Distinct clinical endpoints of Staphylococcus aureus bacteraemia complicate assessment of outcome.

BACKGROUND: We aimed to test the hypothesis that development of metastatic infection represents a distinct clinical endpoint from death due to SAB. METHODS: We conducted a retrospective observational study of adults with SAB between 20/12/2019 and 23/08/2022 (n=464). Simple logistic regression, odds ratios, and z-scores were used to compare host, clinical and microbiologic features. RESULTS: Co-occurrence of attributable mortality and metastatic infection was infrequent. Charlson Comorbidity Index and age were strongly associated with attributable mortality, but not metastatic infection. We compared patients with fatal SAB (without clinically-apparent metastatic complications, 14·4% of cohort), metastatic SAB (without attributable mortality, 22·2%), neither complication (56·7%), and overlapping fatal/metastatic SAB (6·7%). Compared to SAB without complications, fatal SAB was specifically associated with older age and multi-morbidity. Metastatic SAB was specifically associated with community acquisition, persistent fever, persistent bacteraemia, and recurrence. Endocarditis was over-represented in the fatal/metastatic SAB overlap group, which shared patient characteristics with fatal SAB. In contrast to other (predominantly musculoskeletal) metastatic complications, endocarditis was associated with increased mortality, with death occurring in older multi-morbid patients later after SAB onset. CONCLUSIONS: Patients with SAB experience distinct clinical endpoints: (i) early death, associated with multi-morbidity and age; (ii) metastatic (predominantly musculoskeletal) SAB; (iii) endocarditis, associated with late death occurring in older people with multi-morbidity, and (iv) bacteraemia without complications. These distinctions could be important for selecting appropriate outcomes in clinical trials: different interventions might be required to reduce mortality vs. improve clinical response in patients with metastatic SAB.

The impact of low-mode symmetry on inertial fusion energy output in the burning plasma state.

Indirect Drive Inertial Confinement Fusion Experiments on the National Ignition Facility (NIF) have achieved a burning plasma state with neutron yields exceeding 170 kJ, roughly 3 times the prior record and a necessary stage for igniting plasmas. The results are achieved despite multiple sources of degradations that lead to high variability in performance. Results shown here, for the first time, include an empirical correction factor for mode-2 asymmetry in the burning plasma regime in addition to previously determined corrections for radiative mix and mode-1. Analysis shows that including these three corrections alone accounts for the measured fusion performance variability in the two highest performing experimental campaigns on the NIF to within error. Here we quantify the performance sensitivity to mode-2 symmetry in the burning plasma regime and apply the results, in the form of an empirical correction to a 1D performance model. Furthermore, we find the sensitivity to mode-2 determined through a series of integrated 2D radiation hydrodynamic simulations to be consistent with the experimentally determined sensitivity only when including alpha-heating.

Design of the first fusion experiment to achieve target energy gain G>1.

In this work we present the design of the first controlled fusion laboratory experiment to reach target gain G>1 N221204 (5 December 2022) [Phys. Rev. Lett. 132, 065102 (2024)10.1103/PhysRevLett.132.065102], performed at the National Ignition Facility, where the fusion energy produced (3.15 MJ) exceeded the amount of laser energy required to drive the target (2.05 MJ). Following the demonstration of ignition according to the Lawson criterion N210808, experiments were impacted by nonideal experimental fielding conditions, such as increased (known) target defects that seeded hydrodynamic instabilities or unintentional low-mode asymmetries from nonuniformities in the target or laser delivery, which led to reduced fusion yields less than 1 MJ. This Letter details design changes, including using an extended higher-energy laser pulse to drive a thicker high-density carbon (also known as diamond) capsule, that led to increased fusion energy output compared to N210808 as well as improved robustness for achieving high fusion energies (greater than 1 MJ) in the presence of significant low-mode asymmetries. For this design, the burnup fraction of the deuterium and tritium (DT) fuel was increased (approximately 4% fuel burnup and a target gain of approximately 1.5 compared to approximately 2% fuel burnup and target gain approximately 0.7 for N210808) as a result of increased total (DT plus capsule) areal density at maximum compression compared to N210808. Radiation-hydrodynamic simulations of this design predicted achieving target gain greater than 1 and also the magnitude of increase in fusion energy produced compared to N210808. The plasma conditions and hotspot power balance (fusion power produced vs input power and power losses) using these simulations are presented. Since the drafting of this manuscript, the results of this paper have been replicated and exceeded (N230729) in this design, together with a higher-quality diamond capsule, setting a new record of approximately 3.88MJ of fusion energy and fusion energy target gain of approximately 1.9.

