Tag: pubmed

JAMA Netw Open. 2023 Dec 1;6(12):e2346901. doi: 10.1001/jamanetworkopen.2023.46901.

ABSTRACT

IMPORTANCE: The effectiveness of goal-directed care to reduce loss of brain-dead potential donors to cardiac arrest is unclear.

OBJECTIVE: To evaluate the effectiveness of an evidence-based, goal-directed checklist in the clinical management of brain-dead potential donors in the intensive care unit (ICU).

DESIGN, SETTING, AND PARTICIPANTS: The Donation Network to Optimize Organ Recovery Study (DONORS) was an open-label, parallel-group cluster randomized clinical trial in Brazil. Enrollment and follow-up were conducted from June 20, 2017, to November 30, 2019. Hospital ICUs that reported 10 or more brain deaths in the previous 2 years were included. Consecutive brain-dead potential donors in the ICU aged 14 to 90 years with a condition consistent with brain death after the first clinical examination were enrolled. Participants were randomized to either the intervention group or the control group. The intention-to-treat data analysis was conducted from June 15 to August 30, 2020.

INTERVENTIONS: Hospital staff in the intervention group were instructed to administer to brain-dead potential donors in the intervention group an evidence-based checklist with 13 clinical goals and 14 corresponding actions to guide care, every 6 hours, from study enrollment to organ retrieval. The control group provided or received usual care.

MAIN OUTCOMES AND MEASURES: The primary outcome was loss of brain-dead potential donors to cardiac arrest at the individual level. A prespecified sensitivity analysis assessed the effect of adherence to the checklist in the intervention group.

RESULTS: Among the 1771 brain-dead potential donors screened in 63 hospitals, 1535 were included. These patients included 673 males (59.2%) and had a median (IQR) age of 51 (36.3-62.0) years. The main cause of brain injury was stroke (877 [57.1%]), followed by trauma (485 [31.6%]). Of the 63 hospitals, 31 (49.2%) were assigned to the intervention group (743 [48.4%] brain-dead potential donors) and 32 (50.8%) to the control group (792 [51.6%] brain-dead potential donors). Seventy potential donors (9.4%) at intervention hospitals and 117 (14.8%) at control hospitals met the primary outcome (risk ratio [RR], 0.70; 95% CI, 0.46-1.08; P = .11). The primary outcome rate was lower in those with adherence higher than 79.0% than in the control group (5.3% vs 14.8%; RR, 0.41; 95% CI, 0.22-0.78; P = .006).

CONCLUSIONS AND RELEVANCE: This cluster randomized clinical trial was inconclusive in determining whether the overall use of an evidence-based, goal-directed checklist reduced brain-dead potential donor loss to cardiac arrest. The findings suggest that use of such a checklist has limited effectiveness without adherence to the actions recommended in this checklist.

TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03179020.

PMID:38095899 | DOI:10.1001/jamanetworkopen.2023.46901

JAMA Oncol. 2023 Dec 14. doi: 10.1001/jamaoncol.2023.5410. Online ahead of print.

ABSTRACT

IMPORTANCE: The KEYNOTE-826 randomized clinical trial showed statistically significant and clinically meaningful survival benefits with the addition of pembrolizumab to chemotherapy with or without bevacizumab in patients with persistent, recurrent, or metastatic cervical cancer. Treatment effects in patient subgroups of the study population are unknown.

OBJECTIVE: To assess efficacy outcomes in patient subgroups of KEYNOTE-826.

DESIGN, SETTING, AND PARTICIPANTS: Exploratory subgroup analyses were conducted in a global, phase 3, randomized, double-blind, placebo-controlled clinical trial. Participants included women with persistent, recurrent, or metastatic adenocarcinoma, adenosquamous carcinoma, or squamous cell carcinoma of the cervix that had not been treated with systemic chemotherapy and was not amenable to curative treatment. This subanalysis was conducted from November 20, 2018, to May 3, 2021.

INTERVENTIONS: Pembrolizumab, 200 mg, every 3 weeks or placebo for up to 35 cycles plus chemotherapy (paclitaxel, 175 mg/m2, plus cisplatin, 50 mg/m2, or carboplatin AUC 5 [area under the free carboplatin plasma concentration vs time curve]) with or without bevacizumab, 15 mg/kg.

MAIN OUTCOMES AND MEASURES: Overall survival (OS) and progression-free survival (PFS) by investigator assessment per Response Evaluation Criteria in Solid Tumors version 1.1 in subgroups defined by use of bevacizumab (yes or no), choice of platinum (carboplatin or cisplatin), prior chemoradiotherapy (CRT) exposure only (yes or no), and histologic type (squamous or nonsquamous) in patients with programmed cell death ligand 1-positive tumors (defined as a combined positive score [CPS] ≥1) and in the intention-to-treat population.

