Category: Nevin Manimala

JCI Insight. 2023 Feb 28:e166901. doi: 10.1172/jci.insight.166901. Online ahead of print.

ABSTRACT

BACKGROUND: Fibrocytes are bone marrow-derived circulating cells that traffic to the injured lungs and contribute to fibrogenesis. The mTOR inhibitor, sirolimus, inhibits fibrocyte CXCR4 expression, reducing fibrocyte traffic and attenuating lung fibrosis in animal models. We sought to test the hypothesis that short-term treatment with sirolimus reduces the concentration of CXCR4+ circulating fibrocytes in patients with idiopathic pulmonary fibrosis (IPF).

METHODS: We conducted a short-term randomised double-blind placebo-controlled crossoverpilot trial to assess the safety and tolerability of sirolimus in IPF. Subjects were randomly assigned to sirolimus or placebo for approximately 6 weeks, and after a 4 week washout, assigned to the alternate treatment. Toxicity, lung function, and the concentration of circulating fibrocytes were measured before and after each treatment.

RESULTS: In the 28 study subjects, sirolimus resulted in a statistically significant 35% decline in the concentration of total fibrocytes, 34% decline in CXCR4+ fibrocytes, and 42% decline in fibrocytes expressing ɑ-smooth muscle actin, but no significant change in these populations occurred on placebo. Respiratory adverse events occurred more frequently during treatment with placebo than sirolimus; the incidence of adverse events and drug tolerability did not otherwise differ during therapy with drug and placebo. Lung function was unaffected by either treatment with the exception of a small decline in gas transfer during treatment with placebo.

CONCLUSIONS: As compared with placebo, short-term treatment with sirolimus resulted inreduction of circulating fibrocyte concentrations in subjects with IPF with an acceptable safety profile.

CLINICALTRIALS: gov identifier number NCT01462006FUNDING. NIH R01HL098329 and American Heart Association 18TPA34170486.

PMID:36853800 | DOI:10.1172/jci.insight.166901

Mod Pathol. 2023 Feb;36(2):100003. doi: 10.1016/j.modpat.2022.100003. Epub 2023 Jan 9.

ABSTRACT

The pathologic diagnosis of bone marrow disorders relies in part on the microscopic analysis of bone marrow aspirate (BMA) smears and the manual counting of marrow nucleated cells to obtain a differential cell count (DCC). This manual process has significant limitations, including the analysis of only a small subset of optimal slide areas and nucleated cells, as well as interobserver variability due to differences in cell selection and classification. To address these shortcomings, we developed an automated machine learning-based pipeline for obtaining 11-component DCCs on whole-slide BMAs. This pipeline uses a sequential process of identifying optimal BMA regions with high proportions of marrow nucleated cells, detecting individual cells within these optimal areas, and classifying these cells into 1 of 11 DCC components. Convolutional neural network models were trained on 396,048 BMA region, 28,914 cell boundary, and 1,510,976 cell class images from manual annotations. The resulting automated pipeline produced 11-component DCCs that demonstrated a high statistical and diagnostic concordance with manual DCCs among a heterogeneous group of testing BMA slides with varying pathologies and cellularities. Additionally, we demonstrated that an automated analysis can reduce the intraslide variance in DCCs by analyzing the whole slide and marrow nucleated cells within all optimal regions. Finally, the pipeline outputs of region classification, cell detection, and cell classification can be visualized using whole-slide image analysis software. This study demonstrates the feasibility of a fully automated pipeline for generating DCCs on scanned whole-slide BMA images, with the potential for improving the current standard of practice for utilizing BMA smears in the laboratory analysis of hematologic disorders.

PMID:36853796 | DOI:10.1016/j.modpat.2022.100003

Mod Pathol. 2023 Feb;36(2):100006. doi: 10.1016/j.modpat.2022.100006. Epub 2023 Jan 9.

