Nevin Manimala

Proc Natl Acad Sci U S A. 2021 Jun 29;118(26):e2100474118. doi: 10.1073/pnas.2100474118.

ABSTRACT

During synthesis of membrane proteins, transmembrane segments (TMs) of nascent proteins emerging from the ribosome are inserted into the central pore of the translocon (SecYEG in bacteria) and access the phospholipid bilayer through the open lateral gate formed of two helices of SecY. Here we use single-molecule fluorescence resonance energy transfer to monitor lateral-gate fluctuations in SecYEG embedded in nanodiscs containing native membrane phospholipids. We find the lateral gate to be highly dynamic, sampling the whole range of conformations between open and closed even in the absence of ligands, and we suggest a statistical model-free approach to evaluate the ensemble dynamics. Lateral gate fluctuations take place on both short (submillisecond) and long (subsecond) timescales. Ribosome binding and TM insertion do not halt fluctuations but tend to increase sampling of the open state. When YidC, a constituent of the holotranslocon, is bound to SecYEG, TM insertion facilitates substantial opening of the gate, which may aid in the folding of YidC-dependent polytopic membrane proteins. Mutations in lateral gate residues showing in vivo phenotypes change the range of favored states, underscoring the biological significance of lateral gate fluctuations. The results suggest how rapid fluctuations of the lateral gate contribute to the biogenesis of inner-membrane proteins.

PMID:34162707 | DOI:10.1073/pnas.2100474118

CMAJ Open. 2021 Jun 23;9(2):E703-E710. doi: 10.9778/cmajo.20200181. Print 2021 Apr-Jun.

ABSTRACT

BACKGROUND: Recreational cannabis use was legalized in Canada in October 2018. We aimed to determine the prevalence and correlates of cannabis consumption among pregnant individuals in a single Canadian city following national legalization.

METHODS: Over the period May to October 2019, we distributed an anonymous cross-sectional survey to pregnant patients attending family practice, midwifery, and low-risk and high-risk obstetrics clinics in Hamilton, Ontario. Eligibility was based on English literacy and current pregnancy. The survey included questions regarding lifetime and in-pregnancy cannabis use, intent for postpartum use and patterns of use. We also collected demographic information. We calculated descriptive statistics and performed logistic regression analyses to explore the relations between cannabis consumption and demographic characteristics.

RESULTS: Of 531 pregnant individuals approached, 478 agreed and were able to participate, for a 90% participation rate. Among these 478 respondents, 54 (11%) reported consuming cannabis at some point during the pregnancy and 20 (4%) reported currently consuming cannabis. Among the 460 respondents who intended to breastfeed, 23 (5%) planned to consume cannabis during the postpartum period. Of 20 current users, 13 (65%) reported consuming cannabis at least weekly and 19 (95%) reported nausea, sleep problems or anxiety as reasons for use. Respondents without postsecondary education had 10.0-fold (95% confidence interval [CI] 4.6-23.5) greater odds of prenatal cannabis consumption than university-educated respondents. In addition, respondents who reported that their partners used cannabis had 3.9-fold (95% CI 2.2-7.3) greater odds of prenatal cannabis consumption than those who reported that their partners did not use cannabis.

INTERPRETATION: Lower educational attainment and partners’ cannabis consumption were associated with greater odds of inpregnancy cannabis use. These results may help to inform early intervention strategies to decrease cannabis consumption during this vulnerable period of fetal and neonatal development.

PMID:34162662 | DOI:10.9778/cmajo.20200181

Cancer Epidemiol Biomarkers Prev. 2021 Jun 22:cebp.1727.2021. doi: 10.1158/1055-9965.EPI-20-1727. Online ahead of print.

ABSTRACT

BACKGROUND: The American Cancer Society (ACS) and the National Cancer Institute collaborate every 5-8 years to update the methods for estimating numbers of new cancer cases and deaths in the current year in the U.S. and in every state and the District of Columbia. In this paper, we re-evaluate the statistical method for estimating unavailable historical incident cases which are needed for projecting the current year counts.

