Nevin Manimala

Mol Cancer Ther. 2021 Nov 2:molcanther.0511.2021. doi: 10.1158/1535-7163.MCT-21-0511. Online ahead of print.

ABSTRACT

The pro-survival MCL1 protein is overexpressed in many cancers, including B-cell non-Hodgkin lymphomas (B-NHL). S63845 is a highly specific inhibitor of MCL1. We analyzed mechanisms of sensitivity/resistance to S63845 in preclinical models of diffuse large B-cell lymphoma (DLBCL) and Burkitt lymphoma (BL). Annexin V-based cytotoxic assays, western blot, protein co-immunoprecipitation, and cell clones with manipulated expression of BCL2 family proteins were used to analyze mechanisms of sensitivity to S63845. Experimental in vivo therapy with S63845 and/or venetoclax was performed using patient-derived xenografts (PDX) of treatment-refractory B-NHL. A subset of DLBCL and majority of BL cell lines were sensitive to S63845. The level of BCL2 protein expression was the major determinant of resistance to S63845: BCL2 serves as a buffer for pro-apoptotic proteins released from MCL1 upon exposure to S63845. While BCL2-negative lymphomas were effectively eliminated by single-agent S63845, its combination with venetoclax was synthetically lethal in BCL2-positive PDX models. Concerning MCL1, both, the level of MCL1 protein expression, and its occupational status represent key factors mediating sensitivity to S63845. In contrast to MCL1-BIM / BAK1 complexes that prime lymphoma cells for S63845-mediated apoptosis, MCL1-NOXA complexes are associated with S63845 resistance. In conclusion, MCL1 represents a critical survival molecule for most BLs and a subset of BCL2-negative DLBCLs. The level of BCL2 and MCL1 expression and occupational status of MCL1 belong to the key modulators of sensitivity/resistance to S63845. Co-treatment with venetoclax can overcome BCL2-mediated resistance to S63845, and enhance efficacy of MCL1 inhibitors in BCL2-positive aggressive B-NHL.

PMID:34728569 | DOI:10.1158/1535-7163.MCT-21-0511

Proc Natl Acad Sci U S A. 2021 Nov 9;118(45):e2103619118. doi: 10.1073/pnas.2103619118.

ABSTRACT

After the 2020 US presidential election Donald Trump refused to concede, alleging widespread and unparalleled voter fraud. Trump’s supporters deployed several statistical arguments in an attempt to cast doubt on the result. Reviewing the most prominent of these statistical claims, we conclude that none of them is even remotely convincing. The common logic behind these claims is that, if the election were fairly conducted, some feature of the observed 2020 election result would be unlikely or impossible. In each case, we find that the purportedly anomalous fact is either not a fact or not anomalous.

PMID:34728563 | DOI:10.1073/pnas.2103619118

J Psychiatry Neurosci. 2021 Nov 2;46(6):E583-E591. doi: 10.1503/jpn.200154. Print 2021 Nov-Dec.

ABSTRACT

BACKGROUND: Whether infection with the hepatitis C virus (HCV) causes schizophrenia – and whether the associated risk reverses after anti-HCV therapy – is unknown; we aimed to investigate these topics.

METHODS: We conducted a nationwide, population-based cohort study using the Taiwan National Health Insurance Research Database (TNHIRD). A diagnosis of schizophrenia was based on criteria from the International Classification of Diseases, 9th revision (295.xx).

RESULTS: From 2003 to 2012, from a total population of 19 298 735, we enrolled 3 propensity-score-matched cohorts (1:2:2): HCV-treated (8931 HCV-infected patients who had received interferon-based therapy for ≥ 6 months); HCV-untreated (17 862); and HCV-uninfected (17 862) from the TNHIRD. Of the total sample (44 655), 82.81% (36 980) were 40 years of age or older. Of the 3 cohorts, the HCV-untreated group had the highest 9-year cumulative incidence of schizophrenia (0.870%, 95% confidence interval [CI] 0.556%-1.311%; p < 0.001); the HCV-treated (0.251%, 95% CI 0.091%-0.599%) and HCV-uninfected (0.118%, 95% CI 0.062%-0.213%) cohorts showed similar cumulative incidence of schizophrenia (p = 0.33). Multivariate Cox analyses showed that HCV positivity (hazard ratio [HR] 3.469, 95% CI 2.168-5.551) was independently associated with the development of schizophrenia. The HCV-untreated cohort also had the highest cumulative incidence of overall mortality (20.799%, 95% CI 18.739%-22.936%; p < 0.001); the HCV-treated (12.518%, 95% CI 8.707%-17.052%) and HCV uninfected (6.707%, 95% CI 5.533%-8.026%) cohorts showed similar cumulative incidence of mortality (p = 0.12).

