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Targeting Meis1 and Hoxb13 transcriptional activity could be a viable therapeutic strategy for heart regeneration. In this study, we performd an in silico screening to identify FDA-approved drugs that can inhibit Meis1 and Hoxb13 transcriptional activity based on the resolved crystal structure of Meis1 and Hoxb13 bound to DNA. Paromomycin (Paro) and neomycin (Neo) induced proliferation of neonatal rat ventricular myocytes in vitro and displayed dose-dependent inhibition of Meis1 and Hoxb13 transcriptional activity by luciferase assay and disruption of DNA binding by electromobility shift assay. X-ray crystal structure revealed that both Paro and Neo bind to Meis1 near the Hoxb13-interacting domain. Administration of Paro-Neo combination in adult mice and in pigs after cardiac ischemia/reperfusion injury induced cardiomyocyte proliferation, improved left ventricular systolic function and decreased scar formation. Collectively, we identified FDA-approved drugs with therapeutic potential for induction of heart regeneration in mammals., Competing Interests: Competing interests M.G. is founder, consultant, member of the board and equity holder in Forcefield Therapeutics, Heqet Therapeutics and Purespring Therapeutics. All other authors declare no competing interests.

Objective: To evaluate the role of social and geographic factors on the likelihood of receiving transoral robotic surgery (TORS) or non-robotic transoral endoscopic surgery treatment in early stage oropharyngeal squamous cell carcinoma (OPSCC)., Materials and Methods: The National Cancer Database was queried to form a cohort of patients with T1-T2 N0-N1 M0 OPSCC (AJCC v.7) who underwent treatment from 2010 to 2016. Demographics, tumor characteristics, treatment type, social, and geographic factors were all collected. Univariate analysis and multivariate logistic regression were then performed., Results: Among 9267 identified patients, 1774 (19.1%) received transoral robotic surgery (TORS), 1191 (12.9%) received transoral endoscopic surgery, and 6302 (68%) received radiation therapy. We found that lower cancer stage, lower comorbidity burden and HPV- positive status predicted a statistically significant increased likelihood of receiving surgery. Patients who reside in suburban or small urban areas (>1 million population), were low-to- middle income, or rely on Medicaid were less likely to receive surgery. Patients that reside in Medicaid-expansion states were more likely to receive TORS (p > .0001). Patients that reside in states that expanded Medicaid January 2014 and after were more likely to receive non-robotic transoral endoscopic surgery (p > .0001)., Conclusions: Poorer baseline health, lower socioeconomic status and residence in small urban areas may act as barriers to accessing minimally invasive transoral surgery while residence in a Medicaid-expansion state may improve access. Barriers to accessing robotic surgery may be greater than accessing non-robotic surgery., (Copyright © 2021. Published by Elsevier Inc.)

