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Genome-wide screens that have viability as a readout have been instrumental to identify essential genes. The development of gene knockout screens with the use of CRISPR-Cas has provided a more sensitive method to identify these genes. Here, we performed an exhaustive genome-wide CRISPR/Cas9 phenotypic rescue screen to identify modulators of cytotoxicity induced by the pioneer transcription factor, DUX4. Misexpression of DUX4 due to a failure in epigenetic repressive mechanisms underlies facioscapulohumeral muscular dystrophy (FHSD), a complex muscle disorder that thus far remains untreatable. As the name implies, FSHD generally starts in the muscles of the face and shoulder girdle. Our CRISPR/Cas9 screen revealed no key effectors other than DUX4 itself that could modulate DUX4 cytotoxicity, suggesting that treatment efforts in FSHD should be directed towards direct modulation of DUX4 itself. Our screen did however reveal some rare and unexpected genomic events, that had an important impact on the interpretation of our data. Our findings may provide important considerations for planning future CRISPR/Cas9 phenotypic survival screens.In the continuous review reorder point, base-stock (s, S) policy, the replenishment order is launched when the inventory position reaches the reorder point, s. It is commonly assumed that the inventory position is exactly equal to the reorder point at the moment the order is launched, when actually it could be lower at that moment. This implies neglecting the possible undershoots at the reorder point, which has a direct impact on the calculation of the expected shortages per replenishment cycle. This article presents a method for an exact calculation of the fill rate (fraction of demand that is immediately satisfied from shelf) which takes explicit account of the existence of undershoots and is applicable to any discrete demand distribution function in a context of lost sales. This method is based on the determination of the stock probability vector at the moment the replenishment order is launched. Furthermore, neglecting the undershoots is shown to lead to an overestimation of the fill rate, particularly when we move farther away from the unitary demand assumption. From a practical point of view, this behaviour involves underestimating the base-stock level, S, when a target fill rate is set for its determination. The method proposed in this paper overcomes these shortcomings.The incidence of vaccine preventable disease in Pakistan remains high despite a long-standing Expanded Program on Immunization (EPI). We describe vaccine completeness, timeliness and determinants of coverage from a remote rural cohort (2012-2014). Vaccination histories were taken from EPI records. Vaccination was complete if all doses were received according to the EPI schedule and timely if doses were not ≥3 days early or ≥ 28 days late. Three models are presented a multivariable logistic regression of household demographic and socioeconomic factors associated with complete vaccination, a multivariable mixed effects logistic regression assessing whether or not the vaccine was administered late (versus on-time), and a mixed effects multivariable Poisson regression model analysing the interval (in days) between vaccine doses. Of 959 enrolled children with full vaccination histories, 88.2 and 65.1% were fully vaccinated following either the pentavalent or DPT/HBV schedules if measles was excluded; coverage dropped to 50.0 and 27.1% when both doses of measles were included. Sixty-four (6.7%) were unvaccinated. Coverage and timeliness declined with subsequent doses. Migrating into the village after 1995 (95%CI 1.88 to 5.17) was associated with late vaccination. Being male, having an older father, and having parents with at least some formal education reduced the likelihood of a late dose. The interval between doses was consistent at 5 weeks (compared with the 4 weeks recommended by EPI). None of the socio-demographic variables were related to the likelihood of receiving full coverage. Vaccine coverage in Oshikhandass was higher than national averages. Measles vaccine coverage and timeliness were low; special consideration should be paid to this vaccine. The local vaccination schedule differed from the EPI, but the consistency suggests good local administration.Differences in drug responses in individuals are partly due to genetic variations in pharmacogenes, which differ among populations. Here, genome sequencing of 171 unrelated Thai individuals from all regions of Thailand was used to call star alleles of 51 pharmacogenes by Stargazer, determine allele and genotype frequencies, predict phenotype and compare high-impact variant frequencies between Thai and other populations. Three control genes, EGFR, VDR, and RYR1, were used, giving consistent results. Every individual had at least three genes with variant or altered phenotype. Forty of the 51 pharmacogenes had at least one individual with variant or altered phenotype. Moreover, thirteen genes had at least 25% of individuals with variant or altered phenotype including SLCO1B3 (97.08%), CYP3A5 (88.3%), CYP2C19 (60.82%), CYP2A6 (60.2%), SULT1A1 (56.14%), G6PD (54.39%), CYP4B1 (50.00%), CYP2D6 (48.65%), CYP2F1 (46.41%), NAT2 (40.35%), SLCO2B1 (28.95%), UGT1A1 (28.07%), and SLCO1B1 (26.79%). Allele frequencies of high impact variants from our samples were most similar to East Asian. Remarkably, we identified twenty predicted high impact variants which have not previously been reported. Our results provide information that contributes to the implementation of pharmacogenetic testing in Thailand and other Southeast Asian countries, bringing a step closer to personalized medicine.Surgical training using live animals such as pigs is one of the best ways of achieving skilled techniques and fostering confidence in preclinical medical students and surgeon trainees. However, due to animal welfare ethics, laboratory animals' usage for training should be kept to a minimum. We have developed a novel