Deployment and validation of the CLL treatment infection model adjoined to an EHR system.

Research algorithms are seldom externally validated or integrated into clinical practice, leaving unknown challenges in deployment. In such efforts, one needs to address challenges related to data harmonization, the performance of an algorithm in unforeseen missingness, automation and monitoring of predictions, and legal frameworks. We here describe the deployment of a high-dimensional data-driven decision support model into an EHR and derive practical guidelines informed by this deployment that includes the necessary processes, stakeholders and design requirements for a successful deployment. For this, we describe our deployment of the chronic lymphocytic leukemia (CLL) treatment infection model (CLL-TIM) as a stand-alone platform adjoined to an EPIC-based Danish Electronic Health Record (EHR), with the presentation of personalized predictions in a clinical context. CLL-TIM is an 84-variable data-driven prognostic model utilizing 7-year medical patient records and predicts the 2-year risk composite outcome of infection and/or treatment post-CLL diagnosis. As an independent validation cohort for this deployment, we used a retrospective population-based cohort of patients diagnosed with CLL from 2018 onwards (n = 1480). Unexpectedly high levels of missingness for key CLL-TIM variables were exhibited upon deployment. High dimensionality, with the handling of missingness, and predictive confidence were critical design elements that enabled trustworthy predictions and thus serves as a priority for prognostic models seeking deployment in new EHRs. Our setup for deployment, including automation and monitoring into EHR that meets Medical Device Regulations, may be used as step-by-step guidelines for others aiming at designing and deploying research algorithms into clinical practice.

Early trajectories of virological and immunological biomarkers and clinical outcomes in patients admitted to hospital for COVID-19: an international, prospective cohort study.

BACKGROUND: Serial measurement of virological and immunological biomarkers in patients admitted to hospital with COVID-19 can give valuable insight into the pathogenic roles of viral replication and immune dysregulation. We aimed to characterise biomarker trajectories and their associations with clinical outcomes. METHODS: In this international, prospective cohort study, patients admitted to hospital with COVID-19 and enrolled in the Therapeutics for Inpatients with COVID-19 platform trial within the Accelerating COVID-19 Therapeutic Interventions and Vaccines programme between Aug 5, 2020 and Sept 30, 2021 were included. Participants were included from 108 sites in Denmark, Greece, Poland, Singapore, Spain, Switzerland, Uganda, the UK, and the USA, and randomised to placebo or one of four neutralising monoclonal antibodies: bamlanivimab (Aug 5 to Oct 13, 2020), sotrovimab (Dec 16, 2020, to March 1, 2021), amubarvimab-romlusevimab (Dec 16, 2020, to March 1, 2021), and tixagevimab-cilgavimab (Feb 10 to Sept 30, 2021). This trial included an analysis of 2149 participants with plasma nucleocapsid antigen, anti-nucleocapsid antibody, C-reactive protein (CRP), IL-6, and D-dimer measured at baseline and day 1, day 3, and day 5 of enrolment. Day-90 follow-up status was available for 1790 participants. Biomarker trajectories were evaluated for associations with baseline characteristics, a 7-day pulmonary ordinal outcome, 90-day mortality, and 90-day rate of sustained recovery. FINDINGS: The study included 2149 participants. Participant median age was 57 years (IQR 46-68), 1246 (58·0%) of 2149 participants were male and 903 (42·0%) were female; 1792 (83·4%) had at least one comorbidity, and 1764 (82·1%) were unvaccinated. Mortality to day 90 was 172 (8·0%) of 2149 and 189 (8·8%) participants had sustained recovery. A pattern of less favourable trajectories of low anti-nucleocapsid antibody, high plasma nucleocapsid antigen, and high inflammatory markers over the first 5 days was observed for high-risk baseline clinical characteristics or factors related to SARS-CoV-2 infection. For example, participants with chronic kidney disease demonstrated plasma nucleocapsid antigen 424% higher (95% CI 319-559), CRP 174% higher (150-202), IL-6 173% higher (144-208), D-dimer 149% higher (134-165), and anti-nucleocapsid antibody 39% lower (60-18) to day 5 than those without chronic kidney disease. Participants in the highest quartile for plasma nucleocapsid antigen, CRP, and IL-6 at baseline and day 5 had worse clinical outcomes, including 90-day all-cause mortality (plasma nucleocapsid antigen hazard ratio (HR) 4·50 (95% CI 3·29-6·15), CRP HR 3·37 (2·30-4·94), and IL-6 HR 5·67 (4·12-7·80). This risk persisted for plasma nucleocapsid antigen and CRP after adjustment for baseline biomarker values and other baseline factors. INTERPRETATION: Patients admitted to hospital with less favourable 5-day biomarker trajectories had worse prognosis, suggesting that persistent viral burden might drive inflammation in the pathogenesis of COVID-19, identifying patients that might benefit from escalation of antiviral or anti-inflammatory treatment. FUNDING: US National Institutes of Health.