Background & Aims: Known risk factors for hepatocellular adenoma (HCA) bleeding are size >5 cm, growth rate, visible vascularity, exophytic lesions, β-catenin and Sonic Hedgehog activated HCAs. Most studies are based on European cohorts. The objective of this study is to identify additional risk factors for HCA bleeding in a US cohort., Methods: Retrospective chart review was performed on patients diagnosed with HCA on magnetic resonance imaging (n = 184) at an academic tertiary institution. Clinical, pathological, and imaging data were collected. Primary outcomes measured were HCA bleeding and malignancy. Statistical analysis was performed with SAS 9.4 using Chi-Square, Fisher's exact test, sample t test, non-parametric Wilcoxon test, and logistic regression., Results: After excluding patients whose pathology showed focal nodular hyperplasia and non-adenoma lesions, follow-up data were available for 167 patients. 16% experienced microscopic or macroscopic bleeding and 1.2% had malignancy. HCA size predicted bleeding (P < .0001) and no patients with lesion size <1.8 cm bled. In unadjusted analysis, hepatic adenomatosis (≥10 lesions) trended towards 2.8-fold increased risk of bleeding. Of patients with a single lesion that bled, 77% bled from a lesion >5 cm. In patients with multiple HCAs that bled, 50% bled from lesions <5 cm. In patients with multiple adenomas, size (P = .001) independently predicted bleeding and hepatic steatosis trended towards increased risk of bleeding (P = .05)., Conclusions: In a large US cohort, size predicted increased risk of HCA bleeding while hepatic adenomatosis trended towards increased risk of bleeding. In patients with multiple HCAs, size predicted bleeding and hepatic steatosis trended toward increased risk of bleeding., (© 2021 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Benefits of surgical resection for early-stage nonepithelioid malignant pleural mesothelioma (MPM) have not been clearly elucidated. This study investigated whether cancer-directed surgery affects overall survival compared with nonsurgical therapies for T1-T2 N0 M0 sarcomatoid or biphasic MPM patients., Methods: Adult patients with clinical stage I or II MPM were identified in the National Cancer Database from 2004 to 2103. Patients who underwent cancer-directed surgery were matched by propensity score with patients who had received chemotherapy/radiotherapy or no treatments. Overall survival was compared using a Cox proportional hazard regression model., Results: From National Cancer Database queries, 878 patients with clinical stage I or II MPM with sarcomatoid (n = 524) or biphasic (n = 354) histology were identified. Overall median survival was 5.5 months for patients with sarcomatoid mesothelioma. The cancer-directed surgery improved overall survival compared with no operation (median survival, 7.56 months vs 4.21 months, respectively; p < 0.01). In the biphasic group, median overall survival was 12.2 months. Again, the cancer-directed surgery improved survival compared with no operation (15.8 months vs 9.3 months, p < 0.01). For both histologies, the cancer-directed surgery improved overall survival compared with those who underwent chemotherapy or radiotherapy, or both, without resection (p < 0.05). Perioperative mortality was 6.0% at 30 days and 21.4% at 90 days., Conclusions: The cancer-directed surgery is associated with improved survival in early-stage MPM patients with nonepithelioid histology compared with those who did not undergo resection or chose medical therapy. Given the high perioperative mortality, a careful patient selection and multidisciplinary evaluation is recommended., (Copyright © 2019 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Schizophrenia is closely associated with cardiovascular risk factors which are consequently attributable to the development of chronic kidney disease and end-stage renal disease (ESRD). However, no study has been conducted to examine ESRD-related epidemiology and quality of care before starting dialysis for patients with schizophrenia. By using nationwide health insurance databases, we identified 54,361 ESRD-free patients with schizophrenia and their age-/gender-matched subjects without schizophrenia for this retrospective cohort study (the schizophrenia cohort). We also identified a cohort of 1,244 adult dialysis patients with and without schizophrenia (1:3) to compare quality of renal care before dialysis and outcomes (the dialysis cohort). Cox proportional hazard models were used to estimate the hazard ratio (HR) for dialysis and death. Odds ratio (OR) derived from logistic regression models were used to delineate quality of pre-dialysis renal care. Compared to general population, patients with schizophrenia were less likely to develop ESRD (HR = 0.6; 95% CI 0.4-0.8), but had a higher risk for death (HR = 1.2; 95% CI, 1.1-1.3). Patients with schizophrenia at the pre-ESRD stage received suboptimal pre-dialysis renal care; for example, they were less likely to visit nephrologists (OR = 0.6; 95% CI, 0.4-0.8) and received fewer erythropoietin prescriptions (OR = 0.7; 95% CI, 0.6-0.9). But they had a higher risk of hospitalization in the first year after starting dialysis (OR = 1.4; 95% CI, 1.0-1.8, P < .05). Patients with schizophrenia undertaking dialysis had higher risk for mortality than the general ESRD patients. A closer collaboration between psychiatrists and nephrologists or internists to minimize the gaps in quality of general care is recommended.

