Nevin Manimala

PLoS Comput Biol. 2021 Nov 19;17(11):e1009579. doi: 10.1371/journal.pcbi.1009579. Online ahead of print.

ABSTRACT

Organisms are composed of various cell types with specific states. To obtain a comprehensive understanding of the functions of organs and tissues, cell types have been classified and defined by identifying specific marker genes. Statistical tests are critical for identifying marker genes, which often involve evaluating differences in the mean expression levels of genes. Differentially expressed gene (DEG)-based analysis has been the most frequently used method of this kind. However, in association with increases in sample size such as in single-cell analysis, DEG-based analysis has faced difficulties associated with the inflation of P-values. Here, we propose the concept of discriminative feature of cells (DFC), an alternative to using DEG-based approaches. We implemented DFC using logistic regression with an adaptive LASSO penalty to perform binary classification for discriminating a population of interest and variable selection to obtain a small subset of defining genes. We demonstrated that DFC prioritized gene pairs with non-independent expression using artificial data and that DFC enabled characterization of the muscle satellite/progenitor cell population. The results revealed that DFC well captured cell-type-specific markers, specific gene expression patterns, and subcategories of this cell population. DFC may complement DEG-based methods for interpreting large data sets. DEG-based analysis uses lists of genes with differences in expression between groups, while DFC, which can be termed a discriminative approach, has potential applications in the task of cell characterization. Upon recent advances in the high-throughput analysis of single cells, methods of cell characterization such as scRNA-seq can be effectively subjected to the discriminative methods.

PMID:34797848 | DOI:10.1371/journal.pcbi.1009579

PLoS One. 2021 Nov 19;16(11):e0257979. doi: 10.1371/journal.pone.0257979. eCollection 2021.

ABSTRACT

Public health interventions such as social distancing and mask wearing decrease the incidence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, but it is unclear whether they decrease the viral load of infected patients and whether changes in viral load impact mortality from coronavirus disease 2019 (COVID-19). We evaluated 6923 patients with COVID-19 at six New York City hospitals from March 15-May 14, 2020, corresponding with the implementation of public health interventions in March. We assessed changes in cycle threshold (CT) values from reverse transcription-polymerase chain reaction tests and in-hospital mortality and modeled the impact of viral load on mortality. Mean CT values increased between March and May, with the proportion of patients with high viral load decreasing from 47.7% to 7.8%. In-hospital mortality increased from 14.9% in March to 28.4% in early April, and then decreased to 8.7% by May. Patients with high viral loads had increased mortality compared to those with low viral loads (adjusted odds ratio 2.34). If viral load had not declined, an estimated 69 additional deaths would have occurred (5.8% higher mortality). SARS-CoV-2 viral load steadily declined among hospitalized patients in the setting of public health interventions, and this correlated with decreases in mortality.

PMID:34797838 | DOI:10.1371/journal.pone.0257979

PLoS One. 2021 Nov 19;16(11):e0257335. doi: 10.1371/journal.pone.0257335. eCollection 2021.

ABSTRACT

Political elites both respond to public opinion and influence it. Elite policy messages can shape individual policy attitudes, but the extent to which they do is difficult to measure in a dynamic information environment. Furthermore, policy messages are not absorbed in isolation, but spread through the social networks in which individuals are embedded, and their effects must be evaluated in light of how they spread across social environments. Using a sample of 358 participants across thirty student organizations at a large Midwestern research university, we experimentally investigate how real social groups consume and share elite information when evaluating a relatively unfamiliar policy area. We find a significant, direct effect of elite policy messages on individuals’ policy attitudes. However, we find no evidence that policy attitudes are impacted indirectly by elite messages filtered through individuals’ social networks. Results illustrate the power of elite influence over public opinion.

PMID:34797826 | DOI:10.1371/journal.pone.0257335

J Orthop Trauma. 2021 Dec 1;35(12):e475-e480. doi: 10.1097/BOT.0000000000002127.

ABSTRACT

OBJECTIVES: (1) To evaluate adequacy and reproducibility of the gravity and manual stress imaging in the diagnosis of unstable ankle fractures and (2) to evaluate the diagnostic utility of lateral talar displacement ratio (LTDR) derived in relation to the talar body width on ankle stress imaging.

DESIGN: Retrospective cohort study.

SETTING: Level 1 Trauma Center.