Observations and properties of the first laboratory fusion experiment to exceed a target gain of unity.

An indirect-drive inertial fusion experiment on the National Ignition Facility was driven using 2.05 MJ of laser light at a wavelength of 351 nm and produced 3.1±0.16 MJ of total fusion yield, producing a target gain G=1.5±0.1 exceeding unity for the first time in a laboratory experiment [Phys. Rev. E 109, 025204 (2024)10.1103/PhysRevE.109.025204]. Herein we describe the experimental evidence for the increased drive on the capsule using additional laser energy and control over known degradation mechanisms, which are critical to achieving high performance. Improved fuel compression relative to previous megajoule-yield experiments is observed. Novel signatures of the ignition and burn propagation to high yield can now be studied in the laboratory for the first time.

Discovery Elbow System arthroplasty polyethylene bearing exchange: outcomes and experience.

BACKGROUND: The Discovery Elbow System (DES) utilizes a polyethylene bearing within the ulnar component. An exchange bearing requires preoperative freezing and implantation within 2 minutes of freezer removal to allow insertion. We report our outcomes and experience using this technique. METHODS: This was an analysis of a two-surgeon consecutive series of DES bearing exchange. Inclusion criteria included patients in which exchange was attempted with a minimum 1-year follow-up. Clinical and radiographic review was performed 1, 2, 3, 5, 8 and 10 years postoperative. Outcome measures included range of movement, Oxford Elbow Score (OES), Mayo Elbow Performance Score (MEPS), complications and requirement for revision surgery. RESULTS: Eleven DESs in 10 patients were included. Indications were bearing wear encountered during humeral component revision (n=5); bearing failure (n=4); and infection treated with debridement, antibiotics and implant retention (DAIR; n=2). Bearing exchange was conducted on the first attempt in 10 cases. One case required a second attempt. One patient developed infection postoperatively managed with two-stage revision. Mean follow-up of the bearing exchange DES was 3 years. No further surgery was required, with no infection recurrence in DAIR cases. Mean elbow flexion-extension and pronosupination arcs were 107° (±22°) and 140° (±26°). Mean OES was 36/48 (±12) and MEPS was 83/100 (±19). CONCLUSIONS: Our results support the use of DES bearing exchange in cases of bearing wear with well-fixed stems or acute infection. This series provides surgeons managing DES arthroplasty with management principles, successful and reproducible surgical techniques and expected clinical outcomes in performing DES polyethylene bearing exchange. Level of evidence: IV.

Plasma steroid concentrations reflect acute disease severity and normalise during recovery in people hospitalised with COVID-19.

OBJECTIVE: Endocrine systems are disrupted in acute illness, and symptoms reported following coronavirus disease 2019 (COVID-19) are similar to those found with clinical hormone deficiencies. We hypothesised that people with severe acute COVID-19 and with post-COVID symptoms have glucocorticoid and sex hormone deficiencies. DESIGN/PATIENTS: Samples were obtained for analysis from two UK multicentre cohorts during hospitalisation with COVID-19 (International Severe Acute Respiratory Infection Consortium/World Health Organisation [WHO] Clinical Characterization Protocol for Severe Emerging Infections in the UK study), and at follow-up 5 months after hospitalisation (Post-hospitalisation COVID-19 study). MEASUREMENTS: Plasma steroids were quantified by liquid chromatography-mass spectrometry. Steroid concentrations were compared against disease severity (WHO ordinal scale) and validated symptom scores. Data are presented as geometric mean (SD). RESULTS: In the acute cohort (n = 239, 66.5% male), plasma cortisol concentration increased with disease severity (cortisol 753.3 [1.6] vs. 429.2 [1.7] nmol/L in fatal vs. least severe, p < .001). In males, testosterone concentrations decreased with severity (testosterone 1.2 [2.2] vs. 6.9 [1.9] nmol/L in fatal vs. least severe, p < .001). In the follow-up cohort (n = 198, 62.1% male, 68.9% ongoing symptoms, 165 [121-192] days postdischarge), plasma cortisol concentrations (275.6 [1.5] nmol/L) did not differ with in-hospital severity, perception of recovery, or patient-reported symptoms. Male testosterone concentrations (12.6 [1.5] nmol/L) were not related to in-hospital severity, perception of recovery or symptom scores. CONCLUSIONS: Circulating glucocorticoids in patients hospitalised with COVID-19 reflect acute illness, with a marked rise in cortisol and fall in male testosterone. These findings are not observed 5 months from discharge. The lack of association between hormone concentrations and common post-COVID symptoms suggests steroid insufficiency does not play a causal role in this condition.