METHODS: We compared the current county-level model developed in 2012 (M0) to three new models, including a state-level mixed effects model (M1) and two state-level hierarchical Bayes models with varying random effects (M2 and M3). We used 1996-2014 incidence data for 16 sex-specific cancer sites to fit the models. An average absolute relative deviation (AARD) comparing the observed to the model-specific predicted counts was calculated for each site. Models were also cross validated for 6 selected sex-specific cancer sites.

RESULTS: For the cross-validation, the AARD ranged from 2.8% to 33.0% for M0, 3.3% to 31.1% for M1, 6.6% to 30.5% for M2, and 10.4% to 393.2% for M3. M1 encountered the least technical issues in terms of model convergence and running time.

CONCLUSIONS: The state-level mixed effect model (M1) was overall superior in accuracy and computational efficiency and will be the new model for the ACS current year projection project.

IMPACT: In addition to predicting the unavailable state-level historical incidence counts for cancer surveillance, the updated algorithms have broad applicability for disease mapping and other activities of public health planning, advocacy and research.

PMID:34162657 | DOI:10.1158/1055-9965.EPI-20-1727

Cancer Epidemiol Biomarkers Prev. 2021 Jun 22:cebp.0058.2021. doi: 10.1158/1055-9965.EPI-21-0058. Online ahead of print.

ABSTRACT

BACKGROUND: The inverse observational association between body mass index (BMI) and lung cancer risk remains unclear. We assessed whether the association is explained by metabolic aberrations, residual confounding and within-person variability in smoking, and compared against other smoking-related cancers.

METHODS: We investigated the association between BMI, and its combination with a metabolic score (MS) of mid-blood pressure, glucose and triglycerides, with lung cancer and other smoking-related cancers in 778,828 individuals. We used Cox regression, adjusted and corrected for within-person variability in smoking (status/pack-years), calculated from 600,201 measurements in 221,958 participants.

RESULTS: Over a median follow-up of 20 years, 20,242 smoking-related cancers (6,735 lung cancers) were recorded. Despite adjustment and correction for substantial within-person variability in smoking, BMI remained inversely associated with lung cancer (hazard ratio per standard deviation increase, 0.87 [95% confidence interval 0.85-0.89]). Individuals with BMI<25 kg/m2 and high MS had the highest risk (hazard ratio 1.52 [1.44-1.60] vs BMI{greater than or equal to}25 with low MS). These associations were weaker and non-significant amongst non-smokers. Similar associations were observed for head and neck cancers and oesophageal squamous cell carcinoma, whereas for other smoking-related cancers, we generally observed positive associations with BMI.

CONCLUSIONS: The increased lung cancer risk with low BMI and high MS is unlikely due to residual confounding and within-person variability in smoking. However, similar results for other cancers strongly related to smoking suggests a remaining, unknown, effect of smoking.

IMPACT: Extensive smoking-adjustments may not capture all the effects of smoking on the relationship between obesity-related factors and risk of smoking-related cancers.

PMID:34162656 | DOI:10.1158/1055-9965.EPI-21-0058

BMJ Open. 2021 Jun 23;11(6):e045897. doi: 10.1136/bmjopen-2020-045897.

ABSTRACT

INTRODUCTION: Respiratory distress syndrome is a complication of prematurity and extremely preterm infants born before 28 weeks’ gestation often require endotracheal intubation and mechanical ventilation. In this high-risk population, mechanical ventilation is associated with lung injury and contributes to bronchopulmonary dysplasia. Therefore, clinicians attempt to extubate infants as quickly and use non-invasive respiratory support such as nasal continuous positive airway pressure (CPAP) to facilitate the transition. However, approximately 60% of extremely preterm infants experience ‘extubation failure’ and require reintubation. While CPAP pressures of 5-8 cm H2O are commonly used, the optimal CPAP pressure is unknown, and higher pressures may be beneficial in avoiding extubation failure. Our trial is the Extubation CPAP Level Assessment Trial (ÉCLAT). The aim of this trial is to compare higher CPAP pressures 9-11 cm H2O with a current standard pressures of 6-8 cmH2O on extubation failure in extremely preterm infants.