The association between single-nucleotide polymorphisms within type 1 interferon pathway genes and human immunodeficiency virus type 1 viral load in antiretroviral-naïve participants.

BACKGROUND: Human genetic contribution to HIV progression remains inadequately explained. The type 1 interferon (IFN) pathway is important for host control of HIV and variation in type 1 IFN genes may contribute to disease progression. This study assessed the impact of variations at the gene and pathway level of type 1 IFN on HIV-1 viral load (VL). METHODS: Two cohorts of antiretroviral (ART) naïve participants living with HIV (PLWH) with either early (START) or advanced infection (FIRST) were analysed separately. Type 1 IFN genes (n = 17) and receptor subunits (IFNAR1, IFNAR2) were examined for both cumulated type 1 IFN pathway analysis and individual gene analysis. SKAT-O was applied to detect associations between the genotype and HIV-1 study entry viral load (log10 transformed) as a proxy for set point VL; P-values were corrected using Bonferroni (P < 0.0025). RESULTS: The analyses among those with early infection included 2429 individuals from five continents. The median study entry HIV VL was 14,623 (IQR 3460-45100) copies/mL. Across 673 SNPs within 19 type 1 IFN genes, no significant association with study entry VL was detected. Conversely, examining individual genes in START showed a borderline significant association between IFNW1, and study entry VL (P = 0.0025). This significance remained after separate adjustments for age, CD4+ T-cell count, CD4+/CD8+ T-cell ratio and recent infection. When controlling for population structure using linear mixed effects models (LME), in addition to principal components used in the main model, this was no longer significant (p = 0.0244). In subgroup analyses stratified by geographical region, the association between IFNW1 and study entry VL was only observed among African participants, although, the association was not significant when controlling for population structure using LME. Of the 17 SNPs within the IFNW1 region, only rs79876898 (A > G) was associated with study entry VL (p = 0.0020, beta = 0.32; G associated with higher study entry VL than A) in single SNP association analyses. The findings were not reproduced in FIRST participants. CONCLUSION: Across 19 type 1 IFN genes, only IFNW1 was associated with HIV-1 study entry VL in a cohort of ART-naïve individuals in early stages of their infection, however, this was no longer significant in sensitivity analyses that controlled for population structures using LME.

Increased [18F]Fluorodeoxyglucose Uptake in the Left Pallidum in Military Veterans with Blast-Related Mild Traumatic Brain Injury: Potential as an Imaging Biomarker and Mediation with Executive Dysfunction and Cognitive Impairment.

