Computation-guided scaffold exploration of 2E,6E-1,10-trans/cis-eunicellanes.

Eunicellane diterpenoids are a unique family of natural products containing a foundational 6/10-bicyclic framework and can be divided into two main classes, cis and trans, based on the configurations of their ring fusion at C1 and C10. Previous studies on two bacterial diterpene synthases, Bnd4 and AlbS, revealed that these enzymes form cis- and trans-eunicellane skeletons, respectively. Although the structures of these diterpenes only differed in their configuration at a single position, C1, they displayed distinct chemical and thermal reactivities. Here, we used a combination of quantum chemical calculations and chemical transformations to probe their intrinsic properties, which result in protonation-initiated cyclization, Cope rearrangement, and atropisomerism. Finally, we exploited the reactivity of the trans-eunicellane skeleton to generate a series of 6/6/6 gersemiane-type diterpenes via electrophilic cyclization.

Force-field perturbations and muscle vibration strengthen stability-related foot placement responses during steady-state gait in healthy adults.

Mediolateral gait stability can be maintained by coordinating our foot placement with respect to the center-of-mass (CoM) kinematic state. Neurological impairments can reduce the degree of foot placement control. For individuals with such impairments, interventions that could improve foot placement control could thus contribute to improved gait stability. In this study we aimed to better understand two potential interventions, by investigating their effect in neurologically intact individuals. The degree of foot placement control can be quantified based on a foot placement model, in which the CoM position and velocity during swing predict subsequent foot placement. Previously, perturbing foot placement with a force-field resulted in an enhanced degree of foot placement control as an after-effect. Moreover, timed muscle vibration enhanced the degree of foot placement control whilst the vibration was applied. Here, we replicated these two findings and further investigated whether Q1) timed muscle vibration leads to an after-effect and Q2) whether combining timed muscle vibration with force-field perturbations leads to a larger after-effect, as compared to force-field perturbations only. In addition, we evaluated several potential contributors to the degree of foot placement control, by considering foot placement errors, CoM variability and the CoM position gain (ßpos) of the foot placement model, next to the R2 measure as the degree of foot placement control. Timed muscle vibration led to a higher degree of foot placement control as an after-effect (Q1). However, combining timed muscle vibration and force-field perturbations did not lead to a larger after-effect, as compared to following force-field perturbations only (Q2). Furthermore, we showed that the improved degree of foot placement control following force-field perturbations and during/following muscle vibration, did not reflect diminished foot placement errors. Rather, participants demonstrated a stronger active response (higher ßpos) as well as higher CoM variability.

Identification of cross reactive T cell responses in adenovirus based COVID 19 vaccines.

Vaccination has proven to be a valuable tool to combat SARS-CoV-2. However, reports of rare adverse reactions such as thrombosis/thrombocytopenia syndrome after ChAdOx1 nCoV-19 vaccination have caused scientific, public and media concern. ChAdOx1 was vectorised from the Y25 chimpanzee adenovirus, which was selected due to low human seroprevalence to circumvent pre-existing immunity. In this study, we aimed to explore patterns of T-cell activation after SARS-CoV-2 COVID-19 vaccine exposure in vitro using PBMCs collected from pre-pandemic ChAdOx1 nCoV-19 naïve healthy donors (HDs), and ChAdOx1 nCoV-19 and Pfizer vaccinated controls. PBMCs were assessed for T-cell proliferation using the lymphocyte transformation test (LTT) following exposure to SARS-CoV-2 COVID-19 vaccines. Cytokine analysis was performed via intracellular cytokine staining, ELISpot assay and LEGENDplex immunoassays. T-cell assays performed in pre-pandemic vaccine naïve HDs, revealed widespread lymphocyte stimulation after exposure to ChAdOx1 nCoV-19 (95%), ChAdOx-spike (90%) and the Ad26.COV2. S vaccine, but not on exposure to the BNT162b2 vaccine. ICS analysis demonstrated that CD4+ CD45RO+ memory T-cells are activated by ChAdOx1 nCoV-19 in vaccine naïve HDs. Cytometric immunoassays showed ChAdOx1 nCoV-19 exposure was associated with the release of proinflammatory and cytotoxic molecules, such as IFN-γ, IL-6, perforin, granzyme B and FasL. These studies demonstrate a ubiquitous T-cell response to ChAdOx1 nCoV-19 and Ad26.COV2. S in HDs recruited prior to the SARS-CoV-2 pandemic, with T-cell stimulation also identified in vaccinated controls. This may be due to underlying T-cell cross-reactivity with prevalent human adenoviruses and further study will be needed to identify T-cell epitopes involved.

