The Polyanalgesic Consensus Conference (PACC)®: Updates on Clinical Pharmacology and Comorbidity Management in Intrathecal Drug Delivery for Cancer Pain.

INTRODUCTION: The International Neuromodulation Society convened a multispecialty group of physicians based on expertise with international representation to establish evidence-based guidance on using intrathecal drug delivery in chronic pain treatment. This Polyanalgesic Consensus Conference (PACC)® project's scope is to provide evidence-based guidance for clinical pharmacology and best practices for intrathecal drug delivery for cancer pain. MATERIALS AND METHODS: Authors were chosen on the basis of their clinical expertise, familiarity with the peer-reviewed literature, research productivity, and contributions to the neuromodulation literature. Section leaders supervised literature searches using Medline, EMBASE, Cochrane CENTRAL, BioMed Central, Web of Science, Google Scholar, PubMed, Current Contents Connect, Meeting Abstracts, and Scopus from 2017 (when the PACC last published guidelines) to the present. Identified studies were graded using the United States Preventive Services Task Force criteria for evidence and certainty of net benefit. Recommendations were based on the strength of evidence, and when evidence was scant, recommendations were based on expert consensus. RESULTS: The PACC evaluated the published literature and established evidence- and consensus-based expert opinion recommendations to guide best practices in treating cancer pain. Additional guidance will occur as new evidence is developed in future iterations of this process. CONCLUSIONS: The PACC recommends best practices regarding the use of intrathecal drug delivery in cancer pain, with an emphasis on managing the unique disease and patient characteristics encountered in oncology. These evidence- and consensus-based expert opinion recommendations should be used as a guide to assist decision-making when clinically appropriate.

Plasma Adsorption with the MTx.100 Column in Critically Ill COVID-19 Patients: A Prospective Study and Propensity Score Analysis.

BACKGROUND: Early in the COVID-19 pandemic, patients with severe disease admitted to the intensive care unit (ICU) had a high incidence of mortality. We aimed to investigate whether plasma adsorption with the MTx.100 Column could improve survival. METHODS: We performed a prospective, single-arm, multicenter, Emergency Use Authorization (EUA) trial in patients admitted to the ICU with severe COVID-19 who were worsening despite standard therapy. The primary outcome was all-cause mortality on day 28. Outcomes were analyzed using both a pre-specified performance goal (PG), and a propensity score-matched (PSM) analysis from the highest enrolling center, in which patients treated with the standard of care (SOC) plus the MTx.100 Column (n = 70) were compared to a contemporaneous cohort treated at the same center with SOC only (n = 244). FINDINGS: Between May 21, 2020, and November 2, 2021, 107 patients with severe COVID-19 (mean age 58.1) at 7 US centers were enrolled and had at least one plasma adsorption treatment initiated. All-cause mortality on day 28 was 37.4% (40/107), an improvement over the prespecified PG (88.1%, p < 0.0001). There were no serious adverse events attributable to the MTx.100 Column or plasmapheresis. Improvements in most metabolic and inflammatory markers were also noted. The PSM analysis showed that survival odds were three times higher for MTx.100 Column-treated patients (95% CI: 1.56-5.88) than for those treated with SOC only. INTERPRETATION: The MTx.100 Column treatment in severe COVID-19 resulted in a lower mortality than SOC by both pre-specified PG and PSM analysis. TRIAL REGISTRATION: clinicaltrials.gov (NCT04358003).

Influences of quality of maternal care and environmental enrichment on associative memory function in rats with early life lead exposure.