kidney organ model utilizing a simple procedure in which the kidney is first refluxed with N-vinyl-2-pyrrolidone (NVP) solution for 1 hour in its bath, followed by permeation for 23 hours, with a subsequent freshwater refluxed for 48 hours in the washing step. Surgical simulation of the prepared kidney model (NVP-fixed kidney) was compared with three types of other basic known simulation models (fresh kidney, freeze-thaw kidney, and FA-fixed kidney) by various evaluations. We found the NVP-fixed kidney to mimicked fresh kidney function the most, pertaining to the hardness, and strength of the renal parenchyma. Moreover, the NVP-fixed kidney demonstrated successful blood-like fluids perfusion and electrocautery. Further, we confirmed that surgical training could be performed under conditions closer to actual clinical practice. Our findings suggest that our model does not only contribute to improving surgical skills but also inspires the utilization of otherwise, discarded inedible livestock organs as models for surgical training.Neck circumference (NC) reflects the fat deposition in upper body and has potential to be used as a predictor of Non-Alcoholic Fatty Liver Disease (NAFLD). Our objectives were to examine the association of NC with NAFLD prevalence, and to determine the optimal cut-off of NC in identifying the presence of NAFLD among the employees of an academic institution in Bangkok, Thailand. click here In this cross-sectional study, 635 employees of an academic institution underwent anthropometric measurement and transient elastography following an overnight fast. NAFLD was defined as a CAP value >238 dB.m-1. The NAFLD prevalence in men and women were 66.17% and 46.22%, respectively. The mean NCs for men and women with NAFLD were higher (38.53±0.31 cm and 35.83±0.48 cm, respectively) than those without NAFLD (33.58±0.24 and 31.098±0.14 cm, respectively) (p less then 0.001). Metabolic markers including age, weight, BMI, NC, WC, WHR, FBS, triglycerides were significantly higher, HDL was significantly lower among participants with NAFLD compared to those without NAFLD (p less then 0.05). NC was independently associated with NAFLD among women with OR (95%CI) of 1.17 (1.05, 1.32). The optimal cut-offs of NC to predict NAFLD were 37.07 cm (sensitivity 70.50%; specificity 68.90%) and 32.07 cm (sensitivity 70.70%; specificity 62.10%), respectively for men and women. NC significantly correlated with NAFLD in women. The optimal cut-off points of 32 cm and 37 cm for men and women, which similar to Chinese populations. Therefore, it can be used as a cost-effective tool to predict NAFLD. Trial Registration Thai Clinical Trials Registry (TCTR20210329006).
Chronic diseases like diabetes, cardiovascular diseases and cancers are on the rise. Most of the risk factors of these diseases commence in Adolescence. Therefore, a cluster randomised controlled trial is designed to evaluate the effect of school-based health promotion intervention on the risk factors of chronic diseases.
Considering school as a cluster, twelve schools will be randomly selected from the public schools of Chandigarh, a city in India. After baseline assessment, six schools will be randomly allocated to intervention and six to the control arm. Study participants will be students of 8th grade (age 10-16 years), their parents and teachers. A sample of 360 students (12 clusters x 30 students) has been estimated to provide statistically valid inference. The PRECEDE PROCEED Model will be used to develop health promotion interventions to prevent the use of an unbalanced diet, physical inactivity, alcohol, and tobacco. Interventions will be implemented for six-months in the school setting. For studther health promotion interventions implemented in the school setting simultaneously targeting adolescents, teachers, and parents are effective. Using the PRECEDE-PROCEED model for planning, implementing, and evaluating the intervention as part of a cluster Randomized Controlled Trial design with DID analysis, could objectively assess the impact.
Epilepsy is one of the commonest chronic neurological disorders with serious health consequences. Treatment adherence is one of the determinants of seizure control. This study was designed to determine factors affecting antiepileptic drug adherence among children with epilepsy.
A cross sectional study was conducted on 192 children with epilepsy (≤14 years of age) on follow-up at a pediatric neurology clinic in Southern Ethiopia from January 1st to August 30th, 2019. Medication Adherence was measured using the eight-item Morisky's medication adherence scale. Logistic regression analysis was done to determine factors associated with antiepileptic drug adherence.
One hundred twenty-five (65%) of the study subjects were adherent to their medication. On multivariable analysis, factors predictive of good adherence included family size of ≤5 [AOR = 2.34, (95% CI 1.07, 5.10); P = 0.03] and duration of epilepsy (<1year [AOR = 5.83, (95% CI 1.48, 22.92); P = 0.012] and 1-2year [AOR = 4.58, (95% CI 1.12, 18.77); P = 0.035]). Monthly family income of <1000 Ethiopian Birr [AOR = 0.18, (95% CI 0.06, 0.61); P = 0.005] and presence of seizure attack in the past 3months [AOR = 0.23, 95% (CI 0.10, 0.55); P = 0.001] predicted poor antiepileptic drug adherence.
Adherence to antiepileptic drugs in children is low in our setting; low family income and occurrence of seizures while on treatment predicted poor adherence. Supplying free antiepileptic drugs to poor children and regular provision of information about expected treatment response to children with epilepsy and their caretakers may help improve adherence.
Adherence to antiepileptic drugs in children is low in our setting; low family income and occurrence of seizures while on treatment predicted poor adherence. Supplying free antiepileptic drugs to poor children and regular provision of information about expected treatment response to children with epilepsy and their caretakers may help improve adherence.
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