Objectives:Cardiovascular disease(CVD)in low and middle-income countries(LMICs),accounts for over 80％of global CVD-related deaths.The high cost of drugs is a major concern in not of managing CVD.This study aimed to conduct a comprehensive review to identify interventions for cost containment of CVD drugs and use the inter-vention scalability assessment tool(ISAT)to examine the acceptability and application of relevant interventions in the Sri Lankan context,that can also be adaptable to other LMICs.Methods:A systematic search across three databases(Medline,Web of Science and Embase)was completed to identify relevant health system interventions.The ISAT assessed the feasibility of adapting the identified interven-tions to Sri Lanka,using structured interviews with 25 Sri Lankan stakeholders representing five groups:health managers,cardiologists,pharmacists,nursing officers,and patients.Results:The search yielded nine publications.Five were conducted on a national scale,while others were con-ducted at the regional levels.Seven were published in developed countries.The identified interventions were categorised into six intervention themes:Imposing a ceiling price or reference price;introduction of the polypill;introduction of volume price contract initiatives;prescribing generic and essential drugs;one intervention pack-age including generics,essential medicine,90-day drugs,and free delivery;and a second intervention package including discounts,rebates,cost-free medicine,and bundling.Assessment of six intervention themes revealed that methods of setting ceiling prices and controlling generic drug prescribing were the most popular,while other interventions were least popular.Conclusions:The study provides a roadmap for future interventions based on successful scaling,emphasizing the importance of understanding contextual variables and encourages stakeholder participation in policy assessments and advocacy.The findings highlighted the potential for enhancing the access to affordable CVD drugs not only in Sri Lanka,but also adaptable to other LMICs.These outcomes can contribute to policy decisions,aimed at reducing the significant global burden of CVD.

Objectives:Cardiovascular disease(CVD)in low and middle-income countries(LMICs),accounts for over 80％of global CVD-related deaths.The high cost of drugs is a major concern in not of managing CVD.This study aimed to conduct a comprehensive review to identify interventions for cost containment of CVD drugs and use the inter-vention scalability assessment tool(ISAT)to examine the acceptability and application of relevant interventions in the Sri Lankan context,that can also be adaptable to other LMICs.Methods:A systematic search across three databases(Medline,Web of Science and Embase)was completed to identify relevant health system interventions.The ISAT assessed the feasibility of adapting the identified interven-tions to Sri Lanka,using structured interviews with 25 Sri Lankan stakeholders representing five groups:health managers,cardiologists,pharmacists,nursing officers,and patients.Results:The search yielded nine publications.Five were conducted on a national scale,while others were con-ducted at the regional levels.Seven were published in developed countries.The identified interventions were categorised into six intervention themes:Imposing a ceiling price or reference price;introduction of the polypill;introduction of volume price contract initiatives;prescribing generic and essential drugs;one intervention pack-age including generics,essential medicine,90-day drugs,and free delivery;and a second intervention package including discounts,rebates,cost-free medicine,and bundling.Assessment of six intervention themes revealed that methods of setting ceiling prices and controlling generic drug prescribing were the most popular,while other interventions were least popular.Conclusions:The study provides a roadmap for future interventions based on successful scaling,emphasizing the importance of understanding contextual variables and encourages stakeholder participation in policy assessments and advocacy.The findings highlighted the potential for enhancing the access to affordable CVD drugs not only in Sri Lanka,but also adaptable to other LMICs.These outcomes can contribute to policy decisions,aimed at reducing the significant global burden of CVD.

Objective: Schizophrenia is associated with impairment in multiple cognitive domains. There is a paucity of research on the effect of prolonged illness duration (≥ 15 years) on cognitive performance along multiple domains. In this pilot study, we used the Global Neuropsychological Assessment (GNA), a brief cognitive battery, to explore the patterns of cognitive impairment in recent-onset (≤ 2 years) compared to chronic schizophrenia (≥ 15 years), and correlate cognitive performance with brain morphometry in patients and healthy adults. Methods: We assessed cognitive performance in patients with recent-onset (n = 17, illness duration ≤ 2 years) and chronic schizophrenia (n = 14, duration ≥ 15 years), and healthy adults (n = 16) using the GNA and examined correlations between cognitive scores and gray matter volumes computed from T1-weighted magnetic resonance imaging images. Results: We observed cognitive deficits affecting multiple domains in the schizophrenia samples. Selectively greater impairment of perceptual comparison speed was found in adults with chronic schizophrenia (p = 0.009, η2partial = 0.25).In the full sample (n = 47), perceptual comparison speed correlated significantly with gray matter volumes in the anterior and medial temporal lobes (TFCE, FWE p ＜ 0.01). Conclusion Along with generalized deficit across multiple cognitive domains, selectively greater impairment of perceptual comparison speed appears to characterize chronic schizophrenia. This pattern might indicate an accelerated or premature cognitive aging. Anterior-medial temporal gray matter volumes especially of the left hemisphere might underlie the impairment noted in this domain in schizophrenia.

