Comparison of Home Sleep Devices and Sleep Study Testing in Hypoglossal Nerve Stimulation Patients.

OBJECTIVE: Hypoglossal nerve stimulation (HGNS) is an implantable therapy for obstructive sleep apnea (OSA). Therapy efficacy is currently confirmed by a formal sleep study after empiric adjustment by the patient at home based on their subjective experience with the device. Home-based longitudinal apnea hypopnea index (AHI) measurements have the potential to refine HGNS therapeutic amplitude selection with objective data. Our objective was to compare AHI derived from routine sleep studies and two different home sleep devices in new HGNS recipients. METHODS: Prospectively enrolled patients receiving HGNS therapy were provided a Sleep Tracking Mat (Withings, Issy-les-Moulineaux, France) and NightOwl peripheral arterial tonometry (PAT) sensor (Ectosense, Leuven, Belgium) for longitudinal, home AHI monitoring from 1 to 6 months post-implant. Therapy efficacy was assessed at 3 and 6 months post-implant using in-lab polysomnography (PSG) or home sleep apnea test (HSAT). The sleep mat and PAT sensor AHI were compared against PSG and HSAT for accuracy of OSA severity identification. RESULTS: Sixty patients were enrolled across 5 centers and followed for 6 months. The sleep mat had sensitivity and specificity for identifying AHI <15 of 61% and 82% and AHI <30 of 77% and 100%. The PAT device had sensitivity and specificity for identifying AHI <15 of 57% and 77% and AHI <30 of 81% and 80%. CONCLUSIONS: The sleep mat and PAT sensor demonstrated high sensitivity and specificity for detection of mild and moderate OSA in patients with HGNS therapy and may enable longitudinal objective monitoring of HGNS efficacy in the home setting. LEVEL OF EVIDENCE: 3 Laryngoscope, 2024.

Evaluation of an OSA Risk Screening Smartphone App in a General, Non-Symptomatic Population Sample (ESOSA).

Background: Obstructive Sleep apnea (OSA) is a prevalent sleep disorder, risk factor for cardiovascular disease and imposes a substantial global socioeconomic and health burden. OSA is insufficiently diagnosed as it often presents with unspecific or no symptoms. This study compares the effectiveness of a smartphone-based screening method to polysomnography (PSG) in a general, non-symptomatic population sample. Methods: Adult subjects were recruited from the general population. Subjects reporting OSA-related symptoms suggesting an increased OSA risk were excluded. Included subjects underwent Type-II PSG and a parallel breathing sound analysis using the Snorefox M smartphone app. The PSG scores were compared with the results of the Snorefox M app for its ability to detect moderate to severe OSA (AHI ≥ 15). Results: 150 subjects were included. All subjects completed the diagnostic night, no adverse events occurred. A valid analysis result was obtained for 142 subjects. A total of 24% of subjects had moderate to severe OSA based on the PSG results. The Snorefox M software app showed a sensitivity of 0.91 (0.76, 0.98), specificity of 0.83, PPV of 0.63 (0.48, 0.77), and NPV of 0.97 (0.91, 0.99) to detect AHI ≥ 15 compared with the reference PSG (95% CI). Conclusions: This study compares for the first time, the performance of an app-based OSA screening tool with PSG in a non-symptomatic population sample. Easily accessible screening tools can play a role in complementing existing diagnostic possibilities, helping to increase the diagnosis rate, with a positive effect on cardiovascular health in a relevant population share.

Cystatin C as a Marker of Kidney Function in Children.

This review examines the reliability of cystatin C as a biomarker for kidney function in paediatric populations. Chronic kidney disease (CKD) affects a significant number of children globally, leading to severe health complications such as anaemia, hypertension, and growth disorders. Traditionally, kidney function has been assessed using the estimated glomerular filtration rate derived from serum creatinine, though this method is flawed due to variability in muscle mass, age, gender, and diet. Cystatin C offers an alternative as it is less influenced by these factors. Evidence from various studies indicates that cystatin C provides a more accurate assessment of kidney function, especially in neonates and children with urinary tract malformations. Additionally, it is more reliable in early detection of acute kidney injury in paediatric intensive care units. Despite its potential, cystatin C is not yet widely adopted in clinical guidelines, primarily due to a lack of large-scale paediatric studies. Nonetheless, existing research supports its utility in providing a consistent and precise measure of kidney function across different paediatric age groups, suggesting that it could enhance early diagnosis and management of CKD in children if more extensive validation studies are conducted.

