate in predicting postoperative mortality after a hip fracture. The forecasting predictors associated with postoperative mortality identified in this study can also bae used to educate candidates for hip fracture surgery with respect to the course of recovery and health outcomes.

Hinokitiol suppresses growth of B16 melanoma by activating ERK/MKP3/proteosome pathway to downregulate survivin expression.

Metastasis is the major cause of treatment failure in patients with cancer. Hinokitiol, a metal chelator derived from natural plants, has anti-inflammatory and antioxidant activities as well as anticancer effects. We investigated the potential anticancer effects of hinokitiol in metastatic melanoma cell line B16-F10. Exposure of the melanoma B16-F10 cells to hinokitiol significantly inhibited colony formation and cell viability in a time and concentration-dependent manner. The hinokitiol-treated cells exhibited apoptotic features in morphological assay. Results from Western blot and immunoprecipitation showed that hinokitiol treatment decreased survivin protein levels and increased suvivin ubiquitination. Pretreatment with proteosome inhibitors effectively prevented hinokitiol-induced decrease in survivin expression, implying that ubiquitin/proteosome pathway involved in hinokitiol-reduced survivin expression. Hinokitiol rapidly induced ERK phosphorylation followed by a sustained dephosphorylation, which accompanied with an increase in expression of tumor suppressor MKP-3 (mitogen-activated protein kinase phosphatase-3). Inhibition of hinokitiol-induced ERK activation by MEK inhibitor U0126 completely blocked expression of MKP-3. More importantly, inhibition of MKP-3 activity by NSC 95397 significantly inhibited hinokitiol-induced ERK dephosphorylation, ubiquitination and downregulation of survivin. These results suggested that hinokitiol inhibited growth of B16-F10 melanoma through downregulation of survivin by activating ERK/MKP-3/proteosome pathway. Hinokitiol-inhibition of survivin may be a novel and potential approach for melanoma therapy. Hinokitiol can be useful for developing therapeutic agent for melanoma.

Two highly similar DEAD box proteins, OsRH2 and OsRH34, homologous to eukaryotic initiation factor 4AIII, play roles of the exon junction complex in regulating growth and development in rice.

BACKGROUND: The exon junction complex (EJC), which contains four core components, eukaryotic initiation factor 4AIII (eIF4AIII), MAGO/NASHI (MAGO), Y14/Tsunagi/RNA-binding protein 8A, and Barentsz/Metastatic lymph node 51, is formed in both nucleus and cytoplasm, and plays important roles in gene expression. Genes encoding core EJC components have been found in plants, including rice. Currently, the functional characterizations of MAGO and Y14 homologs have been demonstrated in rice. However, it is still unknown whether eIF4AIII is essential for the functional EJC in rice. RESULTS: This study investigated two DEAD box RNA helicases, OsRH2 and OsRH34, which are homologous to eIF4AIII, in rice. Amino acid sequence analysis indicated that OsRH2 and OsRH34 had 99 % identity and 100 % similarity, and their gene expression patterns were similar in various rice tissues, but the level of OsRH2 mRNA was about 58-fold higher than that of OsRH34 mRNA in seedlings. From bimolecular fluorescence complementation results, OsRH2 and OsRH34 interacted physically with OsMAGO1 and OsY14b, respectively, which indicated that both of OsRH2 and OsRH34 were core components of the EJC in rice. To study the biological roles of OsRH2 and OsRH34 in rice, transgenic rice plants were generated by RNA interference. The phenotypes of three independent OsRH2 and OsRH34 double-knockdown transgenic lines included dwarfism, a short internode distance, reproductive delay, defective embryonic development, and a low seed setting rate. These phenotypes resembled those of mutants with gibberellin-related developmental defects. In addition, the OsRH2 and OsRH34 double-knockdown transgenic lines exhibited the accumulation of unspliced rice UNDEVELOPED TAPETUM 1 mRNA. CONCLUSIONS: Rice contains two eIF4AIII paralogous genes, OsRH2 and OsRH34. The abundance of OsRH2 mRNA was about 58-fold higher than that of OsRH34 mRNA in seedlings, suggesting that the OsRH2 is major eIF4AIII in rice. Both OsRH2 and OsRH34 are core components of the EJC, and participate in regulating of plant height, pollen, and seed development in rice.

Atrial Fibrillation, Atrial Myopathy, and Thromboembolism: The Additive Value of Echocardiography and Possible New Horizons for Risk Stratification.