Development of thoracolumbar vertebra (TLV) and rib primordium (RP) is a common evolutionary feature across vertebrates, although whole-organism analysis of the expression dynamics of TLV- and RP-related genes has been lacking. Here, we investigated the single-cell transcriptome landscape of thoracic vertebra (TV), lumbar vertebra (LV), and RP cells from a pig embryo at 27 days post-fertilization (dpf) and identified six cell types with distinct gene expression signatures. In-depth dissection of the gene expression dynamics and RNA velocity revealed a coupled process of osteogenesis and angiogenesis during TLV and RP development. Further analysis of cell type-specific and strand-specific expression uncovered the extremely high level of HOXA10 3'-UTR sequence specific to osteoblasts of LV cells, which may function as anti-HOXA10-antisense by counteracting the HOXA10-antisense effect to determine TLV transition. Thus, this work provides a valuable resource for understanding embryonic osteogenesis and angiogenesis underlying vertebrate TLV and RP development at the cell type-specific resolution, which serves as a comprehensive view on the transcriptional profile of animal embryo development.

Rett syndrome (RTT) is a progressive neurodevelopmental disorder, mainly caused by mutations in MeCP2 and currently with no cure. We report here that neurons from R106W MeCP2 RTT human iPSCs as well as human embryonic stem cells after MeCP2 knockdown exhibit consistent and long-lasting impairment in maturation as indicated by impaired action potentials and passive membrane properties as well as reduced soma size and spine density. Moreover, RTT-inherent defects in neuronal maturation could be pan-neuronal and occurred in neurons with both dorsal and ventral forebrain features. Knockdown of MeCP2 led to more severe neuronal deficits as compared to RTT iPSC-derived neurons, which appeared to retain partial function. Strikingly, consistent deficits in nuclear size, dendritic complexity and circuitry-dependent spontaneous postsynaptic currents could only be observed in MeCP2 knockdown neurons but not RTT iPSC-derived neurons. Both neuron-intrinsic and circuitry-dependent deficits of MeCP2-deficient neurons could be fully or partially rescued by re-expression of wild type or T158M MeCP2, strengthening the dosage dependency of MeCP2 on disease phenotypes and also the partial function of the mutant. Our findings thus reveal stable neuronal maturation deficits and unexpectedly, graded sensitivities of neuron-inherent and neural transmission phenotypes towards the extent of MeCP2 deficiency, which is informative for future therapeutic development.

Piao chicken,a rare Chinese native poultry breed,lacks primary tail structures,such as pygostyle,caudal vertebra,uropygial gland,and tail feathers.So far,the molecular mechanisms underlying tail absence in this breed remain unclear.In this study,we comprehensively employed comparative transcriptomic and genomic analyses to unravel potential genetic underpinnings of rum-plessness in Piao chicken.Our results reveal many biological factors involved in tail development and several genomic regions under strong positive selection in this breed.These regions contain can-didate genes associated with rumplessness,including Irx4,Il18,Hspb2,and Cryab.Retrieval of quantitative trait loci(QTL)and gene functions implies that rumplessness might be consciously or unconsciously selected along with the high-yield traits in Piao chicken.We hypothesize that strong selection pressures on regulatory elements might lead to changes in gene activity in mes-enchymal stem cells of the tail bud.The ectopic activity could eventually result in tail truncation by impeding differentiation and proliferation of the stem cells.Our study provides fundamental insights into early initiation and genetic basis of the rumpless phenotype in Piao chicken.