Blast-related mild traumatic brain injury (blast-mTBI) can result in a spectrum of persistent symptoms leading to substantial functional impairment and reduced quality of life. Clinical evaluation and discernment from other conditions common to military service can be challenging and subject to patient recall bias and the limitations of available assessment measures. The need for objective biomarkers to facilitate accurate diagnosis, not just for symptom management and rehabilitation but for prognostication and disability compensation purposes is clear. Toward this end, we compared regional brain [18F]fluorodeoxyglucose-positron emission tomography ([18F]FDG-PET) intensity-scaled uptake measurements and motor, neuropsychological, and behavioral assessments in 79 combat Veterans with retrospectively recalled blast-mTBI with 41 control participants having no lifetime history of TBI. Using an agnostic and unbiased approach, we found significantly increased left pallidum [18F]FDG-uptake in Veterans with blast-mTBI versus control participants, p < 0.0001; q = 3.29 × 10-9 [Cohen's d, 1.38, 95% confidence interval (0.96, 1.79)]. The degree of left pallidum [18F]FDG-uptake correlated with the number of self-reported blast-mTBIs, r2 = 0.22; p < 0.0001. Greater [18F]FDG-uptake in the left pallidum provided excellent discrimination between Veterans with blast-mTBI and controls, with a receiver operator characteristic area under the curve of 0.859 (p < 0.0001) and likelihood ratio of 21.19 (threshold:SUVR ≥ 0.895). Deficits in executive function assessed using the Behavior Rating Inventory of Executive Function-Adult Global Executive Composite T-score were identified in Veterans with blast-mTBI compared with controls, p < 0.0001. Regression-based mediation analyses determined that in Veterans with blast-mTBI, increased [18F]FDG-uptake in the left pallidum-mediated executive function impairments, adjusted causal mediation estimate p = 0.021; total effect estimate, p = 0.039. Measures of working and prospective memory (Auditory Consonant Trigrams test and Memory for Intentions Test, respectively) were negatively correlated with left pallidum [18F]FDG-uptake, p < 0.0001, with mTBI as a covariate. Increased left pallidum [18F]FDG-uptake in Veterans with blast-mTBI compared with controls did not covary with dominant handedness or with motor activity assessed using the Unified Parkinson's Disease Rating Scale. Localized increased [18F]FDG-uptake in the left pallidum may reflect a compensatory response to functional deficits following blast-mTBI. Limited imaging resolution does not allow us to distinguish subregions of the pallidum; however, the significant correlation of our data with behavioral but not motor outcomes suggests involvement of the ventral pallidum, which is known to regulate motivation, behavior, and emotions through basal ganglia-thalamo-cortical circuits. Increased [18F]FDG-uptake in the left pallidum in blast-mTBI versus control participants was consistently identified using two different PET scanners, supporting the generalizability of this finding. Although confirmation of our results by single-subject-to-cohort analyses will be required before clinical deployment, this study provides proof of concept that [18F]FDG-PET bears promise as a readily available noninvasive biomarker for blast-mTBI. Further, our findings support a causative relationship between executive dysfunction and increased [18F]FDG-uptake in the left pallidum.

SARS-CoV-2 Delta and Omicron community transmission networks as added value to contact tracing.

OBJECTIVES: Calculations of SARS-CoV-2 transmission networks at a population level have been limited. Networks that estimate infections between individuals and whether this results in a mutation, can be a way to evaluate fitness of a mutational clone by how much it expands in number as well as determining the likelihood a transmission results in a new variant. METHODS: Australian Delta and Omicron SARS-CoV-2 sequences were downloaded from GISAID. Transmission networks of infection between individuals were estimated using a novel mathematical method. RESULTS: Many of the sequences were identical, with clone sizes following power law distributions driven by negative binomial probability distributions for both the number of infections per individual and the number of mutations per transmission (median 0.74 nucleotide changes for Delta and 0.71 for Omicron). Using these distributions, an agent-based model was able to replicate the observed clonal network structure, providing a basis for more detailed COVID-19 modelling. Possible recombination events, tracked by insertion/deletion (indel) patterns, were identified for each variant in these outbreaks. CONCLUSIONS: This modelling approach reveals key transmission characteristics of SARS-CoV-2 and may complement traditional contact tracing. This methodology can also be applied to other diseases as genetic sequencing of viruses becomes more commonplace.

Long-Term Patient Outcomes for Treatment of Difficult Osteochondral Lesions of the Talus with Particulated Juvenile Allograft Cartilage Implantation ± Calcaneal Autograft: A Cohort Study.

BACKGROUND: Osteochondral lesions of the talus (OCLT) are common injuries that can be difficult to treat. To date, long-term patient reported outcome measures (PROMs) of patients with particulated juvenile allograft cartilage implantation with or without calcaneal autograft have not been compared. METHODS: Thirteen patients with difficult to treat OCLTs underwent arthroscopic-assisted implantation of particulated juvenile allograft cartilage (DeNovo NT®) with or without autogenous calcaneal bone grafting by a single surgeon. Calcaneal bone graft use was determined by lesion size > 150 mm2 and/or deeper than 5 mm. Patients were evaluated using physical examination, patient interviews, and PROMs. RESULTS: When comparing patients in regards to calcaneal bone graft implantation, no difference in age, BMI, pre-operative PROMs, or follow-up was noted, however, calcaneal bone graft patients did have a significantly larger lesion size (188.5 ± 50.9 vs. 118.7 ± 29.4 mm2 respectively; p value = 0.027). VAS and FAAM ADL scores during final follow-up improvement did not significantly differ between cohorts. The FAAM Sports score improved significantly more for the DeNovo alone group compared to the bone graft cohort (p value = 0.032). The AOFAS score improvement did not differ between cohorts (p value = 0.944), however, the SF-36 PCS improved significantly more for the DeNovo alone group compared to the bone graft cohort (p value = 0.038). No intraoperative/perioperative complications were observed with calcaneal bone grafting. CONCLUSION: While patients followed over the course of ~ 8 years after implantation of particulated juvenile allograft cartilage (DeNovo NT®) with/without autogenous calcaneal bone graft had positive post-operative PROMs, patients without calcaneal bone graft had significantly greater improvement in functional outcome scores. Whether these differences are due to graft incorporation or larger lesion size is unclear. LEVEL OF EVIDENCE: III, retrospective cohort study.

