Citations

Abstract Introduction Despite AASM scoring guidelines encouraging classifying hypopneas as central or obstructive, classification is underutilized in practice. However, without that effort patients may receive an incorrect primary diagnosis and suboptimal treatment. The remedē® System Pivotal Trial studied transvenous phrenic nerve stimulation (TPNS) to treat adult patients with moderate to severe central sleep apnea (CSA). Entry criteria required apnea hypopnea index (AHI)≥20 with the central apnea index (CAI) greater than the obstructive apnea index and obstructive apneas< 20% of AHI but did not consider hypopnea differentiation. This analysis re-examined sleep studies from the trial to assess how hypopnea classification might lead to better patient selection for this therapy. Methods Hypopneas were classified as central versus obstructive by a sleep core laboratory following a modified version of AASM recommended criteria. The AHI composition was assessed at baseline and after 6 months of therapy. Results At baseline, 91% (138/151) of patients had ≥50% of events classified as central when accounting for hypopnea classification. If all hypopneas were assumed to be obstructive, only 63% (95/151) would have had ≥50% central events. Additionally, 95% (144/151) of patients had central AHI ≥15/hour, compared to 73% (110/151) with a central apnea index (CAI) ≥15/hour. The likelihood of achieving a ≥50% AHI reduction increased with the percentage of baseline events that were central: responder rates were 37.5% for patients with < 50% central events at baseline, incrementally increasing to 76.5% for those with ≥90% central events. At 6 months, the residual AHI predominantly consisted of obstructive events. Central events decreased by 89% with treatment, from a baseline median of 32/hour [1st and 3rd quartiles: 22, 50]. Obstructive apneas rose by 2/hour and obstructive hypopneas increased by 2/hour from a baseline median of 5 obstructive events/hour [2, 12]. Conclusion Distinguishing central from obstructive hypopneas is required to accurately determine if a patient has central sleep apnea/Cheyne Stokes respiration, and is crucial for epidemiologic studies, appropriate therapy selection, and managing patient expectations about treatment outcomes. This analysis suggests that accurate hypopnea classification may prevent disqualification of patients who could benefit from TPNS therapy, which effectively treats central sleep apnea syndrome. Support (if any) ZOLL Respicardia, Inc.

Abstract Introduction Adherence with mask-based therapies remains a significant challenge for optimal treatment of patients with sleep disordered breathing. Transvenous phrenic nerve stimulation (TPNS) to treat central sleep apnea offers a novel, automated approach to enhance nightly adherence by initiating therapy based on patient-specific programmed conditions such as sleep schedule, activity, and body position. Therapy automatically pauses when the patient sits up or changes position, facilitating re-initiation of sleep. This research aimed to determine the degree of adherence achieved with TPNS’s automated activation approach. Methods Device data from 128 remedē® System Pivotal Trial participants were analyzed to calculate hours of therapy activation. Daily use from device data within the 14 days prior to scheduled visits were used to calculate median daily hours of therapy per patient, and subsequently the overall median daily use for all patients. Therapy duration was defined as the sum of time of delivered therapy when all conditions to activate therapy were met between the first time therapy came on to the last time off during the night, excluding time when activity or body position did not meet the programmed criteria for therapy activation. Results The median [Q1-Q3] nightly therapy duration at 6, 12, 18, and 24 months was 5.9 [4.9-6.6], 5.7 [5.0-6.8], 6.0 [5.3-6.8], and 5.9 [4.9-6.5] hours, respectively. Using a definition for adequate therapy as the percentage of patients with usage ≥4 hours/night for at least 70% of nights, 86%, 82%, 83%, and 90% of patients met the criteria at these visits. Only two patients (< 2%) who had therapy activated discontinued treatment prior to 6 months due to stimulation intolerance. Patients with median delivered therapy ≥4 hours/night reported more quality of life improvement than patients with < 4 hours of therapy. Conclusion The automatic activation of TPNS therapy resulted in a higher duration of nightly usage and higher rate of adequate delivered therapy than generally are reported for mask-based therapies. This high usage may yield a greater overall reduction in central sleep apnea burden over the whole night compared to therapies that require the patient to initiate the therapy. Support (if any) ZOLL Respicardia, Inc.