METHODS AND ANALYSIS: 200 extremely preterm infants will be recruited prior to their first extubation from mechanical ventilation to CPAP. This is a parallel group randomised controlled trial. Infants will be randomised to one of two set CPAP pressures: CPAP 10 cmH2O (intervention) or CPAP 7 cmH2O (control). The primary outcome will be extubation failure (reintubation) within 7 days. Statistical analysis will follow standard methods for randomised trials on an intention to treat basis. For the primary outcome, this will be by intention to treat, adjusted for the prerandomisation strata (GA and centre). We will use the appropriate parametric and non-parametric statistical tests.

ETHICS AND DISSEMINATION: Ethics approval has been granted by the Monash Health Human Research Ethics Committees. Amendments to the trial protocol will be submitted for approval. The findings of this study will be written into a clinical trial report manuscript and disseminated via peer-reviewed journals (on-line or in press) and presented at national and international conferences.Trial registration numberACTRN12618001638224; pre-results.

PMID:34162644 | DOI:10.1136/bmjopen-2020-045897

Emerg Med J. 2021 Jun 23:emermed-2020-210586. doi: 10.1136/emermed-2020-210586. Online ahead of print.

ABSTRACT

BACKGROUND: The COVID-19 pandemic has led to a surge in critically unwell patients with type 1 respiratory failure. In an attempt to reduce the number of patients requiring mechanical ventilation, prone positioning (PP) of non-intubated patients has been added to many hospital guidelines around the world. We set out to conduct a systematic review of the evidence relating to PP in the non-intubated patient with type 1 respiratory failure secondary to COVID-19 and other causes.

METHODS: The review was conducted in accordance with the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) statement. A literature search of major databases and grey sources was conducted. Studies were assessed for inclusion by two authors according to prespecified criteria. Data collection processes, analysis and risk of bias assessment were planned.

RESULTS: 31 studies were included for analysis. These consisted of prospective and retrospective case series, cohort studies and case reports. None of the studies included a comparison group. No statistical analysis was performed. Descriptive data of included studies and narrative synthesis are presented.

CONCLUSIONS: No high-quality randomised controlled trials were found and thus evidence in relation to PP as a treatment for non-intubated patients with type 1 respiratory failure is lacking.

PMID:34162630 | DOI:10.1136/emermed-2020-210586

BMJ. 2021 Jun 23;373:n1343. doi: 10.1136/bmj.n1343.

ABSTRACT

OBJECTIVE: To estimate changes in life expectancy in 2010-18 and during the covid-19 pandemic in 2020 across population groups in the United States and to compare outcomes with peer nations.

DESIGN: Simulations of provisional mortality data.

SETTING: US and 16 other high income countries in 2010-18 and 2020, by sex, including an analysis of US outcomes by race and ethnicity.

POPULATION: Data for the US and for 16 other high income countries from the National Center for Health Statistics and the Human Mortality Database, respectively.

MAIN OUTCOME MEASURES: Life expectancy at birth, and at ages 25 and 65, by sex, and, in the US only, by race and ethnicity. Analysis excluded 2019 because life table data were not available for many peer countries. Life expectancy in 2020 was estimated by simulating life tables from estimated age specific mortality rates in 2020 and allowing for 10% random error. Estimates for 2020 are reported as medians with fifth and 95th centiles.