Objectives: This study sought to examine the discrepancy in counting injury deaths according to two definitions, that is, (a) external cause of injury as the underlying cause of death (UCOD), and (b) with mention of external cause of injury, and differences in certification practices between Taiwan and the USA., Methods: We calculated the percentage (U/M%) in which external cause of injury was selected as the UCOD (U) among deaths with mention (M) of external cause of injury anywhere on the death certificate to assess the discrepancy between the two definitions in counting injury deaths., Results: The discrepancy was small in Taiwan and in the USA for transport injuries (with U/M% 99% and 98%) and intentional self-harm (100% and 100%) and large for accidental suffocation (64% and 29%) as well as complications of medical and surgical care (61% and 10%). The magnitude of discrepancy was not consistent between countries in accidental falls (96% vs 81%) and accidental drowning (80% vs 97%). Certifiers in Taiwan were more likely to report an accidental fall in Part I of the death certificate and less likely to report medical conditions (such as stroke, Alzheimer's disease or Parkinson's disease, etc) with accidental suffocation than their counterpart US certifiers., Conclusions: The counting of injury deaths according to two definitions varied by external cause of injury as well as between countries. For some external causes of injury with high discrepancies, we suggest presenting the number of injury deaths according to two definitions., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)

Background: Evidence suggests glucose transporter-1 (GLUT1) genetic variation affects diabetic nephropathy and albuminuria. Our aim was to evaluate associations with albuminuria of six GLUT1 single nucleotide polymorphisms(SNPs), particularly XbaI and the previously associated Enhancer-2 (Enh2) SNP., Methods: A two-stage case-control study was nested in a prospective cohort study of 2156 African Americans and 8122 European Americans with urinary albumin-to-creatinine ratio (ACR). Cases comprised albuminuria (N = 825; ≥ 30 μg/mg) and macroalbuminuria (N = 173; ≥ 300 μg/mg). ACR < 30 μg/mg classified controls (n = 9453). Logistic regression and odds ratios (OR) assessed associations. The evaluation phase (stage 1, n = 2938) tested associations of albuminuria (n = 305) with six GLUT1 SNPs: rs841839, rs3768043, rs2297977, Enh2(rs841847) XbaI (rs841853), and rs841858. Enh2 was examined separately in the replication phase (stage 2, n = 7340) and the total combined sample (n = 10,278), with all analyses stratified by race and type 2 diabetes., Results: In European Americans, after adjusting for diabetes and other GLUT1 SNPs in stage 1, Enh2 risk genotype (TT) was more common in albuminuric cases (OR = 3.37, P = 0.090) whereas XbaI (OR = 0.94, p = 0.931) and remaining SNPs were not. In stage 1, the Enh2 association with albuminuria was significant among diabetic European Americans (OR = 2.36, P = 0.025). In African Americans, Enh2 homozygosity was rare (0.3%); XbaI was common (18.0% AA) and not associated with albuminuria. In stage 2 (n = 7,340), Enh2 risk genotype had increased but non-significant OR among diabetic European Americans (OR = 1.66, P = 0.192) and not non-diabetics (OR = 0.99, p = 0.953), not replicating stage 1. Combining stages 1 and 2, Enh2 was associated with albuminuria (OR 2.14 [1.20-3.80], P = 0.009) and macroalbuminuria (OR 2.69, [1.02-7.09], P = 0.045) in diabetic European Americans. The Enh2 association with macroalbuminuria among non-diabetic European Americans with fasting insulin (OR = 1.84, P = 0.210) was stronger at the highest insulin quartile (OR = 4.08, P = 0.040)., Conclusions: As demonstrated with type 1 diabetic nephropathy, the GLUT1 Enh2 risk genotype, instead of XbaI, may be associated with type 2 diabetic albuminuria among European Americans, though an association is not conclusive. The association among diabetic European Americans found in stage 1 was not replicated in stage 2; however, this risk association was evident after combining all diabetic European Americans from both stages. Additionally, our results suggest this association may extend to non-diabetics with high insulin concentrations. Rarity of the Enh2 risk genotype among African Americans precludes any definitive conclusions, although data suggest a risk-enhancing role.