Effect of Neutralizing Monoclonal Antibody Treatment on Early Trajectories of Virologic and Immunologic Biomarkers in Patients Hospitalized With COVID-19.

BACKGROUND: Neutralizing monoclonal antibodies (nmAbs) failed to show clear benefit for hospitalized patients with coronavirus disease 2019 (COVID-19). Dynamics of virologic and immunologic biomarkers remain poorly understood. METHODS: Participants enrolled in the Therapeutics for Inpatients with COVID-19 trials were randomized to nmAb versus placebo. Longitudinal differences between treatment and placebo groups in levels of plasma nucleocapsid antigen (N-Ag), anti-nucleocapsid antibody, C-reactive protein, interleukin-6, and D-dimer at enrollment, day 1, 3, and 5 were estimated using linear mixed models. A 7-point pulmonary ordinal scale assessed at day 5 was compared using proportional odds models. RESULTS: Analysis included 2149 participants enrolled between August 2020 and September 2021. Treatment resulted in 20% lower levels of plasma N-Ag compared with placebo (95% confidence interval, 12%-27%; P < .001), and a steeper rate of decline through the first 5 days (P < .001). The treatment difference did not vary between subgroups, and no difference was observed in trajectories of other biomarkers or the day 5 pulmonary ordinal scale. CONCLUSIONS: Our study suggests that nmAb has an antiviral effect assessed by plasma N-Ag among hospitalized patients with COVID-19, with no blunting of the endogenous anti-nucleocapsid antibody response. No effect on systemic inflammation or day 5 clinical status was observed. CLINICAL TRIALS REGISTRATION: NCT04501978.

Correlating Conformational Equilibria with Catalysis in the Electron Bifurcating EtfABCX of Thermotoga maritima.

Electron bifurcation (BF) is an evolutionarily ancient energy coupling mechanism in anaerobes, whose associated enzymatic machinery remains enigmatic. In BF-flavoenzymes, a chemically high-potential electron forms in a thermodynamically favorable fashion by simultaneously dropping the potential of a second electron before its donation to physiological acceptors. The cryo-EM and spectroscopic analyses of the BF-enzyme Fix/EtfABCX from Thermotoga maritima suggest that the BF-site contains a special flavin-adenine dinucleotide and, upon its reduction with NADH, a low-potential electron transfers to ferredoxin and a high-potential electron reduces menaquinone. The transfer of energy from high-energy intermediates must be carefully orchestrated conformationally to avoid equilibration. Herein, anaerobic size exclusion-coupled small-angle X-ray scattering (SEC-SAXS) shows that the Fix/EtfAB heterodimer subcomplex, which houses BF- and electron transfer (ET)-flavins, exists in a conformational equilibrium of compacted and extended states between flavin-binding domains, the abundance of which is impacted by reduction and NAD(H) binding. The conformations identify dynamics associated with the T. maritima enzyme and also recapitulate states identified in static structures of homologous BF-flavoenzymes. Reduction of Fix/EtfABCX's flavins alone is insufficient to elicit domain movements conducive to ET but requires a structural "trigger" induced by NAD(H) binding. Models show that Fix/EtfABCX's superdimer exists in a combination of states with respect to its BF-subcomplexes, suggesting a cooperative mechanism between supermonomers for optimizing catalysis. The correlation of conformational states with pathway steps suggests a structural means with which Fix/EtfABCX may progress through its catalytic cycle. Collectively, these observations provide a structural framework for tracing Fix/EtfABCX's catalysis.

When does too little pressure become too much? A case of spontaneous intracranial hypotension presenting with acute loss of consciousness.