INTRODUCTION: Children in low socioeconomic status (SES) communities are at higher risk of exposure to lead (Pb) and potentially more severe adverse outcomes from Pb exposures. While the factors encompassing SES are complex, low SES households often have less enriching home environments and parent-child interactions. This study investigated the extent to which environmental/behavioral factors (quality of maternal care and richness of the postnatal environment) may modify adverse effects from Pb exposure. METHODS: Long-Evans female rats were randomly assigned to Control (no Pb), Early Postnatal (EPN: birth through weaning), or Perinatal (PERI: 14 days pre-mating through weaning) Pb exposure groups. From postnatal days (PNDs) 2-9, maternal care behaviors were observed, and dams were classified as low or high maternal care based on amounts of licking/grooming and arched back nursing. At weaning, pups were randomly assigned to enriched or non-enriched environments. At PND 55, animals began trace fear conditioning and associative memory was tested on days 1, 2, and 10 postconditioning. RESULTS: Control offspring showed no significant effects of maternal care or enrichment on task performance. Females with EPN-Pb exposure and males with PERI-Pb exposure living in the non-enriched environment and having an LMC mother had significant memory impairments at days 2 and 10 that were not observed in comparably housed animals with HMC mothers. Enriched animals had no deficits, regardless of maternal care status. CONCLUSION: These results show the potential for modulatory influences of maternal care and housing environment on protecting against or reversing at least one aspect of Pb-induced cognitive/behavioral dysfunction.

Evidence-Based Clinical Practice Guidelines on Regenerative Medicine Treatment for Chronic Pain: A Consensus Report from a Multispecialty Working Group.

Purpose: Injectable biologics have not only been described and developed to treat dermal wounds, cardiovascular disease, and cancer, but have also been reported to treat chronic pain conditions. Despite emerging evidence supporting regenerative medicine therapy for pain, many aspects remain controversial. Methods: The American Society of Pain and Neuroscience (ASPN) identified the educational need for an evidence-based guideline on regenerative medicine therapy for chronic pain. The executive board nominated experts spanning multiple specialties including anesthesiology, physical medicine and rehabilitation, and sports medicine based on expertise, publications, research, and clinical practice. A steering committee selected preliminary questions, which were reviewed and refined. Evidence was appraised using the United States Preventive Services Task Force (USPSTF) criteria for evidence level and degree of recommendation. Using a modified Delphi approach, consensus points were distributed to all collaborators and each collaborator voted on each point. If collaborators provided a decision of "disagree" or "abstain", they were invited to provide a rationale in a non-blinded fashion to the committee chair, who incorporated the respective comments and distributed revised versions to the committee until consensus was achieved. Results: Sixteen questions were selected for guideline development. Questions that were addressed included type of injectable biologics and mechanism, evidence in treating chronic pain indications (eg, tendinopathy, muscular pathology, osteoarthritis, intervertebral disc disease, neuropathic pain), role in surgical augmentation, dosing, comparative efficacy between injectable biologics, peri-procedural practices to optimize therapeutic response and quality of injectate, federal regulations, and complications with mitigating strategies. Conclusion: In well-selected individuals with certain chronic pain indications, use of injectable biologics may provide superior analgesia, functionality, and/or quality of life compared to conventional medical management or placebo. Future high-quality randomized clinical trials are warranted with implementation of minimum reporting standards, standardization of preparation protocols, investigation of dose-response associations, and comparative analysis between different injectable biologics.

Reversal of Pharmacologically Induced Mydriasis with Phentolamine Ophthalmic Solution.