One-hundred Consecutive Physician-modified Fenestrated Endovascular Aneurysm Repair of Pararenal and Thoracoabdominal Aortic Aneurysms using the Terumo TREO Stent-Graft.

OBJECTIVE: Fenestrated endovascular aortic aneurysm repair (FEVAR) has been widely applied for the treatment of pararenal (PAA) and thoracoabdominal aortic aneurysms (TAAA). If custom-made devices or off-the-shelf devices are not available, physician-modified endografts (PMEG) are an alternative device option. Several different endograft platforms have been used for PMEG; however, minimal data exists on utilizing the Terumo TREO Abdominal stent-graft system in this setting. The purpose of this study was to evaluate our single-center experience treating PAA and TAAA with a physician-modified FEVAR using the TREO platform. METHODS: A prospective database of consecutive patients with PAA and TAAA treated at a single-center with a FEVAR utilizing a PMEG device between March 2021 and September 2023 was queried for those having a Terumo TREO device implanted. Demographics, operative details, and postoperative complications were analyzed. Rates of technical success, type I or III endoleak, branch vessel status, reintervention, and 2-year survival were also assessed. RESULTS: Of the 153 patients who underwent FEVAR with a PMEG device during the study period, 100 had repair using a Terumo TREO stent-graft. The mean age of the cohort was 73.7±7.0years with the majority suffering from hypertension (n=94, 94%), coronary artery disease (n=51, 51%), and COPD (n=40, 40%). Thirty-four patients (34%) had a prior failed EVAR device in place. Mean aneurysm size was 66.0±13.7mm, with 58 (50%) patients classified as PAA and 30 (30%) patients as an extent IV TAAA. Six (6%) patients presented with symptomatic/ruptured aneurysms. The average number of target arteries incorporated per patient was 3.8±0.6. Overall technical success was 99%, procedure time was 218±116 minutes, contrast volume was 82±21mL, and cumulative air kerma was 3,054±1,560mGy. Postoperative complications were present in 20 patients (20%) and 2 patients (2%) died within 30-days. Rates of type I or III endoleak, branch vessel stenosis/occlusion, and reintervention were 2%, 1%, and 7%, respectively. Two-year overall survival was 87%. CONCLUSIONS: Treatment of pararenal and extent IV TAAA using a physician-modified fenestrated Terumo TREO endograft is safe and effective. This large, early experience using the Terumo TREO platform supports preferential use of this device in this setting due to the device design and low likelihood of type I or III endoleak.

Combined Computational and Experimental Study Reveals Complex Mechanistic Landscape of Brønsted Acid-Catalyzed Silane-Dependent P═O Reduction.

