Melatonin Therapy Prevents Programmed Hypertension and Nitric Oxide Deficiency in Offspring Exposed to Maternal Caloric Restriction

Nitric oxide (NO) deficiency is involved in the development of hypertension, a condition that can originate early in life. We examined whether NO deficiency contributed to programmed hypertension in offspring from mothers with calorie-restricted diets and whether melatonin therapy prevented this process. We examined 3-month-old male rat offspring from four maternal groups: untreated controls, 50% calorie-restricted (CR) rats, controls treated with melatonin (0.01% in drinking water), and CR rats treated with melatonin (CR + M). The effect of melatonin on nephrogenesis was analyzed using next-generation sequencing. The CR group developed hypertension associated with elevated plasma asymmetric dimethylarginine (ADMA, a nitric oxide synthase inhibitor), decreased L-arginine, decreased L-arginine-to-ADMA ratio (AAR), and decreased renal NO production. Maternal melatonin treatment prevented these effects. Melatonin prevented CR-induced renin and prorenin receptor expression. Renal angiotensin-converting enzyme 2 protein levels in the M and CR + M groups were also significantly increased by melatonin therapy. Maternal melatonin therapy had long-term epigenetic effects on global gene expression in the kidneys of offspring. Conclusively, we attributed these protective effects of melatonin on CR-induced programmed hypertension to the reduction of plasma ADMA, restoration of plasma AAR, increase of renal NO level, alteration of renin-angiotensin system, and epigenetic changes in numerous genes

Cardiovascular diseases morbidity and mortality among children, adolescents and young adults with dialysis therapy

BackgroundThe age-specific burden of cardiovascular disease (CVD) and mortality in pediatric and young adult patients with end-stage kidney disease (ESKD) remains unclear. We aimed to examine the prevalence and incidence of CVD and all-cause mortality in children and adolescents compared with adults with dialysis in Taiwan.MethodsThis retrospective observational cohort study comprised 3,910 patients with more than 2 time point receipts of dialysis therapy in a year, including 156 aged <12 years (children), 250 aged 13–20 years (adolescents), 1,036 aged 21–30 years (young adults) and 2,468 aged 31–40 years (adults) in a large healthcare delivery system in Taiwan (2003–2017). Age groups were classified by the date of first receipt of dialysis therapy. The outcomes include the composite of CVD events and any cause of death. Death-censored Cox proportional hazard models were used to evaluate the composite outcome risk of CVD in the four age groups.ResultsAmong patients receiving dialysis treatment, the risk of composite CVD events [HR, 1.63 (1.22–2.19)] and mortality [HR, 1.76 (1.38–2.25)] was greater in children than the dialysis initiated in older patients. Non-atherosclerotic CVD was more prevalent, especially in younger patients, within the first 6 months after the initiation of dialysis. After 6 months of initial dialysis, the risk of atherosclerotic CVD was higher in adults than those for adolescents and children. The magnitude of CVD risk in adolescents who initiated dialysis therapy was higher in females [HR, 2.08 (1.50–2.88)] than in males [HR, 0.75 (0.52–1.10)].ConclusionYounger patients undergoing chronic dialysis with a higher risk of CVD events than older patients are associated with a faster onset of non-atherosclerotic CVD and a higher risk of both CVD- and non-CVD-related mortality

Trajectory of low-density lipoprotein cholesterol in patients with chronic kidney disease and its association with cardiovascular disease