RESULTS: A total of 617 patients (median age, 51 years; range, 22-82 years) were enrolled in the trial. In the CPS greater than or equal to 1 population, hazard ratios (HRs) for OS favored the pembrolizumab group in all subgroups: with bevacizumab (HR, 0.62; 95% CI, 0.45-0.87) and without bevacizumab (HR, 0.67; 95% CI, 0.47-0.96), use of carboplatin (HR, 0.65; 95% CI, 0.50-0.85) and cisplatin (HR, 0.53; 95% CI, 0.27-1.04), with prior CRT only (HR, 0.56; 95% CI, 0.39-0.81) and without prior CRT only (HR, 0.72; 95% CI, 0.52-1.00), and squamous (HR, 0.60; 95% CI, 0.46-0.79) and nonsquamous (HR, 0.70; 95% CI, 0.41-1.20) histologic type. In the intention-to-treat population, HRs for OS also favored the pembrolizumab group in all subgroups: with bevacizumab (HR, 0.63; 95% CI, 0.47-0.87) and without bevacizumab (HR, 0.74; 95% CI, 0.53-1.04), use of carboplatin (HR, 0.69; 95% CI, 0.54-0.89) or cisplatin (HR, 0.59; 95% CI, 0.32-1.09), with prior CRT only (HR, 0.64; 95% CI, 0.45-0.91) and without prior CRT only (HR, 0.71; 95% CI, 0.53-0.97), and squamous (HR, 0.61; 95% CI, 0.47-0.80) and nonsquamous (HR, 0.76; 95% CI, 0.47-1.23) histologic type. Similar to OS, the addition of pembrolizumab prolonged PFS across all subgroups in the CPS greater than or equal to 1 and intention-to-treat populations.

CONCLUSIONS AND RELEVANCE: The findings of this trial suggest that adding pembrolizumab to chemotherapy with or without bevacizumab improved OS across subgroups of patients with persistent, recurrent, or metastatic cervical cancer.

TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03635567.

PMID:38095881 | DOI:10.1001/jamaoncol.2023.5410

Brief Bioinform. 2023 Nov 22;25(1):bbad456. doi: 10.1093/bib/bbad456.

ABSTRACT

Molecular dynamics (MD) is the primary computational method by which modern structural biology explores macromolecule structure and function. Boltzmann generators have been proposed as an alternative to MD, by replacing the integration of molecular systems over time with the training of generative neural networks. This neural network approach to MD enables convergence to thermodynamic equilibrium faster than traditional MD; however, critical gaps in the theory and computational feasibility of Boltzmann generators significantly reduce their usability. Here, we develop a mathematical foundation to overcome these barriers; we demonstrate that the Boltzmann generator approach is sufficiently rapid to replace traditional MD for complex macromolecules, such as proteins in specific applications, and we provide a comprehensive toolkit for the exploration of molecular energy landscapes with neural networks.

PMID:38095857 | DOI:10.1093/bib/bbad456

Clin Drug Investig. 2023 Dec 14. doi: 10.1007/s40261-023-01331-1. Online ahead of print.

ABSTRACT

The approval of lecanemab by the US Food and Drug Administration has been touted as a defining moment in the treatment of Alzheimer’s disease. Lecanemab, an anti-amyloid beta monoclonal antibody, is the first Alzheimer’s disease drug targeting amyloid beta that has shown statistically significant cognitive benefits in phase III trials. However, there have been many questions raised over the clinical relevance of the otherwise minimal cognitive improvements. Furthermore, its rapid approval has been mired in controversy, in addition to the reports of adverse events such as amyloid-related imaging abnormalities and several deaths of participants in the lecanemab trials. Here, we analyze the evidence supporting lecanemab as an amyloid beta therapy and also discuss the concerns raised about its efficacy and safety.

PMID:38095822 | DOI:10.1007/s40261-023-01331-1

Breast Cancer Res Treat. 2023 Dec 14. doi: 10.1007/s10549-023-07174-w. Online ahead of print.

ABSTRACT

PURPOSE: There are differences in the distributions of breast cancer incidence and risk factors by race and ethnicity. Given the strong association between breast density and breast cancer, it is of interest describe racial and ethnic variation in the determinants of breast density.