Background and Aims: In the global phase III HIMALAYA study in unresectable HCC, STRIDE significantly improved overall survival (OS) versus sorafenib; durvalumab was noninferior to sorafenib. Immune checkpoint inhibitor studies have shown an association between the occurrence of immune-mediated adverse events (imAEs) and improved OS. We assessed potential associations between the occurrence of imAEs and OS, and temporal patterns of imAEs, in HIMALAYA. Approach and Results: OS in participants who did and did not experience imAEs and the frequency and timing of imAEs were assessed for STRIDE and durvalumab in the safety analysis set of HIMALAYA. imAEs occurred in 139/388 (35.8%) and 64/388 (16.5%) participants with STRIDE and durvalumab, respectively; most were low grade. OS HRs (95% CI) in participants who experienced imAEs versus those who did not were 0.73 (0.56–0.95) for STRIDE and 1.14 (0.82–1.57) for durvalumab. The 36-month OS rate (95% CI) for STRIDE was 36.2% (28.1–46.7) and 27.7% (22.4–34.2) in participants who did and did not experience imAEs, respectively. The most common imAE category with STRIDE was endocrine events (16.5%). Most imAEs occurred ≤3 months after treatment initiation. Conclusions: Participants who experienced imAEs with STRIDE had a numerical improvement in OS versus those who did not, which was not observed for durvalumab. Long-term OS with STRIDE was observed regardless of imAEs. Most imAEs were low grade, manageable, and occurred in the first 3 months after treatment initiation. Results continue to support the benefits of STRIDE in a diverse population that reflects unresectable HCC globally.

Background/Objectives: Staphylococci are the most common causes of periprosthetic joint infection (PJI); new antimicrobials are needed to manage these difficult infections. Nisin A is a lantibiotic peptide derived from Lactococcus lactis that has antimicrobial activity against Gram-positive bacteria, including staphylococci, and is an FDA-approved preservative used in the food and dairy industry. Here, the in vitro nisin A susceptibility of PJI-associated staphylococci was assessed. Methods: The minimum inhibitory concentrations (MICs), minimum biofilm inhibitory concentrations (MBICs), and minimum biofilm bactericidal concentrations (MBBCs) of nisin A were measured by broth microdilution against 106 staphylococcus isolates isolated from PJI. MICs were assessed using 5 × 105 CFU/mL plus nisin A. For MBICs, biofilms were grown on pegged lids for 6 h, followed by 20 h of treatment. For MBBCs, pegged lids were transferred to plates containing media only for 20 h. The results were determined as the lowest concentrations with no visual growth. Two-dimensional MICs with nisin A and vancomycin were assessed for 20 isolates. Fractional inhibitory concentrations (FICs) were calculated to determine synergistic, additive, antagonistic, or indifferent interactions. Results: The MIC that inhibited 90% of S. aureus and S. epidermidis was 4 µg/mL, apart from for the MRSA subset (8 µg/mL). The MBIC that inhibited 90% of isolates was 4 µg/mL. The MBBCs ranged from 4 to 256 µg/mL. When tested together, nisin A and vancomycin yielded an FIC between 1.25 and 1.5, indicative of indifference, except for one isolate each of MRSA and MSSA, for which an additive effect (FIC of 1) was observed. Conclusions: Nisin A showed inhibitory activity against staphylococci that cause PJI.