PURPOSE: Evaluate safety and efficacy of 0.75% phentolamine ophthalmic solution (POS), an alpha-1 antagonist, in reversal of pharmacologically induced mydriasis. DESIGN: Two Phase 3, multicenter, placebo-controlled, randomized, double-masked clinical trials in healthy subjects. SUBJECTS: 553 healthy 12 to 80 year old subjects were randomized 1:1 (MIRA-2) and 2:1 (MIRA-3) to receive either POS or placebo eye drops OU. METHODS: Subjects received POS or placebo administered 1 hour after mydriasis, induced by instillation of either 2.5% phenylephrine, 1% tropicamide, or Paremyd (1% hydroxyamphetamine / 0.25% tropicamide). MAIN OUTCOME MEASURES: Primary endpoint was percent of subjects returning to ≤0.2 mm greater than baseline pupil diameter in study eye at 90 minutes after POS administration. Safety measures included treatment-emergent adverse events (TEAEs) and tolerability measures, including conjunctival hyperemia. RESULTS: In MIRA-2, 185 subjects were randomized to treatment with placebo (94) or POS (91). In MIRA-3, 368 subjects were randomized to treatment with placebo (124) or POS (244). A statistically significant greater percentage of subjects treated with POS had study eyes that showed reversal of mydriasis at 90 minutes (primary endpoint) compared with the placebo treatment (48.9% vs 6.6% for MIRA-2; p<0.0001 and 58% VS 6% for MIRA-3; p<0.0001) and as early as 60 minutes (24.5% vs 5.5% for MIRA-2; p<0.0003 and 42% VS 2% for MIRA-3; p<0.0001). Between 28 to 34% of placebo-treated subjects had not returned to baseline PD at 24 hours following pharmacological dilation compared to 8 to 11% treated with POS (p<0.0001). CONCLUSION: POS treatment had a rapid onset in reducing PD within 60- to 90-minutes, with a statistically significant time savings of 3 to 4 hours to return to baseline PD compared to placebo. One or 2 drops of POS rapidly reversed mydriasis in all subjects regardless of mydriatic agent or iris color. More subjects receiving POS reported a perceived benefit in the resolution of visual symptoms caused by pharmacologically induced mydriasis compared to placebo, with statistically significant differences noted as early as 1 hour. The safety profile was favorable, with the most common adverse effects being mild transient conjunctival hyperemia (11.2%), instillation site discomfort (10.9%), and dysgeusia (3.6%).

Extended Intraocular Drug-Delivery Platforms for the Treatment of Retinal and Choroidal Diseases.

Purpose: To review sustained-release intraocular platforms used to treat diseases of the retina and choroid. Methods: A literature review of the current applications of biomaterials for sustained-release therapy in retinal and choroidal diseases was performed. Results: Retinal and choroidal diseases, such as neovascular age-related macular degeneration (nAMD), diabetic retinopathy (DR), diabetic macular edema (DME), and uveitis, are commonly treated using intravitreal (IVT) therapies that require frequent IVT injections. Multiple sustained-release options for IVT therapy have been approved by the US Food and Drug Administration for the treatment of inflammatory eye diseases, including noninfectious uveitis, infectious diseases, and exudative retinal diseases (eg, retinal venous occlusive disease and DME) using drugs such as fluocinolone acetonide, ganciclovir, and dexamethasone. The platforms for these drugs are biodegradable or nonbiodegradable. They use biomaterials such as polymers and hydrogels and are typically implanted surgically or injected into the vitreous, where they release the drug gradually over months or years. Building on these technologies, novel platforms are being studied that are intended to treat conditions including nAMD, DR, DME, and uveitis. These platforms are being tested for their safety, efficacy, and ability to reduce the injection and visit burden. Conclusions: Multiple sustained-release ocular drug-delivery platforms are currently commercially available, and many new sustained-release IVT platforms are being investigated. The hope is that meaningfully reducing the injection burden by extending intervals between treatments while maintaining optimal efficacy will improve long-term outcomes.

Assessing core outcome set uptake in randomized controlled trials for chronic kidney disease: Cross-sectional analysis.

Main problem: Chronic kidney disease (CKD) is a progressive condition that affects millions of people worldwide. A standardized core outcome set (COS) was developed for CKD by the International Consortium for Health Outcomes and Measurements in 2019. This study aims to evaluate the frequency of measurement for these outcomes before and after the publication of the COS. Methods: A literature search was done to gather the phase III/IV clinical trials evaluating chronic kidney disease through ClinicalTrials.gov. Data extraction of included studies was completed in a masked, duplicate fashion. The included studies were evaluated for characteristics such as survival, burden of disease, patient-reported health-related quality of life, and treatment modality-specific outcomes. Results: Our results showed that the majority of all COS domains were inadequately measured in CKD clinical trials before and after publication of the COS. Despite the increase in COS measurements following publication, the average percent of COS outcomes measured was less than 40 % per year even after four years. Conclusion: There is a notable deficiency in the complete measurement of COS among all domains both before and after COS publication. We suggest efforts be made to improve the adoption of consistent outcome measures that would benefit the growing population of patients affected by CKD.

