Category: Statistics

Nat Commun. 2023 Dec 21;14(1):8515. doi: 10.1038/s41467-023-44208-9.

ABSTRACT

Relative binding free energy calculations have become an integral computational tool for lead optimization in structure-based drug design. Classical alchemical methods, including free energy perturbation or thermodynamic integration, compute relative free energy differences by transforming one molecule into another. However, these methods have high operational costs due to the need to perform many pairwise perturbations independently. To reduce costs and accelerate molecular design workflows, we present a method called λ-dynamics with bias-updated Gibbs sampling. This method uses dynamic biases to continuously sample between multiple ligand analogues collectively within a single simulation. We show that many relative binding free energies can be determined quickly with this approach without compromising accuracy. For five benchmark systems, agreement to experiment is high, with root mean square errors near or below 1.0 kcal mol^-1. Free energy results are consistent with other computational approaches and within statistical noise of both methods (0.4 kcal mol^-1 or less). Notably, large efficiency gains over thermodynamic integration of 18-66-fold for small perturbations and 100-200-fold for whole aromatic ring substitutions are observed. The rapid determination of relative binding free energies will enable larger chemical spaces to be more readily explored and structure-based drug design to be accelerated.

PMID:38129400 | DOI:10.1038/s41467-023-44208-9

Can J Anaesth. 2023 Dec 21. doi: 10.1007/s12630-023-02666-1. Online ahead of print.

ABSTRACT

PURPOSE: Agitation is a common behavioural problem following traumatic brain injury (TBI). Intensive care unit (ICU) physicians’ perspectives regarding TBI-associated agitation are unknown. Our objective was to describe physicians’ beliefs and perceived importance of TBI-associated agitation in critically ill patients.

METHODS: Following current standard guidance, we built an electronic, self-administrated, 42-item survey, pretested it for reliability and validity, and distributed it to 219 physicians working in 18 ICU level-1 trauma centres in Canada. We report the results using descriptive statistics.

RESULTS: The overall response rate was 93/219 (42%), and 76/93 (82%) respondents completed the full survey. Most respondents were men with ten or more years of experience. Respondents believed that pre-existing dementia (90%) and regular recreational drug use (86%) are risk factors for agitation. Concerning management, 91% believed that the use of physical restraints could worsen agitation, 90% believed that having family at the bedside reduces agitation, and 72% believed that alpha-2 adrenergic agonists are efficacious for managing TBI agitation. Variability was observed in beliefs on epidemiology, sex, gender, age, socioeconomic status, and other pharmacologic options. Respondents considered TBI agitation frequent enough to justify the implementation of management protocols (87%), perceived the current level of clinical evidence on TBI agitation management to be insufficient (84%), and expressed concerns about acute and long-term detrimental outcomes and burden to patients, health care professionals, and relatives (85%).

CONCLUSION: Traumatic brain injury-associated agitation in critically ill patients was perceived as an important issue for most ICU physicians. Physicians agreed on multiple approaches to manage TBI-associated agitation although agreement on epidemiology and risk factors was variable.

PMID:38129356 | DOI:10.1007/s12630-023-02666-1

J Clin Immunol. 2023 Dec 22;44(1):15. doi: 10.1007/s10875-023-01606-4.

ABSTRACT

PURPOSE: Patients with auto-antibodies neutralizing type I interferons (anti-IFN auto-Abs) are at risk of severe forms of coronavirus disease 19 (COVID-19). The chest computed tomography (CT) scan characteristics of critically ill COVID-19 patients harboring these auto-Abs have never been reported.

METHODS: Bicentric ancillary study of the ANTICOV study (observational prospective cohort of severe COVID-19 patients admitted to the intensive care unit (ICU) for hypoxemic acute respiratory failure between March 2020 and May 2021) on chest CT scan characteristics (severity score, parenchymal, pleural, vascular patterns). Anti-IFN auto-Abs were detected using a luciferase neutralization reporting assay. Imaging data were collected through independent blinded reading of two thoracic radiologists of chest CT studies performed at ICU admission (± 72 h). The primary outcome measure was the evaluation of severity by the total severity score (TSS) and the CT severity score (CTSS) according to the presence or absence of anti-IFN auto-Abs.