Atrial fibrillation (AF) is the most common cardiac sustained arrhythmia, and it is associated with increased stroke and dementia risk. While the established paradigm attributes these complications to blood stasis within the atria and subsequent thrombus formation with cerebral embolization, recent evidence suggests that atrial myopathy (AM) may play a key role. AM is characterized by structural and functional abnormalities of the atria, and can occur with or without AF. Moving beyond classifications based solely on episode duration, the 4S-AF characterization has offered a more comprehensive approach, incorporating patient's stroke risk, symptom severity, AF burden, and substrate assessment (including AM) for tailored treatment decisions. The "ABC" pathway emphasizes anticoagulation, symptom control, and cardiovascular risk modification and emerging evidence suggests broader benefits of early rhythm control strategies, potentially reducing stroke and dementia risk and improving clinical outcomes. However, a better integration of AM assessment into the current framework holds promise for further personalizing AF management and optimizing patient outcomes. This review explores the emerging concept of AM and its potential role as a risk factor for stroke and dementia and in AF patients' management strategies, highlighting the limitations of current risk stratification methods, like the CHA2DS2-VASc score. Echocardiography, particularly left atrial (LA) strain analysis, has shown to be a promising non-invasive tool for AM evaluation and recent studies suggest that LA strain analysis may be a more sensitive risk stratifier for thromboembolic events than AF itself, with some studies showing a stronger association between LA strain and thromboembolic events compared to traditional risk factors. Integrating it into routine clinical practice could improve patient management and targeted therapies for AF and potentially other thromboembolic events. Future studies are needed to explore the efficacy and safety of anticoagulation in AM patients with and without AF and to refine the diagnostic criteria for AM.

Tetrameric Transthyretin as a Protective Factor Against Alzheimer's Disease.

Transthyretin (TTR) is a tetrameric protein traditionally recognized for its role in transporting thyroxine and retinol. Recent research has highlighted the potential neuroprotective functions of TTR in the setting of Alzheimer's disease (AD), which is the most common form of dementia and is caused by the deposition of amyloid beta (Aß) and the resulting cytotoxic effects. This paper explores the mechanisms of TTR protective action, including its interaction with Aß to prevent fibril formation and promote Aß clearance from the brain. It also synthesizes experimental evidence suggesting that enhanced TTR stability may mitigate neurodegeneration and cognitive decline in AD. Potential therapeutic strategies such as small molecule stabilizers of TTR are discussed, highlighting their role in enhancing TTR binding to Aß and facilitating its clearance. By consolidating current knowledge and proposing directions for future research, this review aims to underscore the significance of TTR as a neuroprotective factor in AD and the potential implications for future research.

MRCK as a Potential Target for Claudin-Low Subtype of Breast Cancer.

To find new molecular targets for triple negative breast cancer (TNBC), we analyzed a large-scale drug screening dataset based on breast cancer subtypes. We discovered that BDP-9066, a specific MRCK inhibitor (MRCKi), may be an effective drug against TNBC. After confirming the efficacy and specificity of BDP-9066 against TNBC in vitro and in vivo, we further analyzed the underlying mechanism of specific activity of BDP-9066 against TNBC. Comparing the transcriptome of BDP-9066-sensitive and -resistant cells, the activation of the focal adhesion and YAP/TAZ pathway were found to play an important role in the sensitive cells. Furthermore, YAP/TAZ is indeed repressed by BDP-9066 in the sensitive cells, and active form of YAP suppresses the effects of BDP-9066. YAP/TAZ expression and activity are high in TNBC, especially the Claudin-low subtype, consistent with the expression of focal adhesion-related genes. Interestingly, NF-κB functions downstream of YAP/TAZ in TNBC cells and is suppressed by BDP-9066. Furthermore, the PI3 kinase pathway adversely affected the effects of BDP-9066 and that alpelisib, a PI3 kinase inhibitor, synergistically increased the effects of BDP-9066, in PIK3CA mutant TNBC cells. Taken together, we have shown for the first time that MRCKi can be new drugs against TNBC, particularly the Claudin-low subtype.

Wild-type transthyretin cardiac amyloidosis is not rare in elderly subjects: the CATCH screening study.