Differential Item Functioning in Reports of Delinquent Behavior Between Black and White Youth: Evidence of Measurement Bias in Self-Reports of Arrest in the Adolescent Brain Cognitive Development Study.

Youth self-reports are a mainstay of delinquency assessment; however, making valid inferences about delinquency using these assessments requires equivalent measurement across groups of theoretical interest. We examined whether a brief 10-item delinquency measure exhibited measurement invariance across non-Hispanic White (n = 6,064) and Black (n = 1,666) youth (ages 10-11 years old) in the Adolescent Brain Cognitive Developmentsm Study (ABCD Study®). We detected differential item functioning (DIF) in two items. Black youth were more likely to report being arrested or picked up by police than White youth with the same score on the latent delinquency trait. Although multiple covariates (income, urgency, and callous-unemotional traits) reduced mean-level difference in overall delinquency, they were generally unrelated to the DIF in the Arrest item. However, the DIF in the Arrest item was reduced in size and no longer significant after adjusting for neighborhood safety. Results illustrate the importance of considering measurement invariance when using self-reported delinquency scores to draw inferences about group differences, and the utility of measurement invariance analyses for helping to identify mechanisms that contribute to group differences generally.

Intravenous Levothyroxine for Unstable Brain-Dead Heart Donors.

BACKGROUND: Hemodynamic instability and myocardial dysfunction are major factors preventing the transplantation of hearts from organ donors after brain death. Intravenous levothyroxine is widely used in donor care, on the basis of observational data suggesting that more organs may be transplanted from donors who receive hormonal supplementation. METHODS: In this trial involving 15 organ-procurement organizations in the United States, we randomly assigned hemodynamically unstable potential heart donors within 24 hours after declaration of death according to neurologic criteria to open-label infusion of intravenous levothyroxine (30 µg per hour for a minimum of 12 hours) or saline placebo. The primary outcome was transplantation of the donor heart; graft survival at 30 days after transplantation was a prespecified recipient safety outcome. Secondary outcomes included weaning from vasopressor therapy, donor ejection fraction, and number of organs transplanted per donor. RESULTS: Of the 852 brain-dead donors who underwent randomization, 838 were included in the primary analysis: 419 in the levothyroxine group and 419 in the saline group. Hearts were transplanted from 230 donors (54.9%) in the levothyroxine group and 223 (53.2%) in the saline group (adjusted risk ratio, 1.01; 95% confidence interval [CI], 0.97 to 1.07; P = 0.57). Graft survival at 30 days occurred in 224 hearts (97.4%) transplanted from donors assigned to receive levothyroxine and 213 hearts (95.5%) transplanted from donors assigned to receive saline (difference, 1.9 percentage points; 95% CI, -2.3 to 6.0; P<0.001 for noninferiority at a margin of 6 percentage points). There were no substantial between-group differences in weaning from vasopressor therapy, ejection fraction on echocardiography, or organs transplanted per donor, but more cases of severe hypertension and tachycardia occurred in the levothyroxine group than in the saline group. CONCLUSIONS: In hemodynamically unstable brain-dead potential heart donors, intravenous levothyroxine infusion did not result in significantly more hearts being transplanted than saline infusion. (Funded by Mid-America Transplant and others; ClinicalTrials.gov number, NCT04415658.).

Delayed mucosal anti-viral responses despite robust peripheral inflammation in fatal COVID-19.

BACKGROUND: While inflammatory and immune responses to SARS-CoV-2 infection in peripheral blood are extensively described, responses at the upper respiratory mucosal site of initial infection are relatively poorly defined. We sought to identify mucosal cytokine/chemokine signatures that distinguished COVID-19 severity categories, and relate these to disease progression and peripheral inflammation. METHODS: We measured 35 cytokines and chemokines in nasal samples from 274 patients hospitalised with COVID-19. Analysis considered the timing of sampling during disease, as either the early (0-5 days post-symptom onset) or late (6-20 days post-symptom onset). RESULTS: Patients that survived severe COVID-19 showed IFN-dominated mucosal immune responses (IFN-γ, CXCL10 and CXCL13) early in infection. These early mucosal responses were absent in patients that would progress to fatal disease despite equivalent SARS-CoV-2 viral load. Mucosal inflammation in later disease was dominated by IL-2, IL-10, IFN-γ, and IL-12p70, which scaled with severity but did not differentiate patients who would survive or succumb to disease. Cytokines and chemokines in the mucosa showed distinctions from responses evident in the peripheral blood, particularly during fatal disease. CONCLUSIONS: Defective early mucosal anti-viral responses anticipate fatal COVID-19 but are not associated with viral load. Early mucosal immune responses may define the trajectory of severe COVID-19.