Improving the Sensitivity of Protein Quantification by Immunoaffinity Liquid Chromatography─Triple Quadrupole Mass Spectrometry Using an Iterative Transition Summing Technique.

The desire to reach ever-diminishing lower limits of quantification (LLOQ) to probe changes in low abundance protein targets has led to enormous progress in sample preparation and liquid chromatography-tandem mass spectrometry (LC-MS/MS) instrumentation. To maximize signal and reduce noise, many approaches have been employed, including specific immunoaffinity (IA) enrichment and reducing the LC flow to the nanoflow (nLC) level; however, additional sensitivity gains may still be required. Recently, a technique termed "echo summing" has been described for small-molecular-weight analytes on a triple quadrupole (QqQ) MS where multiple iterations of the same, single selected reaction monitoring (SRM) transition are collected, summed, and integrated, yielding significant analyte dependent signal-to-noise (S/N) improvements. Herein, the direct applicability of echo summing to protein quantification by sequential IA combined with nLC-MS/MS (IA-nLC-MS/MS) is described for a beta nerve growth factor (NGF) and a soluble asialoglycoprotein receptor (sASGPR) assay from human serum. Five iterations of echo summing outperformed traditional collection in relative average accuracy (-1.5 ± 7.7 vs -41.7 ± 10.7% bias) and precision (7.8 vs 18.4% coefficient of variation (CV)) of the low-end quality control (QC) sample (N = 4) for NGF and improved functional sensitivity of serially diluted serum QC samples (N = 5 each population) approximately 2-fold (1.96 and 2.00-fold) for two peptides of sASGPR. Echo summing also extended the minimum quantifiable QC level for sASGPR 4-fold lower. Similar gains are believed to be achievable for most protein IA-nLC-MS/MS assays.

Identification of small molecule inhibitors of the Chloracidobacterium thermophilum type IV pilus protein PilB by ensemble virtual screening.

Antivirulence strategy has been explored as an alternative to traditional antibiotic development. The bacterial type IV pilus is a virulence factor involved in host invasion and colonization in many antibiotic resistant pathogens. The PilB ATPase hydrolyzes ATP to drive the assembly of the pilus filament from pilin subunits. We evaluated Chloracidobacterium thermophilum PilB (CtPilB) as a model for structure-based virtual screening by molecular docking and molecular dynamics (MD) simulations. A hexameric structure of CtPilB was generated through homology modeling based on an existing crystal structure of a PilB from Geobacter metallireducens. Four representative structures were obtained from molecular dynamics simulations to examine the conformational plasticity of PilB and improve docking analyses by ensemble docking. Structural analyses after 1 µs of simulation revealed conformational changes in individual PilB subunits are dependent on ligand presence. Further, ensemble virtual screening of a library of 4234 compounds retrieved from the ZINC15 database identified five promising PilB inhibitors. Molecular docking and binding analyses using the four representative structures from MD simulations revealed that top-ranked compounds interact with multiple Walker A residues, one Asp-box residue, and one arginine finger, indicating these are key residues in inhibitor binding within the ATP binding pocket. The use of multiple conformations in molecular screening can provide greater insight into compound flexibility within receptor sites and better inform future drug development for therapeutics targeting the type IV pilus assembly ATPase.

Automated radiosynthesis and preclinical imaging of a novel [18F]fluorolidocaine analogue via sequential C-H radiolabelling.

The most prominent myocardial voltage-gated sodium channel, NaV1.5, is a major drug target for treating cardiovascular disease. However, treatment determination and therapeutic development are complicated partly by an inadequate understanding of how the density of SCN5A, the gene that encodes NaV1.5, relates to treatment response and disease prognosis. To address these challenges, imaging agents derived from NaV1.5 blocking therapeutics have been employed in positron emission tomography (PET) imaging to infer how SCN5A expression relates to human disease in vivo. Herein, we describe the preparation of a novel fluorine-18 labelled analogue of lidocaine, a known NaV1.5 inhibitor, and compare this agent to a previously described analogue. Evidence from rodent and non-human primate PET imaging experiments suggests that the imaging utility of these agents may be limited by rapid metabolism and clearance.