Abstract RATIONALE: Understanding co-isolation patterns between fungi and other potentially pathogenic microorganisms in the airways of bronchiectasis patients is important for uncovering possible microbial interactions and informing treatment. Although numerous organisms have been identified in respiratory cultures, the specific patterns of their co-isolation are underexplored. OBJECTIVES: To examine the patterns of co-isolation between fungi and bacteria or mycobacteria in respiratory samples from patients with bronchiectasis across a large national health system. METHODS: We reviewed 58,170 respiratory culture tests from 8,194 patients with bronchiectasis (identified using ICD-10-CM codes J47.0, J47.1, and J47.9) across Mayo Clinic. These tests were analyzed for fungal, bacterial, and mycobacterial growth, focusing on co-isolation from the same sample. Chi-square statistics were used to compute p-values. RESULTS: Of all 18,983 samples cultured for fungi, 59% were positive. Of these, 72% yielded yeasts and 40% molds. Among the 11,372 samples cultured for both fungi and bacteria, 681 (6%) showed co-isolation, representing 54% of positive bacterial cultures. The odds of bacterial co-isolation with fungi were 1.4 (95% CI: 1.3-1.6; p < 0.01), driven by yeasts (OR: 1.5, 95% CI: 1.3-1.7; p < 0.01), rather than molds (OR: 1.0, 95% CI: 0.9-1.2; p = 0.8). Pseudomonas species, the most common bacterial isolate, had a higher likelihood of co-isolation with fungi (OR: 1.6, 95% CI: 1.3-1.9; p < 0.01), particularly yeasts (OR: 1.6, 95% CI: 1.4-2.0; p < 0.01). Molds, including those from genera such as aspergillus and penicillium, did not show a significant association with the isolation of pseudomonas. On the other hand, among the 15,859 samples cultured for both fungi and mycobacteria, 1352 (9%) showed co-isolation, representing 62% of positive mycobacterial cultures. Odds of co-isolation were 1.7 (95% CI: 1.5-1.8; p < 0.01). Molds showed a stronger association with isolation of mycobacteria (OR: 1.7, 95% CI: 1.5-1.9; p < 0.01) compared to bacteria, while yeasts also had elevated odds (OR: 1.4, 95% CI: 1.2-1.5). CONCLUSIONS: Distinct patterns of fungal co-isolation with bacteria and mycobacteria have been observed in bronchiectasis, which may influence key aspects of the disease, such as inflammation and mucociliary dysfunction. Advanced metagenomic and immunoprofiling techniques could provide deeper insights into these co-isolation patterns while considering other factors like clinical demographics, previous antibiotic exposure, and disease severity. Understanding whether altering the mycobiome could modify these aspects and improve outcomes remains an important avenue for research.

Importance A subset of Union for International Cancer Control ( UICC )/ American Joint Committee on Cancer ( AJCC ) eighth edition TNM stage I and II human papillomavirus–positive oropharyngeal carcinoma has undesirable outcomes, which might have contributed to a lack of success in phase III deintensification trials. Refining clinical stage groups, especially in the overabundant cN1/stage I group, has become important for treatment selection. Objective To assess the prognostic importance of pretreatment lymph node (LN) characteristics to optimize case distribution and outcome homogeneity within the N classification system. Design, Setting, and Participants This is an international multi-institutional retrospective prognostic cohort study. Analysis of human papillomavirus–positive oropharyngeal carcinoma treated curatively from 4 institutions (International Collaboration of Oropharyngeal Cancer Network for N-Classification [ICON-N] dataset) provided a refined clinical staging proposal; an independent dataset (Centre Hospitalier de l’Université de Montréal [CHUM] dataset) validated the proposal. Neuroradiologists reviewed pretreatment computed tomography and/or magnetic resonance imaging for nodal features, including presence or absence of abnormal LN(s), retropharyngeal LN, laterality, number of abnormal LN, and imaging-detected extranodal extension (iENE). Data were collected from February to May 2023, and data were analyzed from June to July 2023. Exposures Definitive chemoradiotherapy/radiotherapy or definitive surgery with or without postoperative chemoradiotherapy/radiotherapy. Main Outcomes and Measures The primary end point was overall survival. A Cox proportional hazards multivariable model was used to estimate adjusted hazard ratios (AHRs) and to derive an optimal clinical TNM stage classification (AHR-stage schema) incorporating the strongest prognostic nodal features within the UICC/AJCC eighth edition TNM framework after confirming the prognostication of iENE status. The performance (according to overall normalized scores and ranking) of the AHR-stage schema against the current UICC/AJCC eighth edition TNM staging system was evaluated for hazard consistency, hazard discrimination, prognostic importance, and sample size balance. Validation was performed in the CHUM dataset. Results The ICON-N dataset comprised 2053 patients, including 1898 (92.5%) with cN-positive disease and 155 (7.5%) with cN0 disease; a total of 298 (14.5%) were female, and the mean (SD) age was 60.6 (9.3) years. iENE-positive disease was identified in 710 of 1898 patients with cN-positive disease (37.4%). The median (range) follow-up was 5.1 (0.1-14.7) years. iENE was the strongest prognostic nodal feature in multivariable analysis; the AHR for iENE-positive vs iENE-positive disease was 2.43 (95% CI, 1.96-3.03) in the ICON-N dataset and 2.04 (95% CI, 1.28-3.23) in the CHUM dataset (n = 451). Reclassifying iENE-positive cases 1 stratum higher for N categorization without altering iENE-negative cases yielded an AHR-stage schema that outperformed the current TNM staging system in disease-free and overall survival with a lower (ie, better) overall normalized score (2 vs 3). Conclusions and Relevance In this study, reclassifying each N category 1 stratum higher for iENE-positive disease resulted in better disease-free and overall survival. The proposed new classification outperformed the currently TNM staging system in risk stratification and may facilitate future clinical trial design, outcomes research, and patient care.

