Citations

Abstract Infective endocarditis (IE) is a relatively rare but life-threatening systemic infection, which remains associated with high morbidity and mortality. The epidemiology of IE has shifted to involve an increasing numbers of older patients with both cardiovascular and other types of prosthetic devices, multiple comorbid conditions often requiring invasive procedures, increasingly virulent pathogens, in particular Staphylococcus aureus, or that can harbour anti-microbial resistance, and an escalation of injection drug use in many areas of the world. In parallel, advancements in diagnostic and therapeutic options have led to complex strategies in patients’ management. Despite these epidemiologic shifts, clinical trials have been rare and most of the evidence guiding IE management derives from expert consensus or analysis of large registries. Because of this, a multi-disciplinary IE team-based approach has been recommended as the standard of care. The aim of this review is to explore the rationale for a multi-disciplinary team-based approach to the management of IE. This approach has proved to be potentially beneficial based on multiple investigations that have evaluated patient outcomes. In addition, implementation strategies, feasibility and options of the team approach have also been highlighted.

AbstractObjectiveTo assess relations between Ménière's disease and suicidality, measured by suicidal ideation, suicidal behaviors, and death by suicide.Data SourcesCINAHL, Cochrane Library, PubMed, PsycINFO, and SCOPUS databases were searched from inception through July 2, 2024.Review MethodsObservational studies related to suicidality in patients with Ménière's disease were included. Non‐English language papers, editorials, and studies on vestibular disorders not specified as Ménière's disease were excluded. The Risk Of Bias In Nonrandomized Studies‐of Exposure tool was used for cohort and qualitative studies, and the Joanna Briggs Institute critical appraisal checklist was used for case‐control studies.ResultsFour studies (n = 168,566) were included in our review. Two cohort studies found significantly increased adjusted hazard ratios of 2.1 (95% CI: 2.0‐2.2) for death by suicide and 7.6 (95% CI: 4.4‐13.3) for suicidal behaviors, respectively, in patients with Ménière's disease compared to the control population after their diagnosis. However, a case‐control study found no significant difference in the prevalence of suicidal ideation or behaviors prior to the date of diagnosis in patients with Ménière's disease compared to the control population (0.9% vs 0.8%; P = .44). In addition, one patient with Ménière's disease expressed suicidal ideation in the qualitative study.ConclusionPatients may experience variable responses to Ménière's disease. Thus, otolaryngologists should be mindful of the potential for suicidality in patients with Ménière's disease.

Summary of Background Data: Intraductal papillary mucinous neoplasm (IPMN)-derived pancreatic cancer is typically managed like pancreatic intraepithelial neoplasia (PanIN)-derived pancreatic cancer. However, in IPMN-derived pancreatic cancer, the role of chemotherapy remains controversial, particularly in the neoadjuvant setting (NAT). Objective: To evaluate the role of neoadjuvant chemotherapy in IPMN-derived pancreatic cancer. Methods: Patients with IPMN-derived pancreatic cancer treated with either upfront surgery (US) or NAT were identified from eight international centers (2000-2023). Clinicopathologic data were compared. Date of first treatment was used for Kaplan-Meier and log-rank tests to compare overall (OS) and recurrence free survival (RFS). Multivariable Cox-regression was performed in patients that underwent NAT. Results: In 1,019 patients, 76 (7%) underwent NAT. Patients who received NAT had higher baseline CA19-9 levels (P<0.001). Of these 76 patients, 27 (36%), 20 (26%), and 29 (38%) had resectable, borderline resectable, or locally advanced pancreatic cancer at diagnosis, respectively. Advanced resectability stage was significantly more common in the NAT patients as compared to those who underwent US (P<0.001). OS for US patients was 38.0 months (95%CI: 33.7.1-44.3), which was not statistically different than those that received NAT [27.5 mo (95%CI: 23.1-46.7), P=0.121]. This was also valid for patients with resectable disease [US: 38.1 mo vs. NAT: 35.6 mo, P=0.920)]. Complete or marked pathological treatment response (P=0.046) and serological CA19-9 normalization after NAT (P=0.017) were associated with improved survival. On Cox-regression for OS, N2 disease [HR: 4.15 (95%CI: 1.71-10.10)], elevated CA19-9 [HR: 2.02 (95%CI:1.06-3.85)] and R1 margin [HR: 2.36 (95%CI:1.20-4.61)] was independently associated with OS after NAT, while resectability status was not. Conclusion: After NAT and resection, advanced resectability stage was not associated with worse OS indicating the value of this approach for borderline resectable and locally advanced IPMN-derived pancreatic cancer. The benefit of NAT in resectable disease is unclear and may require an individualized approach. Biological treatment effect can be assessed with CA19-9 and confirmed by pathologic response.