Sex-Specific Dysregulation of Placental Lipid Metabolism in Preeclampsia.

Background: Preeclampsia (PE) is a hypertensive disorder of pregnancy associated with adverse maternal and fetal outcomes. While placental dysfunction is implicated in PE pathogenesis, the impact of PE on placental lipid metabolism and its potential sexual dimorphism remains poorly understood. Methods: We conducted a comprehensive analysis of term placentas from PE and normotensive pregnancies with male and female fetuses. Lipid profiles were quantified using mass spectrometry, and mRNA expression of genes involved in fatty acid oxidation, esterification, and transport was assessed using qPCR. Results: Placentas from PE pregnancies exhibited elevated lipid levels, with male placentas showing a more pronounced increase in triacylglycerols, cholesteryl esters, and free cholesterol compared to female placentas. Gene expression analysis revealed sexually dimorphic alterations, with male PE placentas exhibiting upregulation of genes involved in fatty acid uptake, oxidation, and esterification, while female PE placentas showed a more complex response with both upregulation and downregulation of certain genes. Notably, peroxisomal fatty acid oxidation was upregulated in male PE placentas but suppressed in female PE placentas. Conclusions: Our findings reveal sexually dimorphic alterations in placental lipid metabolism in PE, suggesting that male placentas may be more vulnerable to lipotoxicity. These insights may have implications for understanding the pathogenesis of PE and developing sex-specific interventions to improve maternal and fetal outcomes.

Long-Term Follow-up of Patients With Cytomegalovirus Retinitis Treated With a Ganciclovir Implant.

Purpose: To assess the long-term safety and clinical outcomes of a ganciclovir intravitreal implant in patients with cytomegalovirus (CMV) retinitis. Methods: A retrospective study was performed of patients with CMV retinitis treated with a ganciclovir intravitreal implant. Results: The study included 13 patients (16 eyes) previously treated with a ganciclovir intravitreal implant. The mean time since the last implant placement was 21.3 years and the mean total duration of follow-up, 22.7 years. Visual acuity (VA) ranged from 20/25 to light perception, with 56% of eyes maintaining a VA of 20/60 or better at the most recent follow-up examination. Common ocular complications included epiretinal membrane (38%), macular fibrosis/scarring (25%), retinal detachment (RD) (25%), implant dislocation (25%), and immune reactivation uveitis (19%). Intraocular surgery was required in 10 eyes (63%), with the most frequent being cataract extraction (31%), pars plana vitrectomy (PPV) for implant removal (19%), and PPV for RD (13%). Conclusions: Results show the long-term safety of the ganciclovir intravitreal implant despite its residual inactive inert shell. Complication rates are consistent with those expected from infectious sequelae.

Mapping the Course of Recovery Following Limb-Salvage Surgery for Soft-Tissue Sarcoma of the Extremities.