LIMITATIONS: We were unable to determine the precise mechanism of the increased risk of schizophrenia in patients with HCV infection.

CONCLUSION: In a population-based cohort (most aged ≥ 40 years), HCV positivity was a potential risk factor for the development of schizophrenia; the HCV-associated risk of schizophrenia might be reversed by interferon-based antiviral therapy.

PMID:34728558 | DOI:10.1503/jpn.200154

RMD Open. 2021 Nov;7(3):e001694. doi: 10.1136/rmdopen-2021-001694.

ABSTRACT

OBJECTIVES: To compare current all-cause mortality rates in rheumatoid arthritis (RA), ankylosing spondylitis (AS), psoriatic arthritis (PsA), systemic lupus erythematosus (SLE) and systemic sclerosis (SSc) versus general population.

METHODS: In this population-based, retrospective cohort study, anonymised data on 11 186 586 citizens, including all patients with RA (42 735, 79% female), AS (9707, 43% female), PsA (13 779, 55% female), SLE (10 440, 89% female) and SSc (2277, 88% female), (median age of 64/47/54/53/59 years at study entry, respectively), under prescribed treatment between 2015 and 2019, were extracted from the electronic database covering nearly 99% of the Greek population.

RESULTS: After 1:5 (patients:general population) matching for gender/age, we found that survival was worse in SSc, followed by SLE and inflammatory arthritis. Compared with the general population HRs for death increased from the first 3 years to 5 years of observation possibly due to increases in disease duration: RA (from 0.63 to 1.13 (95% CI: 1.05 to 1.22), AS (from 0.62 to 1.01, (95% CI: 0.76 to 1.33)), PsA (from 0.68 to 1.06, (95% CI: 0.88 to 1.28)), SLE (from 1.52 to 1.98, (95% CI: 1.67 to 2.33)) and SSc (from 2.27 to 4.24, (95% CI: 3.19 to 5.63)). In both SLE and SSc mortality was increased in men than women and in patients younger than 50 years.

CONCLUSIONS: Survival rates over 5 years in inflammatory arthritis under treatment are currently becoming comparable (AS/PsA) or slightly higher (RA) than those of the general population. However, all-cause mortality is almost twofold and fourfold higher in SLE and SSc, respectively, being even higher for male and younger patients.

PMID:34728554 | DOI:10.1136/rmdopen-2021-001694

J Neurointerv Surg. 2021 Nov 2:neurintsurg-2021-018017. doi: 10.1136/neurintsurg-2021-018017. Online ahead of print.

ABSTRACT

BACKGROUND: Acute isolated posterior cerebral artery occlusions (aPCAOs) were excluded or under-represented in major randomized trials of mechanical thrombectomy (MT). The benefit of MT in comparison to intravenous tissue plasminogen activator (alteplase; IV-tPA) alone in these patients remains controversial and uncertain.

METHODS: We performed a systematic search of PubMed, MEDLINE, and EMBASE databases for articles comparing MT with or without bridging IV-tPA and IV-tPA alone for aPCAO using keywords (‘posterior cerebral artery’, ‘thrombolysis’ and ‘thrombectomy’) with Boolean operators. Extracted data from patients reported in the studies were pooled into groups (MT vs IV-tPA alone) for comparison. Estimated rates for favorable outcome (modified Rankin scale score 0-2), symptomatic intracranial hemorrhage (sICH), and mortality were extracted.

RESULTS: Seven articles (201 MT patients, 64 IV-tPA) were included, all retrospective. There was no statistically significant difference between pooled groups in median age, median presentation National Institutes of Health Stroke Scale (NIHSS) score, PCAO segment, and median time from symptom onset to puncture or needle. The recanalization rate was significantly higher in the MT group than the IV-tPA group (85.6% vs 53.1%, p<0.00001). Odds ratios for favorable outcome (OR 1.5, 95% CI 0.8 to 2.5), sICH (OR 1.1, 95% CI 0.2 to 5.5), and mortality (OR 1.4, 95% CI 0.5 to 3.6) did not significantly favor any modality.

CONCLUSIONS: We found no significant differences in odds of favorable outcome, sICH, and mortality in MT and IV-tPA in comparable aPCAO patients, despite superior MT recanalization rates. Equipoise remains regarding the optimal treatment modality for these patients.

PMID:34728545 | DOI:10.1136/neurintsurg-2021-018017

Diabetes Care. 2021 Nov 2:dc210278. doi: 10.2337/dc21-0278. Online ahead of print.

ABSTRACT

OBJECTIVE: The aim of the study was to evaluate remission of type 2 diabetes following a short-term intervention with insulin glargine, sitagliptin/metformin, and lifestyle approaches.