BackgroundThe role of longitudinal temporal trends in LDL-C in cardiovascular disease (CVD) in patients with chronic kidney disease (CKD) and diabetes is unclear. This study categorized the long-term LDL-C trajectory and determined its association with the incidence of atherosclerotic CVD in patients with CKD according to diabetes status and estimated glomerular filtration rate (eGFR).MethodsThe risk of atherosclerotic CVD was estimated in 137,127 Taiwanese patients with CKD using six LDL-C trajectory classes determined by the latent class mixed model as optimal, near optimal, above optimal, borderline, sustained high, and declined high over 5 years.ResultsThe risk of CVD was higher in the sustained high LDL-C [>160 mg/dL over time; adjusted hazard ratio (aHR) = 1.68, 95% CI = 1.45–1.94], declined high LDL-C (>160 to <100 mg/dL; aHR = 1.23, 95% CI = 1.11–1.38), and borderline LDL-C (approximately 140 mg/dL over time; aHR = 1.16, 95% CI = 1.07–1.26) groups than in the optimal LDL-C group (<100 mg/dL over time). There was no such association in patients with an eGFR <15 mL/min/1.73 m2. Persistent diabetes was associated with a 1.15–2.47-fold increase in CVD in patients with high LDL-C (>120 mg/dL).ConclusionThe LDL-C trajectory pattern was associated with the phenotype of CVD risk. The degree of risk varied according to eGFR and diabetes status. A stable low LDL-C over time was potentially beneficial for prevention of CVD. Intensive lipid management and periodic assessment of LDL-C is essential to reduce the risk of CVD in patients with CKD and diabetes

Toward Joint Language Modeling for Speech Units and Text

Speech and text are two major forms of human language. The research community has been focusing on mapping speech to text or vice versa for many years. However, in the field of language modeling, very little effort has been made to model them jointly. In light of this, we explore joint language modeling for speech units and text. Specifically, we compare different speech tokenizers to transform continuous speech signals into discrete units and use different methods to construct mixed speech-text data. We introduce automatic metrics to evaluate how well the joint LM mixes speech and text. We also fine-tune the LM on downstream spoken language understanding (SLU) tasks with different modalities (speech or text) and test its performance to assess the model's learning of shared representations. Our results show that by mixing speech units and text with our proposed mixing techniques, the joint LM improves over a speech-only baseline on SLU tasks and shows zero-shot cross-modal transferability.Comment: EMNLP findings 202

Risk Analysis of Cargos Damages for Aquatic Products of Refrigerated Containers: Shipping Operators’ Perspective in Taiwan

As the development of refrigerated container, transportation of aquatic products is growing rapidly in recent years. It is very important to avoid cargos damages for aquatic products of refrigerated containers, while the shipping operators are running this scope of business. Hence, the risk issue of adopting various improvement strategies would be important for the container shipping operators. In the light of this, the main purpose of this paper is to analyze the risks of cargos damages for aquatic products of refrigerated containers based on the container shipping operators’ perspective in Taiwan. We use four risk assessment procedures - risk identification, risk analysis and evaluation, risk strategies, and risk treatment - as the research method in this paper. The risk factors are generated from literature review and experts interviewing. Then, three dimensions with nineteen risk factors are preliminary identified. We used these risk factors to proceed with the empirical study via questionnaires. Three points of empirical results are presented. At first, the top factor of perceived risk as well as of risk severity is ‘container data setting errors.’ Secondly, the top factor of risk frequency is ‘lack of the goods’ pre-cooling themselves.’ Thirdly, three risk factors are classified into the low-risk area, whereas sixteen risk factors are placed on the medium-risk area. There is no risk factor fix on the high-risk area. Furthermore, three risk strategies - risk prevention, risk reduction, and risk transfer - are suggested to adopt by different risk factors

Dioscorea Phytocompounds Enhance Murine Splenocyte Proliferation Ex Vivo and Improve Regeneration of Bone Marrow Cells In Vivo

Specific cytokines have been tested clinically for immunotherapy of cancers; however, cytotoxicity has often impaired their usefulness. Consequently, alternative approaches are increasingly desirable. Dioscorea spp. tuber is a widely used traditional Chinese medicinal herb claimed to confer immunostimulatory activity. In this study, we evaluated Dioscorea as an adjuvant therapy for use alongside chemotherapy for cancer. Phytocompounds from Dioscorea tubers were ethanol fractioned and used for ex vivo splenocyte proliferation assay or in vivo force-feeding of mice pre-treated with the chemotherapy agent 5-fluorouracil. Co-treatment with a 50–75% ethanol-partitioned fraction of the tuber extract of D. batatas (DsCE-II) and interleukin (IL)-2 resulted in a significantly higher rate of murine splenocyte cell proliferation ex vivo than treatment with DsCE-II or IL-2 alone. This DsCE-II fraction, which contains a polysaccharide with a high proportion of β-1,4-linkage mannose (≥64%), also promoted the regeneration of specific progenitor cell populations in damaged bone marrow tissues of 5-fluorouracil-treated mice. Colony-forming unit (CFU) analyses demonstrated that the population of CFU-GM cells, but not CFU-GEMM or BFU-E cells, preferentially recovered to ~67% in the bone marrow of immune-suppressed mice fed with DsCE-II. DsCE-II efficacy level was ~85% of that obtained by subcutaneous administration of recombinant G-CSF proteins (5 μg kg−1) in mice tested in parallel. This study suggests that the DsCE-II fraction of D. batatas extract may be considered for further development as a dietary supplement for use alongside chemotherapy during cancer treatment