Emerging genetic technologies informing personalized medicine in Shwachman-Diamond syndrome and other inherited BMF disorders.

ABSTRACT: Ribosomopathy Shwachman-Diamond syndrome (SDS) is a rare autosomal recessive inherited bone marrow failure syndrome (IBMFS) caused by mutations in the Shwachman-Bodian-Diamond syndrome gene, which is associated with an increased risk of myeloid malignancy. Tracking how hematopoietic stem cell (HSC) clonal dynamics change over time, assessing whether somatic genetic rescue mechanisms affect these dynamics, and mapping out when leukemic driver mutations are acquired is important to understand which individuals with SDS may go on to develop leukemia. In this review, we discuss how new technologies that allow researchers to map mutations at the level of single HSC clones are generating important insights into genetic rescue mechanisms and their relative risk for driving evolution to leukemia, and how these data can inform the future development of personalized medicine approaches in SDS and other IBMFSs.

Derivation of an Annualized Claims-Based Major Adverse Cardiovascular Event Estimator in Type 2 Diabetes.

Background: Major adverse cardiovascular events (MACE) are a leading cause of morbidity and mortality among adults with type 2 diabetes. Currently, available MACE prediction models have important limitations, including reliance on data that may not be routinely available, narrow focus on primary prevention, limited patient populations, and longtime horizons for risk prediction. Objectives: The purpose of this study was to derive and internally validate a claims-based prediction model for 1-year risk of MACE in type 2 diabetes. Methods: Using medical and pharmacy claims for adults with type 2 diabetes enrolled in commercial, Medicare Advantage, and Medicare fee-for-service plans between 2014 and 2021, we derived and internally validated the annualized claims-based MACE estimator (ACME) model to predict the risk of MACE (nonfatal acute myocardial infarction, nonfatal stroke, and all-cause mortality). The Cox proportional hazards model was composed of 30 covariates, including patient age, sex, comorbidities, and medications. Results: The study cohort comprised 6,623,526 adults with type 2 diabetes, mean age 68.1 ± 10.6 years, 49.8% women, and 73.0% Non-Hispanic White. ACME had a concordance index of 0.74 (validation index range: 0.739-0.741). The predicted 1-year risk of the study cohort ranged from 0.4% to 99.9%, with a median risk of 3.4% (IQR: 2.3%-6.5%). Conclusions: ACME was derived in a large usual care population, relies on routinely available data, and estimates short-term MACE risk. It can support population risk stratification at the health system and payer levels, participant identification for decentralized clinical trials of cardiovascular disease, and risk-stratified observational studies using real-world data.

Percutaneous Approaches to Hypoglossal Nerve Stimulation: A Pilot Study During Drug-Induced Sleep Endoscopy.

Hypoglossal nerve stimulation (HNS) is a surgical treatment option for select patients with obstructive sleep apnea that currently requires intraoperative dissection of the hypoglossal nerve (HGN) for implantation of an electrode array. Most HNS strategies target select HGN protrusor muscle branches and exclude undesirable retractor branches. We hypothesized that the target HGN branches could instead be selectively stimulated with a percutaneously delivered electrode array under ultrasound guidance via several anatomic approaches. Five different anatomic approaches were iteratively developed and evaluated during drug-induced sleep endoscopy across 14 patients: posterior, intraoral, anteromedial, anterolateral, and paracoronal. The paracoronal and anterolateral approaches were the most successful, with comparable changes in pharyngeal critical closing and opening pressures. Our data suggest that percutaneous delivery of an HGN electrode is feasible and may decrease the morbidity of HNS therapy implantation. Further work is necessary to ascertain what anatomic approach is optimal for percutaneous electrode delivery.