BACKGROUND: Despite the goal of an acceptable functional result, the surgical treatment of soft-tissue sarcoma can portend a prolonged course of recovery. More comprehensive data on the expected course of recovery following extremity sarcoma surgery are needed to help to inform physicians and patients. The purpose of the present study was to describe the typical course of functional recovery following limb-salvage resection of a soft-tissue sarcoma and to identify factors associated with a delayed postoperative course of recovery. METHODS: A retrospective review of a prospectively maintained institutional database was performed for all patients undergoing surgical treatment with limb salvage of a soft-tissue sarcoma of the extremities or pelvis with at least 1 year of follow-up after the definitive surgical procedure. All patients were required to have preoperative functional outcomes recorded for either the Toronto Extremity Salvage Score (TESS) or the Musculoskeletal Tumor Society (MSTS) score and functional outcome measures at 1 year postoperatively. The primary outcome measures were time to recovery and maximal functional improvement. RESULTS: In this study, 916 patients met inclusion criteria following surgical resection of a soft-tissue sarcoma of the extremities. The median follow-up was 74 months. Patients typically achieved a return to their baseline preoperative level of function for all functional outcome measures by 1 to 2 years and achieved maximal functional recovery by 2 years postoperatively. Older age, female sex, deep tumor location, larger tumor size, pelvic location, osseous resection, motor nerve resection, free and/or rotational soft-tissue coverage, and postoperative complications were independently associated with worse TESS and/or MSTS scores (p ≤ 0.05). Tumor recurrence was associated with worse functional outcomes scores. An analysis was performed to determine which patients had a prolonged course of recovery (i.e., were considered to still be recovering). Older age, female sex, larger tumor size, osseous resection, and motor nerve resection were associated with a delayed course of recovery (p ≤ 0.04). Complications and tumor recurrence were associated with delayed functional recovery across all domains. CONCLUSIONS: Most patients will achieve maximal recovery by 2 to 3 years following surgical resection for soft-tissue sarcoma of the extremities. Older age, female sex, larger tumor size, osseous resection, motor nerve resection, postoperative complications, and tumor recurrence portend poorer functional outcomes and a delayed course of recovery. LEVEL OF EVIDENCE: Prognostic Level IV. See Instructions for Authors for a complete description of levels of evidence.

Synthesis of geometrically realistic and watertight neuronal ultrastructure manifolds for in silico modeling.

Understanding the intracellular dynamics of brain cells entails performing three-dimensional molecular simulations incorporating ultrastructural models that can capture cellular membrane geometries at nanometer scales. While there is an abundance of neuronal morphologies available online, e.g. from NeuroMorpho.Org, converting those fairly abstract point-and-diameter representations into geometrically realistic and simulation-ready, i.e. watertight, manifolds is challenging. Many neuronal mesh reconstruction methods have been proposed; however, their resulting meshes are either biologically unplausible or non-watertight. We present an effective and unconditionally robust method capable of generating geometrically realistic and watertight surface manifolds of spiny cortical neurons from their morphological descriptions. The robustness of our method is assessed based on a mixed dataset of cortical neurons with a wide variety of morphological classes. The implementation is seamlessly extended and applied to synthetic astrocytic morphologies that are also plausibly biological in detail. Resulting meshes are ultimately used to create volumetric meshes with tetrahedral domains to perform scalable in silico reaction-diffusion simulations for revealing cellular structure-function relationships. Availability and implementation: Our method is implemented in NeuroMorphoVis, a neuroscience-specific open source Blender add-on, making it freely accessible for neuroscience researchers.

Pre-operative pectoralis muscle area index is associated with biomarkers of inflammation and endotoxemia and predicts clinical outcomes after left ventricular assist device implantation: A cohort study.

BACKGROUND: Pre-left ventricular assist device (LVAD) pectoralis muscle assessment, an estimate of sarcopenia, has been associated with postoperative mortality and gastrointestinal bleeding, though its association with inflammation, endotoxemia, length-of-stay (LOS), and readmissions remains underexplored. METHODS: This was a single-center cohort study of LVAD patients implanted 1/2015-10/2018. Preoperative pectoralis muscle area was measured on chest computed tomography (CT), adjusted for height squared to derive pectoralis muscle area index (PMI). Those with PMI in the lowest quintile were defined as low-PMI cohort; all others constituted the reference cohort. Biomarkers of inflammation (interleukin-6, adiponectin, tumor necrosis factor-α [TNFα]) and endotoxemia (soluble (s)CD14) were measured in a subset of patients. RESULTS: Of the 254 LVAD patients, 95 had a preoperative chest CT (median days pre-LVAD: 7 [IQR 3-13]), of whom 19 (20.0%) were in the low-PMI cohort and the remainder were in the reference cohort. Compared with the reference cohort, the low-PMI cohort had higher levels of sCD14 (2594 vs. 1850 ng/mL; p = 0.04) and TNFα (2.9 vs. 1.9 pg/mL; p = 0.03). In adjusted analyses, the low-PMI cohort had longer LOS (incidence rate ratio 1.56 [95% confidence interval 1.16-2.10], p = 0.004) and higher risk of 90-day and 1-year readmissions (subhazard ratio 5.48 [1.88-16.0], p = 0.002; hazard ratio 1.73 [1.02-2.94]; p = 0.04, respectively). CONCLUSIONS: Pre-LVAD PMI is associated with inflammation, endotoxemia, and increased LOS and readmissions.