METHODS: We characterized racial and ethnic variation in reproductive history and several measures of breast density for Hispanic (n = 286), non-Hispanic Black (n = 255), and non-Hispanic White (n = 1694) women imaged at a single hospital. We quantified associations between reproductive factors and percent volumetric density (PVD), dense volume (DV), non-dense volume (NDV), and a novel measure of pixel intensity variation (V) using multivariable-adjusted linear regression, and tested for statistical heterogeneity by race and ethnicity.

RESULTS: Reproductive factors most strongly associated with breast density were age at menarche, parity, and oral contraceptive use. Variation by race and ethnicity was most evident for the associations between reproductive factors and NDV (minimum p-heterogeneity:0.008) and V (minimum p-heterogeneity:0.004) and least evident for PVD (minimum p-heterogeneity:0.042) and DV (minimum p-heterogeneity:0.041).

CONCLUSION: Reproductive choices, particularly those related to childbearing and oral contraceptive use, may contribute to racial and ethnic variation in breast density.

PMID:38095811 | DOI:10.1007/s10549-023-07174-w

J Gastrointest Cancer. 2023 Dec 14. doi: 10.1007/s12029-023-00999-0. Online ahead of print.

ABSTRACT

INTRODUCTION: Hepatocellular carcinoma is a lethal disease and there has been a debate regarding the first-line treatment of its advanced and unresectable form. Observational studies have explored atezolizumab plus bevacizumab versus lenvatinib, yielding mixed results. This systematic review and meta-analysis aim to compare efficacy and safety of both treatment arms.

METHODS: A systematic literature review was conducted in accordance with PRISMA guidelines. Randomized control trials, cohort studies, or case-control that included patients above age 60 with unresectable hepatocellular carcinoma confirmed by radiological imaging were included. At least one of the outcomes: overall survival (OS), progression-free survival (PFS), objective response rate (ORR), duration of response, or adverse events was included in the selected studies.

RESULTS: Ten cohorts were included in the analysis with a total of 6493 patients. Nine of the included studies had patients with advanced HCC (BCLC-C) or intermediate HCC (BCLC-B) and 1 study included patients with all three stages (BCLC-A, BCLC-B, and BCLC-C). Of these patients, 2524 patients received atezolizumab plus bevacizumab (A + B) combination while 3969 received lenvatinib. The overall survival was better statistically in the A + B group then the lenvatinib group (MD: – 5.06; 95% CI: – 7.79 to – 2.33; p = 0.0003, I² = 0%). The progression-free survival was significantly improved in A + B arm as well group (MD: – 4.96; 95% CI: – 7.67 to – 2.26; I² = 0%, p = 0. 0003). There was no significant difference in objective response rate, disease control rate, and frequency of adverse events in either of the group.

CONCLUSION: Our study concluded that combination therapy with atezolizumab plus bevacizumab could increase the survival duration without affecting the disease course. Moreover, while the severity of adverse events was greater in the A + B group, their frequency was comparable to the lenvatinib group.

PMID:38095799 | DOI:10.1007/s12029-023-00999-0

Environ Sci Pollut Res Int. 2023 Dec 14. doi: 10.1007/s11356-023-31362-2. Online ahead of print.

ABSTRACT

In this study, a new hybrid bench-scale electrocoagulation-sand filtration (FECF) reactor was developed for purifying nitrate-contaminated samples. Before and after electrochemical treatment, two sand filters were included in this continuous system to facilitate the purification procedure, and the contaminated water flows horizontally through the entire system according to a specific hydraulic gradient within the reactor, resulting in water purification. Significant improvement in treatment performance was observed due to the presence of metal hydroxides in the second filter media that were not fully involved in the electrocoagulation treatment. Energy dispersive X-ray (EDX) analysis was performed to detect metal hydroxide species in the sand media, and the need for filter regeneration was evaluated by monitoring changes in the system flow rate. Moreover, an evaluation of the effects of different factors including operating time, current intensity, initial pH, type of anode and cathode, initial nitrate concentration, hydraulic head level inside the reactor, number of electrodes, and NaCl electrolyte concentration on the performance of nitrate removal was conducted through the Taguchi design. Further, ANOVA analysis verified the accuracy of the predicted model, and the variables were classified based on their relative importance in the FECF process. According to the regression model, 97% of nitrates were removed with Al electrodes as anode and Fe as cathode, 70 min purification time, current intensity of 3 A, 100 mg/l initial nitrate concentration, pH 8, electrolyte concentration of 1 g/l, electrode number of 6, and 1.5 cm head level.

PMID:38095796 | DOI:10.1007/s11356-023-31362-2

Environ Sci Pollut Res Int. 2023 Dec 14. doi: 10.1007/s11356-023-30478-9. Online ahead of print.