ImportanceAmyotrophic lateral sclerosis (ALS) is a fatal disease. The sigma-1 (σ1) receptor emerged as a target for intervention.ObjectiveTo determine the effects of pridopidine, a σ1-receptor agonist, in ALS.Design, Settings, and ParticipantsPridopidine was tested as a regimen of the HEALEY ALS Platform Trial, a phase 2/3, multicenter, randomized, double-blind, platform trial. The study was conducted at 54 sites in the US from January 2021 to July 2022 (final follow-up, July 14, 2022). A total of 163 participants with ALS were randomized to receive pridopidine or placebo. An additional 122 concurrently randomized participants were assigned to receive placebo in other regimens and included in the analyses.InterventionsEligible participants were randomized 3:1 to receive oral pridopidine 45 mg twice daily (n = 121) or matching oral placebo (n = 42) for a planned duration of 24 weeks.Main Outcomes and MeasuresThe primary efficacy outcome was change from baseline through week 24 in ALS disease severity, analyzed using a bayesian shared parameter model, which has components for function (Revised Amyotrophic Lateral Sclerosis Functional Rating Scale [ALSFRS-R]) and survival that were linked through an integrated estimate of treatment-dependent disease slowing across these 2 components. This was denoted as the disease rate ratio (DRR), with DRR less than 1 indicating a slowing in disease progression on pridopidine relative to placebo. There were 5 key secondary end points: time to 2-point or greater reduction in ALSFRS-R total score among participants with bulbar dysfunction at baseline, rate of decline in slow vital capacity among participants with bulbar dysfunction at baseline, percentage of participants with no worsening in the ALSFRS-R bulbar domain score, time to 1-point or greater change in the ALSFRS-R bulbar domain score, and time to death or permanent assisted ventilation.ResultsAmong 162 patients (mean age, 57.5 years; 35% female) who were randomized to receive the pridopidine regimen and included in the primary efficacy analysis, 136 (84%) completed the trial. In the primary analysis comparing pridopidine vs the combined placebo groups, there was no significant difference between pridopidine and placebo in the primary end point (DRR, 0.99 [95% credible interval, 0.80-1.21]; probability of DRR &amp;lt;1, 0.55) and no differences were seen in the components of ALSFRS-R or survival. There was no benefit of pridopidine on the secondary end points. In the safety dataset (pridopidine, n = 121; placebo, n = 163), the most common adverse events were falls (28.1% vs 29.3%, respectively) and muscular weakness (24.0% vs 31.7%, respectively).Conclusions and RelevanceIn this 24-week study, pridopidine did not impact the progression of ALS.Trial RegistrationClinicalTrials.gov Identifiers: NCT04297683, NCT04615923

Importance The etiology of amyotrophic lateral sclerosis (ALS), a fatal neurodegenerative disease, is unknown. However, neuroinflammation and complement activation may play a role in disease progression. Objective To determine the effects of zilucoplan, an inhibitor of complement C5, in individuals with ALS. Design, Setting, and Participants Zilucoplan was tested as regimen A of the HEALEY ALS Platform Trial, a phase 2 to 3 multicenter, randomized, double-blind, placebo-controlled perpetual platform clinical trial with sharing of trial infrastructure and placebo data across multiple regimens. Regimen A was conducted from August 17, 2020, to May 4, 2022. A total of 162 participants were randomized to receive zilucoplan (122 [75.3%]) or regimen-specific placebo (40 [24.7%]). An additional 124 concurrently randomized participants were randomized to receive placebo in other regimens. Interventions Eligible participants were randomized in a 3:1 ratio to receive zilucoplan or matching placebo within strata of edaravone and/or riluzole use for a planned duration of 24 weeks. Active drug (zilucoplan, 0.3 mg/kg) and placebo were provided for daily subcutaneous dosing. Main Outcomes and Measures The primary end point was change in disease severity from baseline through 24 weeks as measured by the Amyotrophic Lateral Sclerosis Functional Rating Scale–Revised (ALSFRS-R) total score and survival, analyzed using a bayesian shared-parameter model and reported as disease rate ratio (DRR; &amp;lt;1 indicating treatment benefit). The study included prespecified rules for early stopping for futility. Outcome analyses were performed in the full analysis set comparing the zilucoplan group with the total shared placebo group (n = 164). Results Among the 162 participants who were randomized (mean [SD] age, 59.6 [11.3]; 99 [61.1%] male), 115 (71.0%) completed the trial. The estimated DRR common to ALSFRS-R and survival was 1.08 (95% credible interval, 0.87-1.31; posterior probability of superiority, 0.24). The trial was stopped early for futility. No unexpected treatment-related risks were identified. Conclusions and Relevance In this randomized clinical trial of zilucoplan in ALS, treatment did not alter disease progression. The adaptive platform design of the HEALEY ALS Platform Trial made it possible to test a new investigational product with efficient use of time and resources. Trial Registration ClinicalTrials.gov Identifier: NCT04297683