Kidney outcomes with SGLT2is for type 2 diabetes patients: does background treatment with metformin or RASis matter?

IntroductionThere is a lack of real-world evidence regarding the impact of concomitant metformin and renin-angiotensin system inhibitors (RASis) on sodium-glucose cotransporter-2 inhibitor (SGLT2i)-associated kidney outcomes. This study was aimed to investigate whether SGLT2i-associated kidney outcomes were modified by the concomitant use of metformin or RASis in patients with type 2 diabetes.MethodsSGLT2i users were identified from three electronic health record databases during May 2016 and December 2017 and categorized into those with and without concomitant use of metformin or RASis. Propensity score matching was performed to minimize baseline differences between groups. Study outcomes were mean estimated glomerular filtration rate (eGFR) change and time to 30%, 40%, and 50% eGFR reductions. A meta-analysis was performed to combine the estimates across databases.ResultsAfter matching, there were 6,625 and 3,260 SGLT2i users with and without metformin, and 6,654 and 2,746 SGLT2i users with and without RASis, respectively. The eGFR dip was similar in SGLT2i users with and without metformin therapy, but was greater in SGLT2i users with RASis compared to those without RASis. Neither metformin nor RASi use had a significant effect on SGLT2i-associated eGFR reductions, as evidenced by the hazard ratios (95% CIs) of 30% eGFR reductions for SGLT2is with versus without metformin/RASis, namely 1.02 (0.87–1.20)/1.09 (0.92–1.31). Such findings were also observed in the outcomes of 40% and 50% eGFR reductions.ConclusionUsing metformin or RASis did not modify SGLT2i-associated kidney outcomes in type 2 diabetes

Newborn Genetic Screening for Hearing Impairment: A Preliminary Study at a Tertiary Center

Universal newborn hearing screening (UNHS) is of paramount importance for early identification and management of hearing impairment in children. However, infants with slight/mild, progressive, or late-onset hearing impairment might be missed in conventional UNHS. To investigate whether genetic screening for common deafness-associated mutations could assist in identifying these infants, 1017 consecutive newborns in a tertiary hospital were subjected to both newborn hearing screening using a two-step distortion-product otoacoustic emissions (DPOAE) screening and newborn genetic screening (NGS) for deafness. The NGS targeted 4 deafness-associated mutations commonly found in the Taiwanese population, including p.V37I (c.109G>A) and c.235delC of the GJB2 gene, c.919-2A>G of the SLC26A4 gene, and mitochondrial m.1555A>G of the 12S rRNA gene. The results of the NGS were then correlated to the results of the NHS. Of the 1017 newborns, 16 (1.6%) had unilateral DPOAE screening failure, and 22 (2.2%) had bilateral DPOAE screening failure. A total of 199 (19.6%) babies were found to have at least 1 mutated allele on the NGS for deafness, 11 (1.1%) of whom were homozygous for GJB2 p.V37I, 6 (0.6%) compound heterozygous for GJB2 p.V37I and c.235delC, and 1 (0.1%) homoplasmic for m.1555A>G, who may potentially have hearing loss. Among them, 3 babies, 5 babies, and 1 baby, respectively, passed the NHS at birth. Comprehensive audiological assessments in the 9 babies at 3 months identified 1 with slight hearing loss and 2 with mild hearing loss. NGS for common deafness-associated mutations may identify infants with slight/mild or potentially progressive hearing impairment, thus compensating for the inherent limitations of the conventional UNHS