The reaction mechanism of Brønsted acid-catalyzed silane-dependent P═O reduction has been elucidated through combined computational and experimental methods. Due to its remarkable chemo- and stereoselective nature, the Brønsted acid/silane reduction system has been widely employed in organophosphine-catalyzed transformations involving P(V)/P(III) redox cycle. However, the full mechanistic profile of this type of P═O reduction has yet to be clearly established to date. Supported by both DFT and experimental studies, our research reveals that the reaction likely proceeds through mechanisms other than the widely accepted "dual activation mode by silyl ester" or "acid-mediated direct P═O activation" mechanism. We propose that although the reduction mechanisms may vary with the substitution patterns of silane species, Brønsted acid generally activates the silane rather than the P═O group in transition structures. The proposed activation mode differs significantly from that associated with traditional Brønsted acid-catalyzed C═O reduction. The uniqueness of P═O reduction originates from the dominant Si/O═P orbital interactions in transition structures rather than the P/H-Si interactions. The comprehensive mechanistic landscape provided by us will serve as a guidance for the rational design and development of more efficient P═O reduction systems as well as novel organophosphine-catalyzed reactions involving P(V)/P(III) redox cycle.

Heavy Atom Quantum Mechanical Tunneling in Total Synthesis.

Contributions from quantum mechanical tunneling to the rates of several radical coupling reactions between carbon sp2 centers used as key steps in natural product total syntheses were computed using density functional theory. Contributions ranging from ∼15-52% from tunneling were predicted at room temperature, thereby indicating that tunneling plays an important role in the rates of these reactions and should perhaps be considered when designing complex synthetic schemes.

Endovascular Salvage of Type Ia and Ib Endoleaks Using a Physician-Modified Fenestrated/Branched Endograft and an Iliac Branch Device Via Unilateral Transfemoral Arterial Access.

PURPOSE: This study aims to explore the feasibility and effectiveness of a unilateral transfemoral access endovascular salvage technique for complex abdominal aortic aneurysms with concurrent type Ia and Ib endoleaks following previous endovascular repair. CASE REPORT: A 69-year-old female with multiple comorbidities presented with an extent IV thoracoabdominal aortic aneurysm complicated by type Ia and Ib endoleaks and chronically occluded left iliac endoprosthesis after prior endovascular repair. Given the patient's medical complexities, open explant repair was deemed high risk. The case was successfully managed using a physician-modified fenestrated/branched endograft (PM-F/BEVAR) and an iliac branch device (IBD) deployed through a single percutaneous transfemoral access. CONCLUSION: The presented case demonstrates the safety and efficacy of PM-F/BEVAR with concomitant IBD deployment via unilateral transfemoral access. This innovative approach allows endovascular salvage in cases with restricted iliofemoral access and avoids the complexities associated with upper extremity or aortic arch manipulation. While acknowledging the technical challenges, this technique offers a viable alternative for salvaging failed endovascular repairs, emphasizing the importance of real-time modifications in achieving successful outcomes. Further studies and long-term follow-up are warranted to validate the broader applicability and durability of this approach in the management of complex abdominal aortic aneurysms with multiple endoleaks. CLINICAL IMPACT: Although not the conventional approach, unilateral transfemoral access can be utilized to implant either a physician-modified fenestrated aortic endograft or an iliac branch device. Such an approach avoids complicating issues related to upper extremity access. This innovative technique may be necessary when there is a failed prior EVAR in the setting of significant contralateral iliofemoral occlusive disease. Doing both procedures in the same setting to resolve a type Ia and Ib endoleak is feasible as demonstrated in this case report. Expanding the endovascular armamentarium to address EVAR failure will be increasingly useful in the future, especially given the morbidity profile of EVAR explantation.

Cutdown is Associated with Higher 30-day Unplanned Readmissions and Wound Complications than Percutaneous Access for EVAR.