ABSTRACT

Adenoid cystic carcinoma (AdCC) is an uncommon type of invasive breast carcinoma with a favorable prognosis. However, some cases are aggressive. The study aims to define the clinicopathologic predictors of outcome. Clinical, radiological, and pathologic variables were recorded for 76 AdCC cases from 11 institutions. The following histologic characteristics were evaluated by the breast pathologist in each respective institution, including Nottingham grade (NG), percentages of various growth patterns (solid, cribriform, trabecular-tubular), percentage of basaloid component, tumor borders (pushing, infiltrative), perineural invasion, lymphovascular invasion, necrosis, and distance from the closest margin. Various grading systems were evaluated, including NG, salivary gland-type grading systems, and a new proposed grading system. The new grading system incorporated the growth pattern (percent solid, percent cribriform), percent basaloid morphology, and mitotic count using the Youden index criterion. All variables were correlated with recurrence-free survival. Nineteen (25%) women developed local and/or distant recurrence. Basaloid morphology (≥25% of the tumor) was identified in 20 (26.3%) cases and a solid growth pattern (using ≥60% cutoff) in 22 (28.9%) cases. In the univariate analysis, the following variables were significantly correlated with worse recurrence-free survival: solid growth pattern, basaloid morphology, lymphovascular invasion, necrosis, perineural invasion, and pN-stage. In the multivariate analysis including basaloid morphology, pN-stage, lymphovascular invasion, and perineural invasion, basaloid morphology was statistically significant, with a hazard ratio of 3.872 (95% CI, 1.077; 13.924; P =.038). The NG and the new grading system both correlated with recurrence-free survival. However, grade 2 had a similar risk as grade 3 in the NG system and a similar risk as grade 1 in the new grading system. For solid growth patterns and basaloid morphology, using a 2-tier system with 1 cutoff was better than a 3-tier system with 2 cutoffs. Basaloid morphology and solid growth pattern have prognostic values for AdCC, with a 2-tier grading system performing better than a 3-tier system.

PMID:36853781 | DOI:10.1016/j.modpat.2022.100006

J Med Internet Res. 2023 Feb 28;25:e43116. doi: 10.2196/43116.

ABSTRACT

BACKGROUND: Formative experiences in adolescence lay the foundation for healthy and pleasurable romantic and sexual relationships. Exposure to pornography may affect these experiences.

OBJECTIVE: We aimed to synthesize evidence published in the past decade on the relationship between exposure to pornography and sexual behavior (earlier age of first sex [<16 years], condomless sex, past-year multiple partners [>1], lifetime multiple partners [>1], group sex, sexual aggression including forced sex, paid sex, teenage pregnancy, and history of sexually transmitted infection) in adolescents aged between 10 and 19 years.

METHODS: We identified 19 eligible studies by searching MEDLINE, PsycINFO, Cochrane, CINAHL, Embase, and Web of Science databases from January 2010 to November 2022.

RESULTS: Out of 8 studies that assessed earlier age of first sex, 5 studies, including 1 longitudinal study, found a statistically significant association with exposure to pornography. Given that most studies were cross-sectional or had substantial limitations, causal inference could not be made. Also, exposure to pornography was not measured consistently. The evidence was conflicting or insufficient to draw any conclusions regarding other outcomes.

CONCLUSIONS: More quantitative research is needed to elucidate the association between pornography exposure and sexual behavior, and sex education should adopt evidence-based approaches to minimize the potential harms from pornography.

TRIAL REGISTRATION: PROSPERO International Prospective Register of Systematic Reviews CRD42021227390; https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=227390.

PMID:36853749 | DOI:10.2196/43116

J Med Internet Res. 2023 Feb 28;25:e42131. doi: 10.2196/42131.

ABSTRACT

BACKGROUND: Scientific researchers who wish to reuse health data pertaining to individuals can obtain consent through an opt-in procedure or opt-out procedure. The choice of procedure may have consequences for the consent rate and representativeness of the study sample and the quality of the research, but these consequences are not well known.

OBJECTIVE: This review aimed to provide insight into the consequences for the consent rate and consent bias of the study sample of opt-in procedures versus opt-out procedures for the reuse of routinely recorded health data for scientific research purposes.

METHODS: A systematic review was performed based on searches in PubMed, Embase, CINAHL, PsycINFO, Web of Science Core Collection, and the Cochrane Library. Two reviewers independently included studies based on predefined eligibility criteria and assessed whether the statistical methods used in the reviewed literature were appropriate for describing the differences between consenters and nonconsenters. Statistical pooling was conducted, and a description of the results was provided.

RESULTS: A total of 15 studies were included in this meta-analysis. Of the 15 studies, 13 (87%) implemented an opt-in procedure, 1 (7%) implemented an opt-out procedure, and 1 (7%) implemented both the procedures. The average weighted consent rate was 84% (60,800/72,418 among the studies that used an opt-in procedure and 96.8% (2384/2463) in the single study that used an opt-out procedure. In the single study that described both procedures, the consent rate was 21% in the opt-in group and 95.6% in the opt-out group. Opt-in procedures resulted in more consent bias compared with opt-out procedures. In studies with an opt-in procedure, consenting individuals were more likely to be males, had a higher level of education, higher income, and higher socioeconomic status.

CONCLUSIONS: Consent rates are generally lower when using an opt-in procedure compared with using an opt-out procedure. Furthermore, in studies with an opt-in procedure, participants are less representative of the study population. However, both the study populations and the way in which opt-in or opt-out procedures were organized varied widely between the studies, which makes it difficult to draw general conclusions regarding the desired balance between patient control over data and learning from health data. The reuse of routinely recorded health data for scientific research purposes may be hampered by administrative burdens and the risk of bias.