Background: and Purpose Paroxysmal atrial fibrillation (PAF) underlying acute stroke frequently evades detection by standard practice, considered to be a combination of routine electrocardiogram (ECG) monitoring, and 24-hour Holter recordings. We hypothesized that nurse-led in-hospital intermittent monitoring approach would increase PAF detection rate. Methods: We recruited patients hospitalised for stroke/transient ischemic attack, without history of atrial fibrillation (AF), in a prospective multi-centre observational study. Patients were monitored using a smartphone-enabled handheld ECG (iECG) during routine nursing observations, and underwent 24-hour Holter monitoring according to local practice. The primary outcome was comparison of AF detection by nurse-led iECG versus Holter monitoring in patients who received both tests: secondary outcome was oral anticoagulant commencement at 3-month following PAF detection. Results: One thousand and seventy-nine patients underwent iECG monitoring: 294 had iECG and Holter monitoring. AF was detected in 25/294 (8.5%) by iECG, and 8/294 (2.8%) by 24-hour Holter recordings (P<0.001). Median duration from stroke onset to AF detection for iECG was 3 days (interquartile range [IQR], 2 to 6) compared with 7 days (IQR, 6 to 10) for Holter recordings (P=0.02). Of 25 patients with AF detected by iECG, 11 were commenced on oral anticoagulant, compared to 5/8 for Holter. AF was detected in 8.8% (69/785 patients) who underwent iECG recordings only (P=0.8 vs. those who had both iECG and 24-hour Holter). Conclusions Nurse-led in-hospital iECG surveillance after stroke is feasible and effective and detects more PAF earlier and more frequently than routine 24-hour Holter recordings. Screening with iECG could be incorporated into routine post-stroke nursing observations to increase diagnosis of PAF, and facilitate institution of guideline-recommended anticoagulation.

A 48-year-old woman in her 40’s with end-stage renal disease and tertiary hyperparathyroidism (HPT) presented for a rapidly progressive maxillary tumor. Initial workup was notable for elevated intact parathyroid hormone (PTH) and diffuse thickening of skull and facial bones on computed tomography, and maxillary tumor biopsy with multinucleated giant cells. She underwent subtotal parathyroidectomy (with removal of a parathyroid adenoma and 2 hyperplastic glands) and partial resection of maxillary brown tumor. The patient’s post-operative course was complicated by hungry bone syndrome, with hypocalcemia refractory to aggressive calcium repletion. Teriparatide (recombinant PTH) was utilized with rapid resolution of hypocalcemia. To our knowledge, this is the first case of maxillary brown tumor in tertiary HPT to be reported in the USA. This case also supports teriparatide as a novel therapeutic for hungry bone syndrome refractory to aggressive calcium repletion.

ETS-1 is a transcription factor that is a member of the E26 transformation-specific (ETS) family. Galanin receptor 2 (GalR2), a subtype of receptors of the neuropeptide galanin, has been shown to have an antidepressant-like effect after activation in rodents. Our previous study has shown that overexpression of ETS-1 increases the expression of GalR2 in PC12 phaeochromocytoma cells. However, whether ETS-1 has an antidepressant-like effect is still unclear. In this study, we found that chronic mild stress (CMS) decreased the expression of both ETS-1 and GalR2 in the ventral hippocampus of rats. Meanwhile, we demonstrated that overexpression of ETS-1 increased the expression of GalR2 in primary hippocampal neurons. Importantly, we showed that overexpression of ETS-1 in the ventral hippocampus counteracted the depression-like behaviors of CMS rats. Furthermore, we found that overexpression of ETS-1 increased the level of downstream phosphorylated extracellular signal-regulated protein kinases 1 and 2 (p-ERK1/2) of GalR2 in the ventral hippocampus of CMS rats. Taken together, our findings suggest that ETS-1 has an antidepressant-like effect in rats, which might be mediated by increasing the level of GalR2 and its downstream p-ERK1/2 in the ventral hippocampus.

BACKGROUND: Placenta previa and placenta accreta associate with high morbidity and mortality for both mothers and fetus. Metal exposure may have relationships with placenta previa and placenta accreta. This study analyzed the associations between maternal metal (cadmium [Cd], lead [Pb], mercury [Hg], selenium [Se], and manganese [Mn]) concentrations and placenta previa and placenta accreta. METHODS: We recruited 17,414 women with singleton pregnancies. Data from a self-administered questionnaire regarding the first trimester and medical records after delivery were analyzed. Maternal blood samples were collected to measure metal concentrations. The subjects were classified into four quartiles (Q1, Q2, Q3, and Q4) according to metal concentrations. RESULTS: The odds ratio for placenta previa was significantly higher among subjects with Q4 Cd than those with Q1 Cd. The odds ratio for placenta previa was significantly higher for subjects with Q2 Pb than those with Q1 Pb. CONCLUSION Participants with placenta previa had higher Cd concentrations. However, this study was cross-sectional and lacked important information related to Cd concentration, such as detailed smoking habits and sources of Cd intake. In addition, the subjects in this study comprised ordinary pregnant Japanese women, and it was impossible to observe the relationship between a wide range of Cd exposure and placenta previa. Therefore, epidemiological and experimental studies are warranted to verify the relationship between Cd exposure and pregnancy abnormalities.
Adult ; Cross-Sectional Studies ; Female ; Humans ; Japan ; Metals, Heavy ; blood ; metabolism ; Placenta Accreta ; metabolism ; Placenta Previa ; metabolism ; Pregnancy ; Selenium ; blood ; metabolism