Impact of COVID-19 on Pharmacy Education and Practice: Strategies to Boost Advocacy and Unity among Health Care Organizations.

The global COVID-19 pandemic impacted pharmacy education and changed the pharmacists' scope of practice at the federal and state levels. Based on the Amended Public Readiness and Emergency Preparedness Act, pharmacists were authorized to provide essential services, including testing, treatments, and immunizations at various practice settings. Specifically, the United States Food and Drug Administration issued emergency use authorization for several medications, vaccines, and medical devices. The pandemic also affected the regulatory landscape for pharmacists, pharmacy education, access to care, and delivery of pharmacy services in-person and through telehealth. The pandemic's specific impact on pharmacy education heightened awareness of the well-being of the Academy. This commentary will highlight the impact of COVID-19 on both pharmacy education and practice. It will also provide strategies that educators, researchers, and practitioners can take into future research and action to help promote advocacy and unity among pharmacy organizations.

Single-cell Transcriptional Analysis of the Cellular Immune Response in the Oral Mucosa of Mice.

Periodontal health is dependent on a symbiotic relationship of the host immune response with the oral microbiota. Pathologic shifts of the microbial plaque elicit an immune response that eventually leads to the recruitment and activation of osteoclasts and matrix metalloproteinases and the eventual tissue destruction that is evident in periodontal disease. Once the microbial stimulus is removed, an active process of inflammatory resolution begins. The goal of this work was to use scRNAseq to demonstrate the unique cellular immune response across three distinct conditions of periodontal health, disease, and resolution using mouse models. Periodontal disease was induced using a ligature model. Resolution was modeled by removing the ligature and allowing the mouse to recover. Immune cells (Cd45+) were isolated from the periodontium and analyzed via scRNAseq. Gene signature shifts across the three conditions were characterized and shown to be largely driven by macrophage and neutrophils during the periodontal disease and resolution conditions. Resolution of periodontal disease was characterized by the differential regulation of unique gene subsets. Clustering analysis characterized multiple cellular subpopulations within B Cells, macrophages, and neutrophils that demonstrated differential expansion and contraction across conditions of periodontal health, disease, and resolution. Interestingly, we identified a transcriptionally distinct macrophage subpopulation that expanded during the resolution condition and demonstrated an immunoregulatory gene signature. We identified a cell surface marker for this resolution-associated macrophage subgroup (Cd74) and validated the expansion of this subgroup during resolution via flow cytometry. This work presents a robust immune cell atlas for study of the immunological changes in the oral mucosa during three distinct conditions of periodontal health, disease, and resolution and it improves our understanding of the cellular and molecular markers that characterize health from disease for the development of future diagnostics and therapies.

Reduced mixing in inertial confinement fusion with early-time interface acceleration.

In inertial confinement fusion (ICF) implosions, the interface between the cryogenic DT fuel and the ablator is unstable to shock acceleration (the Richtmyer-Meshkov instability, RM) and constant acceleration (Rayleigh-Taylor instability, RT). Instability growth at this interface can reduce the final compression, limiting fusion burnup. If the constant acceleration is in the direction of the lighter material (negative Atwood number), the RT instability produces oscillatory motion that can stabilize against RM growth. Theory and simulations suggest this scenario occurred at early times in some ICF experiments on the National Ignition Facility, possibly explaining their favorable performance compared to one-dimensional simulations. This characteristic is being included in newer, lower adiabat designs, seeking to improve compression while minimizing ablator mixing into the fuel.

Associations between polygenic risk of substance use and use disorder and alcohol, cannabis, and nicotine use in adolescence and young adulthood in a longitudinal twin study.