Importance Bioenergetic failure has been proposed as a driver of amyotrophic lateral sclerosis (ALS). CNM-Au8 is a suspension of gold nanocrystals that catalyzes the conversion of nicotinamide adenine dinucleotide hydride into NAD + , resulting in an increase of cellular adenosine triphosphate production. Objective To determine the effects of CNM-Au8 on ALS disease progression. Design, Setting, and Participants CNM-Au8 was tested as a regimen of the HEALEY ALS Platform Trial, a phase 2/3, multicenter, randomized, double-blind platform trial. The study was conducted at 54 sites in the US from July 2020 to March 2022 (final follow-up, March 17, 2022). A total of 161 participants with ALS were randomized to receive CNM-Au8 (n = 120) or regimen-specific placebo (n = 41). Data from 123 concurrently randomized placebo participants in other regimens were combined for analyses. Interventions Eligible participants were randomized in a 3:3:2 ratio to receive CNM-Au8 60 mg daily (n = 61), CNM-Au8 30 mg daily (n = 59), or matching placebo (n = 41) for 24 weeks. Main Outcomes and Measures The primary efficacy outcome was change from baseline through week 24 in ALS disease severity measured by a bayesian shared parameter model of function (based on the Revised Amyotrophic Lateral Sclerosis Functional Rating Scale) and survival, which provided an estimate of the rate of disease progression measured by the disease rate ratio (DRR), with a DRR of less than 1 indicating treatment benefit. Secondary end points included a Combined Assessment of Function and Survival using a joint-rank test, rate of decline in slow vital capacity (percent predicted), and survival free of permanent assisted ventilation. Results Among 161 participants who were randomized within the CNM-Au8 regimen (mean age, 58.4 years; 61 [37.9%] female), 145 (90%) completed the trial. In the primary analysis comparing the combined CNM-Au8 dosage groups vs the combined placebo groups, the primary end point (DRR, 0.97 [95% credible interval, 0.783-1.175]; posterior probability of DRR &amp;lt;1, 0.65) and the 3 secondary end points suggested no benefit or harm of CNM-Au8. In the active (n = 120) vs placebo (n = 163) groups, the most common adverse events were diarrhea (23 [19%] vs 12 [7%]), nausea (17 [14.2%] vs 14 [8.6%]), fatigue (12 [10.8%] vs 30 [18.4%]), and muscular weakness (24 [20%] vs 45 [27.6%]). Conclusions and Relevance No benefit of CNM-Au8 on ALS disease progression was observed at 24 weeks. Trial Registration ClinicalTrials.gov Identifiers: NCT04297683 , NCT04414345

