Citations

Abstract INTRODUCTION Clinicians’ views on the clinical readiness of Alzheimer's disease (AD) blood biomarkers (BBMs) are not well understood. METHODS The Alzheimer's Association International Society to Advance Alzheimer's Research and Treatment Biofluid‐Based Biomarkers Professional Interest Area conducted a survey to elicit clinician opinions on AD BBM implementation, including contexts of use, assay selection, reporting, and result interpretation. RESULTS Clinician respondents ( n = 212) practiced in Europe (56%), North America (24%), the Caribbean and Central/South America (11%), and other continents (9%). Most respondents were medical doctors (80%) practicing in secondary or tertiary care (88%). For 56%, cerebrospinal fluid AD biomarkers or amyloid positron emission tomography were accessible, but 48% agreed and 52% disagreed with the implementation of AD BBMs in any clinical context. Respondents emphasized the need for data from diverse populations and educational resources to support test interpretation. DISCUSSION Surveyed clinicians generally agreed with published appropriate use recommendations but were divided on AD BBM readiness for clinical use. Highlights A survey of clinicians was conducted regarding clinical readiness of Alzheimer's disease (AD) blood biomarkers (BBMs). Views were split on AD BBM clinical readiness: 48% agreed, 52% disagreed. Most responders supported AD BBM use for treatment decisions. Most responders opposed AD BBM testing in asymptomatic individuals. Test performance data and educational materials to aid interpretation were of high importance.

Heart transplantation is a well-established treatment for end-stage heart failure, but many patients present in poor physical condition, complicating outcomes. The Impella 5.5 device, used in cardiogenic shock, may support pretransplant rehabilitation by stabilizing organ function and promoting functional improvement. This retrospective cohort study assessed the relationship between functional status, measured by standardized Activity Measure for Post-Acute Care Basic Mobility (AM-PAC) scores, and days alive outside the hospital within 30 days post-transplant (DAOH-30). Patients who received Impella 5.5 support before transplantation between January 2019 and October 2023 were included, excluding those without AM-PAC scores within 24 hours pretransplant. Among 65 patients, the median DAOH-30 was 15 days (interquartile range [IQR], 8–19). Higher pretransplant standardized AM-PAC scores correlate with increased DAOH-30 (adjusted coefficient 0.3; 95% confidence interval [CI] = 0.01–0.6; p = 0.04), as did AM-PAC score improvement during rehabilitation (adjusted coefficient 0.35; 95% CI = 0.01–0.6; p = 0.04). Extended rehabilitation was associated with greater functional gains. These findings suggest that better pretransplant functional status and rehabilitation-related improvements were associated with increased DAOH-30. The Impella 5.5 device facilitates rehabilitation and may enhance post-transplant outcomes. Further research should refine strategies to optimize rehabilitation and recovery in this high-risk population.

Transbronchial cryobiopsies (CB) are increasingly replacing surgical biopsies (video-assisted thoracoscopic/VATS biopsies) for diagnosing diffuse parenchymal lung disease (interstitial lung disease, ILD), but there is very little guidance for pathologists on CB interpretation. Here we propose a fairly simple approach. First, if the diagnosis can be made on a traditional forceps biopsy, it can be made on a cryobiopsy. Many diseases with specific features will fall into this category (eg, sarcoidosis or Langerhans cell histiocytosis). More problematic are patterns such as usual interstitial pneumonia (UIP) or nonspecific interstitial pneumonia (NSIP), in which low-power architecture is the key to diagnosis. In this circumstance, an adequate sample is crucial to look for features such as fibroblast foci, because a combination of fibroblast foci plus any patchy old fibrosis, fibrotic architectural remodeling, or honeycombing, allows a diagnosis of a UIP pattern. However, in most instances, CB will not separate the UIP patterns seen in idiopathic pulmonary fibrosis, fibrotic hypersensitivity pneumonitis, or connective tissue disease-interstitial lung disease (CTD-ILD), although giant cells/granulomas (uncommon findings) in this setting favor fibrotic hypersensitivity pneumonitis. Fibroblast foci can be difficult to differentiate from organizing pneumonia (OP), but granulation tissue plugs clearly in airspaces favor OP. Absent fibroblast foci, patchy old fibrosis, architectural distortion, and honeycombing by themselves do not allow a specific diagnosis. NSIP in CB microscopically looks like NSIP in VATS biopsies, and the presence of an NSIP or an NSIP+OP pattern is typical of CTD-ILD. All the above diagnoses require correlation with clinical and radiologic findings.