Background: We present a unique case of spontaneous intracranial hypotension (SIH) presenting with acute collapse and loss of consciousness. Case Description: The affected patient suffered an abrupt decline in level of consciousness several weeks after initial diagnosis. The patient was urgently transferred to a specialist neurosurgical unit. Imaging showed bilateral subdural fluid collections with significant associated local mass effect. The treating team faced a clinical conundrum with a lack of clarity as to whether this sudden deterioration was secondary to the local pressure effect on brainstem traction from reduced intracranial pressure. A decision was made to proceed with urgent burr-hole decompression of the bilateral subdural fluid collections. Conclusion: After a protracted, complex postoperative course, the patient recovered to full functional independence. To the author's knowledge, this is the first case in literature describing successful surgical management of SIH, with bilateral burr-hole evacuation to relieve the paradoxical mass effect of bilateral subdural fluid collections.

Domain crossover in the reductase subunit of NADPH-dependent assimilatory sulfite reductase.

NADPH-dependent assimilatory sulfite reductase (SiR) from Escherichia coli performs a six-electron reduction of sulfite to the bioavailable sulfide. SiR is composed of a flavoprotein (SiRFP) reductase subunit and a hemoprotein (SiRHP) oxidase subunit. There is no known high-resolution structure of SiR or SiRFP, thus we do not yet fully understand how the subunits interact to perform their chemistry. Here, we used small-angle neutron scattering to understand the impact of conformationally restricting the highly mobile SiRFP octamer into an electron accepting (closed) or electron donating (open) conformation, showing that SiR remains active, flexible, and asymmetric even with these conformational restrictions. From these scattering data, we model the first solution structure of SiRFP. Further, computational modeling of the N-terminal 52 amino acids that are responsible for SiRFP oligomerization suggests an eight-helical bundle tethers together the SiRFP subunits to form the SiR core. Finally, mass spectrometry analysis of the closed SiRFP variant show that SiRFP is capable of inter-molecular domain crossover, in which the electron donating domain from one polypeptide is able to interact directly with the electron accepting domain of another polypeptide. This structural characterization suggests that SiR performs its high-volume electron transfer through both inter- and intramolecular pathways between SiRFP domains and, thus, cis or trans transfer from reductase to oxidase subunits. Such highly redundant potential for electron transfer makes this system a potential target for designing synthetic enzymes.

Metabolic Profiling Early Post-Allogeneic Haematopoietic Cell Transplantation in the Context of CMV Infection.

Immune dysfunction resulting from allogeneic haematopoietic stem cell transplantation (aHSCT) predisposes one to an elevated risk of cytomegalovirus (CMV) infection. Changes in metabolism have been associated with adverse outcomes, and in this study, we explored the associations between metabolic profiles and post-transplantation CMV infection using plasma samples collected 7-33 days after aHSCT. We included 68 aHSCT recipients from Rigshospitalet, Denmark, 50% of whom experienced CMV infection between days 34-100 post-transplantation. First, we investigated whether 12 metabolites selected based on the literature were associated with an increased risk of post-transplantation CMV infection. Second, we conducted an exploratory network-based analysis of the complete metabolic and lipidomic profiles in relation to clinical phenotypes and biological pathways. Lower levels of trimethylamine N-oxide were associated with subsequent CMV infection (multivariable logistic regression: OR = 0.63; 95% CI = [0.41; 0.87]; p = 0.01). Explorative analysis revealed 12 clusters of metabolites or lipids, among which one was predictive of CMV infection, and the others were associated with conditioning regimens, age upon aHSCT, CMV serostatus, and/or sex. Our results provide evidence for an association between the metabolome and CMV infection post-aHSCT that is independent of known risk factors.

Associations of functional human leucocyte antigen class I groups with HIV viral load in a heterogeneous cohort.

OBJECTIVE: Human leucocyte antigen (HLA) class I alleles are the main host genetic factors involved in controlling HIV-1 viral load (VL). Nevertheless, HLA diversity has proven a significant challenge in association studies. We assessed how accounting for binding affinities of HLA class I alleles to HIV-1 peptides facilitate association testing of HLA with HIV-1 VL in a heterogeneous cohort. DESIGN: Cohort from the Strategic Timing of AntiRetroviral Treatment (START) study. METHODS: We imputed HLA class I alleles from host genetic data (2546 HIV+ participants) and sampled immunopeptidomes from 2079 host-paired viral genomes (targeted amplicon sequencing). We predicted HLA class I binding affinities to HIV-1 and unspecific peptides, grouping alleles into functional clusters through consensus clustering. These functional HLA class I clusters were used to test associations with HIV VL. RESULTS: We identified four clades totaling 30 HLA alleles accounting for 11.4% variability in VL. We highlight HLA-B∗57:01 and B∗57:03 as functionally similar but yet overrepresented in distinct ethnic groups, showing when combined a protective association with HIV+ VL (log, ß -0.25; adj. P-value < 0.05). We further demonstrate only a slight power reduction when using unspecific immunopeptidomes, facilitating the use of the inferred functional HLA groups in other studies. CONCLUSION: The outlined computational approach provides a robust and efficient way to incorporate HLA function and peptide diversity, aiding clinical association studies in heterogeneous cohorts. To facilitate access to the proposed methods and results we provide an interactive application for exploring data.

