Nevin Manimala

Blood. 2022 Jun 16:blood.2021015325. doi: 10.1182/blood.2021015325. Online ahead of print.

ABSTRACT

Detailed genomic and epigenomic analyses of MECOM (the MDS1 and EVI1 complex locus) have revealed that inversion or translocation of chromosome 3 drive inv(3)/t(3;3) myeloid leukemias via structural rearrangement of an enhancer which upregulates transcription of EVI1. Here we identify a novel, previously unannotated oncogenic RNA-splicing derived isoform of EVI1 which is frequently present in inv(3)/t(3;3) AML and directly contributes to leukemic transformation. This EVI1 isoform is generated by oncogenic mutations in the core RNA splicing factor SF3B1, which is mutated in >30% of inv(3)/t(3;3) myeloid neoplasm patients and thereby represents the single most commonly co-occurring genomic alteration in inv(3)/t(3;3) patients. SF3B1 mutations are statistically uniquely enriched in inv(3)/t(3;3) myeloid neoplasm patients and patient-derived cell lines compared with other forms of AML and promote mis-splicing of EVI1 generating an in-frame insertion of six amino acids at the 3′ end of the second Zinc finger domain of EVI1. Expression of this EVI1 splice variant enhanced the self-renewal of hematopoietic stem cells and introduction of mutant SF3B1 in mice bearing the humanized inv(3)(q21q26) allele resulted in generation of this novel EVI1 isoform in mice and hastened leukemogenesis in vivo. The mutant SF3B1 spliceosome depends upon an exonic splicing enhancer within EVI1 exon 13 to promote usage of a cryptic branch point and aberrant 3′ splice site within intron 12 resulting in the generation of this isoform. These data provide a mechanistic basis for the frequent co-occurrence of SF3B1 mutations as well as new insights into the pathogenesis of myeloid leukemias harboring inv(3)/t(3;3).

PMID:35709354 | DOI:10.1182/blood.2021015325

Traffic Inj Prev. 2022 Jun 16:1-7. doi: 10.1080/15389588.2022.2086979. Online ahead of print.

ABSTRACT

OBJECTIVE: While a large amount of work has been conducted on different types of crash injury severity models, model selection uncertainty remains a critical issue in traffic safety research. The objective of this study is to handle model selection uncertainty by combining multiple models.

METHODS: Motorcycle crashes in Michigan from 2010 to 2014 are collected for the analysis. A model averaging approach is used to integrate useful information from three commonly used crash injury severity models: multinomial logit model, ordered logit model, and ordered probit model to deal with the situation where the model selection uncertainty exists in crash data analysis. The ratios of model posterior probabilities between models are used to quantify the model selection uncertainty. In addition, the effectiveness of the method is illustrated by comparing it with the single-best model.

RESULTS: The ratios of model posterior probabilities among models approximate to 1. It means that three models have the same importance in statistical analysis of motorcycle injury severity, resulting in model selection uncertainty. The comparison between the results of model averaging approach and single-best model shows that the single-best model tends to overestimate the effects of risk factors on motorcycle injury severities because of ignoring the model selection uncertainty; parameter errors and confidence intervals of model averaging are greater and wider than those of the single-best model due to between-model uncertainty included in the model averaging; some risk factors are significant in the model averaging approach while not in the single-best model. Results from model averaging approach reveal that drunk or riding under influence, angle/sideswipe/head on crashes, speed limit of 35 mph or higher, and signal control play significant roles in the motorcycle crashes.

CONCLUSIONS: The study contributes to the existing crash injury-severity literature by developing a model averaging approach to explore the relationship between motorcyclist’s injury-severity and its contributing factors. The model averaging approach overcomes the limitations of the current crash injury-severity modeling approaches by (1) revealing the potential model selection uncertainty among injury-severity models with model posterior probabilities; (2) more reliably accounting for the effects of risk factors on motorcyclist’ injury severities through integrating all information from the candidate models; and (3) better presenting the underlying unreliability of the analysis results from each individual model.

PMID:35709312 | DOI:10.1080/15389588.2022.2086979

Eur J Prev Cardiol. 2022 Jun 16:zwac079. doi: 10.1093/eurjpc/zwac079. Online ahead of print.