Abstract Introduction Emerging evidence suggests that positive airway pressure (PAP) treatment for moderate-to-severe obstructive sleep apnea (OSA) in elderly patients does not improve daytime sleepiness, or quality of life outcomes, despite improving apnea-hypopnea index (AHI). While oral appliance therapy (OAT) is known to be an effective treatment for mild-to-moderate OSA, its efficacy in treatment of elderly patients with severe OSA is unknown. Methods Retrospective chart review of patients ≥ 65 years old with diagnosis of OSA, treated with OAT, who underwent subsequent follow-up sleep testing and clinical assessments, including Epworth Sleepiness Scale (ESS), a measure of daytime sleepiness. Results We studied 66 elderly patients with OSA (31 women, 35 men), including 58 with mild-to-moderate OSA (AHI < 30) and 8 with severe OSA (AHI ≥ 30) treated with OAT. At baseline, patients with mild-to-moderate OSA had a median AHI of 11.6 compared to 41.3 in patients with severe OSA (p < 0.0001). There was no difference in ESS score between patients with mild-to-moderate OSA (median ESS = 8; IQR = 4-12) and severe OSA (median ESS = 6; IQR = 3-9). Following their OSA diagnosis, OAT was offered due to PAP intolerance (n = 32), patient preference (n = 28), or as an alternative treatment option (n = 4). After initiation of OAT, 42 patients with mild-to-moderate and 7 with severe OSA underwent follow-up assessment with home sleep testing (n = 32), oximetry (n = 15), or polysomnography (n = 2). At follow-up assessment, ESS was decreased in patients with mild-to-moderate OSA (median ESS = 5; IQR = 3-8) and severe OSA (median ESS = 5; IQR = 3-7), indicating reduction in daytime sleepiness in response to OAT in both groups. Moreover, 50% of patients with mild-to-moderate OSA and 50% of severe OSA patients saw ≥ 50% reduction in AHI. Conclusion Our study findings suggest that treatment with OAT in mild-to-moderate and severe OSA is tolerable and effective in elderly patients who do not have contraindication for this treatment. OAT should be considered as an alternative treatment specifically for elderly adults with severe OSA not tolerating or improving with PAP therapy. Support (if any)

ABSTRACT Background and hypothesis Podocytopathy associated with likely pathogenic/pathogenic variants of Transient receptor potential cation channel subfamily C member 6 (TRPC6) (TRPC6-AP) has been recognized for about 20 years. As a result of its rarity however, the spectrum of clinical phenotypes and genotype–phenotype correlation of TRPC6-AP remains poorly understood. Here, we characterized clinical, histological and genetic correlates of familial and sporadic patients with TRPC6-AP. Methods In this multicentre observational study, an online questionnaire followed by a systematic literature review was performed to create a cohort with comprehensive data on genetic and clinical outcomes [age of onset, clinical presentation, treatment response, kidney biopsy findings and progression to kidney failure (KF)]. Logistic regression, Cox proportional hazards model and Kaplan–Meier analyses investigated the associations between genetic variants and disease progression. Results Among 87 families (96 familial and 45 sporadic cases), 31 distinct missense TRPC6 variants (including 2 novel) were identified, with c.2683C>T p.(Arg895Cys) and c.523C>T p.(Arg175Trp) the commonest variants. Proteinuric kidney disease/nephrotic syndrome was the most common clinical presentation (83.7%), while focal segmental glomerulosclerosis was the most common histological finding (89.4%). By 33 (interquartile range 17–40) years, 48.9% (69/141) of patients had progressed to KF. Sporadic TRPC6-AP demonstrated an earlier progression to KF than familial cases (P = .001) and were more likely to present with nephrotic syndrome [odds ratio 4.34 (1.85–10.15); P = .001]. Gain-of-function TRPC6 variants were more frequent in familial than sporadic TRPC6-AP (70.8% vs 44.4%; P = .004). Compared with patients with other TRPC6 variants, patients with TRPC6 p.R175W and p.R895C variants progressed to KF earlier [median kidney survival of 21 years, hazard ratio 2.985 (95% confidence interval 1.40–5.79); and 38 years, hazard ratio 1.65 (95% confidence interval 1.01–2.81), respectively, log-rank P = .005]. Conclusion Our study shows unique clinical and genetic correlations of TRPC6-AP, which may enable personalized care and promising novel therapies.