RESULTS: Two hundred thirty-one critically ill COVID-19 patients were included in the study (mean age 59.5 ± 12.7 years; males 74.6%). Day 90 mortality was 29.5% (n = 72/244). There was a trend towards more severe radiological lesions in patients with anti-IFN auto-Abs than in others, not reaching statistical significance (median CTSS 27.5 (21.0-34.8) versus 24.0 (19.0-30.0), p = 0.052; median TSS 14.5 (10.2-17.0) versus 12.0 (9.0-15.0), p = 0.070). The extra-parenchymal evaluation found no difference in the proportion of patients with pleural effusion, mediastinal lymphadenopathy, or thymal abnormalities in the two populations. The prevalence of pulmonary embolism was not significantly different between groups (8.7% versus 5.3%, p = 0.623, n = 175).

CONCLUSION: There was no significant difference in disease severity as evaluated by chest CT in severe COVID-19 patients admitted to the ICU for hypoxemic acute respiratory failure with or without anti-IFN auto-Abs.

PMID:38129345 | DOI:10.1007/s10875-023-01606-4

Zhonghua Shao Shang Za Zhi. 2023 Dec 20;39(12):1168-1174. doi: 10.3760/cma.j.cn501225-20231030-00154.

ABSTRACT

Objective: To explore the expression of endosialin, i.e., CD248 in human hypertrophic scars (HSs) and its regulatory effect on the phenotype of hypertrophic scar fibroblasts (HSFs). Methods: The method of experimental research was used. From March to May, 2023, 3 pediatric patients with HS were admitted to the Department of Burns and Cutaneous Surgery of the First Affiliated Hospital of Air Force Medical University, including 2 females and 1 male, aged one year ten months to two years. The HS tissue resected during the surgery and the remaining full-thickness skin graft, i.e., normal skin tissue after full-thickness skin grafting were collected from the aforementioned pediatric patients for subsequent experiments. Using the aforementioned two types of tissue, the histological structures were observed by hematoxylin-eosin staining, collagen distribution was observed by Masson staining, and the expression of CD248 was observed and measured by immunohistochemical staining. The primary HSFs were isolated from HS tissue using explant culture technique, and the 3^rd to 5^th passages of HSFs were used in subsequent experiments. According to the random number table, HSFs were divided into immunoglobulin G78 (IgG78)-treated group and IgG control group, which were treated with 200 nmol/L human CD248 monoclonal antibody IgG78 and human IgG control antibody for 24 h, respectively. The mRNA expressions of collagen type Ⅰ (Col Ⅰ) and α-smooth muscle actin (α-SMA) in HSFs were measured by real-time fluorescence quantitative reverse transcription polymerase chain reaction, the protein expressions of Col Ⅰ and α-SMA in HSFs were detected by Western blotting, and the intracellular location and protein expressions of Col Ⅰ and α-SMA were detected by immunofluorescence method. The number of samples in each experiment was 3. Data were statistically analyzed with paired sample t test and independent sample t test. Results: Compared with those in normal skin tissue, the epidermis and dermis in HS tissue were significantly thicker, with massive accumulation and disordered arrangement of collagen in the dermis. The expression of CD248 in HS tissue was significantly upregulated compared with that in normal skin tissue (t=5.29, P<0.05). At post treatment hour 24, the mRNA expressions of Col Ⅰ and α-SMA of HSFs in IgG78-treated group were 0.39±0.05 and 0.56±0.09, respectively, which were significantly lower than 1.00±0.07 and 1.00±0.08 in IgG control group, respectively (with t values of 11.87 and 6.49, respectively, P values all <0.05). The protein expressions of Col Ⅰ and α-SMA of HSFs in IgG78-treated group were 0.617±0.011 and 0.67±0.14, respectively, which were significantly lower than 1.259±0.052 and 1.23±0.16 in IgG control group, respectively (with t values of 20.92 and 4.52, respectively, P values all <0.05). At post treatment hour 24, immunofluorescence staining showed that Col Ⅰ and α-SMA mainly located in the cytoplasm of HSFs in the two groups, and the protein expressions of Col Ⅰ and α-SMA of HSFs in IgG78-treated group were obviously downregulated compared with those in IgG control group. Conclusions: The expression of CD248 is significantly upregulated in human HS. Targeted blockade of CD248 can significantly inhibit the collagen synthesis by HSFs and the transdifferentiation of HSFs into myofibroblasts.

PMID:38129304 | DOI:10.3760/cma.j.cn501225-20231030-00154

J Am Med Inform Assoc. 2023 Dec 21:ocad235. doi: 10.1093/jamia/ocad235. Online ahead of print.

ABSTRACT

OBJECTIVES: Distributed computations facilitate multi-institutional data analysis while avoiding the costs and complexity of data pooling. Existing approaches lack crucial features, such as built-in medical standards and terminologies, no-code data visualizations, explicit disclosure control mechanisms, and support for basic statistical computations, in addition to gradient-based optimization capabilities.

