Gene expression signatures affected by alcohol-induced DNA methylomic deregulation in human embryonic stem cells

AbstractStem cells, especially human embryonic stem cells (hESCs), are useful models to study molecular mechanisms of human disorders that originate during gestation. Alcohol (ethanol, EtOH) consumption during pregnancy causes a variety of prenatal and postnatal disorders collectively referred to as fetal alcohol spectrum disorders (FASDs). To better understand the molecular events leading to FASDs, we performed a genome-wide analysis of EtOH's effects on the maintenance and differentiation of hESCs in culture. Gene Co-expression Network Analysis showed significant alterations in gene profiles of EtOH-treated differentiated or undifferentiated hESCs, particularly those associated with molecular pathways for metabolic processes, oxidative stress, and neuronal properties of stem cells. A genome-wide DNA methylome analysis revealed widespread EtOH-induced alterations with significant hypermethylation of many regions of chromosomes. Undifferentiated hESCs were more vulnerable to EtOH's effect than their differentiated counterparts, with methylation on the promoter regions of chromosomes 2, 16 and 18 in undifferentiated hESCs most affected by EtOH exposure. Combined transcriptomic and DNA methylomic analysis produced a list of differentiation-related genes dysregulated by EtOH-induced DNA methylation changes, which likely play a role in EtOH-induced decreases in hESC pluripotency. DNA sequence motif analysis of genes epigenetically altered by EtOH identified major motifs representing potential binding sites for transcription factors. These findings should help in deciphering the precise mechanisms of alcohol-induced teratogenesis

New Variant of Multidrug-Resistant Salmonella enterica Serovar Typhimurium Associated with Invasive Disease in Immunocompromised Patients in Vietnam.

Nontyphoidal Salmonella (NTS), particularly Salmonella enterica serovar Typhimurium, is among the leading etiologic agents of bacterial enterocolitis globally and a well-characterized cause of invasive disease (iNTS) in sub-Saharan Africa. In contrast, S Typhimurium is poorly defined in Southeast Asia, a known hot spot for zoonotic disease with a recently described burden of iNTS disease. Here, we aimed to add insight into the epidemiology and potential impact of zoonotic transfer and antimicrobial resistance (AMR) in S Typhimurium associated with iNTS and enterocolitis in Vietnam. We performed whole-genome sequencing and phylogenetic reconstruction on 85 human (enterocolitis, carriage, and iNTS) and 113 animal S Typhimurium isolates isolated in Vietnam. We found limited evidence for the zoonotic transmission of S Typhimurium. However, we describe a chain of events where a pandemic monophasic variant of S Typhimurium (serovar I:4,[5],12:i:- sequence type 34 [ST34]) has been introduced into Vietnam, reacquired a phase 2 flagellum, and acquired an IncHI2 multidrug-resistant plasmid. Notably, these novel biphasic ST34 S Typhimurium variants were significantly associated with iNTS in Vietnamese HIV-infected patients. Our study represents the first characterization of novel iNTS organisms isolated outside sub-Saharan Africa and outlines a new pathway for the emergence of alternative Salmonella variants into susceptible human populations.IMPORTANCESalmonella Typhimurium is a major diarrheal pathogen and associated with invasive nontyphoid Salmonella (iNTS) disease in vulnerable populations. We present the first characterization of iNTS organisms in Southeast Asia and describe a different evolutionary trajectory from that of organisms causing iNTS in sub-Saharan Africa. In Vietnam, the globally distributed monophasic variant of Salmonella Typhimurium, the serovar I:4,[5],12:i:- ST34 clone, has reacquired a phase 2 flagellum and gained a multidrug-resistant plasmid to become associated with iNTS disease in HIV-infected patients. We document distinct communities of S Typhimurium and I:4,[5],12:i:- in animals and humans in Vietnam, despite the greater mixing of these host populations here. These data highlight the importance of whole-genome sequencing surveillance in a One Health context in understanding the evolution and spread of resistant bacterial infections