Importance Circulating tumor human papillomavirus DNA (ctHPVDNA) is an important biomarker for the presence of HPV-associated oropharyngeal squamous cell carcinoma (OPSCC), but little is known about early postoperative kinetics of ctHPVDNA clearance. Objective To investigate early postoperative kinetics of ctHPVDNA in patients with HPV-associated OPSCC. Design, Setting, and Participants This prospective cohort study was conducted at a single tertiary care center from January 4, 2020, to January 26, 2023. Patients with newly diagnosed HPV-associated OPSCC undergoing surgical management were enrolled. HPV status was defined as positive if findings of p16 immunohistochemistry and/or HPV DNA in situ hybridization and/or E6/E7 RNA in situ hybridization were positive. Exclusion criteria included history of prior head and neck cancer and metastatic disease at presentation. Data were analyzed from September 1, 2024, to April 25, 2025. Exposures Transoral robotic surgery with concurrent neck dissection. Main Outcomes and Measures Blood was drawn prior to surgery (pretreatment), 1 to 2 days after surgery (postoperative days 1 to 2), and approximately 2 weeks after surgery (postoperative week 2; range, 8 to 20 days). ctHPVDNA was quantified by a tumor tissue–modified viral (TTMV) HPV DNA test. Correlations were tested between the pretreatment and postoperative day 1 to 2 TTMV HPV DNA levels using Gaussian regression. Concordance between detectability at postoperative day 1 to 2 and postoperative week 2 was explored using negative predictive value and positive predictive value. Results Of 57 included patients with detectable pretreatment TTMV HPV DNA, 51 (89%) were male, and the median (IQR) age was 59 (54-66) years. A total of 35 patients (61%) had blood draws at all 3 time points; 16 (28%) had detectable TTMV HPV DNA on postoperative day 1 to 2. Pretreatment and postoperative day 1 to 2 TTMV HPV DNA levels had a medium positive linear correlation ( r = 0.31; 95% CI, 0.04-0.54). Undetectable TTMV HPV DNA on postoperative day 1 to 2 blood draw had a negative predictive value of 0.95 (95% CI, 0.74-1.00) for an undetectable level on postoperative week 2 blood draw, but a detectable level on postoperative day 1 to 2 blood draw only had a positive predictive value of 0.19 (95% CI, 0.04-0.46). Of the 16 patients with detectable TTMV HPV DNA pretreatment and at postoperative day 1 to 2, only 3 (19%) continued to have detectable TTMV HPV DNA at postoperative week 2. One patient had undetectable levels at postoperative day 1 to 2 and detectable levels at postoperative week 2. Conclusions and Relevance In this study, ctHPVDNA detectability early after surgery did not predict detectability at 2 weeks after surgery. ctHPVDNA clearance early after surgery could predict a negative test at 2 weeks. A negative blood draw finding on postoperative day 1 may be used to omit a postoperative blood draw at 2 weeks for minimal residual disease detection in future clinical trials.

OBJECTIVE Transforaminal lumbar interbody fusion (TLIF) offers both indirect decompression and segmental correction through restoration of disc height. However, stresses exerted on the vertebral endplates by the interbody device can result in implant subsidence and loss of correction. The present time-to-event analysis aimed to identify predictors of interbody subsidence. METHODS Patients who underwent 1- or 2-level TLIF were identified. Data on demographics, surgical details, preoperative bone quality using CT-based Hounsfield units (HU), and pre- and postoperative lumbopelvic parameters were collected. Univariable analyses were conducted to identify predictors of subsidence (≥ 2-mm intrusion of interbody into cranial or caudal vertebrae) and significant subsidence (≥ 4-mm intrusion). Multivariable Cox regression was performed to identify independent predictors of subsidence, expressed as hazard ratios with 95% confidence intervals. RESULTS A total of 198 patients treated at 241 levels were included (median age 66.6 years, IQR 59.5, 73.7 years; 56.6% were women). In 92 levels (38.2%) there was some subsidence and in 25 (10.4%) there was significant subsidence. Implanted levels demonstrating subsidence (≥ 2 mm) were associated with lower HU in cranial and caudal vertebrae; had interbodies positioned farther from the anterior apophyseal ring; were implanted with taller, more lordotic interbodies; and underwent greater disc height restoration. Those showing significant subsidence (≥ 4 mm) were similarly associated with lower HU in the cranial and caudal vertebrae; had interbodies positioned farther from the anterior apophyseal ring of the caudal vertebrae; and underwent greater disc height restoration. Multivariable Cox regression showed that time to subsidence was predicted by greater implant height (HR 1.20/mm, 95% CI 1.05–1.38; p = 0.009), greater postoperative disc height (HR 1.21/mm, 95% CI 1.09–1.34; p < 0.001), and greater disc height restoration (HR 1.11/mm, 95% CI 1.04–1.19; p = 0.002). The time-to-subsidence analysis for significant (≥ 4 mm) subsidence showed that it was predicted by lower HU in the cranial vertebrae (HR 0.98/unit, 95% CI 0.97–0.99; p = 0.001); increasing number of levels instrumented (HR 1.26, 95% CI 1.04–1.52; p = 0.016); and greater disc height restoration (HR 1.33/mm, 95% CI 1.18–1.51; p < 0.001). CONCLUSIONS This time-to-event analysis suggests that interbody subsidence following TLIF is best predicted by implantation of a taller interbody and aggressive disc height restoration. Significant subsidence is similarly predicted by aggressive disc height restoration along with poor baseline bone quality. The results suggest the need to balance aggressive correction at the time of surgery against the increased risk of subsequent interbody subsidence.