PATIENTS: One hundred seventy consecutive patients who presented with supination-external rotation 2 ankle fractures (OTA/AO 44-B2.1) requiring dynamic stress testing.

INTERVENTION: Dynamic stress imaging to determine ankle stability.

MAIN OUTCOME MEASURE: Ankle instability and subsequent need for surgical fixation as determined by dynamic stress imaging.

RESULTS: No statistical significant difference was found between the adequacy of gravity stress radiographs and manual stress images in regards to surgical decision-making (P = 0.595). Using manual and gravity stress images, receiver operating characteristic curves were generated for medial clear space (MCS) (area under the curve = 0.793, 0.901) and LTDR (0.849, 0.850), corresponding to thresholds of 10.5% and 10.2% for manual and gravity, respectively. Seventy-three of 105 patients (69.5%) with MCS > 5 mm and 62 of 75 patients (82.7%) with LTDR > 10% were offered surgical intervention. Sixty-two of the 77 patients (80.5%) offered surgery had both MCS > 5 mm and LTDR > 10%.

CONCLUSION: This study shows that manual stress radiographs are just as effective as gravity stress radiographs in making an assessment of ankle fracture stability as there was no difference in diagnostic value between gravity and manual stress imaging in regards to surgical decision-making. Use of additional radiographic measurements such as the LTDR can provide additional information in determining stability when MCS is within a clinical gray area.

LEVEL OF EVIDENCE: Diagnostic Level III. See Instructions for Authors for a complete description of levels of evidence.

PMID:34797783 | DOI:10.1097/BOT.0000000000002127

J Orthop Trauma. 2021 Dec 1;35(12):654-659. doi: 10.1097/BOT.0000000000002117.

ABSTRACT

OBJECTIVES: To identify factors associated with the need for reoperations in patients treated surgically for fracture nonunion.

DESIGN: Retrospective cohort study.

SETTING: One urban Level 1 trauma center and an orthopaedic specialty hospital.

PATIENTS/PARTICIPANTS: This study included 365 patients who did not and 95 patients who did undergo a reoperation after nonunion repair.

INTERVENTION: All patients who underwent fracture nonunion repair were identified. Baseline demographic, injury, and surgical information were collected. These factors were compared between patients who did and did not require an unplanned reoperation.

MAIN OUTCOME MEASUREMENTS: An unplanned reoperation after index fracture nonunion surgery.

RESULTS: When compared with patients who did not undergo a reoperation after their index fracture nonunion surgery, patients who underwent at least 1 reoperation had a greater proportion of those who sustained an open fracture, a high-energy injury, initial neurologic or vascular injuries, the need for a flap or soft tissue graft at initial treatment, and lower extremity injuries with univariate analysis. Unplanned reoperation was also associated with diagnosis of “infected” nonunion at initial nonunion surgery. Multivariate analysis confirmed initial nerve or vascular injuries and positive infection status were statistically significant predictors of a reoperation.

CONCLUSIONS: Initial injury characteristics such as nerve or vascular injury at initial injury and positive infection status at the index nonunion surgery were associated with the need for a secondary surgery after nonunion repair. Appropriate care of these patients should be aimed at adjusting expectations of unplanned reoperation in the future and potentially enhanced treatment strategies.

LEVEL OF EVIDENCE: Prognostic Level III. See Instructions for Authors for a complete description of levels of evidence.

PMID:34797782 | DOI:10.1097/BOT.0000000000002117

Ann Am Thorac Soc. 2021 Nov 19. doi: 10.1513/AnnalsATS.202012-1562OC. Online ahead of print.