PMID:36853745 | DOI:10.2196/42131

STAR Protoc. 2023 Jan 28;4(1):102074. doi: 10.1016/j.xpro.2023.102074. Online ahead of print.

ABSTRACT

In vivo brainstem imaging with miniature microscopy has been challenging due to surgical difficulty, high motion, and correlated activity between neurons. Here, we present a protocol for brainstem imaging in freely moving mice using the dorsal raphe nucleus as an example. We describe surgical procedures to inject a virus encoding GCaMP6m and securely implant a GRIN lens in the brainstem. We then detail motion correction and cell segmentation from the data to parse single-cell activity from correlated networks. For complete details on the use and execution of this protocol, please refer to Paquelet et al. (2022).¹.

PMID:36853724 | DOI:10.1016/j.xpro.2023.102074

STAR Protoc. 2023 Jan 25;4(1):102069. doi: 10.1016/j.xpro.2023.102069. Online ahead of print.

ABSTRACT

Understanding cellular metabolism is important across biotechnology and biomedical research and has critical implications in a broad range of normal and pathological conditions. Here, we introduce the user-friendly web-based platform ImmCellFie, which allows the comprehensive analysis of metabolic functions inferred from transcriptomic or proteomic data. We explain how to set up a run using publicly available omics data and how to visualize the results. The ImmCellFie algorithm pushes beyond conventional statistical enrichment and incorporates complex biological mechanisms to quantify cell activity. For complete details on the use and execution of this protocol, please refer to Richelle et al. (2021).¹.

PMID:36853701 | DOI:10.1016/j.xpro.2023.102069

Hosp Top. 2023 Feb 28:1-8. doi: 10.1080/00185868.2023.2185172. Online ahead of print.

ABSTRACT

The significant and apparent variance in hospital charges and inpatient care in the U.S. has perplexed the general public including many stakeholders such as the healthcare regulators and insurers. While the clinical side of inpatient care has been undergoing tremendous progress and standardization, the overall cost of healthcare has been ballooning. The purpose of this research is to conduct statistical analyses that reveal the sources of variance in hospital charges and inpatient care using the annual data from the AHRQ’s (Agency for Healthcare Research and Quality) HCUP’s (Hospital Cost and Utilization Project) NIS (National Inpatient Sample) database. Our focus is on non-clinical factors such as patient age, gender, income and race and hospital location data as independent variables to investigate their impact on hospital charges and inpatient care. Our research sample is the liver transplant cases in 2019 sampled in the NIS 2019 database. Our regression results show patient age and gender as well as payer affect the number of diagnoses; and hospital charges are affected by age, payer and hospital location. Number of procedures was not affected by any of these non-clinical factors except the hospital location. Implications suggest that there is more room for standardization of the number of diagnoses and procedures across regions in the US. Results also reveal that race and income do not have any effect on hospital charges and inpatient care. Our study contributes to an empirical understanding of non-clinical factors in the explanation of variance in hospital charges and inpatient care.

PMID:36853649 | DOI:10.1080/00185868.2023.2185172

JAMA Netw Open. 2023 Feb 1;6(2):e230380. doi: 10.1001/jamanetworkopen.2023.0380.

ABSTRACT

IMPORTANCE: Sepsis is associated with long-term cognitive impairment and worse psychological and functional outcomes. Potential mechanisms include intracerebral oxidative stress and inflammation, yet little is known about the effects of early antioxidant and anti-inflammatory therapy on cognitive, psychological, and functional outcomes in sepsis survivors.

OBJECTIVE: To describe observed differences in long-term cognitive, psychological, and functional outcomes of vitamin C, thiamine, and hydrocortisone between the intervention and control groups in the Vitamin C, Thiamine, and Steroids in Sepsis (VICTAS) randomized clinical trial.

DESIGN, SETTING, AND PARTICIPANTS: This prespecified secondary analysis reports the 6-month outcomes of the multicenter, double-blind, placebo-controlled VICTAS randomized clinical trial, which was conducted between August 2018 and July 2019. Adult patients with sepsis-induced respiratory and/or cardiovascular dysfunction who survived to discharge or day 30 were recruited from 43 intensive care units in the US. Participants were randomized 1:1 to either the intervention or control group. Cognitive, psychological, and functional outcomes at 6 months after randomization were assessed via telephone through January 2020. Data analyses were conducted between February 2021 and December 2022.