Long-Term Benefits from Early Antiretroviral Therapy Initiation in HIV Infection.

BACKGROUND: For people with HIV and CD4+ counts >500 cells/mm3, early initiation of antiretroviral therapy (ART) reduces serious AIDS and serious non-AIDS (SNA) risk compared with deferral of treatment until CD4+ counts are <350 cells/mm3. Whether excess risk of AIDS and SNA persists once ART is initiated for those who defer treatment is uncertain. METHODS: The Strategic Timing of AntiRetroviral Treatment (START) trial, as previously reported, randomly assigned 4684 ART-naive HIV-positive adults with CD4+ counts .500 cells/mm3 to immediate treatment initiation after random assignment (n = 2325) or deferred treatment (n= 2359). In 2015, a 57% lower risk of the primary end point (AIDS, SNA, or death) for the immediate group was reported, and the deferred group was offered ART. This article reports the follow-up that continued to December 31, 2021. Cox proportional-hazards models were used to compare hazard ratios for the primary end point from randomization through December 31, 2015, versus January 1, 2016, through December 31, 2021. RESULTS: Through December 31, 2015, approximately 7 months after the cutoff date from the previous report, the median CD4+ count was 648 and 460 cells/mm3 in the immediate and deferred groups, respectively, at treatment initiation. The percentage of follow-up time spent taking ART was 95% and 36% for the immediate and deferred groups, respectively, and the time-averaged CD4+ difference was 199 cells/mm3. After January 1, 2016, the percentage of follow-up time on treatment was 97.2% and 94.1% for the immediate and deferred groups, respectively, and the CD4+ count difference was 155 cells/mm3. After January 1, 2016, a total of 89 immediate and 113 deferred group participants experienced a primary end point (hazard ratio of 0.79 [95% confidence interval, 0.60 to 1.04] versus hazard ratio of 0.47 [95% confidence interval, 0.34 to 0.65; P<0.001]) before 2016 (P=0.02 for hazard ratio difference). CONCLUSIONS: Among adults with CD4+ counts >500 cells/mm3, excess risk of AIDS and SNA associated with delaying treatment initiation was diminished after ART initiation, but persistent excess risk remained. (Funded by the National Institute of Allergy and Infectious Diseases and others.).

Development of a machine learning model for early prediction of plasma leakage in suspected dengue patients.

BACKGROUND: At least a third of dengue patients develop plasma leakage with increased risk of life-threatening complications. Predicting plasma leakage using laboratory parameters obtained in early infection as means of triaging patients for hospital admission is important for resource-limited settings. METHODS: A Sri Lankan cohort including 4,768 instances of clinical data from N = 877 patients (60.3% patients with confirmed dengue infection) recorded in the first 96 hours of fever was considered. After excluding incomplete instances, the dataset was randomly split into a development and a test set with 374 (70%) and 172 (30%) patients, respectively. From the development set, five most informative features were selected using the minimum description length (MDL) algorithm. Random forest and light gradient boosting machine (LightGBM) were used to develop a classification model using the development set based on nested cross validation. An ensemble of the learners via average stacking was used as the final model to predict plasma leakage. RESULTS: Lymphocyte count, haemoglobin, haematocrit, age, and aspartate aminotransferase were the most informative features to predict plasma leakage. The final model achieved the area under the receiver operating characteristics curve, AUC = 0.80 with positive predictive value, PPV = 76.9%, negative predictive value, NPV = 72.5%, specificity = 87.9%, and sensitivity = 54.8% on the test set. CONCLUSION: The early predictors of plasma leakage identified in this study are similar to those identified in several prior studies that used non-machine learning based methods. However, our observations strengthen the evidence base for these predictors by showing their relevance even when individual data points, missing data and non-linear associations were considered. Testing the model on different populations using these low-cost observations would identify further strengths and limitations of the presented model.

The weekend effect in aneurysmal subarachnoid haemorrhage: a single centre experience and review.