PURPOSE The combination of the Bruton tyrosine kinase inhibitor ibrutinib with bendamustine-rituximab for first-line treatment of mantle cell lymphoma (MCL) prolonged progression-free survival (PFS), but without improvement in overall survival (OS), likely because of toxicity. Acalabrutinib was shown to be efficacious and less toxic than ibrutinib in a head-to-head trial in chronic lymphocytic leukemia and therefore might lead to better outcomes in MCL. METHODS Patients 65 years and older with previously untreated MCL received acalabrutinib (100 mg twice daily) or placebo (until disease progression or unacceptable toxicity), plus six cycles of bendamustine (90 mg/m 2 once daily; days 1 and 2) and rituximab (375 mg/m 2 as a single dose; day 1) followed by rituximab maintenance in responding patients for 2 years. Crossover to acalabrutinib at disease progression was permitted. The primary end point was PFS per the independent review committee; overall response rate and OS were secondary end points. RESULTS In total, 598 patients were randomly assigned, with 299 in each arm. At a median follow-up of 49.8 months using the reverse Kaplan-Meier method, the median PFS was 66.4 months in the acalabrutinib arm and 49.6 months in the placebo arm (hazard ratio [HR], 0.73 [95% CI, 0.57 to 0.94]; P = .0160). Benefit was seen across all subgroups, including those with high-risk features. Overall response/complete response rates were 91.0%/66.6% and 88.0%/53.5% in the acalabrutinib and placebo arms, respectively. OS was not significantly different (HR, 0.86 [95% CI, 0.65 to 1.13]; P = .27). Grade 3 or greater adverse events were reported in 88.9% and 88.2% in the acalabrutinib and placebo arms, respectively. CONCLUSION The combination of acalabrutinib with bendamustine-rituximab significantly improved PFS. Clinical benefit of acalabrutinib with bendamustine-rituximab was achieved with manageable toxicity.

Abstract Background Instruments to assess patient-reported outcomes (PRO) should generate high-quality evidence. Reliable PRO evidence is essential to policymakers, in conjunction with outcomes such as survival and radiological response, to understand the net clinical benefit of antitumor treatments. This study aimed to establish the content validity of 215 identified PRO measures used in patients with brain tumors. Methods A survey (n = 148 items) was developed reflecting aspects of the WHO International Classification of Functioning, Disability, and Health (ICF) framework. Patients with brain tumors, their proxies, and healthcare professionals (HCPs) were asked to rate each survey item on relevance. An item was considered a relevant issue if ≥25% of the patients or proxies or ≥50% of the HCPs considered that item to be an issue. Next, all items in the identified PRO measures were linked to ICF and relevant items in the survey, and the percentage of content coverage was calculated. Results In total, 114 patients, 71 proxies, and 65 HCPs from different countries completed the survey. Fifty-six of 148 (37.8%) items in the survey were considered relevant. The most important aspects mentioned by both patients and proxies were difficulty concentrating, difficulty remembering, multitasking, and handling stress. Depending on the definition, between 35% and 49% of PRO measures were considered to have sufficient content validity (≥80% coverage). Conclusion The content validity was insufficient in more than half of the identified PRO measures, particularly multidimensional measures. Future research should investigate whether different approaches to PRO assessment better meet the needs of all stakeholders.

ABSTRACT Contezolid has activity against methicillin-resistant Staphylococcus aureus (MRSA), a common cause of orthopedic infection. In a rat model of foreign body osteomyelitis, 1.3 log 10 cfu/g bone and 0.5 log 10 cfu/k-wire reduction in MRSA was found in tibiae ( P = 0.0186) and K-wires, respectively, of contezolid-treated compared to untreated rats. No MRSA was recovered from animals receiving rifampin alone or in combination with contezolid or vancomycin. There was no emergence of resistance to contezolid, vancomycin, or rifampin.