BACKGROUND: A 2023 Cochrane review showed no difference in bleeding/wound infection complications, short-term mortality and aneurysm exclusion between the percutaneous and cut-down approach for femoral access in endovascular aortic aneurysm repair (EVAR). In contrast, single-center studies have shown bilateral cutdown resulting in higher readmission rates due to higher rates of groin wound infections. Whether 30-day readmission rates vary by type of access during EVAR procedures is unknown. The goal of this study was to ascertain which femoral access approach for EVAR is associated with the lowest risk of 30-day readmission. METHODS: The Targeted Vascular Module from the American College of Surgeons National Surgical Quality Improvement Program was queried to identify patients undergoing EVAR for aortic disease from 2012-2021. All ruptures and other emergency cases were excluded. Cohorts were divided into bilateral cutdown, unilateral cutdown, failed percutaneous attempt converted to open and successful percutaneous access. The primary 30-day outcomes were unplanned readmission and wound complications. Univariate analyses were performed using the Fisher's exact test, Chi-Square test and the Student's t-test. Multivariable analysis was performed using logistic regression. RESULTS: From 2012 to 2021, 14,002 patients met study criteria. Most (7,395 [53%]) underwent completely percutaneous access, 5,616 (40%) underwent bilateral cutdown, 849 (6%) underwent unilateral cutdown, and 146 (1%) had a failed percutaneous access which was converted to open. Unplanned readmissions by access strategy included 7.6% for bilateral cutdown, 7.3% for unilateral cutdown, 7.8% for attempted percutaneous converted to cutdown, and 5.7% for completely percutaneous access (P < 0.001, Figure 1). After multivariable analysis, unplanned readmissions compared to percutaneous access yielded: percutaneous converted to cutdown adjusted odds ratio (AOR): 1.38, 95% CI [0.76-2.53], P = 0.29; unilateral cutdown AOR: 1.18, 95% CI [0.92-1.51], P = 0.20; bilateral cutdown AOR: 1.26, 95% CI [1.09-1.43], P = 0.001. Bilateral cutdown was also associated with higher wound complications compared to percutaneous access (AOR: 4.41, CI [2.86-6.79], P < 0.001), as was unilateral cutdown (AOR: 3.04, CI [1.46-6.32], P = 0.003). CONCLUSIONS: Patients undergoing cutdown for EVAR are at higher risk for 30-day readmission compared to completely percutaneous access. If patient anatomy allows for percutaneous EVAR, this access option should be prioritized.

The Night-Time Sleep and Autonomic Activity of Male and Female Professional Road Cyclists Competing in the Tour de France and Tour de France Femmes.

BACKGROUND: Sleep is a critical component of recovery, but it can be disrupted following prolonged endurance exercise. The objective of this study was to examine the capacity of male and female professional cyclists to recover between daily race stages while competing in the 2022 Tour de France and the 2022 Tour de France Femmes, respectively. The 17 participating cyclists (8 males from a single team and 9 females from two teams) wore a fitness tracker (WHOOP 4.0) to capture recovery metrics related to night-time sleep and autonomic activity for the entirety of the events and for 7 days of baseline before the events. The primary analyses tested for a main effect of 'stage classification'-i.e., rest, flat, hilly, mountain or time trial for males and flat, hilly or mountain for females-on the various recovery metrics. RESULTS: During baseline, total sleep time was 7.2 ± 0.3 h for male cyclists (mean ± 95% confidence interval) and 7.7 ± 0.3 h for female cyclists, sleep efficiency was 87.0 ± 4.4% for males and 88.8 ± 2.6% for females, resting HR was 41.8 ± 4.5 beats·min-1 for males and 45.8 ± 4.9 beats·min-1 for females, and heart rate variability during sleep was 108.5 ± 17.0 ms for males and 119.8 ± 26.4 ms for females. During their respective events, total sleep time was 7.2 ± 0.1 h for males and 7.5 ± 0.3 h for females, sleep efficiency was 86.4 ± 1.2% for males and 89.6 ± 1.2% for females, resting HR was 44.5 ± 1.2 beats·min-1 for males and 50.2 ± 2.0 beats·min-1 for females, and heart rate variability during sleep was 99.1 ± 4.2 ms for males and 114.3 ± 11.2 ms for females. For male cyclists, there was a main effect of 'stage classification' on recovery, such that heart rate variability during sleep was lowest after mountain stages. For female cyclists, there was a main effect of 'stage classification' on recovery, such that the percentage of light sleep (i.e., lower-quality sleep) was highest after mountain stages. CONCLUSIONS: Some aspects of recovery were compromised after the most demanding days of racing, i.e., mountain stages. Overall however, the cyclists obtained a reasonable amount of good-quality sleep while competing in these physiologically demanding endurance events. This study demonstrates that it is now feasible to assess recovery in professional athletes during multiple-day endurance events using validated fitness trackers.