ABSTRACT

AIMS: In patients with coronary heart disease (CHD), we investigated whether it is possible to accurately assess the probability of short-term control of risk factors (blood pressure, cholesterol, smoking) based on individual and large-area residential characteristics.

METHODS AND RESULTS: We merged individual data of participants from EUROASPIRE V who were hospitalized for CHD (2014-2017) and interviewed and examined for risk factor control (2016-2017), with large-area residential data provided by Eurostat for Nomenclature of Territorial Units for Statistics (NUTS) regions using postal codes. Data from 2562 CHD patients in 16 countries were linked to data from 60 NUTS 2 and 121 NUTS 3 regions. The median time between hospitalization and interview was 14 months. We developed prediction models to assess the probability of risk factor control at interview using data from the time of hospitalization: (i) baseline models including 35 variables on patients’ demographic, clinical, and socio-economic characteristics and (ii) extended models additionally considering nine variables on large-area residential characteristics. We calculated and internally validated c-indices to assess the discriminative ability of prediction models. Baseline models showed good discrimination with c-indices of 0.69, 0.70, and 0.76 for blood pressure control, cholesterol control, and smoking cessation, respectively. Extended models for blood pressure, cholesterol, and smoking yielded improved c-indices of 0.72, 0.71, and 0.78, respectively.

CONCLUSION: Our results indicate that the probability of risk factor control in CHD patients can be accurately assessed using individual and large-area residential characteristics, allowing for an identification of patients who are less likely to achieve risk factor targets.

PMID:35709302 | DOI:10.1093/eurjpc/zwac079

PLoS One. 2022 Jun 16;17(6):e0266371. doi: 10.1371/journal.pone.0266371. eCollection 2022.

ABSTRACT

PURPOSE: Higher levels of serum 25-hydroxyvitamin D 25(OHD) are associated with better prognosis in breast and colorectal cancer. However, the evidence is still inconclusive for bladder cancer (BC). Herein, we investigated the diagnosis and prognosis roles of serum levels of 25(OHD) in suspected BC patients presented by hematuria.

METHODS: This prospective cohort study involved suspected patients of BC presented with hematuria. Patients were evaluated by CT urogram, office cystoscopy and urine cytology with subsequent inpatient biopsy for positive findings. Baseline blood samples were collected for measurement of 25(OHD) by electrochemiluminescence binding assay at the time of diagnosis. Patients with non-muscle-invasive BC (NMIBC) underwent transurethral resection of bladder tumor (TURBT) and adjuvant intravesical chemotherapy or BCG instillation. Patients were followed up for their recurrence status during 10 to 24 months. Recurrence was defined as the first time of NMIBC pathological relapse during the follow up period.

RESULTS: A total of 115 patients were included in the final analysis. Patients had proven pathological BC (64 with NMIBC, and 20 with muscle invasive) and 31 patients were considered as control group. Controls were those patients with BC-free workup (including cytology, cystoscopy, and upper tract imaging). BC group showed a lower level of 25(OHD) than control group 16.47±5.88 versus 28.99±3.19 ng/mL (p<0.001). In addition, muscle invasive group also showed a lower level than NMIBC group 13.17±4.5 versus 17.49±5.04 ng/mL (P = 0.003). During the follow-up period of, tumor recurrence occurred in 16 (25%) of NMIBC patients. The baseline 25(OHD) were decreased in patients who experienced early recurrence; without being statistically significant (15.99 ± 5.17 vs. 18.38 ± 5.14 ng/mL; p = 0.08). 25(OHD) deficiency/insufficiency occurred in 5 (16.1%) and 64 (76.2%) in control and BC patients, respectively, (odds-ratios (OR): 2.13; 95% confidence intervals (CI), 1.52-2.99; P < 0.0001).

CONCLUSION: Serum 25(OHD) is significantly decreased in BC patients especially those with tumor muscle invasive group. However, the baseline serum 25(OHD) does not predict the recurrence in the NMIBC patients.

PMID:35709298 | DOI:10.1371/journal.pone.0266371

PLoS Genet. 2022 Jun 16;18(6):e1010251. doi: 10.1371/journal.pgen.1010251. Online ahead of print.