The seasonal distribution of immune thrombotic thrombocytopenic purpura is influenced by geography: Epidemiologic findings from a multi-center analysis of 719 disease episodes.

Prior studies have suggested that immune thrombotic thrombocytopenic purpura (iTTP) may display seasonal variation; however, methodologic limitations and sample sizes have diminished the ability to perform a rigorous assessment. This 5-year retrospective study assessed the epidemiology of iTTP and determined whether it displays a seasonal pattern. Patients with both initial and relapsed iTTP (defined as a disintegrin and metalloprotease with thrombospondin type motifs 13 activity <10%) from 24 tertiary centers in Australia, Canada, France, Greece, Italy, Spain, and the US were included. Seasons were defined as: Northern Hemisphere-winter (December-February); spring (March-May); summer (June-August); autumn (September-November) and Southern Hemisphere-winter (June-August); spring (September-November); summer (December-February); autumn (March-May). Additional outcomes included the mean temperature in months with and without an iTTP episode at each site. A total of 583 patients experienced 719 iTTP episodes. The observed proportion of iTTP episodes during the winter was significantly greater than expected if equally distributed across seasons (28.5%, 205/719, 25.3%-31.9%; p = .03). Distance from the equator and mean temperature deviation both positively correlated with the proportion of iTTP episodes during winter. Acute iTTP episodes were associated with the winter season and colder temperatures, with a second peak during summer. Occurrence during winter was most pronounced at sites further from the equator and/or with greater annual temperature deviations. Understanding the etiologies underlying seasonal patterns of disease may assist in discovery and development of future preventative therapies and inform models for resource utilization.

Effectiveness of Updated 2023-2024 (Monovalent XBB.1.5) COVID-19 Vaccination Against SARS-CoV-2 Omicron XBB and BA.2.86/JN.1 Lineage Hospitalization and a Comparison of Clinical Severity-IVY Network, 26 Hospitals, October 18, 2023-March 9, 2024.

BACKGROUND: Assessing variant-specific COVID-19 vaccine effectiveness (VE) and severity can inform public health risk assessments and decisions about vaccine composition. BA.2.86 and its descendants, including JN.1 (referred to collectively as "JN lineages"), emerged in late 2023 and exhibited substantial divergence from co-circulating XBB lineages. METHODS: We analyzed patients hospitalized with COVID-19-like illness at 26 hospitals in 20 U.S. states admitted October 18, 2023-March 9, 2024. Using a test-negative, case-control design, we estimated effectiveness of an updated 2023-2024 (Monovalent XBB.1.5) COVID-19 vaccine dose against sequence-confirmed XBB and JN lineage hospitalization using logistic regression. Odds of severe outcomes, including intensive care unit (ICU) admission and invasive mechanical ventilation (IMV) or death, were compared for JN versus XBB lineage hospitalizations using logistic regression. RESULTS: 585 case-patients with XBB lineages, 397 case-patients with JN lineages, and 4,580 control-patients were included. VE in the first 7-89 days after receipt of an updated dose was 54.2% (95% CI = 36.1%-67.1%) against XBB lineage hospitalization and 32.7% (95% CI = 1.9%-53.8%) against JN lineage hospitalization. Odds of ICU admission (adjusted odds ratio [aOR] 0.80; 95% CI = 0.46-1.38) and IMV or death (aOR 0.69; 95% CI = 0.34-1.40) were not significantly different among JN compared to XBB lineage hospitalizations. CONCLUSIONS: Updated 2023-2024 COVID-19 vaccination provided protection against both XBB and JN lineage hospitalization, but protection against the latter may be attenuated by immune escape. Clinical severity of JN lineage hospitalizations was not higher relative to XBB.