Twelve tips for LGBT+-inclusive undergraduate and postgraduate medical education.

Sexual and gender minority (LGBT+) populations continue to experience worse health outcomes and reduced healthcare access compared to their cisgender, heterosexual counterparts, perpetuated by a lack of sufficient LGBT+-specific healthcare education within medical schools. Developing educational material that encourages self-reflective, proactive, and affirmative practice has been identified as a mechanism for increasing the quality of doctor-patient relationships and breaking down barriers in healthcare access for LGBT + communities. In this article, we provide twelve tips for those designing and delivering undergraduate and postgraduate medical curricula. We summarise evidence-based approaches to inclusive care, key overarching concepts that curricula should include and common issues to be avoided. We hope these tips provide a standard against which existing curricula and teaching practices can be appraised and form the basis of future educational material.

Clinical value of Alzheimer's disease biomarker testing.

INTRODUCTION: In the Investigating the Impact of Alzheimer's Disease Diagnostics in British Columbia (IMPACT-AD BC) study, we aimed to understand how Alzheimer's disease (AD) cerebrospinal fluid (CSF) biomarker testing-used in medical care-impacted medical decision-making (medical utility), personal decision-making (personal utility), and health system economics. METHODS: The study was designed as an observational, longitudinal cohort study. A total of 149 patients were enrolled between February 2019 and July 2021. Patients referred to memory clinics were approached to participate if their dementia specialist ordered AD CSF biomarker testing as part of their routine medical care, and the clinical scenario met the appropriate use criteria for lumbar puncture and AD CSF biomarker testing. For the medical utility pillar, detailed clinical management plans were collected via physician questionnaires pre- and post-biomarker disclosure. RESULTS: Patients with completed management questionnaires (n = 142) had a median age of 64 (interquartile range: 59-69) years, 48% were female, and 60% had CSF biomarker profiles on the AD continuum. Clinical management changed in 89.4% of cases. AD biomarker testing was associated with decreased need for other diagnostic procedures, including brain imaging (-52.0%) and detailed neuropsychological assessments (-63.2%), increased referrals and counseling (57.0%), and guided AD-related drug prescriptions (+88.4% and -50.0% in biomarker-positive and -negative cases, respectively). DISCUSSION: AD biomarker testing was associated with significant and positive changes in clinical management, including decreased health care resource use, therapy optimization, and increased patient and family member counseling. While certain changes in management were linked to the AD biomarker profile (e.g., referral to clinical trials), the majority of changes were independent of baseline clinical presentation and level of cognitive impairment, demonstrating a broad value for AD biomarker testing in individuals meeting the appropriate use criteria for testing.

Coronary intravascular lithotripsy for severe coronary artery calcification: The disrupt CAD I-IV trials.

Coronary artery calcification (CAC) severity is associated with increased vessel inflammation, atherosclerosis, stent failure, and risk of percutaneous coronary intervention-related complications. Current modalities for CAC modification include atherectomy techniques (rotational, orbital, and laser) and balloon modification (cutting and scoring). However, these methods are limited by their risk of slow flow/no reflow, coronary dissection, perforation, and myocardial infarction. Intravascular lithotripsy (IVL) emits high-energy sonic waves that induce calcium fractures within a target lesion to improve vessel compliance for stent placement. Low rates of major cardiac adverse events (MACE) and high rates of procedural and angiographic success were observed with IVL in the Disrupt CAD I-IV trials. Optical coherence tomography sub-studies identified calcium fracture as the likely etiology of improved vessel compliance and increased luminal diameter post-IVL. Rates of MACE, procedural, and angiographic success were consistent across the Disrupt CAD trials, suggesting IVL is less operator-dependent compared to other calcium-modifying techniques. Coronary IVL offers interventional cardiologists a safe and effective method of severe CAC modification, while providing reproducible outcomes.