ABSTRACT

More than a decade of genome-wide association studies (GWASs) have identified genetic risk variants that are significantly associated with complex traits. Emerging evidence suggests that the function of trait-associated variants likely acts in a tissue- or cell-type-specific fashion. Yet, it remains challenging to prioritize trait-relevant tissues or cell types to elucidate disease etiology. Here, we present EPIC (cEll tyPe enrIChment), a statistical framework that relates large-scale GWAS summary statistics to cell-type-specific gene expression measurements from single-cell RNA sequencing (scRNA-seq). We derive powerful gene-level test statistics for common and rare variants, separately and jointly, and adopt generalized least squares to prioritize trait-relevant cell types while accounting for the correlation structures both within and between genes. Using enrichment of loci associated with four lipid traits in the liver and enrichment of loci associated with three neurological disorders in the brain as ground truths, we show that EPIC outperforms existing methods. We apply our framework to multiple scRNA-seq datasets from different platforms and identify cell types underlying type 2 diabetes and schizophrenia. The enrichment is replicated using independent GWAS and scRNA-seq datasets and further validated using PubMed search and existing bulk case-control testing results.

PMID:35709291 | DOI:10.1371/journal.pgen.1010251

PLoS One. 2022 Jun 16;17(6):e0270150. doi: 10.1371/journal.pone.0270150. eCollection 2022.

ABSTRACT

We urgently need answers to basic epidemiological questions regarding SARS-CoV-2 infection in pregnant and postpartum women and its effect on their newborns. While many national registries, health facilities, and research groups are collecting relevant data, we need a collaborative and methodologically rigorous approach to better combine these data and address knowledge gaps, especially those related to rare outcomes. We propose that using a sequential, prospective meta-analysis (PMA) is the best approach to generate data for policy- and practice-oriented guidelines. As the pandemic evolves, additional studies identified retrospectively by the steering committee or through living systematic reviews will be invited to participate in this PMA. Investigators can contribute to the PMA by either submitting individual patient data or running standardized code to generate aggregate data estimates. For the primary analysis, we will pool data using two-stage meta-analysis methods. The meta-analyses will be updated as additional data accrue in each contributing study and as additional studies meet study-specific time or data accrual thresholds for sharing. At the time of publication, investigators of 25 studies, including more than 76,000 pregnancies, in 41 countries had agreed to share data for this analysis. Among the included studies, 12 have a contemporaneous comparison group of pregnancies without COVID-19, and four studies include a comparison group of non-pregnant women of reproductive age with COVID-19. Protocols and updates will be maintained publicly. Results will be shared with key stakeholders, including the World Health Organization (WHO) Maternal, Newborn, Child, and Adolescent Health (MNCAH) Research Working Group. Data contributors will share results with local stakeholders. Scientific publications will be published in open-access journals on an ongoing basis.

PMID:35709239 | DOI:10.1371/journal.pone.0270150

PLoS One. 2022 Jun 16;17(6):e0269893. doi: 10.1371/journal.pone.0269893. eCollection 2022.

ABSTRACT

This Korean population-based study aimed to describe the patterns of hypothyroidism after adjuvant radiation therapy (RT) in patients with breast cancer. The Korean Health Insurance Review and Assessment Service database was searched for patients with invasive breast carcinomas. We calculated the cumulative incidence and incidence rates per 1,000 person-years of subsequent hypothyroidism and compared them using the log-rank test and the Cox proportional hazards model. Between 2007 and 2018, 117,135 women diagnosed with breast cancer with a median follow-up time of 4.6 years were identified. The 8-year incidence of hypothyroidism was 9.3% in patients treated with radiation and 8.6% in those treated without radiation (p = 0.002). The incidence rates per 1,000 person-years in the corresponding treatment groups were 6.2 and 5.7 cases, respectively. The hazard ratio (HR) in patients receiving RT was 1.081 (95% confidence interval [CI], 1.013-1.134; p = 0.002). After mastectomy, RT showed a trend toward a higher risk of hypothyroidism (HR = 1.248; 95% CI, 0.977-1.595; p = 0.076). Our study provides one of the largest population-based data analyses regarding the risk of hypothyroidism among Korean patients with breast cancer. The adjusted risk for patients treated with RT exceeded that for patients with breast cancer treated without RT. The effect was evident immediately after treatment and lasted up to approximately 9 years.

PMID:35709221 | DOI:10.1371/journal.pone.0269893

PLoS One. 2022 Jun 16;17(6):e0270019. doi: 10.1371/journal.pone.0270019. eCollection 2022.