BACKGROUND: Recent well-powered genome-wide association studies have enhanced prediction of substance use outcomes via polygenic scores (PGSs). Here, we test (1) whether these scores contribute to prediction over-and-above family history, (2) the extent to which PGS prediction reflects inherited genetic variation v. demography (population stratification and assortative mating) and indirect genetic effects of parents (genetic nurture), and (3) whether PGS prediction is mediated by behavioral disinhibition prior to substance use onset. METHODS: PGSs for alcohol, cannabis, and nicotine use/use disorder were calculated for Minnesota Twin Family Study participants (N = 2483, 1565 monozygotic/918 dizygotic). Twins' parents were assessed for histories of substance use disorder. Twins were assessed for behavioral disinhibition at age 11 and substance use from ages 14 to 24. PGS prediction of substance use was examined using linear mixed-effects, within-twin pair, and structural equation models. RESULTS: Nearly all PGS measures were associated with multiple types of substance use independently of family history. However, most within-pair PGS prediction estimates were substantially smaller than the corresponding between-pair estimates, suggesting that prediction is driven in part by demography and indirect genetic effects of parents. Path analyses indicated the effects of both PGSs and family history on substance use were mediated via disinhibition in preadolescence. CONCLUSIONS: PGSs capturing risk of substance use and use disorder can be combined with family history measures to augment prediction of substance use outcomes. Results highlight indirect sources of genetic associations and preadolescent elevations in behavioral disinhibition as two routes through which these scores may relate to substance use.

A Survey of Orthopedic Surgical Management of Pressure Ulcer-Related Pelvic Osteomyelitis.

Pressure-ulcer related pelvic osteomyelitis is managed with little high-quality evidence. We undertook an international survey of orthopedic surgical management, covering diagnostic parameters, multidisciplinary input, and surgical approaches (indications, timing, wound closure, and adjunctive therapies). This identified areas of consensus and disagreement, representing a starting point for future discussion and research.

Increase of Severe Pulmonary Infections in Adults Caused by M1UK Streptococcus pyogenes, Central Scotland, UK.

We characterized the epidemiology, host-pathogen characteristics, and outcomes of severe adult pulmonary Streptococcus pyogenes infections that coincided with a high community caseload in central Scotland, UK. The pulmonary infections had high illness and death rates and were associated with socioeconomic deprivation, influenza A co-infection, and the M1UK lineage of S. pyogenes.

GWAS and meta-analysis identifies 49 genetic variants underlying critical COVID-19.

Critical illness in COVID-19 is an extreme and clinically homogeneous disease phenotype that we have previously shown1 to be highly efficient for discovery of genetic associations2. Despite the advanced stage of illness at presentation, we have shown that host genetics in patients who are critically ill with COVID-19 can identify immunomodulatory therapies with strong beneficial effects in this group3. Here we analyse 24,202 cases of COVID-19 with critical illness comprising a combination of microarray genotype and whole-genome sequencing data from cases of critical illness in the international GenOMICC (11,440 cases) study, combined with other studies recruiting hospitalized patients with a strong focus on severe and critical disease: ISARIC4C (676 cases) and the SCOURGE consortium (5,934 cases). To put these results in the context of existing work, we conduct a meta-analysis of the new GenOMICC genome-wide association study (GWAS) results with previously published data. We find 49 genome-wide significant associations, of which 16 have not been reported previously. To investigate the therapeutic implications of these findings, we infer the structural consequences of protein-coding variants, and combine our GWAS results with gene expression data using a monocyte transcriptome-wide association study (TWAS) model, as well as gene and protein expression using Mendelian randomization. We identify potentially druggable targets in multiple systems, including inflammatory signalling (JAK1), monocyte-macrophage activation and endothelial permeability (PDE4A), immunometabolism (SLC2A5 and AK5), and host factors required for viral entry and replication (TMPRSS2 and RAB2A).

Intimate Partner Violence Fear-11 Scale: An Item Response Analysis.

Objective: Victims of intimate partner violence (IPV) often fear their intimate partners and the abuse they perpetrate against them. Fear in the context of IPV has been studied for decades yet, we lack a rigorously validated measure. The purpose of this study was to comprehensively evaluate the psychometric properties of a multi-item scale measuring fear of an abusive male partner and/or the abuse he perpetrates. Method: We used Item Response modeling to evaluate the psychometric properties of a scale measuring women's fear of IPV by their male partner across two distinct samples: 1) a calibration sample of 412 women and 2) a confirmation sample of 298 women. Results: Results provide a detailed overview of the psychometric functioning of the Intimate Partner Violence Fear-11 Scale. Items were strongly related to the latent fear factor, with discrimination values universally above a = 0.80 in both samples. Overall, the IPV Fear-11 Scale is psychometrically robust across both samples. All items were highly discriminating and the full scale was reliable across the range of the latent fear trait. Reliability was exceptionally high for measuring individuals experiencing moderate to high levels of fear. Finally, the IPV Fear-11 Scale was moderately to strongly correlated with depression symptoms, posttraumatic stress symptoms and physical victimization. Conclusions: The IPV Fear-11 Scale was psychometrically robust across both samples and was associated with a number of relevant covariates. Results support the utility of the IPV Fear-11 Scale for assessing fear of an abusive partner among women in relationships with men.