Implementation of a ketamine programme for treatment-resistant depression in the public health system: Lessons from the first Australian public hospital clinic.

One could argue that we are living through a period of innovation and change in psychiatry unlike that seen before, with repurposed medications emerging as novel treatments. However, despite evidence of enhanced clinical outcomes and potential medium-term savings, delivering these promising interventions is resource-intensive and perceived as difficult in the public sector. Consequently, they are generally only available in the private sector, often at great cost, effectively making them inaccessible to the 'Have Nots'. The arrival of these paradigm-shifting treatments has inadvertently highlighted a growing mental health inequity. The Royal Prince Alfred Hospital's Ketamine Treatment Clinic was the first public-sector ketamine treatment clinic for complex mood disorders in Australia. Based on 3 years' experience establishing, developing and running a public-sector ketamine treatment service, we review the progress, perils and pitfalls for clinicians and health services contemplating establishing a public-sector ketamine treatment service of their own.

Management strategies and prognosis of patients ineligible for transcatheter mitral valve replacement.

BACKGROUND: Transcatheter mitral valve replacement (TMVR) faces anatomical challenges, currently limiting widespread adoption. OBJECTIVES: To describe the natural history and prognosis of patients ineligible for various TMVR devices. METHODS: During a 4-year period (2019-2023) 3 TMVR devices (SAPIEN M3, Intrepid and Alta Valve) became available at a single institution (The Christ Hospital, Cincinnati, OH) in the setting of pivotal clinical trials or early feasibility study. Consenting patients who were deemed ineligible ≥1 of these trials were prospectively studied to capture anatomical reasons for ineligibility, cross-over to alternative mitral valve therapies (surgery or high-risk mitral transcatheter edge to edge repair [M-TEER]), and clinical events. RESULTS: A total of 61 patients (out of 71 consenting patients or 85.9 %) were deemed ineligible for TMVR during the study period. The mean age was 79.2 ± 8.8 years, 65.6 % were female, with elevated surgical risk (median STS 4.3, IQR: 2.7-7.3). The 2 most common anatomical reasons for ineligibility were increased risk of left ventricular outflow tract obstruction (LVOTO) (n = 24, 39.3 %) and annular size (n = 29, 47.5 %). During follow-up (median 277 [162-555] days) there were 7 deaths (11.5 %) and 12 (19.7 %) hospitalizations for heart failure. Management strategies included high-risk M-TEER in 11 patients (1 death [9.0 %], 0 HF hospitalizations [0 %]), surgery in 9 patients (0 deaths, 1 HF hospitalizations [11.1 %]), and medical management in 41 patients (6 deaths [14.6 %], 11 HF hospitalizations [26.8 %]) (p = 0.715 for mortality and p = 0.093 for HF hospitalizations). Residual MR ≥ moderate was 0 %, 50 %, and 100 % for surgery, M-TEER and medical treatment, respectively (p < 0.001). CONCLUSIONS: One third of patients deemed ineligible for TMVR are candidates for high-risk M-TEER or surgery with acceptable morbidity and mortality. Our results have practical implications for patient management.

Thio-Induced Organophosphate Breakdown Promoted by Methimazole: an Experimental and Theoretical Study.