Effectiveness of glucose-lowering medications on cardiovascular outcomes in patients with type 2 diabetes at moderate cardiovascular risk.

Cardiovascular disease (CVD) is the leading cause of death among people with type 2 diabetes1-5, most of whom are at moderate CVD risk6, yet there is limited evidence on the preferred choice of glucose-lowering medication for CVD risk reduction in this population. Here, we report the results of a retrospective cohort study where data for US adults with type 2 diabetes and moderate risk for CVD are used to compare the risks of experiencing a major adverse cardiovascular event with initiation of glucagon-like peptide-1 receptor agonists (GLP-1RA; n = 44,188), sodium-glucose cotransporter 2 inhibitors (SGLT2i; n = 47,094), dipeptidyl peptidase-4 inhibitors (DPP4i; n = 84,315) and sulfonylureas (n = 210,679). Compared to DPP4i, GLP-1RA (hazard ratio (HR) 0.87; 95% confidence interval (CI) 0.82-0.93) and SGLT2i (HR 0.85; 95% CI 0.81-0.90) were associated with a lower risk of a major adverse cardiovascular event, whereas sulfonylureas were associated with a higher risk (HR 1.19; 95% CI 1.16-1.22). Thus, GLP-1RA and SGLT2i may be the preferred glucose-lowering agents for cardiovascular risk reduction in patients at moderate baseline risk for CVD. ClinicalTrials.gov registration: NCT05214573.

Palate Shape, Drug-Induced Sleep Endoscopy Findings, and Obstructive Sleep Apnea Pharyngeal Surgery Outcomes.

OBJECTIVE: Pharyngeal surgery is a treatment option for patients with obstructive sleep apnea (OSA) unable to tolerate positive pressure therapy. This study aims to determine the association between palate shape as described by Woodson and pharyngeal surgical outcomes. STUDY DESIGN: Exploratory analysis of retrospective cohort. SETTING: Multicenter. METHODS: Three blinded reviewers assessed palate shape using drug-induced sleep endoscopy (DISE) videos from a previously-assembled cohort of adults undergoing pharyngeal surgery. Palate shape scores were examined for association with surgical outcomes with univariate and multivariate analyses. Multivariate analyses included adjustment for consensus DISE findings determined previously. RESULTS: Two hundred nine study subjects were included from 13 centers. Age was 53.7 ± 11.5 years, body mass index (BMI) was 30.3 ± 5.0 kg/m2, and 21% were female. In isolated soft palate surgery, greater GenuAP narrowing was associated with lesser odds of surgical response, whereas greater GenuLW narrowing was associated with greater odds of surgical response. These findings largely persisted after adjustment for key DISE findings, age, gender, OSA severity, BMI, and tonsil size. Other palate-shape findings were not clearly associated with surgical outcomes, although some palate-shape findings demonstrated trends toward an association with outcomes (P < .10). CONCLUSION: Greater GenuAP narrowing and GenuLW narrowing were associated with lesser and greater, respectively, odds of surgical response after isolated soft palate surgery. Palate shape and other palate shape level scores were not clearly associated with surgical outcomes. Larger studies may determine more precisely the association between palate shape and pharyngeal surgery outcomes.

Impact of the PATH Statement on Analysis and Reporting of Heterogeneity of Treatment Effect in Clinical Trials: A Scoping Review.