15-Gene Expression Profile and PRAME as Integrated Prognostic Test for Uveal Melanoma: First Report of Collaborative Ocular Oncology Group Study No. 2 (COOG2.1).

PURPOSE: Validated and accurate prognostic testing is critical for precision medicine in uveal melanoma (UM). Our aims were to (1) prospectively validate an integrated prognostic classifier combining a 15-gene expression profile (15-GEP) and PRAME RNA expression and (2) identify clinical variables that enhance the prognostic accuracy of the 15-GEP/PRAME classifier. MATERIALS AND METHODS: This study included 1,577 patients with UM of the choroid and/or ciliary body who were enrolled in the Collaborative Ocular Oncology Group Study Number 2 (COOG2) and prospectively monitored across 26 North American centers. Test results for 15-GEP (class 1 or class 2) and PRAME expression status (negative or positive) were available for all patients. The primary end point was metastasis-free survival (MFS). RESULTS: 15-GEP was class 1 in 1,082 (68.6%) and class 2 in 495 (31.4%) patients. PRAME status was negative in 1,106 (70.1%) and positive in 471 (29.9%) patients. Five-year MFS was 95.6% (95% CI, 93.9 to 97.4) for class 1/PRAME(-), 80.6% (95% CI, 73.9 to 87.9) for class 1/PRAME(+), 58.3% (95% CI, 51.1 to 66.4) for class 2/PRAME(-), and 44.8% (95% CI, 37.9 to 52.8) for class 2/PRAME(+). By multivariable Cox proportional hazards analysis, 15-GEP was the most important independent predictor of MFS (hazard ratio [HR], 5.95 [95% CI, 4.43 to 7.99]; P < .001), followed by PRAME status (HR, 1.82 [95% CI, 1.42 to 2.33]; P < .001). The only clinical variable demonstrating additional prognostic value was tumor diameter. CONCLUSION: In the largest prospective multicenter prognostic biomarker study performed to date in UM to our knowledge, the COOG2 study validated the superior prognostic accuracy of the integrated 15-GEP/PRAME classifier over 15-GEP alone and clinical prognostic variables. Tumor diameter was found to be the only clinical variable to provide additional prognostic information. This prognostic classifier provides an advanced resource for risk-adjusted metastatic surveillance and adjuvant trial stratification in patients with UM.

Effect modification by statin use status on the association between fine particulate matter (PM2.5) and cardiovascular mortality.

BACKGROUND: Numerous studies have linked fine particulate matter (PM2.5) to increased cardiovascular mortality. Less is known how the PM2.5-cardiovascular mortality association varies by use of cardiovascular medications. This study sought to quantify effect modification by statin use status on the associations between long-term exposure to PM2.5 and mortality from any cardiovascular cause, coronary heart disease (CHD), and stroke. METHODS: In this nested case-control study, we followed 1.2 million community-dwelling adults aged ≥66 years who lived in Ontario, Canada from 2000 through 2018. Cases were patients who died from the three causes. Each case was individually matched to up to 30 randomly selected controls using incidence density sampling. Conditional logistic regression models were used to estimate odds ratios (ORs) for the associations between PM2.5 and mortality. We evaluated the presence of effect modification considering both multiplicative (ratio of ORs) and additive scales (the relative excess risk due to interaction, RERI). RESULTS: Exposure to PM2.5 increased the risks for cardiovascular, CHD, and stroke mortality. For all three causes of death, compared with statin users, stronger PM2.5-mortality associations were observed among non-users [e.g. for cardiovascular mortality corresponding to each interquartile range increase in PM2.5, OR = 1.042 (95% CI, 1.032-1.053) vs OR = 1.009 (95% CI, 0.996-1.022) in users, ratio of ORs = 1.033 (95% CI, 1.019-1.047), RERI = 0.039 (95% CI, 0.025-0.050)]. Among users, partially adherent users exhibited a higher risk of PM2.5-associated mortality than fully adherent users. CONCLUSIONS: The associations of chronic exposure to PM2.5 with cardiovascular and CHD mortality were stronger among statin non-users compared to users.