Muscle samples of 121 and 110 bigeye tuna (Thunnus obesus) caught by Taiwanese long-line fishing vessels in the Atlantic and Indian Oceans, respectively, were used to analyze total mercury (THg) and organic mercury (OHg) content. The overall THg and OHg concentrations were 0.786 ± 0.386 (0.214-3.133) and 0.595 ± 0.238 (0.143-2.222) mg kg⁻¹ wet weight, respectively, similar to the results of previous studies. Our findings, however, reflected the highest THg and OHg concentrations for the species in each ocean among the published data. Mean THg and OHg concentrations in Atlantic tuna were significantly (p < 0.05) higher than those in Indian tuna. Two of 121 samples of tuna from the Atlantic Ocean, but no samples from the Indian Ocean, had levels of OHg above 2 mg kg⁻¹ wet weight set by the Department of Health Taiwan, and 13 of 121 samples of tuna from the Atlantic Ocean and three of 110 samples from the Indian Ocean had levels of OHg above 1 mg kg⁻¹ wet weight set by US FDA and WHO. Accordingly, for adult Taiwanese men and women with average body weight of 65 and 55 kg, respectively, the maximum allowable weekly intake of bigeye tuna is suggested to be 170 and 145 g, respectively.

Background: Albuminuria predicts cardiovascular risk, but its function as a marker of endothelial damage and atherosclerosis is uncertain, as is the complex relationship with hypertension and diabetes., Objective: To determine whether hypertension contributes to albuminuria across levels of atherosclerosis and type 2 diabetes., Methods: Cross-sectional associations of cardiovascular risk factors and albuminuria were examined in 10,113 middle-aged participants in the atherosclerosis risk in communities study divided into four subgroups: type 2 diabetes with marked atherosclerosis, type 2 diabetes without marked atherosclerosis, without diabetes with marked atherosclerosis, and without diabetes without marked atherosclerosis. Marked atherosclerosis was defined as high levels of carotid atherosclerosis or prevalent coronary heart disease., Results: Hyperglycemia and hypertriglyceridemia were associated with albuminuria, but only among patients with type 2 diabetes. In multivariate models, increasing blood pressure levels (but not albuminuria) were significantly associated (P-trend <0.001) with carotid atherosclerosis when stratified by prevalent coronary heart disease. Excluding individuals on hypertension medication, higher blood pressure was associated with albuminuria in all groups (P-trend<0.05). The association was strong even for high-normal blood pressure among individuals without diabetes without marked atherosclerosis (odds ratio 2.7, 95% confidence interval 1.6-4.6) and patients with type 2 diabetes with marked atherosclerosis (12.0, 1.3-108.2)., Conclusion: Blood pressure, even at high-normal levels, is consistently associated with albuminuria across categories of type 2 diabetes and atherosclerosis. Our results suggest that the effects of blood pressure on albuminuria are not solely mediated through generalized vascular damage, as represented by degree of atherosclerosis.

Background: Rare mutations in nephrosis 2 (NPHS2), encoding podocin, are found in patients with familial and sporadic steroid-resistant nephrotic syndrome and focal segmental glomerular sclerosis. The objective of this study is to assess the contribution of the commonly reported functional podocin polymorphism R229Q to kidney disease in the population at large and replicate a prior study of an association of R229Q and albuminuria in the general population., Study Design: Large sample of the Atherosclerosis Risk in Communities (ARIC) Study, a population-based prospective study., Setting & Participants: 4,424 white and 3,746 black middle-aged adults., Predictor: Genotype at the R229Q polymorphism in podocin., Outcomes: Urinary albumin-creatinine ratio (ACR) and decreased estimated glomerular filtration rate (eGFR) as measures of kidney damage/dysfunction., Measurements: Crude and multivariable adjusted linear and logistic regression models., Results: R229Q allele frequencies were 3.7% in 4,424 white and 0.6% in 3,746 black individuals. No significant association of R229Q with increased ACR or decreased eGFR was observed (adjusted odds ratio of ACR > or = 30 mg/g in RQ/QQ versus RR carriers, 1.18; 95% confidence interval, 0.76 to 1.84; adjusted odds ratio of eGFR < 60 mL/min/1.73 m(2) in RQ/QQ versus RR carriers, 1.18; 95% confidence interval, 0.76 to 1.83). As expected, the established kidney disease risk factors hypertension and diabetes mellitus were associated strongly with measures of kidney damage/dysfunction, but the R229Q polymorphism was not associated with an additional increase in kidney disease measures., Limitations: Single measurement of ACR, subsample of all ARIC participants., Conclusion: No significant association of the relatively rare R229Q variant and ACR or eGFR was found in either white or black individuals. The phenotypic effect of a variant as R229Q would have to be of great magnitude to meaningfully contribute to the risk of kidney disease on a population level. The importance of such variants in the general population, as well as replication studies, can be evaluated best in large community-based studies that allow for accounting of established disease risk factors.