RESEARCH DESIGN AND METHODS: In this open multicenter trial, 102 patients with type 2 diabetes were randomized to 1) a 12-week intervention with sitagliptin/metformin, insulin glargine and lifestyle therapy, or 2) control group. Participants with HbA_1c <7.3% (<56 mmol/mol) at 12 weeks were asked to stop diabetes medications and were followed for evidence of relapse over 52 weeks. Diabetes relapse criteria included HbA_1c ≥6.5% (≥48 mmol/mol), ≥50% of capillary glucose readings >10 mmol/L over 1 week, and reinitiation of diabetes medications with or without abnormal fasting plasma glucose (FPG) or 2-h plasma glucose on an oral glucose tolerance test (OGTT). Time-to-relapse analysis was conducted to compare the treatment groups with (primary analysis) and without (supplementary analysis) FPG/OGTT relapse criteria.

RESULTS: With the FPG/OGTT relapse criteria included, the hazard ratio (HR) of relapse was 0.72 (95% CI 0.47-1.10) in the intervention group compared with the control group (primary analysis), and the number of participants remaining in remission was not significantly different between treatment groups at 24, 36, 48, and 64 weeks. In the supplementary analyses without these criteria, HR of relapse was 0.60 (95% CI 0.39-0.95), and the number of participants remaining in remission was significantly higher (26 vs. 10%) in the intervention group at 36 weeks.

CONCLUSIONS: Although our primary outcome was not statistically significant, the tested approach deserves further study with further optimization of its components.

PMID:34728531 | DOI:10.2337/dc21-0278

Diabetes Care. 2021 Nov 2:dc210496. doi: 10.2337/dc21-0496. Online ahead of print.

ABSTRACT

OBJECTIVE: To estimate difference in population-level glycemic control and the emergence of diabetes complications given a theoretical scenario in which non-White youth and young adults (YYA) with type 1 diabetes (T1D) receive and follow an equivalent distribution of diabetes treatment regimens as non-Hispanic White YYA.

RESEARCH DESIGN AND METHODS: Longitudinal data from YYA diagnosed 2002-2005 in the SEARCH for Diabetes in Youth Study were analyzed. Based on self-reported race/ethnicity, YYA were classified as non-White race or Hispanic ethnicity (non-White subgroup) versus non-Hispanic White race (White subgroup). In the White versus non-White subgroups, the propensity score models estimated treatment regimens, including patterns of insulin modality, self-monitored glucose frequency, and continuous glucose monitoring use. An analysis based on policy evaluation techniques in reinforcement learning estimated the effect of each treatment regimen on mean hemoglobin A_1c (HbA_1c) and the prevalence of diabetes complications for non-White YYA.

RESULTS: The study included 978 YYA. The sample was 47.5% female and 77.5% non-Hispanic White, with a mean age of 12.8 ± 2.4 years at diagnosis. The estimated population mean of longitudinal average HbA_1c over visits was 9.2% and 8.2% for the non-White and White subgroup, respectively (difference of 0.9%). Within the non-White subgroup, mean HbA_1c across visits was estimated to decrease by 0.33% (95% CI -0.45, -0.21) if these YYA received the distribution of diabetes treatment regimens of the White subgroup, explaining ∼35% of the estimated difference between the two subgroups. The non-White subgroup was also estimated to have a lower risk of developing diabetic retinopathy, diabetic kidney disease, and peripheral neuropathy with the White youth treatment regimen distribution (P < 0.05), although the low proportion of YYA who developed complications limited statistical power for risk estimations.

CONCLUSIONS: Mathematically modeling an equalized distribution of T1D self-management tools and technology accounted for part of but not all disparities in glycemic control between non-White and White YYA, underscoring the complexity of race and ethnicity-based health inequity.

PMID:34728528 | DOI:10.2337/dc21-0496

Can J Surg. 2021 Nov 2;64(6):E588-E593. doi: 10.1503/cjs.020219. Print 2021 Nov-Dec.

ABSTRACT

BACKGROUND: Given the rising prevalence of subways in combination with an increasing incidence of subway-related injuries, understanding subway-related trauma is becoming ever more relevant. The aim of this study was to characterize the potential causes, injury characteristics and outcomes of subway-related trauma at a level 1 adult trauma centre in Toronto, Ontario.

METHODS: We conducted a retrospective cohort study to identify patients who presented to the emergency department a level 1 adult trauma centre with a subway-related injury between Jan. 1, 2010, and Dec. 31, 2018. Patients were identified via International Statistical Classification of Diseases and Related Health Problems, 10th Revision E-codes (X81, Y02, V050, V051 and W17). We then further screened for descriptions of subway-related injuries. Patients whose injuries did not involve a moving subway train were excluded.