Investigating the reactivity of small nucleophilic scaffolds is a strategic approach for the design of new catalysts aiming at effective detoxification processes of organophosphorus compounds. The drug methimazole (MMZ) is an interesting candidate featuring two non-equivalent nucleophilic centers. Herein, phosphoryl transfer reactions mediated by MMZ were assessed by means of spectrophotometric kinetic studies, mass spectrometry (MS) analyses, and density functional theory (DFT) calculations using the multi-electrophilic compound O,O-diethyl 2,4-dinitrophenyl phosphate (DEDNPP). MMZ anion acts primarily as an S-nucleophile, exhibiting a nucleophilic activity comparable to that of certain oximes featuring alpha-effect. Selective nucleophilic aromatic substitution was observed, consistent with the DFT prediction of a low energy barrier. Overall, the results bring important advances regarding the mechanistic understanding of nucleophilic dephosphorylation reactions, which comprises a strategic tool for neutralizing toxic organophosphates, hence promoting chemical security.

Running Wild through Dirhodium Tetracarboxylate-Catalyzed Combined CH(C)-Functionalization/Cope Rearrangement Landscapes: Does Post-Transition-State Dynamic Mismatching Influence Product Distributions?

A special type of C-H functionalization can be achieved through C-H insertion combined with Cope rearrangement (CHCR) in the presence of dirhodium catalysts. This type of reaction was studied using density functional theory and ab initio molecular dynamics simulations, the results of which pointed to the dynamic origins of low yields observed in some experiments. These studies not only reveal intimate details of the complex reaction network underpinning CHCR reactions but also further cement the generality of the importance of nonstatistical dynamic effects in controlling Rh2L4-promoted reactions.

Viral DNAemia and DNA Virus Seropositivity and Mortality in Pediatric Sepsis.

Importance: Sepsis is a leading cause of pediatric mortality. Little attention has been paid to the association between viral DNA and mortality in children and adolescents with sepsis. Objective: To assess the association of the presence of viral DNA with sepsis-related mortality in a large multicenter study. Design, Setting, and Participants: This cohort study compares pediatric patients with and without plasma cytomegalovirus (CMV), Epstein-Barr virus (EBV), herpes simplex virus 1 (HSV-1), human herpesvirus 6 (HHV-6), parvovirus B19 (B19V), BK polyomavirus (BKPyV), human adenovirus (HAdV), and torque teno virus (TTV) DNAemia detected by quantitative real-time polymerase chain reaction or plasma IgG antibodies to CMV, EBV, HSV-1, or HHV-6. A total of 401 patients younger than 18 years with severe sepsis were enrolled from 9 pediatric intensive care units (PICUs) in the Eunice Kennedy Shriver National Institute of Child Health and Human Development Collaborative Pediatric Critical Care Research Network. Data were collected from 2015 to 2018. Samples were assayed from 2019 to 2022. Data were analyzed from 2022 to 2023. Main Outcomes and Measures: Death while in the PICU. Results: Among the 401 patients included in the analysis, the median age was 6 (IQR, 1-12) years, and 222 (55.4%) were male. One hundred fifty-four patients (38.4%) were previously healthy, 108 (26.9%) were immunocompromised, and 225 (56.1%) had documented infection(s) at enrollment. Forty-four patients (11.0%) died in the PICU. Viral DNAemia with at least 1 virus (excluding TTV) was detected in 191 patients (47.6%) overall, 63 of 108 patients (58.3%) who were immunocompromised, and 128 of 293 (43.7%) who were not immunocompromised at sepsis onset. After adjustment for age, Pediatric Risk of Mortality score, previously healthy status, and immunocompromised status at sepsis onset, CMV (adjusted odds ratio [AOR], 3.01 [95% CI, 1.36-6.45]; P = .007), HAdV (AOR, 3.50 [95% CI, 1.46-8.09]; P = .006), BKPyV (AOR. 3.02 [95% CI, 1.17-7.34]; P = .02), and HHV-6 (AOR, 2.62 [95% CI, 1.31-5.20]; P = .007) DNAemia were each associated with increased mortality. Two or more viruses were detected in 78 patients (19.5%), with mortality among 12 of 32 (37.5%) who were immunocompromised and 9 of 46 (19.6%) who were not immunocompromised at sepsis onset. Herpesvirus seropositivity was common (HSV-1, 82 of 246 [33.3%]; CMV, 107 of 254 [42.1%]; EBV, 152 of 251 [60.6%]; HHV-6, 253 if 257 [98.4%]). After additional adjustment for receipt of blood products in the PICU, EBV seropositivity was associated with increased mortality (AOR, 6.10 [95% CI, 1.00-118.61]; P = .049). Conclusions and Relevance: The findings of this cohort study suggest that DNAemia for CMV, HAdV, BKPyV, and HHV-6 and EBV seropositivity were independently associated with increased sepsis mortality. Further investigation of the underlying biology of these viral DNA infections in children with sepsis is warranted to determine whether they only reflect mortality risk or contribute to mortality.