Background: The Predictive Approaches to Treatment Effect Heterogeneity (PATH) Statement provides guidance for using predictive modeling to identify differences (i.e., heterogeneity) in treatment effects (benefits and harms) among participants in randomized clinical trials (RCTs). It distinguished risk modeling, which uses a multivariable model to predict risk of trial outcome(s) and then examines treatment effects within strata of predicted risk, from effect modeling, which predicts trial outcomes using models that include treatment, individual participant characteristics and interactions of treatment with selected characteristics. Purpose: To describe studies of heterogeneous treatment effects (HTE) that use predictive modeling in RCT data and cite the PATH Statement. Data Sources: The Cited By functions in PubMed, Google Scholar, Web of Science and SCOPUS databases (Jan 7, 2020 - June 5, 2023). Study Selection: 42 reports presenting 45 predictive models. Data Extraction: Double review with adjudication to identify risk and effect modeling and examine consistency with Statement consensus statements. Credibility of HTE findings was assessed using criteria adapted from the Instrument to assess Credibility of Effect Modification Analyses (ICEMAN). Clinical importance of credible HTE findings was also assessed. Data Synthesis: The numbers of reports, especially risk modeling reports, increased year-on-year. Consistency with consensus statements was high, except for two: only 15 of 32 studies with positive overall findings included a risk model; and most effect models explored many candidate covariates with little prior evidence for effect modification. Risk modeling was more likely than effect modeling to identify both credible HTE (14/19 vs 5/26) and clinically important HTE (10/19 vs 4/26). Limitations: Risk of reviewer bias: reviewers assessing credibility and clinical importance were not blinded to adherence to PATH recommendations. Conclusions: The PATH Statement appears to be influencing research practice. Risk modeling often uncovered clinically important HTE; effect modeling was more often exploratory.

The clinical effectiveness of Fidaxomicin compared to Vancomycin in the treatment of Clostridioides difficile infection, a single center real-world experience.

BACKGROUND: The use of fidaxomicin is recommended as first line therapy for all patients with Clostridioides difficile infection (CDI). However, real-world studies have shown conflicting evidence of superiority. METHODS: We conducted a retrospective single center study of patients diagnosed with CDI between 2011-2021. A primary composite outcome of clinical failure, 30-day relapse or CDI-related death was used. A multivariable cause specific Cox proportional hazards model was used to evaluate fidaxomicin compared to vancomycin in preventing the composite outcome. A separate model was fit on a subset of patients with C. difficile ribotypes adjusting for ribotype. RESULTS: There were 598 patients included, of whom 84 received fidaxomicin. The primary outcome occurred in 8 (9.5%) in the fidaxomicin group compared to 111 (21.6%) in the vancomycin group. The adjusted multivariable model showed fidaxomicin was associated with 63% reduction in the risk of the composite outcome compared to vancomycin (HR = 0.37, 95% CI 0.17-0.80). In the 337 patients with ribotype data after adjusting for ribotype 027, the results showing superiority of fidaxomicin were maintained (HR = 0.19, 95% CI 0.05-0.77). CONCLUSION: In the treatment of CDI, we showed that real-world use of fidaxomicin is associated with lower risk of a composite endpoint of treatment failure.

Increased CXCL10 (IP-10) is associated with advanced myeloproliferative neoplasms and its loss dampens erythrocytosis in mouse models.

Key studies in pre-leukemic disorders have linked increases in pro-inflammatory cytokines with accelerated phases of the disease, but the precise role of the cellular microenvironment in disease initiation and evolution remains poorly understood. In myeloproliferative neoplasms (MPNs), higher levels of specific cytokines have been previously correlated with increased disease severity (tumor necrosis factor-alpha [TNF-α], interferon gamma-induced protein-10 [IP-10 or CXCL10]) and decreased survival (interleukin 8 [IL-8]). Whereas TNF-α and IL-8 have been studied by numerous groups, there is a relative paucity of studies on IP-10 (CXCL10). Here we explore the relationship of IP-10 levels with detailed genomic and clinical data and undertake a complementary cytokine screen alongside functional assays in a wide range of MPN mouse models. Similar to patients, levels of IP-10 were increased in mice with more severe disease phenotypes (e.g., JAK2V617F/V617F TET2-/- double-mutant mice) compared with those with less severe phenotypes (e.g., CALRdel52 or JAK2+/V617F mice) and wild-type (WT) littermate controls. Although exposure to IP-10 did not directly alter proliferation or survival in single hematopoietic stem cells (HSCs) in vitro, IP-10-/- mice transplanted with disease-initiating HSCs developed an MPN phenotype more slowly, suggesting that the effect of IP-10 loss was noncell-autonomous. To explore the broader effects of IP-10 loss, we crossed IP-10-/- mice into a series of MPN mouse models and showed that its loss reduces the erythrocytosis observed in mice with the most severe phenotype. Together, these data point to a potential role for blocking IP-10 activity in the management of MPNs.