ABSTRACT

OBJECTIVES: The objective of this research aimed to investigate the correlation involving serum albumin with diabetic retinopathy (DR) in patients with type 2 diabetes mellitus (T2DM).

METHODS: From 2011 to 2020, the National Health and Nutrition Examination Survey (NHANES) surveyed 45462 participants. We used the relevant data to conduct descriptive statistics, linear regression, and Logistic regression analysis.

RESULTS: After adjusting for age, sex, and race, as well as all other variables, serum albumin was significantly negatively related to DR (P<0.001). Furthermore, after controlling for confounding factors, the third quartile (Q3) and the fourth quartile (Q4) had quite a negative significant relationship with the incidence of DR (P<0.01). The second quartile had a significant positive correlation with DR, whereas the observed negative correlations were not statistically meaningful (P>0.05).

CONCLUSION: Albumin levels in the serum have a quantitatively significant negative correlation with DR. Serum albumin levels in the blood can be used as a reference point for protracted follow-up of people with T2DM.

PMID:35709212 | DOI:10.1371/journal.pone.0270019

PLoS One. 2022 Jun 16;17(6):e0267144. doi: 10.1371/journal.pone.0267144. eCollection 2022.

ABSTRACT

BACKGROUND: Since the COVID-19 pandemic, the demand for online courses has increased enormously. Therefore, finding new methods to improve medical education is imperative.

OBJECTIVE: The aim of this study was to compare the self-reports of the individual student-centered virtual teaching techniques (seminar versus fishbowl) in a group of medical students.

METHODS: During the second semester of 2020, students in the clinical phase of the study (n = 144) participated in the optional subject of Sports Medicine. The students were divided into 2 groups. One group (n = 72) received the knowledge transfer in the form of a virtual seminar, the other group (n = 72) in the form of a virtual fishbowl.

RESULTS: Virtual seminar and virtual fishbowl students gave insights into these teaching techniques. Most of the students from the virtual fishbowl group believed that the virtual fishbowl format allowed them to be more actively involved in learning. The mean quiz scores were statistically higher for students in the virtual fishbowl group than students in the virtual seminar group (p < 0. 001).

CONCLUSION: This study concluded that virtual seminars and virtual fishbowl formats could be served as structured learning and teaching formats. At the same time, the virtual fishbowl format can promote an active exchange of knowledge from students’ perspectives.

PMID:35709198 | DOI:10.1371/journal.pone.0267144

PLoS One. 2022 Jun 16;17(6):e0269339. doi: 10.1371/journal.pone.0269339. eCollection 2022.

ABSTRACT

Use of face coverings has been shown to reduce transmission of SARS-CoV-2. Despite encouragements from the CDC and other public health entities, resistance to usage of masks remains, forcing government entities to create mandates to compel use. The state of Oklahoma did not create a state-wide mask mandate, but numerous municipalities within the state did. This study compares case rates in communities with mandates to those without mandates, at the same time and in the same state (thus keeping other mitigation approaches similar). Diagnosed cases of COVID-19 were extracted from the Oklahoma State Department of Health reportable disease database. Daily case rates were established based upon listed city of residence. The daily case rate difference between each locality with a mask mandate were compared to rates for the portions of the state without a mandate. All differences were then set to a d0 point of reference (date of mandate implementation). Piecewise linear regression analysis of the difference in SARS-CoV-2 infection rates between mandated and non-mandated populations before and after adoption of mask mandates was then done. Prior to adopting mask mandates, those municipalities that eventually adopted mandates had higher transmission rates than the rest of the state, with the mean case rate difference per 100,000 people increasing by 0.32 cases per day (slope of difference = 0.32; 95% CI 0.13 to 0.51). For the post-mandate time period, the differences are decreasing (slope of -0.24; 95% CI -0.32 to -0.15). The pre- and post- mandate slopes differed significantly (p<0.001). The change in slope direction (-0.59; 95% CI -0.80 to -0.37) shows a move toward reconvergence in new case diagnoses between the two populations. Compared to rates in communities without mask mandates, transmission rates of SARS-CoV-2 slowed notably in those communities that adopted a mask mandate. This study suggests that government mandates may play a role in reducing transmission of SARS-CoV-2, and other infectious respiratory conditions.

PMID:35709189 | DOI:10.1371/journal.pone.0269339