AIMS: Wild-type transthyretin cardiac amyloidosis (ATTRwt-CA) affects older adults and is currently considered as a rare disorder. We investigated for the first time the prevalence of ATTRwt-CA in elderly individuals from the general population. METHODS AND RESULTS: General practitioners from Pisa, Italy, proposed a screening for ATTRwt-CA to all their patients aged 65-90 years, until 1000 accepted. The following red flags were searched: interventricular septal thickness ≥ 12 mm, any echocardiographic, electrocardiographic or clinical hallmark of CA, or high-sensitivity troponin T ≥ 14 ng/L. Individuals with at least one red flag (n = 346) were asked to undergo the search for a monoclonal protein and bone scintigraphy, and 216 accepted. Four patients received a non-invasive diagnosis of ATTRwt-CA. All complained of dyspnoea on moderate effort. A woman and a man aged 79 and 85 years, respectively, showed an intense cardiac tracer uptake (Grade 3), left ventricular (LV) wall thickening, Grade 2 and 3 diastolic dysfunction, and N-terminal pro-B-type natriuretic peptide (NT-proBNP) > 1000 ng/L. Two other patients (a man aged 74 years and a woman aged 83 years) showed a Grade 2 uptake, an increased LV septal thickness, but preserved diastolic function, and NT-proBNP < 300 ng/L. The prevalence of ATTR-CA in subjects ≥ 65 years was calculated as 0.46% (i.e. 4 out of the 870 subjects completing the screening, namely 654 not meeting the criteria for Step 2 and 216 progressing to Step 2). CONCLUSION: Wild-type transthyretin cardiac amyloidosis is uncommon in elderly subjects from the general population, but more frequent than expected for a rare disease.

Wild-type transthyretin cardiac amyloidosis (ATTRwt-CA) is a heart condition mostly found in older adults. Wild-type transthyretin cardiac amyloidosis is considered a rare disease, although no systematic screening has been performed yet. The study aimed to understand how common this disease is among the general population aged 65­90 years in Pisa, Italy. To do this, general practitioners offered screening for ATTRwt-CA to their patients within this age group. The initial step of the screening involved checking for certain warning signs (red flags), like abnormal thickness in a part of the heart called the interventricular septum, unusual heart function observed through various tests, or elevated levels of a specific heart protein. Out of 1000 individuals who began the screening process, 346 showed at least one of these red flags and were further examined using bone scintigraphy (a type of imaging test) and tests for a specific protein related to this condition. Of these, 216 agreed to proceed with these additional tests. The results showed that four of these patients actually had ATTRwt-CA. Their conditions varied in severity, with some showing more intense signs of the disease on the heart scans, thicker heart walls, and higher levels of heart stress proteins. All four patients experienced mild difficulty in breathing during physical activity. Based on these findings, the study concluded that about 0.46% of elderly individuals in the general population might have ATTRwt-CA, indicating that the disease is somewhat more common in this age group than previously thought.

Effects of sacubitril-valsartan on remodelling, fibrosis and mitochondria in a murine model of isoproterenol-induced left ventricular dysfunction.

BACKGROUND: Sacubitril/valsartan has been demonstrated to promote left ventricular (LV) reverse remodelling and improve outcomes in patients with heart failure (HF) with reduced ejection fraction (EF). Its molecular and tissue effects have not been fully elucidated yet, due to the paucity of preclinical studies, mostly based on ischaemic models. We aimed to evaluate the effects of sacubitril/valsartan on LV remodelling, myocardial fibrosis and mitochondrial biology in a murine model of non-ischaemic LV dysfunction. METHODS: Adult transgenic male mice with cardiac-specific hyperaldosteronism (AS mice) received subcutaneous isoproterenol injections to induce LV systolic dysfunction. After 7 days, mice were randomized to a 2-week treatment with saline (ISO-AS n = 15), valsartan (ISO + V n = 12) or sacubitril/valsartan (ISO + S/V n = 12). Echocardiography was performed at baseline, at day 7, and after each of the 2 weeks of treatment. After sacrifice at day 21, histological and immunochemical assays were performed. A control group of AS mice was also obtained (Ctrl-AS n = 8). RESULTS: Treatment with sacubitril/valsartan, but not with valsartan, induced a significant improvement in LVEF (p = 0.009 vs ISO-AS) and fractional shortening (p = 0.032 vs ISO-AS) after 2- week treatment. In both ISO + V and ISO + S/V groups, a trend toward reduction of the cardiac collagen 1/3 expression ratio was detected. ISO + V and ISO + S/V groups showed a significant recovery of mitochondrial morphology and inner membrane function meant for oxidative phosphorylation. CONCLUSION: In a murine model of non-ischaemic HF, sacubitril/valsartan proved to have beneficial effects on LV systolic function, and on cardiac energetics, by improving mitochondrial activity.

Minimal Clinically Important Difference (MCID) in the Functional Status Measures in Patients with Stroke: Inverse Probability Treatment Weighting.