According to serologic testing, murine norovirus is the most prevalent viral pathogen in contemporary laboratory mice. Previously, murine norovirus 1 (MNV-1) was the only norovirus reported to infect research mice. In this study, 3 novel murine norovirus strains--MNV-2, MNV-3, and MNV-4--were isolated from geographically separate mouse research colonies. All 4 murine norovirus strains used as individual antigens in microsphere fluorescent immunoassays displayed serologic cross-reactivity to serum from mice inoculated with MNV-1, MNV-2, MNV-3, or MNV-4. In addition, reverse transcriptase-polymerase chain reaction analysis at 8 wk postinoculation detected virus in the feces and tissues of all mice experimentally inoculated with MNV-2, MNV-3, or MNV-4. This finding suggests that mice can have prolonged fecal shedding of and can become persistently infected with murine noroviruses.

Murine norovirus 1 (MNV-1) is a newly recognized pathogen of mice that causes lethal infection in mice deficient in components of the innate immune response but not in wild-type 129 mice. In this study, in vitro-propagated MNV-1 was used as antigen to develop a multiplexed fluorescent immunoassay (MFI) to detect antibodies to MNV-1 in infected mice. The MNV-1 MFI was 100% specific and 100% sensitive in detecting anti-MNV-1 antibody in sera from experimentally infected mice. Testing of a large number of mouse serum samples (n = 12,639) submitted from contemporary laboratory mouse colonies in the United States and Canada revealed that 22.1% of these sera contained antibodies to MNV-1, indicating infection with MNV-1 is widespread in research mice. In addition, a reverse transcriptase PCR primer pair with a sensitivity of 25 virus copies was developed and used to demonstrate that MNV-1 RNA could be detected in the spleen, mesenteric lymph node, and jejunum from some experimentally infected mice 5 weeks postinoculation. These diagnostic assays provide the necessary tools to define the MNV-1 infection status of research mice and to aid in the establishment of laboratory mouse colonies free of MNV-1 infection.

Psychological maladjustment and its relation to academic achievement, parental expectations, and parental satisfaction were studied in a cross-national sample of 1,386 American, 1,633 Chinese, and 1,247 Japanese eleventh-grade students. 5 indices of maladjustment included measures of stress, depressed mood, academic anxiety, aggression, and somatic complaints. Asian students reported higher levels of parental expectation and lower levels of parental satisfaction concerning academic achievement than their American peers. Nevertheless, Japanese students reported less stress, depressed mood, aggression, academic anxiety, and fewer somatic complaints than did American students. Chinese students reported less stress, academic anxiety, and aggressive feelings than their American counterparts, but did report higher frequencies of depressed mood and somatic complaints. High academic achievement as assessed by a test of mathematics was generally not associated with psychological maladjustment. The only exception was in the United States, where high achievers indicated more frequent feelings of stress than did low achievers.

Chinese, Japanese, and American children at grades 1 and 5 were given a battery of 10 cognitive tasks and tests of achievement in reading and mathematics. Samples consisted of 240 children in each grade in each culture. 2 major purposes of the study were to determine possible differences in cognitive abilities of Japanese, Chinese, and American children and to investigate the possible differential relation of scores on cognitive tasks to reading by children of the 3 cultures. Similarity was found among children of the 3 cultures in level, variability, and structure of cognitive abilities. Chinese children surpassed Japanese and American children in reading scores; both Chinese and Japanese children obtained higher scores in mathematics than the American children. Prediction of achievement scores from the cognitive tasks showed few differential effects among children of the 3 cultures. The results suggest that the high achievement of Chinese and Japanese children cannot be attributed to higher intellectual abilities, but must be related to their experiences at home and at school.