ABSTRACT

Rationale The long-term natural history of asthma in terms of successive severe exacerbations and the influence of each exacerbation on the course of the disease is not well studied. Objectives To investigate the long-term natural history of asthma among patients who are hospitalized for asthma for the first time in terms of the risk of future severe exacerbations, and heterogeneity in this risk across patients. Methods Using the administrative health databases of British Columbia, Canada (1997/01/01-2016/03/31), we created an incident cohort of patients with at least one asthma exacerbation that required inpatient care. We estimated the 5-year cumulative incidence of severe exacerbations after successive numbers of previous events. We used a joint frailty model to investigate the extent of between-individual variability in exacerbation risk and the associations of each exacerbation with the rate of subsequent events. Analyses were conducted separately for pediatric (<14 years old) and adult (≥14 years old) patients. Results Analyses were based on 3,039 pediatric (mean age at baseline 6.4, 35% female) and 5,442 (mean age at baseline 50.8, 68% female) adult patients. The 5-year rates of severe exacerbations after the first 3 events were 0.16, 0.29, and 0.35 for the pediatric group, and 0.14, 0.33, and 0.49 for the adult group. Both groups exhibited substantial variability in patient-specific risks of exacerbation: the mid-95% interval of 5-year risk of experiencing a severe exacerbation ranged from 11% to 24% in pediatric patients and from 8% to 40% in adult patients. After controlling for potential confounders, the first follow-up exacerbation was associated with an increase of 79% (95%CI 11%-189%) in the rate of subsequent events in the pediatric group, while this increase was 188% (95%CI 35%-615%) for the adult group. The effects of subsequent exacerbations were not statistically significant. Conclusions After the first severe exacerbation, the risk of subsequent events is substantially different among patients. The number of previous severe exacerbations carries nuanced prognostic information about future risk. Our results suggest that severe exacerbations in the early course of asthma detrimentally affect the course of the disease and risk of subsequent exacerbations.

PMID:34797732 | DOI:10.1513/AnnalsATS.202012-1562OC

J Chem Theory Comput. 2021 Nov 19. doi: 10.1021/acs.jctc.1c00919. Online ahead of print.

ABSTRACT

An extended theoretical benchmark set, NS372, for light main-group nuclear shieldings and NMR shifts has been constructed based on high-level GIAO-CCSD(T)/pcSseg-3//CCSD(T)/cc-pVQZ reference data. After removal of the large static-correlation cases O₃, F₃^–, and BH from the statistical evaluations for the ¹⁷O, ¹⁹F, and ¹¹B subsets, the benchmark comprises overall 372 shielding values in 117 molecules with a wide range of electronic-structure situations, containing 124 ¹H, 14 ¹¹B, 93 ¹³C, 43 ¹⁵N, 31 ¹⁷O, 47 ¹⁹F, 14 ³¹P, and 6 ³³S shielding constants. The CCSD(T)/pcSseg-3 data are shown to be close to the basis-set and method limit and thus provide an excellent benchmark to evaluate more approximate methods, such as density functional approaches. This dataset has been used to evaluate Hartree-Fock (HF) and MP2, and a wide range of exchange-correlation functionals from local density approximation (LDA) to generalized gradient approximations (GGAs) and meta-GGAs (focusing on their current-density functional implementations), as well as global hybrid, range-separated hybrid, local hybrid, and double-hybrid functionals. Starting with absolute shielding constants, the DSD-PBEP86 double hybrid is confirmed to provide the highest accuracy, with an aggregate relative mean absolute error (rel. MAE) of only 0.9%, followed by MP2 (1.1%). MP2 and double hybrids only show larger errors for a few systems with the largest static-correlation effects. The double-hybrid B2GP-PLYP, the two local hybrids cLH12ct-SsirPW92 and cLH12ct-SsifPW92, and the current-density functional meta-GGA cB97M-V follow closely behind (all 1.5%), as do some further functionals, cLH20t and cMN15-L (both 1.6%), as well as B2PLYP and KT3 (both 2.0%). Functionals on the lower rungs of the usual ladder offer the advantage of lower computational cost and access to larger molecules. Closer examination also reveals the best-performing methods for individual nuclei in the test set. Different ways of treating τ-dependent functionals are evaluated. When moving from absolute shielding constants to chemical shifts, some of the methods can benefit from systematic error compensation, and the overall error range somewhat narrows. Further methods now achieve the 2% threshold of relative MAEs, including functionals based on TPSS (TPSSh, cmPSTS).

PMID:34797677 | DOI:10.1021/acs.jctc.1c00919

Diagn Cytopathol. 2021 Nov 19. doi: 10.1002/dc.24904. Online ahead of print.

ABSTRACT

BACKGROUND: The Thyroid Imaging Reporting and Data System (TIRADS) was created to assess risk of thyroid nodules through ultrasound. Plenty classifications methods for thyroid nodules have already been created, but none of them have yet achieved global utilization. This study analyzed the performance of the American College of Radiology (ACR) TIRADS, its reproducibility and the impact of its utilization as a screening method in a large Cancer Center cohort.