Introduction Multiple Myeloma (MM) precursors Monoclonal Gammopathy of Undetermined Significance (MGUS) and Smoldering Multiple Myeloma (SMM) have variable risk of progression to active MM, and identifying which patients may progress remains a clinical challenge. Deep proteome profiling of peripheral blood (PB) plasma may advance non-invasive precursor disease staging, monitoring and characterization. Here, we performed plasma proteomic profiling on patients across the MM disease continuum as well as progressive and stable disease to provide insights into MM disease biology and identify protein-based high-risk disease features that may improve prognostication. Methods We performed high-throughput profiling of &gt;5400 proteins using the Olink® Explore HT library and Proximity Extension Assay (PEA) technology. We profiled 529 PB plasma samples from 485 individuals, including MGUS (n=100), SMM (n=203), MM (n=100), and healthy donors (HDs) (n=82). Sequential samples from SMM-MM progressors (n=32) and stable SMM-SMM non-progressors (n=32) were also profiled, where precursor samples ranged 1.04-6.91 years (median 2.33 years) prior to MM progression. T-tests, ANOVAs, and linear mixed effect (LME) models were used to identify significant proteins across disease stages, progression status, and time. Results were adjusted for multiple testing using Benjamini-Hochberg procedure. A subset of 86 individuals (13 HDs, 14 MGUS, 41 SMM, 18 MM) also had single-cell RNA sequencing (scRNA-seq) performed on tumor and immune cells from paired PB/BM collected at the same timepoint to enable cellular mapping of signals detected in plasma. Results We successfully captured significantly dysregulated proteins including proteins highly expressed on the surface of plasma cells, such as BCMA, SLAMF7 and CD38, highlighting the utility of PEA technology to monitor soluble levels of clinically relevant targets. Given SMM patients are clinically heterogeneous and can resemble MGUS or MM, we aimed to improve discrimination of disease states using biological features obtained from the plasma proteome. We developed a classifier using an Elastic Net model for each stage, where plasma proteins such as SLAMF7, BCMA, TACI, FCRL5 and others had the highest importance scores for the model. We demonstrated 97% SMM/MM samples could be identified from healthy samples (AUC=0.82), indicating our classifier could reliably screen disease-related cases. Moreover, 84% of SMM cases were correctly classified as clinically defined SMM, while misclassified samples were labelled as MM cases. Interestingly, the misclassified patients had consistently rising M-spike levels during clinical follow-up but without a shift in clinical stage or risk status, suggesting the plasma proteome may provide earlier indication of evolving disease. Since proteomic information may also hold value for improved risk stratification, we evaluated protein levels in precursor stage timepoint samples from SMM-MM progressors and stable SMM non-progressors. We identified a prognostic five-protein signature that was significantly elevated in SMM-MM progressors, of which BCMA and TACI were top proteins, as well as proteins vital for calcium homeostasis and integrin-mediated cell adhesion. BCMA and TACI levels also had a strong positive correlation with BM plasma cell infiltration, which suggests these proteins may be useful surrogates of BM tumor burden during routine blood-based assessment of precursor patients. Lastly, integrative analysis of scRNA-seq of tumor and immune cells was used to elucidate cell origin level information of the prognostic signature proteins. Four proteins were highly expressed in malignant versus non-malignant plasma cells, suggesting our prognostic signature partially provides a readout of plasma cell biology. Meanwhile, one protein was constitutively expressed on most leukocytes, suggesting that the interplay of other cell types in the immune microenvironment involved in progression may also be reflected in the plasma. Conclusion We performed the first comprehensive analysis of the plasma proteome of MM and its precursor conditions. Overall, we developed a classifier that utilizes plasma proteins alone to accurately classify disease stages and identified a prognostic protein signature associated with progressive disease.

Introduction: Stroke-related mortality poses significant challenges in the US. Increased at-home deaths since COVID-19 pandemic prompted changes in the provision of end-of-life care. Question: What were the settings of stroke deaths in the US during COVID-19 pandemic? Methods: Decedent-level mortality data from death certificates in CDC repository were obtained for the year 2020 (pandemic) and 2019 (comparison). Demographic data include age, sex, race/ethnicity, education, marital status, and place of stroke death, including inpatient, outpatient/emergency room (ER), hospice/nursing facilities (H/NF), and at-home. Multivariable logistic regression models assessed demographic impact on stroke mortality by place-of-death, yielding odds ratios (OR) with significance threshold of p<0.05. Results: A total of 5,400 and 5,712 stroke-related deaths occurred in 2019 and 2020, respectively. During COVID-19, decedents >65 years were more likely to die in H/NF (OR 10.05, p<0.001) but less likely in outpatient/ER (OR 0.32, p<0.001) or at home (OR 0.57, p=0.007) compared to those <35 years. High education level did not significantly influence the place of death than having high school diploma or less (p>0.05). Males were more likely to die at home (OR 1.38, p<0.001) but less likely as inpatient (OR 0.79, p<0.001) than females. Hispanic decedents had a higher likelihood of inpatient death (OR 1.22, p=0.041) but less likely to die in H/NF (OR 0.55, p<0.001) compared to non-Hispanic decedents. Compared to White decedents, Black decedents were more likely to die in outpatient/ER (OR 1.44, p=0.018), while American Indian decedents were more likely to die as inpatient (OR 3.12, p=0.005). Asian/Pacific Islander decedents had a higher chance of inpatient death (OR 1.47, p=0.002) but a lower likelihood of dying in H/NF (OR 0.61, p=0.010). Married decedents were more likely than singles to die as inpatient (OR 1.37, p=0.001) or in outpatient/ER (OR 1.99, p<0.001), but less likely to die in H/NF (OR 0.61, p=0.002) or at home (OR 0.56, p<0.001). Conclusion: Our analysis revealed the influence of demographics on the settings of stroke fatalities during the COVID-19 pandemic. Further investigation is needed to determine contributing factors.