Clinical outcomes for patients admitted to hospital during weekend hours have been reported to be poorer than for those admitted during the week. Aneurysmal subarachnoid haemorrhage (aSAH) is a devastating form of haemorrhagic stroke, with a mortality rate greater than 30%. A number of studies have reported higher mortality for patients with aSAH who are admitted during weekend hours. This study evaluates the effect of weekend admission on patients in our unit with aSAH in terms of time to treatment, treatment type, rebleeding rates, functional outcome, and mortality. We analysed a retrospective database of all patients admitted to our tertiary referral centre with aneurysmal subarachnoid haemorrhage between February 2016 and February 2020. Chi-square tests and t-tests were used to compare weekday and weekend demographic and clinical variables. Univariate and multivariate logistic regression analyses were performed to assess for any association between admission during weekend hours and increased neurological morbidity (assessed via Glasgow Outcome Scale at 3 months) and mortality. Of the 571 patients included in this study, 191 were admitted during on-call weekend hours. There were no significant differences found in time to treatment, type of treatment, rebleeding rates, neurological morbidity, or mortality rates between patients admitted during the week and those admitted during weekend hours. Weekend admission was not associated with worsened functional outcome or increased mortality in this cohort. These results suggest that provision of 7-day cover by vascular neurosurgeons and interventional neuroradiologists in high-volume centres could mitigate the weekend effect sometimes reported in the aSAH cohort.

Network-based multi-omics integration reveals metabolic at-risk profile within treated HIV-infection.

Multiomics technologies improve the biological understanding of health status in people living with HIV on antiretroviral therapy (PWH). Still, a systematic and in-depth characterization of metabolic risk profile during successful long-term treatment is lacking. Here, we used multi-omics (plasma lipidomic, metabolomic, and fecal 16 S microbiome) data-driven stratification and characterization to identify the metabolic at-risk profile within PWH. Through network analysis and similarity network fusion (SNF), we identified three groups of PWH (SNF-1-3): healthy (HC)-like (SNF-1), mild at-risk (SNF-3), and severe at-risk (SNF-2). The PWH in the SNF-2 (45%) had a severe at-risk metabolic profile with increased visceral adipose tissue, BMI, higher incidence of metabolic syndrome (MetS), and increased di- and triglycerides despite having higher CD4+ T-cell counts than the other two clusters. However, the HC-like and the severe at-risk group had a similar metabolic profile differing from HIV-negative controls (HNC), with dysregulation of amino acid metabolism. At the microbiome profile, the HC-like group had a lower α-diversity, a lower proportion of men having sex with men (MSM) and was enriched in Bacteroides. In contrast, in at-risk groups, there was an increase in Prevotella, with a high proportion of MSM, which could potentially lead to higher systemic inflammation and increased cardiometabolic risk profile. The multi-omics integrative analysis also revealed a complex microbial interplay of the microbiome-associated metabolites in PWH. Those severely at-risk clusters may benefit from personalized medicine and lifestyle intervention to improve their dysregulated metabolic traits, aiming to achieve healthier aging.

Visualizing and accessing correlated SAXS data sets with Similarity Maps and Simple Scattering web resources.

Constructing a comprehensive understanding of macromolecular behavior from a set of correlated small angle scattering (SAS) data is aided by tools that analyze all scattering curves together. SAS experiments on biological systems can be performed on specimens that are more easily prepared, modified, and formatted relative to those of most other techniques. An X-ray SAS measurement (SAXS) can be performed in less than a milli-second in-line with treatment steps such as purification or exposure to modifiers. These capabilities are valuable since biological macromolecules (proteins, polynucleotides, lipids, and carbohydrates) change conformation or assembly under specific conditions that often define their biological role. Furthermore, mutation or post-translational modification change their behavior and provides an avenue to tailor their mechanics. Here, we describe tools to combine multiple correlated SAS measurements for analysis and review their application to biological systems. The SAXS Similarity Map (SSM) compares a set of scattering curves and quantifies the similarity between them for display as a color on a grid. Visualizing an entire correlated data set with SSMs helps identify patterns that reveal biological functions. The SSM analysis is available as a web-based tool at https://sibyls.als.lbl.gov/saxs-similarity/. To make data available and promote tool development, we have also deployed a repository of correlated SAS data sets called Simple Scattering (available at https://simplescattering.com). The correlated data sets used to demonstrate the SSM are available on the Simple Scattering website. We expect increased utilization of correlated SAS measurements to characterize the tightly controlled mechanistic properties of biological systems and fine-tune engineered macromolecules for nanotechnology-based applications.