METHODS: Thyroid nodules which underwent fine-needle aspiration (FNA) in a 1-year period were selected, with their ultrasound images retrospectively classified according to the ACR TI-RADS. Cytological evaluation of the nodules and final histology (whenever available) was used to assess risk of neoplasm (RON) and risk of malignancy (ROM) associated to each ACR-TIRADS category. Further analyses were also carried out according to recommendation or not of FNA by the ACR-TIRADS and nodule size. Inter-observer agreement for the system was also assessed.

RESULTS: A total of 1112 thyroid nodules were included. RON for each category according to final cytological diagnosis was 0% for TR1 and TR2, 2.1% for TR3; 15.6% for TR4 and 68.9% for TR5. No significant difference was observed between the RON of the categories for cases above or below 1.0 cm. Nodules that met the criteria for FNA had 3 times greater chance of a positive outcome. Substantial agreement (kappa 0.77) was seen between two different observers.

CONCLUSIONS: ACR TI-RADS scoring system has demonstrated to be an accurate method to stratify thyroid nodules in a Cancer Center, with a high reproducibility.

PMID:34797612 | DOI:10.1002/dc.24904

Transpl Int. 2021 Nov 19. doi: 10.1111/tri.14156. Online ahead of print.

ABSTRACT

Within pregnancies occurring between 1986-2017 in Dutch kidney transplant recipients (KTR), we retrospectively compared short-term maternal and fetal outcomes between patients on calcineurin inhibitor (CNI) based (CNI+) and CNI free -immunosuppression (CNI-). We identified 129 CNI+ and 125 CNI- pregnancies in 177 KTR. Demographics differed with CNI+ having higher body mass index (p=0.045), shorter transplant-pregnancy interval (p<0.01), later year of transplantation and -pregnancy (p<0.01). Serum creatinin levels were numerically higher in CNI+ in all study phases, but only reached statistical significance in third trimester (127 vs 105 µmol/L; p<0.01), where the percentual changes from preconceptional level also differed (+3.1% versus -2.2% in CNI-; p=0.05). Postpartum both groups showed 11-12% serum creatinin rise from preconceptional level. Incidence of low birth weight (LBW) tended to be higher in CNI+ (52% vs 46%; p=0.07). Both groups showed equal high rates of preterm delivery. Using CNIs during pregnancy lead to a rise in creatinin in the third trimester but does not negatively influence the course of graft function in the first year postpartum or direct fetal outcomes. High rates of preterm delivery and LBW in KTR, irrespective of CNI use, classify all pregnancies as high-risk.

PMID:34797607 | DOI:10.1111/tri.14156

Eur J Neurol. 2021 Nov 19. doi: 10.1111/ene.15190. Online ahead of print.

ABSTRACT

BACKGROUND: The causal effect of insulin resistance on small vessel stroke and Alzheimer Disease was controversial in previous studies. We therefore applied Mendelian randomization (MR) analyses to identify causal effect of insulin resistance on small vessel stroke and Alzheimer’s disease (AD).

METHODS: We selected 12 single-nucleotide polymorphisms (SNPs) associated with fasting insulin levels and 5 SNPs associated with gold standard measures of insulin resistance as instrumental variables in MR analyses. Summary statistical data of SNP-small vessel stroke and of SNP-AD associations were derived from the MEGASTROKE and PGC-ALZ of individuals of European ancestry. Two-sample MR estimates were conducted with inverse-variance-weighted, robust inverse-variance-weighted, simple median, weighted median, weighted mode-based estimator, and MR pleiotropy residual sum and outlier methods.

RESULTS: Genetically predicted higher insulin resistance had a higher odds ratio (OR) of small vessel stroke [OR 1.23; 95% confidence intervals (CI) 1.05-1.44; P =0.01 using fasting insulin; OR 1.25; 95% CI 1.07-1.46; P =0.006 using gold standard measure of insulin resistance] and AD (OR 1.13; 95% CI 1.04-1.23; P =0.004 using fasting insulin; OR 1.02; 95% CI 1.00-1.03; P =0.03 using gold standard measures of insulin resistance) using the inverse-variance-weighted method. No evidence of pleiotropy was found using MR-Egger regression.

CONCLUSION: Our findings provide a genetic support for potential causal effect of insulin resistance on small vessel stroke and AD.

PMID:34797599 | DOI:10.1111/ene.15190