Impact of Preexisting Heart Failure on Treatment and Outcomes in Older Patients With Hodgkin Lymphoma.

Background: Older patients with Hodgkin lymphoma (HL) often have comorbid cardiovascular disease; however, the impact of pre-existing heart failure (HF) on the management and outcomes of HL is unknown. Objectives: The aim of this study was to assess the prevalence of pre-existing HF in older patients with HL and its impact on treatment and outcomes. Methods: Linked Surveillance, Epidemiology, and End Results (SEER) and Medicare data from 1999 to 2016 were used to identify patients 65 years and older with newly diagnosed HL. Pre-existing HF, comorbidities, and cancer treatment were ascertained from billing codes and cause-specific mortality from SEER. The associations between pre-existing HF and cancer treatment were estimated using multivariable logistic regression. Cause-specific Cox proportional hazards models adjusted for comorbidities and cancer treatment were used to estimate the association between pre-existing HF and cause-specific mortality. Results: Among 3,348 patients (mean age 76 ± 7 years, 48.6% women) with newly diagnosed HL, pre-existing HF was present in 437 (13.1%). Pre-existing HF was associated with a lower likelihood of using anthracycline-based chemotherapy regimens (OR: 0.42; 95% CI: 0.29-0.60) and a higher likelihood of lymphoma mortality (HR: 1.25; 95% CI: 1.06-1.46) and cardiovascular mortality (HR: 2.57; 95% CI: 1.96-3.36) in models adjusted for comorbidities. One-year lymphoma mortality cumulative incidence was 37.4% (95% CI: 35.5%-39.5%) with pre-existing HF and 26.3% (95% CI: 25.0%-27.6%) without pre-existing HF. The cardioprotective medications dexrazoxane and liposomal doxorubicin were used in only 4.2% of patients. Conclusions: Pre-existing HF in older patients with newly diagnosed HL is common and associated with higher 1-year mortality. Strategies are needed to improve lymphoma and cardiovascular outcomes in this high-risk population.

Patent Foramen Ovale Closure in Older Patients With Stroke: Patient Selection for Trial Feasibility.

BACKGROUND AND OBJECTIVES: Whether patent foramen ovale (PFO) closure benefits older patients with PFO and cryptogenic stroke is unknown because randomized controlled trials (RCTs) have predominantly enrolled patients younger than 60 years of age. Our objective was to estimate anticipated effects of PFO closure in older patients to predict the numbers needed to plan an RCT. METHODS: Effectiveness estimates are derived from major observational studies (Risk of Paradoxical Embolism [RoPE] Study and Oxford Vascular Study, together referred to as the "RoPE-Ox" database) and all 6 major RCTs (Systematic, Collaborative, PFO Closure Evaluation [SCOPE] Consortium). To estimate stroke recurrence risk, observed outcomes were calculated for patients older than 60 years in the age-inclusive observational databases (n = 549). To estimate the reduction in the rate of recurrent stroke associated with PFO closure vs medical therapy based on the RoPE score and the presence of high-risk PFO features, a Cox proportional hazards regression model was developed on the RCT data in the SCOPE database (n = 3,740). These estimates were used to calculate sample sizes required for a future RCT. RESULTS: Five-year risk of stroke recurrence using Kaplan-Meier estimates was 13.7 (95% CI 10.5-17.9) overall, 14.9% (95% CI 10.2-21.6) in those with high-risk PFO features. Predicted relative reduction in the event rate with PFO closure was 12.9% overall, 48.8% in those with a high-risk PFO feature. Using these estimates, enrolling all older patients with cryptogenic stroke and PFO would require much larger samples than those used for prior PFO closure trials, but selectively enrolling patients with high-risk PFO features would require totals of 630 patients for 90% power and 471 patients for 80% power, with an average of 5 years of follow-up. DISCUSSION: Based on our projections, anticipated effect sizes in older patients with high-risk features make a trial in these subjects feasible. With lengthening life expectancy in almost all regions of the world, the utility of PFO closure in older adults is increasingly important to explore.