Spontaneous intracerebral haemorrhage secondary to 5-ALA-induced thrombocytopaenia in a paediatric patient: case report and literature review.

INTRODUCTION: The primary objective of neurosurgical management of malignant gliomas is maximal safe resection of the tumour. One of the main obstacles in achieving this is the ability to accurately discriminate between tumour edges and the surrounding healthy brain tissue. The use of fluorescence-guided surgery utilising 5-aminolevulinic acid (5-ALA), first introduced more than 20 years ago, has become an invaluable adjunct in high-grade glioma surgery in adults. However, as 5-ALA is not licensed for use in paediatric patients, the safety profile for such use remains undetermined. CASE REPORT: We describe the case of a 4-year-old boy who underwent 5-ALA-guided resection of a fourth ventricle anaplastic ependymoma. Although complete resection was achieved and the patient awoke from surgery well with no neurological deficits, the patient developed acute transaminitis, anaemia, thrombocytopaenia and coagulopathy postoperatively. The patient had a sudden neurological deterioration on postoperative day 2; imaging revealed that he had suffered a spontaneous right frontal intracerebral haemorrhage. The patient returned to theatre for surgical decompression and evacuation of the haematoma, and ultimately went on to make a full recovery. CONCLUSION: The use of 5-ALA in paediatric patients can be helpful in maximising surgical resection, but the associated safety profile remains undefined. Further research is urgently warranted in order to characterise the efficacy and risk of the use of 5-ALA in the paediatric population.

Association between ten-eleven methylcytosine dioxygenase 2 genetic variation and viral load in people with HIV.

INTRODUCTION: Identifying genetic factors that influence HIV-pathogenesis is critical for understanding disease pathways. Previous studies have suggested a role for the human gene ten-eleven methylcytosine dioxygenase 2 (TET2) in modulating HIV-pathogenesis. METHODS: We assessed whether genetic variation in TET2 was associated with markers of HIV-pathogenesis using both gene level and single nucleotide polymorphism (SNP) level association in 8512 HIV-positive persons across five clinical trial cohorts. RESULTS: Variation at both the gene and SNP-level of TET2 was found to be associated with levels of HIV viral load (HIV-VL) consistently in the two cohorts that recruited antiretroviral-naïve participants. The SNPs occurred in two clusters of high linkage disequilibrium (LD), one associated with high HIV-VL and the other low HIV-VL, and were predominantly found in Black participants. CONCLUSION: Genetic variation in TET2 was associated with HIV-VL in two large antiretroviral therapy (ART)-naive clinical trial cohorts. The role of TET2 in HIV-pathogenesis warrants further investigation.

Early Biomarker-Guided Prediction of Bloodstream Infection in Critically Ill Patients: C-Reactive Protein, Procalcitonin, and Leukocytes.

Background: Bloodstream infections (BSIs) often lead to critical illness and death. The primary aim of this study was to determine the diagnostic accuracy of the biomarkers C-reactive protein (CRP), procalcitonin (PCT), and leukocyte count for the diagnosis of BSI in critically ill patients. Methods: This was a nested case-control study based on the Procalcitonin And Survival Study (PASS) trial (n = 1200). Patients who were admitted to the intensive care unit (ICU) <24 hours, and not expected to die within <24 hours, were recruited. For the current study, we included patients with a BSI within ±3 days of ICU admission and matched controls without a BSI in a 1:2 ratio. Diagnostic accuracy for BSI for the biomarkers on days 1, 2, and 3 of ICU admission was assessed. Sensitivity, specificity, and negative and positive predictive values were calculated for prespecified thresholds and for a data-driven cutoff. Results: In total, there were 525 patients (n = 175 cases, 350 controls). The fixed low threshold for all 3 biomarkers (CRP = 20 mg/L; leucocytes = 10 × 109/L; PCT = 0.4 ng/mL) resulted in negative predictive values on day 1: CRP = 0.91; 95% CI, 0.75-1.00; leukocyte = 0.75; 95% CI, 0.68-0.81; PCT = 0.91; 95% CI, 0.84-0.96). Combining the 3 biomarkers yielded similar results as PCT alone (P = .5). Conclusions: CRP and PCT could in most cases rule out BSI in critically ill patients. As almost no patients had low CRP and ∼20% had low PCT, a low PCT could be used, along with other information, to guide clinical decisions.