MATERIALS AND METHODS: We describe the development of the Collaborative Data Analysis (CODA) platform, and the design choices undertaken to address the key needs identified during our survey of stakeholders. We use a public dataset (MIMIC-IV) to demonstrate end-to-end multi-modal FL using CODA. We assessed the technical feasibility of deploying the CODA platform at 9 hospitals in Canada, describe implementation challenges, and evaluate its scalability on large patient populations.

RESULTS: The CODA platform was designed, developed, and deployed between January 2020 and January 2023. Software code, documentation, and technical documents were released under an open-source license. Multi-modal federated averaging is illustrated using the MIMIC-IV and MIMIC-CXR datasets. To date, 8 out of the 9 participating sites have successfully deployed the platform, with a total enrolment of >1M patients. Mapping data from legacy systems to FHIR was the biggest barrier to implementation.

DISCUSSION AND CONCLUSION: The CODA platform was developed and successfully deployed in a public healthcare setting in Canada, with heterogeneous information technology systems and capabilities. Ongoing efforts will use the platform to develop and prospectively validate models for risk assessment, proactive monitoring, and resource usage. Further work will also make tools available to facilitate migration from legacy formats to FHIR and DICOM.

PMID:38128123 | DOI:10.1093/jamia/ocad235

J Am Med Inform Assoc. 2023 Dec 21:ocad226. doi: 10.1093/jamia/ocad226. Online ahead of print.

ABSTRACT

OBJECTIVE: High-throughput phenotyping will accelerate the use of electronic health records (EHRs) for translational research. A critical roadblock is the extensive medical supervision required for phenotyping algorithm (PA) estimation and evaluation. To address this challenge, numerous weakly-supervised learning methods have been proposed. However, there is a paucity of methods for reliably evaluating the predictive performance of PAs when a very small proportion of the data is labeled. To fill this gap, we introduce a semi-supervised approach (ssROC) for estimation of the receiver operating characteristic (ROC) parameters of PAs (eg, sensitivity, specificity).

MATERIALS AND METHODS: ssROC uses a small labeled dataset to nonparametrically impute missing labels. The imputations are then used for ROC parameter estimation to yield more precise estimates of PA performance relative to classical supervised ROC analysis (supROC) using only labeled data. We evaluated ssROC with synthetic, semi-synthetic, and EHR data from Mass General Brigham (MGB).

RESULTS: ssROC produced ROC parameter estimates with minimal bias and significantly lower variance than supROC in the simulated and semi-synthetic data. For the 5 PAs from MGB, the estimates from ssROC are 30% to 60% less variable than supROC on average.

DISCUSSION: ssROC enables precise evaluation of PA performance without demanding large volumes of labeled data. ssROC is also easily implementable in open-source R software.

CONCLUSION: When used in conjunction with weakly-supervised PAs, ssROC facilitates the reliable and streamlined phenotyping necessary for EHR-based research.

PMID:38128118 | DOI:10.1093/jamia/ocad226

Cornea. 2023 Dec 20. doi: 10.1097/ICO.0000000000003457. Online ahead of print.

ABSTRACT

PURPOSE: The purpose of this study was to describe the effects of intracameral air on corneal edema.

METHODS: A laboratory investigation was performed on human donor corneas. Baseline pachymetry measurements through anterior segment optical coherence tomography and endothelial cell density were obtained for all corneas. Each pair of corneas was separated and randomly assigned to undergo air injection or Optisol-GS into a BIONIKO artificial anterior chamber for 5 minutes at physiologic intraocular pressure confirmed by digital palpation. Photographs were obtained immediately on connection of the cornea to the artificial anterior chamber and on completion of the 5 minutes of treatment, with anterior chamber air being exchanged for Optisol-GS. Pretreatment and posttreatment photographs were obtained. Immediately after treatment, pachymetry was again obtained on all corneas. Pachymetry data underwent statistical analysis.

RESULTS: Corneal pachymetry improved from 690.5 ± 126.6 to 576.1 ± 87.2 μm, yielding a 114.4 ± 50.4 μm improvement of pachymetry in the group with air injected into the anterior chamber. This was a significant improvement of pachymetry when compared with the group with Optisol-GS injected into the anterior chamber, which showed an improvement from 662.3 ± 126.5 to 613.5 ± 108.0 μm, yielding an improvement of 48.8 ± 34.3 μm.

CONCLUSIONS: Injection of air into the anterior chamber leads to a significant decrease in corneal pachymetry. We thereby propose that injecting air intracamerally is an effective intraoperative intervention when visualization is negatively affected by corneal edema.