Risk Factors of Streptococcus suis Infection in Vietnam. A Case-Control Study

Background: Streptococcus suis infection, an emerging zoonosis, is an increasing public health problem across South East Asia and the most common cause of acute bacterial meningitis in adults in Vietnam. Little is known of the risk factors underlying the disease. Methods and Findings: A case-control study with appropriate hospital and matched community controls for each patient was conducted between May 2006 and June 2009. Potential risk factors were assessed using a standardized questionnaire and investigation of throat and rectal S. suis carriage in cases, controls and their pigs, using real-time PCR and culture of swab samples. We recruited 101 cases of S. suis meningitis, 303 hospital controls and 300 community controls. By multivariate analysis, risk factors identified for S. suis infection as compared to either control group included eating "high risk" dishes, including such dishes as undercooked pig blood and pig intestine (OR1 = 2.22; 95% CI = [1.15-4.28] and OR2 = 4.44; 95% CI = [2.15-9.15]), occupations related to pigs (OR1 = 3.84; 95% CI = [1.32-11.11] and OR2 = 5.52; 95% CI = [1.49-20.39]), and exposures to pigs or pork in the presence of skin injuries (OR1 = 7.48; 95% CI = [1.97-28.44] and OR2 = 15.96; 95% CI = [2.97-85.72]). S. suis specific DNA was detected in rectal and throat swabs of 6 patients and was cultured from 2 rectal samples, but was not detected in such samples of 1522 healthy individuals or patients without S. suis infection. Conclusions: This case control study, the largest prospective epidemiological assessment of this disease, has identified the most important risk factors associated with S. suis bacterial meningitis to be eating 'high risk' dishes popular in parts of Asia, occupational exposure to pigs and pig products, and preparation of pork in the presence of skin lesions. These risk factors can be addressed in public health campaigns aimed at preventing S. suis infectio

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

Interactions between antidepressants, sleep aids and selected breast cancer therapy.

Depression and insomnia are very significant pathologies in cancer patients as they contribute to the patient's overall cure and quality of life. Moreover, untreated depression and ongoing insomnia are associated with decreased immune responses and lower survival rates. With all disease states and especially with cancer, close attention to drug-drug interactions and the potential impact on the efficacy of therapy is paramount. One area of particular interest due to the lack of well-done clinical trials is drug-drug interaction(s) between antidepressants and cancer treatment. Pharmacokinetics of a certain drug allows for prediction of certain drug interactions based on chemical properties of the agents involved. If the agents depend on their metabolites for activity, active drug level will be decreased through this enzyme inhibition. In this paper, we looked at the cytochrome-P450 drug interactions between antidepressants and sleep aids with Selective Estrogen Receptor Modulators (SERM). Newer SERM metabolisms are less influenced by interactions with medications used to treat depression. However, tamoxifen metabolism could be severely altered by several antidepressants. This has direct consequences as patients on tamoxifen and antidepressant can have double the risk of relapse to cancer in two years. We discussed those interactions and made recommendations for clinical use

Interactions between antidepressants, sleep aids and selected breast cancer therapy

Depression and insomnia are very significant pathologies in cancer patients as they contribute to the patient’s overall cure and quality of life. Moreover, untreated depression and ongoing insomnia are associated with decreased immune responses and lower survival rates. With all disease states and especially with cancer, close attention to drug-drug interactions and the potential impact on the efficacy of therapy is paramount. One area of particular interest due to the lack of well-done clinical trials is drug-drug interaction(s) between antidepressants and cancer treatment. Pharmacokinetics of a certain drug allows for prediction of certain drug interactions based on chemical properties of the agents involved. If the agents depend on their metabolites for activity, active drug level will be decreased through this enzyme inhibition. In this paper, we looked at the cytochrome-P450 drug interactions between antidepressants and sleep aids with Selective Estrogen Receptor Modulators (SERM). Newer SERM metabolisms are less influenced by interactions with medications used to treat depression. However, tamoxifen metabolism could be severely altered by several antidepressants. This has direct consequences as patients on tamoxifen and antidepressant can have double the risk of relapse to cancer in two years. We discussed those interactions and made recommendations for clinical use

Smoking Cessation Pharmacotherapy Utilization and Costs to a Medicaid Managed Care Plan.