RESULTS: We identified 51 patients who presented to the emergency department after being hit by a moving subway train. The majority of incidents (39 [76%]) were due to self-harm, 10 (20%) were unintentional injuries, and 2 (4%) were due to assault. The presence of alcohol was detected in 8 patients (80%) with unintentional injuries and 3 (8%) of those with self-inflicted injuries. Thirteen patients (25%) had a systolic blood pressure less than 90 mm Hg. The median Injury Severity Score was 17 (interquartile range 9-29). Seventeen patients (33%) presented with severe injuries (Abbreviated Injury Scale score ≥ 3) in 1 body region, and 19 (37%) had severe injuries in 2 or more body regions. The most common isolated severe injury was in the lower extremity, and the most common combinations of severe injuries were in the head and lower extremity, and head and thorax. Ten patients (20%) were declared dead in the emergency department. Of the 41 patients who survived their initial presentation, 12 (29%) went directly to the operating room, and 17 (41%) were transferred to the intensive care unit. The overall mortality rate was 29%.

CONCLUSION: Patients with subway-related injuries experienced high mortality rates and severe injuries. Most incidents were due to self-harm or alcohol-related. Further research into early identification of those at risk and optimal prevention strategies is necessary to curb further incidents.

PMID:34728524 | DOI:10.1503/cjs.020219

BMJ Glob Health. 2021 Nov;6(11):e007177. doi: 10.1136/bmjgh-2021-007177.

ABSTRACT

Cause-specific mortality estimates for 11 countries located in the WHO’s South East Asia Region (WHO SEAR) are generated periodically by the Global Burden of Disease (GBD) and the WHO Global Health Estimates (GHE) analyses. A comparison of GBD and GHE estimates for 2019 for 11 specific causes of epidemiological importance to South East Asia was undertaken. An index of relative difference (RD) between the estimated numbers of deaths by sex for each cause from the two sources for each country was calculated, and categorised as marginal (RD=±0%-9%), moderate (RD=±10%-19%), high (RD=±20%-39%) and extreme (RD>±40%). The comparison identified that the RD was >10% in two-thirds of all instances. The RD was ‘high’ or ‘extreme’ for deaths from tuberculosis, diarrhoea, road injuries and suicide for most SEAR countries, and for deaths from most of the 11 causes in Bangladesh, DPR Korea, Myanmar, Nepal and Sri Lanka. For all WHO SEAR countries, mortality estimates from both sources are based on statistical models developed from an international historical cause-specific mortality data series that included very limited empirical data from the region. Also, there is no scientific rationale available to justify the reliability of one set of estimates over the other. The characteristics of national mortality statistics systems for each WHO SEAR country were analysed, to understand the reasons for weaknesses in empirical data. The systems analysis identified specific limitations in structure, organisation and implementation that affect data completeness, validity of causes of death and vital statistics production, which vary across countries. Therefore, customised national strategies are required to strengthen mortality statistics systems to meet immediate and long-term data needs for health policy and research, and reduce dependence on current unreliable modelled estimates.

PMID:34728480 | DOI:10.1136/bmjgh-2021-007177

BMJ Glob Health. 2021 Nov;6(11):e006760. doi: 10.1136/bmjgh-2021-006760.

ABSTRACT

This paper describes the lessons from scaling up a verbal autopsy (VA) intervention to improve data about causes of death according to a nine-domain framework: governance, design, operations, human resources, financing, infrastructure, logistics, information technologies and data quality assurance. We use experiences from China, Myanmar, Papua New Guinea, Philippines and Solomon Islands to explore how VA has been successfully implemented in different contexts, to guide other countries in their VA implementation. The governance structure for VA implementation comprised a multidisciplinary team of technical experts, implementers and staff at different levels within ministries. A staged approach to VA implementation involved scoping and mapping of death registration processes, followed by pretest and pilot phases which allowed for redesign before a phased scale-up. Existing health workforce in countries were trained to conduct the VA interviews as part of their routine role. Costs included training and compensation for the VA interviewers, information technology (IT) infrastructure costs, advocacy and dissemination, which were borne by the funding agency in early stages of implementation. The complexity of the necessary infrastructure, logistics and IT support required for VA increased with scale-up. Quality assurance was built into the different phases of the implementation. VA as a source of cause of death data for community deaths will be needed for some time. With the right technical and political support, countries can scale up this intervention to ensure ongoing collection of quality and timely information on community deaths for use in health planning and better monitoring of national and global health goals.

PMID:34728477 | DOI:10.1136/bmjgh-2021-006760