This study proposed to evaluate the temporal trend, define the minimal clinically important difference (MCID) for five functional status measures, and identify risk factors for reaching deterioration in the MCID. This prospective cohort study analyzed 680 patients with ischemic stroke and 151 patients with hemorrhagic stroke at six hospitals between April 2015 and October 2021. All patients completed the functional status measures before rehabilitation (baseline), and at the 12th week and 2nd year after rehabilitation. Patients in the post-acute care (PAC) group exhibited significantly larger improvements for the functional status measures compared to those in the non-PAC group (p < 0.05). Patients with hemorrhagic stroke also displayed larger improvements in the functional status measures when compared to patients with ischemic stroke. Furthermore, the improvement in MCID ranged from 0.01 to 16.18 points when comparing baseline and the 12th week after rehabilitation, but the deterioration in MCID ranged from 0.38 to 16.12 points. Simultaneously, assessing the baseline and the second year after rehabilitation, the improvement in MCID ranged from 0.01 to 18.43 points, but the deterioration in MCID ranged from 0.68 to 17.26 points. Additionally, the PAC program, age, education level, body mass index, smoking, readmission within 30 days, baseline functional status score, use of Foley catheter and nasogastric tube, as well as a history of previous stroke are significantly associated with achieving deterioration in MCID (p < 0.05). These findings suggest that if the mean change scores of the functional status measures have reached the thresholds, the change scores can be perceived by patients as clinically important.

Optimizing age-related hearing risk predictions: an advanced machine learning integration with HHIE-S.

OBJECTIVES: The elderly are disproportionately affected by age-related hearing loss (ARHL). Despite being a well-known tool for ARHL evaluation, the Hearing Handicap Inventory for the Elderly Screening version (HHIE-S) has only traditionally been used for direct screening using self-reported outcomes. This work uses a novel integration of machine learning approaches to improve the predicted accuracy of the HHIE-S tool for ARHL in older adults. METHODS: We employed a dataset that was gathered between 2016 and 2018 and included 1,526 senior citizens from several Taipei City Hospital branches. 80% of the data were used for training (n = 1220) and 20% were used for testing (n = 356). XGBoost, Gradient Boosting, and LightGBM were among the machine learning models that were only used and assessed on the training set. In order to prevent data leakage and overfitting, the Light Gradient Boosting Machine (LGBM) model-which had the greatest AUC of 0.83 (95% CI 0.81-0.85)-was then only used on the holdout testing data. RESULTS: On the testing set, the LGBM model showed a strong AUC of 0.82 (95% CI 0.79-0.86), far outperforming conventional techniques. Notably, several HHIE-S items and age were found to be significant characteristics. In contrast to traditional HHIE research, which concentrates on the psychological effects of hearing loss, this study combines cutting-edge machine learning techniques-specifically, the LGBM classifier-with the HHIE-S tool. The incorporation of SHAP values enhances the interpretability of the model's predictions and provides a more comprehensive comprehension of the significance of various aspects. CONCLUSIONS: Our methodology highlights the great potential that arises from combining machine learning with validated hearing evaluation instruments such as the HHIE-S. Healthcare practitioners can anticipate ARHL more accurately thanks to this integration, which makes it easier to intervene quickly and precisely.

The anti-platelet drug cilostazol enhances heart rate and interrenal steroidogenesis and exerts a scant effect on innate immune responses in zebrafish.

RATIONALE: Cilostazol, an anti-platelet phosphodiesterase-3 inhibitor used for the treatment of intermittent claudication, is known for its pleiotropic effects on platelets, endothelial cells and smooth muscle cells. However, how cilostazol impacts the endocrine system and the injury-induced inflammatory processes remains unclear. METHODS: We used the zebrafish, a simple transparent model that demonstrates rapid development and a strong regenerative ability, to test whether cilostazol influences heart rate, steroidogenesis, and the temporal and dosage effects of cilostazol on innate immune cells during tissue damage and repair. RESULTS: While dosages of cilostazol from 10 to 100 µM did not induce any noticeable morphological abnormality in the embryonic and larval zebrafish, the heart rate was increased as measured by ImageJ TSA method. Moreover, adrenal/interrenal steroidogenesis in larval zebrafish, analyzed by whole-mount 3ß-Hsd enzymatic activity and cortisol ELISA assays, was significantly enhanced. During embryonic fin amputation and regeneration, cilostazol treatments led to a subtle yet significant effect on reducing the aggregation of Mpx-expressing neutrophil at the lesion site, but did not affect the immediate injury-induced recruitment and retention of Mpeg1-expressing macrophages. CONCLUSIONS: Our results indicate that cilostazol has a significant effect on the heart rate and the growth as well as endocrine function of steroidogenic tissue; with a limited effect on the migration of innate immune cells during tissue damage and repair.