RESULTS: Between 2010 and 2018, the gap in life expectancy between the US and the peer country average increased from 1.88 years (78.66 v 80.54 years, respectively) to 3.05 years (78.74 v 81.78 years). Between 2018 and 2020, life expectancy in the US decreased by 1.87 years (to 76.87 years), 8.5 times the average decrease in peer countries (0.22 years), widening the gap to 4.69 years. Life expectancy in the US decreased disproportionately among racial and ethnic minority groups between 2018 and 2020, declining by 3.88, 3.25, and 1.36 years in Hispanic, non-Hispanic Black, and non-Hispanic White populations, respectively. In Hispanic and non-Hispanic Black populations, reductions in life expectancy were 18 and 15 times the average in peer countries, respectively. Progress since 2010 in reducing the gap in life expectancy in the US between Black and White people was erased in 2018-20; life expectancy in Black men reached its lowest level since 1998 (67.73 years), and the longstanding Hispanic life expectancy advantage almost disappeared.

CONCLUSIONS: The US had a much larger decrease in life expectancy between 2018 and 2020 than other high income nations, with pronounced losses among the Hispanic and non-Hispanic Black populations. A longstanding and widening US health disadvantage, high death rates in 2020, and continued inequitable effects on racial and ethnic minority groups are likely the products of longstanding policy choices and systemic racism.

PMID:34162598 | DOI:10.1136/bmj.n1343

Ann Clin Lab Sci. 2021 May;51(3):400-407.

ABSTRACT

OBJECTIVE: Monoclonal protein (MP) exists in various diseases, and capillary electrophoresis (CE) has been widely used to detect MP. However, there is not much research on the application value of MP in the differential diagnosis of monoclonal gammopathies. This study aimed to explore MP’s cutoff value for the differential diagnosis of multiple myeloma (MM) and other monoclonal gammopathies (MGs).

METHODS: A retrospective analysis of 8167 cases was conducted. Serum MP was detected by CE, and the patients’ clinical information was collected from the clinical database of our hospital.

RESULTS: 985 cases had MP with high peaks, and 91.1% were diagnosed with malignant diseases. The MP showed small peaks in 471 cases, and only 24.4% were diagnosed with malignant diseases. Among the MPs, the IgG-κ type was the most common type, followed by the IgG-λ, IgA-κ, IgA-λ, free λ light chain, IgM-κ, free κ light chain, double clone, and IgM-λ types. Differences in the MP of the IgG, IgA, IgM, and FLC types between the MM group and MGUS group were statistically different (P<0.01). The MP of the IgG, IgA, and FLC types showed clear specificity and sensitivity in discriminating MM from other monoclonal gammopathies in ROC curve analysis. Serum IgM had statistical significance in the differential diagnosis between WM and other MGs (P<0.01). However, there was no statistical significance in the differential diagnosis between MM and other MGs (P=0.140). The cutoff values of the MP of the IgG, IgA, and FLC types were >18.67g/L, >13.86g/L, and >10.15g/L, respectively, for the differential diagnosis of MM and other MGs. The cutoff value of the MP of IgM for the WM diagnosis was >37.75 g/L.

CONCLUSION: CE has good clinical application value in the diagnosis of monoclonal gammopathies, and MP can be used in the differential diagnosis of MM and other monoclonal gammopathies.

PMID:34162571

Respir Investig. 2021 Jun 20:S2212-5345(21)00081-2. doi: 10.1016/j.resinv.2021.05.001. Online ahead of print.

ABSTRACT

BACKGROUND: Asthma patients often feel satisfied with their current treatment, even when they have been diagnosed as uncontrolled by physicians. The present study investigated the differences in the evaluation of asthma control levels between patients and physicians, and the prediction of future risks.

METHODS: Asthma patients receiving inhaled corticosteroid/long-acting beta-2 agonists for 4 weeks or more were enrolled and followed-up for 24 weeks. Asthma control levels were evaluated using the following guidelines: Asthma Prevention and Management Guideline, Japan (JGL) and Global Initiative for Asthma (GINA) by physicians, and the Japan Asthma Control Survey (JACS) and a 6-item Asthma Control Questionnaire (ACQ6) by patients, at weeks 0 and 24. Analysis for predictive factors influencing exacerbation was performed using JGL, GINA, JACS, and ACQ6 at week 0.