ABSTRACT

This research explores the theory that cultural factors shape how people feel about the environment. Both theoretical and empirical approaches are used in our investigation of this problem. In the theoretical part of the study, we provide a model for transferring cultural practices from one generation to the next. To provide empirical evidence for the existence of this cultural factor in environmental views, we analyze survey data from the European Values Research. Using a comparative method, we use differences caused by migration patterns in Europe and America. According to our research, cultural influences on migrants’ ecological beliefs are long-lasting and statistically significant. Variations in migrants’ environmental views may be traced back to societal norms that endure in their home countries. We also demonstrate that ecological views are robust in the face of incentives originating from the external environment, demonstrating that migrants’ choices in the host nation are not much influenced by the environmental circumstances they were exposed to in their home countries. We uncover fascinating variations in the cultural transfer procedure, and our results hold up under various hypotheses. These findings suggest that, in light of the prevalence of ecological problems requiring community action, it is crucial to formulate policies that consider the factors that led to the development of ecological cultures.

PMID:38095793 | DOI:10.1007/s11356-023-30478-9

Curr Pain Headache Rep. 2023 Dec 14. doi: 10.1007/s11916-023-01196-1. Online ahead of print.

ABSTRACT

PURPOSE OF REVIEW: Neuropathic pain (NP) remains a challenge to treat, with 50% of patients experiencing limited efficacy from current treatments. Medicinal cannabis, which contains tetrahydrocannabinol (THC), cannabidiol (CBD) and other minor cannabinoids, is garnering attention as an alternative treatment for NP. This paper reviews the clinical evidence for phytocannabinoid treatment of NP.

RECENT FINDINGS: Seventeen randomised controlled trials (RCT) were identified for inclusion in this review. Of these, ten studies using phytocannabinoid preparations containing THC alone had the most evidence for pain relief. Four studies investigating THC/CBD combinations showed some reductions in pain scores, although not all findings were statistically significant, whereas studies investigating CBD (two studies) or cannabidivarin (one study) showed no analgesic effect over placebo. However, CBD studies were of small sample size when compared to other studies in the review and short duration. Results for treatment of diabetic peripheral neuropathy patients with THC showed better improvements over those for NP induced by chemotherapy and multiple sclerosis, with these trials using vaporised whole plant cannabis. This formulation may have trace amounts of other minor cannabinoids, compared with synthetic cannabinoids such as dronabinol or nabilone that were investigated in other studies. This review provides an overview of RCTs that have investigated phytocannabinoid use for the treatment of NP. There appears to be evidence to necessitate further high quality RCTs into novel formulations of phytocannabinoids for the treatment of NP.

PMID:38095748 | DOI:10.1007/s11916-023-01196-1

Intern Emerg Med. 2023 Dec 14. doi: 10.1007/s11739-023-03490-7. Online ahead of print.

ABSTRACT

To develop and internally validate a multivariable logistic regression model (LRM) for the prediction of the probability of 1-year readmission to the emergency department (ED) in patients with acute alcohol intoxication (AAI). We developed and internally validated the LRM on a previously analyzed retrospective cohort of 3304 patients with AAI admitted to the ED of the Sant’Orsola-Malpighi Hospital (Bologna, Italy). The benchmark LRM employed readmission to the same ED for AAI within 1 year as the binary outcome, age as a continuous predictor, and sex, alcohol use disorder, substance use disorder, at least one previous admission for trauma, mental or behavioral disease, and homelessness as the binary predictors. Optimism correction was performed using the bootstrap on 1000 samples without replacement. The benchmark LRM was gradually simplified to get the most parsimonious LRM with similar optimism-corrected overall fit, discrimination and calibration. The 1-year readmission rate was 15.7% (95% CI 14.4-16.9%). A reduced LRM based on sex, age, at least one previous admission for trauma, mental or behavioral disease, and homelessness, performed nearly as well as the benchmark LRM. The reduced LRM had the following optimism-corrected metrics: scaled Brier score 17.0%, C-statistic 0.799 (95% CI 0.778 to 0.821), calibration in the large 0.000 (95% CI – 0.099 to 0.099), calibration slope 0.985 (95% CI 0.893 to 1.088), and an acceptably accurate calibration plot. An LRM based on sex, age, at least one previous admission for trauma, mental or behavioral disease, and homelessness can be used to estimate the probability of 1-year readmission to ED for AAI. To begin proving its clinical utility, this LRM should be validated in external cohorts.

PMID:38095747 | DOI:10.1007/s11739-023-03490-7