Glycolysis: An early marker for vancomycin-specific T-cell activation.

BACKGROUND: Vancomycin, a glycopeptide antibiotic used for Gram-positive bacterial infections, has been linked with drug reaction with eosinophilia and systemic symptoms (DRESS) in HLA-A*32:01-expressing individuals. This is associated with activation of T lymphocytes, for which glycolysis has been isolated as a fuel pathway following antigenic stimulation. However, the metabolic processes that underpin drug-reactive T-cell activation are currently undefined and may shed light on the energetic conditions needed for the elicitation of drug hypersensitivity or tolerogenic pathways. Here, we sought to characterise the immunological and metabolic pathways involved in drug-specific T-cell activation within the context of DRESS pathogenesis using vancomycin as model compound and drug-reactive T-cell clones (TCCs) generated from healthy donors and vancomycin-hypersensitive patients. METHODS: CD4+ and CD8+ vancomycin-responsive TCCs were generated by serial dilution. The Seahorse XFe96 Analyzer was used to measure the extracellular acidification rate (ECAR) as an indicator of glycolytic function. Additionally, T-cell proliferation and cytokine release (IFN-γ) assay were utilised to correlate the bioenergetic characteristics of T-cell activation with in vitro assays. RESULTS: Model T-cell stimulants induced non-specific T-cell activation, characterised by immediate augmentation of ECAR and rate of ATP production (JATPglyc). There was a dose-dependent and drug-specific glycolytic shift when vancomycin-reactive TCCs were exposed to the drug. Vancomycin-reactive TCCs did not exhibit T-cell cross-reactivity with structurally similar compounds within proliferative and cytokine readouts. However, cross-reactivity was observed when analysing energetic responses; TCCs with prior specificity for vancomycin were also found to exhibit glycolytic switching after exposure to teicoplanin. Glycolytic activation of TCC was HLA restricted, as exposure to HLA blockade attenuated the glycolytic induction. CONCLUSION: These studies describe the glycolytic shift of CD4+ and CD8+ T cells following vancomycin exposure. Since similar glycolytic switching is observed with teicoplanin, which did not activate T cells, it is possible the master switch for T-cell activation is located upstream of metabolic signalling.

Analogies between photochemical reactions and ground-state post-transition-state bifurcations shed light on dynamical origins of selectivity.

Revealing the origins of kinetic selectivity is one of the premier tasks of applied theoretical organic chemistry, and for many reactions, doing so involves comparing competing transition states. For some reactions, however, a single transition state leads directly to multiple products, in which case non-statistical dynamic effects influence selectivity control. The selectivity of photochemical reactions-where crossing between excited-state and ground-state surfaces occurs near ground-state transition structures that interconvert competing products-also should be controlled by the momentum of the reacting molecules as they return to the ground state in addition to the shape of the potential energy surfaces involved. Now, using machine-learning-assisted non-adiabatic molecular dynamics and multiconfiguration pair-density functional theory, these factors are examined for a classic photochemical reaction-the deazetization of 2,3-diazabicyclo[2.2.2]oct-2-ene-for which we demonstrate that momentum dominates the selectivity for hexadiene versus [2.2.2] bicyclohexane products.