Background: Little is known about the association between intraplaque hemorrhage (IPH) and other features of high-risk carotid atherosclerotic plaques, such as the presence of plaque ulceration, plaque enhancement, and lipid-rich necrotic core (LRNC). This study set out to assess the relationship between IPH and other vulnerable plaque features. Materials and Methods: A retrospective review was done of 102 patients with IPH in one or both of the internal carotid arteries (ICA) on neck MRA between 1/1/2016 and 3/31/2021. IPH was defined as a ≥200% signal intensity of the adjacent sternocleidomastoid muscle on MPRAGE images. All ICA plaques were assessed for the presence or absence of IPH, plaque ulceration, plaque enhancement, and LRNC, as well as IPH volume. IPH volume was measured manually by outlining the region of interest. Results: A total of 102 patients were included, with 88 (86.3%) being male. The average age was 73.5 years (SD = 9.0). Both IPH and LRNC were more commonly seen in the left carotid artery ( p = .018 and p = .047, respectively). For right-sided ICAs, there was a significant association between IPH and LRNC ( p < .0001). Lesions without IPH were more likely to have plaque enhancement than lesions with IPH ( p = .04). For left-sided ICAs, there was also a significant association between the presence of IPH and LRNC ( p < .0001). Conclusions: There is a significant association between the presence of IPH and LRNC. An inverse relationship was found between the presence of IPH and plaque enhancement for right-sided plaques. No associations were found between IPH and plaque ulceration.

Introduction: Bone health optimization is a key component of the preoperative management of spine surgery patients, as poor bone quality increases the odds of mechanical complications. The present study aimed to achieve the following: (1) compare the relative efficacy of current osteoporosis medications in improving bone quality; (2) identify factors influencing treatment response in preoperative spine surgery patients. Methods: Patients treated at a single, multisite institution who received osteoporosis treatment were identified. Data were gathered on pre- and post-treatment lumbar spine Hounsfield Unit (HU) measurements, patient demographics, frailty scores (modified Frailty Index/mFI, risk analysis index/RAI), and pharmacologic treatment details. The primary outcome was a ≥7 point improvement in lumbar HU, and baseline and logistic regression models were utilized to identify factors associated with this improvement. Medications were grouped as anabolic (teriparatide, romosozumab) and antiresorptive (denosumab, alendronate) therapies. Results: A total of 267 patients were included (median age: 74 years; IQR [66–81]; 67.3% female), with 127 (47.6%) improving by ≥7 HU. The treatment agents used were alendronate (95), denosumab (113), romosozumab (31), and teriparatide (28). Univariable comparisons revealed significant differences across medication groups in age (p < 0.001), sex (p < 0.001), mFI (p < 0.001), RAI (p = 0.004), BMI (p < 0.001), pre-treatment HU (p = 0.022), and treatment duration (p < 0.001). The highest HU improvement rates (ΔHU ≥ 7) were observed in patients receiving the anabolic medications romosozumab (67.7%) and teriparatide (60.7%). Univariable logistic regression identified male sex (OR 0.54, p = 0.019), higher pre-treatment HU (OR 0.99, p = 0.006), and longer treatment duration (OR 0.97, p = 0.003) as factors associated with lower odds of HU improvement. Only romosozumab was associated with significantly higher odds of HU improvement relative to alendronate (OR 3.02, p = 0.012). In our multivariable analysis, male sex (OR 0.53, p = 0.028) and higher pre-treatment HU (OR 0.99, p = 0.002) remained significant predictors of HU improvement. However, medication type was not significant in the multivariable analysis. Conclusions: Our study highlights that male sex and higher pre-treatment HU were independently associated with lower odds of HU improvement, while medication type was not a significant predictor. Additionally, anabolic agents offered superior improvement relative to antiresorptive therapies.