PMID:38128101 | DOI:10.1097/ICO.0000000000003457

Australas Psychiatry. 2023 Dec 21:10398562231222815. doi: 10.1177/10398562231222815. Online ahead of print.

ABSTRACT

OBJECTIVE: Black humour permits expression of what may otherwise be unspeakable and is observed and used by staff working in mental health services. The aim of this study was to identify how humour, particularly black humour, was perceived by different health professionals in psychiatric practice.

METHODS: Participants were invited to complete a survey. Data was collated and statistically analysed by a biostatistician. Chi square and univariate tests were performed to identify associations between categories.

RESULTS: The sub-question relating to the benefits of black humour was analysed. Main findings were that the majority of staff perceived black humour to be beneficial in psychiatric practice (n = 564 of 710 total; 79.4%), particularly if they used general and black humour with patients, families and colleagues. Those who observed black humour being used collegially about patients and families were more likely to find black humour beneficial; and even those uncomfortable with black humour being used by colleagues were more likely to see the benefits of black humour.

CONCLUSION: Black humour was perceived to be beneficial in mental health settings when used mindfully, sensitively and in context. Further study with patients and relatives may shed light on how widely the perception of benefit is shared.

PMID:38128076 | DOI:10.1177/10398562231222815

J Nurs Res. 2023 Dec 22. doi: 10.1097/jnr.0000000000000588. Online ahead of print.

ABSTRACT

BACKGROUND: Electronic health (eHealth) literacy is a relatively new concept used to determine health outcomes. However, it is not well known how eHealth literacy relates to health outcomes such as diabetes self-management.

PURPOSE: This study was designed to examine the relationships among eHealth literacy, self-efficacy, social support, and self-management in people with Type 2 diabetes.

METHODS: A cross-sectional design was used to examine secondary data from a field survey of people with Type 2 diabetes recruited from outpatient clinics from August to December 2021 (N = 453). A structural equation model was used that first analyzed the measurement model using confirmatory factor analysis and then tested the hypothesized structural model to estimate the expected relationships among the study variables. The significance of the statistical estimates for the model was assessed based on the 95% bias-corrected bootstrap confidence interval from 5,000 bootstrap resamples.

RESULTS: Significant, indirect relationships were found between eHealth literacy and self-management via self-efficacy (β = 0.26, B = 0.17, 95% CI [0.10, 0.24]) and via social support and, in turn, self-efficacy (β = 0.08, B = 0.05, 95% CI [0.04, 0.08]). eHealth literacy, social support, and self-efficacy together explained 58.1% of the variance in self-management.

CONCLUSION/IMPLICATIONS FOR PRACTICE: This study provides new evidence regarding how eHealth literacy relates to self-management in people with Type 2 diabetes via two indirect pathways, including self-efficacy alone and social support and self-efficacy in series. An eHealth literacy program for self-management should be developed in clinical practice that includes strategies for inducing synergistic effects from self-efficacy and social support on self-management in people with Type 2 diabetes.

PMID:38128065 | DOI:10.1097/jnr.0000000000000588

Eur J Neurosci. 2023 Dec 21. doi: 10.1111/ejn.16211. Online ahead of print.

ABSTRACT

Children with cerebral palsy (CP) exhibit impaired motor control and significant muscle weakness due to a brain lesion. However, studies that assess the relationship between brain activity and performance on dynamic functional muscle strength assessments in CP are needed. The aim of this study was to determine the effect of a progressive lateral step-up test on prefrontal cortex (PFC) hemodynamic activity in children with CP. Fourteen ambulatory children with spastic CP (Gross Motor Function Classification System level I; 5-11 y) and 14 age- and sex-matched typically developing control children completed a progressive lateral step-up test at incremental step heights (0, 10, 15 and 20 cm) using their non-dominant lower limb. Hemodynamic activity in the PFC was assessed using non-invasive, portable functional neuroimaging (functional near-infrared spectroscopy). Children with CP completed fewer repetitions at each step height and exhibited lower PFC hemodynamic activity across step heights compared to controls. Lower PFC activation in CP was maintained after statistically controlling for the number of repetitions completed at each step height. PFC hemodynamic activity was not associated with LSUT task performance in children with CP, but a positive relationship was observed in controls at the most challenging 20 cm step height. The results suggest there is an altered PFC recruitment pattern in children with CP during a highly dynamic test of functional strength. Further studies are needed to explore the mechanisms underlying the suppressed PFC activation observed in children with CP compared to typically developing children.

PMID:38128061 | DOI:10.1111/ejn.16211