INTERVENTIONS: The intervention group received intravenous vitamin C (1.5 g), thiamine hydrochloride (100 mg), and hydrocortisone sodium succinate (50 mg) every 6 hours for 96 hours or until death or intensive care unit discharge. The control group received matching placebo.

MAIN OUTCOMES AND MEASURES: Cognitive performance, risk of posttraumatic stress disorder and depression, and functional status were assessed using a battery of standardized instruments that were administered during a 1-hour telephone call 6 months after randomization.

RESULTS: After exclusions, withdrawals, and deaths, the final sample included 213 participants (median [IQR] age, 57 [47-67] years; 112 males [52.6%]) who underwent long-term outcomes assessment and had been randomized to either the intervention group (n = 108) or control group (n = 105). The intervention group had lower immediate memory scores (adjusted OR [aOR], 0.49; 95% CI, 0.26-0.89), higher odds of posttraumatic stress disorder (aOR, 3.51; 95% CI, 1.18-10.40), and lower odds of receiving mental health care (aOR, 0.38; 95% CI, 0.16-0.89). No other statistically significant differences in cognitive, psychological, and functional outcomes were found between the 2 groups.

CONCLUSIONS AND RELEVANCE: In survivors of sepsis, treatment with vitamin C, thiamine, and hydrocortisone did not improve or had worse cognitive, psychological, and functional outcomes at 6 months compared with patients who received placebo. These findings challenge the hypothesis that antioxidant and anti-inflammatory therapy during critical illness mitigates the development of long-term cognitive, psychological, and functional impairment in sepsis survivors.

TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03509350.

PMID:36853612 | DOI:10.1001/jamanetworkopen.2023.0380

JAMA Netw Open. 2023 Feb 1;6(2):e230819. doi: 10.1001/jamanetworkopen.2023.0819.

ABSTRACT

IMPORTANCE: In a porcine model of liver transplant, a combined drug approach that targeted the donor graft and graft recipient reduced ischemia-reperfusion injury, a major hurdle to the success of liver transplant.

OBJECTIVE: To assess the effect of a clinical form of a perioperative combined drug approach delivered immediately before implantation to the procured liver and to the liver recipient on the degree of ischemia-reperfusion injury.

DESIGN, SETTING, AND PARTICIPANTS: This unicentric, investigator-driven, open-label randomized clinical trial with 2 parallel arms was conducted in Belgium from September 2013 through February 2018, with 1-year follow-up. Adults wait-listed for a first solitary full-size liver transplant were screened for eligibility. Exclusion criteria were acute liver failure, kidney failure, contraindication to treatment, participation in another trial, refusal, technical issues, and death while awaiting transplant. Included patients were enrolled and randomized at the time of liver offer. Data were analyzed from May 20, 2019, to May 27, 2020.

INTERVENTIONS: Participants were randomized to a combined drug approach with standard of care (static cold storage) or standard of care only (control group). In the combined drug approach group, following static cold preservation, donor livers were infused with epoprostenol (ex situ, portal vein); recipients were given oral α-tocopherol and melatonin prior to anesthesia and intravenous antithrombin III, infliximab, apotransferrin, recombinant erythropoietin-β, C1-inhibitor, and glutathione during the anhepatic and reperfusion phase.

MAIN OUTCOMES AND MEASURES: The primary outcome was the posttransplant peak serum aspartate aminotransferase (AST) level within the first 72 hours. Secondary end points were the frequencies of postreperfusion syndrome, ischemia-reperfusion injury score, early allograft dysfunction, surgical complications, ischemic cholangiopathy, acute kidney injury, acute cellular rejection, and graft and patient survival.

RESULTS: Of 93 randomized patients, 21 were excluded, resulting in 72 patients (36 per study arm) in the per protocol analysis (median recipient age, 60 years [IQR, 51.7-66.2 years]; 52 [72.2%] men). Peak AST serum levels were not different in the combined drug approach and control groups (geometric mean, 1262.9 U/L [95% CI, 946.3-1685.4 U/L] vs 1451.2 U/L [95% CI, 1087.4-1936.7 U/L]; geometric mean ratio, 0.87 [95% CI, 0.58-1.31]; P = .49) (to convert AST to μkat/L, multiply by 0.0167). There also were no significant differences in the secondary end points between the groups.

CONCLUSIONS AND RELEVANCE: In this randomized clinical trial, the combined drug approach targeting the post-cold storage graft and the recipient did not decrease ischemic-reperfusion injury. The findings suggest that in addition to a downstream strategy that targets the preimplantation liver graft and the graft recipient, a clinically effective combined drug approach may need to include an upstream strategy that targets the donor graft during preservation. Dynamic preservation strategies may provide an appropriate delivery platform.

TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02251041.

PMID:36853611 | DOI:10.1001/jamanetworkopen.2023.0819