BACKGROUND: Medicaid coverage for smoking cessation medications has expanded; however, little research has been conducted to evaluate patient-level changes in medication use over time and its associated economic impact on health plans. OBJECTIVE: The aim of this study was to characterize trends in smoking cessation medication utilization between 2006 and 2017 within a Medicaid population and estimate per-member per-month (PMPM) costs to the health plan. METHODS: This study was a retrospective longitudinal analysis conducted among adult members of a Medicaid managed care plan in California. Pharmacy claims data from January 1, 2006 to December 31, 2017 were analyzed to estimate utilization and cost of smoking cessation medications. Additionally, data from 3164 members who filled prescription(s) for cessation medication(s) in 2017 were evaluated to quantify quit attempts and use of combination therapy. For members who had been prescribed bupropion SR, varenicline, or the nicotine patch, the extent to which the durations of therapy were consistent with the manufacturers\u27 recommended minimum duration of therapy were also assessed. RESULTS: The average PMPM expenditures for smoking cessation medications were approximately US$0.15 in 2017, compared with US$0.01-US$0.03 between 2006 and 2013. In 2017, a total of 3164 members initiated an estimated 3850 quit attempts, most commonly using the nicotine patch (57.5%) or varenicline (32.8%). Combination therapy accounted for 2.9% of quit attempts. The median therapy duration for the nicotine patch, varenicline, and bupropion SR was 28, 30, and 33 days, respectively, and for each of these medications, fewer than half of members filled prescriptions for the minimum recommended duration of therapy. CONCLUSIONS: Pharmacy claims data suggest that despite comprehensive coverage, most beneficiaries are underutilizing smoking cessation agents and are not completing the recommended treatment durations

Prevalence, Risk factors and Pharmacological treatment of Atrial Fibrillation in Older Hospitalized Patients in Vietnam

Background: The evidence about prevalence of atrial fibrillation (AF) in Vietnam is very limited and there have been no published studies about the pharmacological treatment of AF in older Vietnamese patients. This study aims to investigate the prevalence of AF, its associated factors and pharmacological treatment in older hospitalized patients in Vietnam.The secondary aim is to investigate the impact of frailty, an emerging geriatric syndrome which is still a new concept in Vietnam, on the pharmacological treatment of AF. Methods: We used data from a study of the prevalence of frailty in older hospitalized patients at the National Geriatric Hospital in Hanoi, Vietnam. Consecutive patients aged ≥60 years were recruited from 4/2015 to 10/2015. Results: A total of 461 patients was recruited, 56.8% were female, and mean age was 76.2±8.9. The prevalence of AF was 3.9% (18 patients). Amongst patients with AF, the most common medical conditions were hypertension (72.2%), followed by stroke (55.6%), heart failure (50.0%), type2 diabetes (44.4%). Living alone (OR=10.2, 95%CI 1.5–70.1), having a habit of using vitamins at home (OR=3.8, 95%CI 1.1–13.4), having heart failure (OR=31.3, 95%CI 9.6–101.8), and having type 2 diabetes (OR=3.5, 95%CI 1.2–10.7) were associated with the presence of AF on admission. All patients with AF had a high risk of stroke (CHA2DS2-VASc score≥2) and 72.2% of them had a high risk of bleeding with anticoagulant medications (HAS-BLED score≥3). Only 22.2% were anticoagulated on admission and 22.2% upon discharge, with no difference between frail and non-frail patients. Conclusions: The prevalence of AF among older hospitalized patients in Vietnam is similar to that reported in other countries. Anticoagulation for stroke prevention was underused, without any significant difference between frail and non-frail patients