RESULTS: A total of 420 patients were enrolled. Comparison of the distribution of asthma control levels assessed by physicians and patients showed no statistically significant difference between JGL and JACS (P = 0.19), suggesting a symmetric distribution, while ACQ6 demonstrated a significant difference versus JGL and GINA (both P < 0.001). The predictive factors for exacerbation were unscheduled visits based on GINA (rate ratio; 0.25, 95% CI; 0.14, 0.44), and the use of oral steroids on 3 consecutive days based on JGL (rate ratio; 0.42, 95% CI 0.22, 0.82) and JACS (rate ratio; 0.22, 95% CI; 0.13, 0,40).

CONCLUSIONS: Our study suggests that evaluation based on treatment guidelines and the questionnaire validated according to the local treatment guidelines is important for improved assessment of asthma control levels and the reduction of future risk.

CLINICAL TRIAL REGISTRATION NUMBER: UMIN000030419.

PMID:34162527 | DOI:10.1016/j.resinv.2021.05.001

J Pediatr Urol. 2021 Jun 10:S1477-5131(21)00304-1. doi: 10.1016/j.jpurol.2021.06.004. Online ahead of print.

ABSTRACT

INTRODUCTION: Incidence of pediatric urinary stone disease (PUSD) has increased over recent decades. Innovations in ureteroscopic technology has expanded the role of endourologic stone management in children. However, there is currently no consensus on the optimal use of ureteroscopy (URS) within the heterogenous PUSD population.

OBJECTIVE: The primary objective was to investigate the rate of 30-day unplanned readmissions in pediatric patients after URS. The secondary objective was to examine the influence of demographic, perioperative, postoperative, and reoperation variables as predictors of an increased risk of unplanned readmission in this sample.

STUDY DESIGN: A secondary analysis was performed on retrospectively collected data from the National Surgical Quality Improvement Program Pediatric between 2015 and 2018. Pediatric patients diagnosed with PUSD and treated with URS were identified. Patients undergoing concurrent or additional surgeries during the URS procedure were excluded. Data on demographic, perioperative, postoperative, and unplanned reoperation variables were examined for their possible influence on 30-day unplanned readmissions. Descriptive statistics were used to characterize the study cohort. Continuous and categorical variables were analyzed using independent samples t-test, one-way ANOVA with Tukey post-hoc test, and Chi-square Tests or Fisher’s Exact Test, respectfully. Multivariate analysis was performed using stepwise logistic regression.

RESULTS: A total of 2510 patients were identified within the study period. The majority of children undergoing URS were between 12 and 18 years of age (66.1%), female (56.9%), and had renal calculi (45.2%). Of these, 162 (6.5%) experienced a 30-day unplanned readmission related to the URS procedure. The most common reasons for an unplanned readmission was urinary tract infection (31.4%), new/unresolved stone (28.3%), and postoperative pain (8.2%). Multivariate modelling showed that females (Relative Risk [RR]: 2.03; 95% Confidence Interval [95%CI]: 1.34-3.07), patients with renal stones (RR: 1.77; 95%CI: 1.10-2.83), and inpatients at the time of surgery (RR: 1.61; 95%CI: 1.03-2.51) were more at risk of an unplanned readmission within 30-days of an URS procedure.

CONCLUSION: This study reports on short-term unplanned readmission rates in pediatric patients who underwent an URS procedure. Further it highlights possible predictors of unplanned readmission rates within a sampling of patients from NSQIP affiliated institutions. The findings from this study can be used to guide future studies around the safe use of URS in pediatric patients.

PMID:34162516 | DOI:10.1016/j.jpurol.2021.06.004