Citations

BACKGROUND: Plasma NT-proBNP (N-terminal pro-B-type natriuretic peptide) is commonly used to diagnose heart failure with preserved ejection fraction (HFpEF), but its diagnostic performance in the ambulatory/outpatient setting is unknown because previous studies lacked objective reference standards. METHODS: Among patients with chronic dyspnea, diagnosis of HFpEF or noncardiac dyspnea was determined conclusively by exercise catheterization in a derivation cohort (n=414), multicenter validation cohort 1 (n=560), validation cohort 2 (n=207), and a nonobese Japanese validation cohort 3 (n=77). Optimal NT-proBNP cut points for HFpEF rule out (optimizing sensitivity) and rule in (optimizing specificity) were derived and tested, stratified by obesity and atrial fibrillation. Derived cut points were tested in 3 additional validation cohorts (cohorts 4–6) in whom HFpEF was diagnosed by resting catheterization only (n=260), previous hospitalization for heart failure (n=447), or exercise echocardiography (n=517), respectively. RESULTS: Current recommended rule-out NT-proBNP threshold <125 pg/mL had 82% sensitivity (95% CI, 77%–88%) with a body mass index (BMI) <35 kg/m 2 , decreasing to 67% (95% CI, 58%–77%) with a BMI ≥35 kg/m 2 . A lower rule-out NT-proBNP threshold <50 pg/mL displayed good sensitivity with a BMI <35 kg/m 2 (97% [95% CI, 95%–99%]), with a modest decline in sensitivity with a BMI ≥35 kg/m 2 (86% [95% CI, 79%–93%]); diagnostic thresholds were confirmed in validation cohorts 1 and 2 (91% [95% CI, 88%–95%] and 86% [95% CI, 80%–93%] with a BMI <35 kg/m 2 ; 80% [95% CI, 74%–87%] and 84% [95% CI, 74%–93%] with a BMI ≥35 kg/m 2 ). Current consensus age- and BMI-stratified rule-in thresholds demonstrated only 65% specificity (95% CI, 57%–72%). Rule-in NT-proBNP threshold ≥500 pg/mL had 85% specificity (95% CI, 78%–91%) with a BMI <35 kg/m 2 (87% [95% CI, 80%–94%] and 90% [95% CI, 81%–99%] in validation cohorts), with 100% specificity at a BMI ≥35 kg/m 2 (93% [95% CI, 81%–100%] and 100% in validation cohorts). With a BMI ≥35 kg/m 2 , lower rule-in thresholds (≥220 pg/mL) provided good specificity (88% [95% CI, 73%–100%]; 93% [95% CI, 81%–100%] and 100% in validation cohorts). Findings were consistent in validation cohorts 3 through 6 (sensitivity of <50 pg/mL, 93%–98%; specificity of ≥500 pg/mL, 82%–89%). NT-proBNP provided no incremental discrimination among patients with history of AF; ≥98% of patients with AF and dyspnea were found to have HFpEF in our cohorts. CONCLUSIONS: In patients with chronic unexplained dyspnea, current rule-in and rule-out NT-proBNP diagnostic thresholds lead to unacceptably high error rates, with important interactions by obesity and AF status. In our study, NT-proBNP provided little value in those with AF and dyspnea because the presence of AF is by itself a robust biomarker of HFpEF. Use of separate rule-in and rule-out diagnostic thresholds stratified by BMI reduces miscategorization and can guide more appropriate use of exercise testing for possible HFpEF.

Purpose: Delivering optimal care to patients with seizures and epilepsy requires all EEGs to be interpreted accurately and reliably. This study investigated neurology professionals' opinions on the ideal standards for EEG in clinical care. Methods: We developed an anonymous e-survey targeting practicing and trainee neurologists focused on participants' demographics, clinical practice characteristics, and views on optimal EEG standards of care—including whether an EEG certification test is needed and whether postresidency/fellowship training in EEG/epilepsy is necessary for neurologists who interpret outpatient/routine EEGs in practice. The survey was hosted by the Neurology Clinical Practice—Practice Current, and it was distributed online through the American Academy of Neurology, American Epilepsy Society, American Clinical Neurophysiology Society, and International League Against Epilepsy, and through social media. Results: Two hundred eighty-three responses were included: 119 from EEG/epilepsy-trained neurologists, 83 from non-EEG/epilepsy-trained neurologists, 75 from trainees, and 6 from advanced care providers. Most participants (78%) agreed that “an objective certification test of ability to interpret EEGs is needed for all those who interpret EEGs in clinical practice.” Most participants (71%) believed that outpatient/routine EEGs may be read only by neurologists with EEG/epilepsy training; this opinion was more prevalent among EEG/epilepsy-trained (83%) versus non-EEG/epilepsy-trained neurologists (55%). Conclusions: Our neurology community should discuss the need to develop and implement a certification test of ability for all neurologists who wish to interpret EEGs in clinical practice. In addition, it is imperative to improve in-residency EEG education to ensure that neurology graduates achieve EEG competence before entering the workforce.

Abstract Nerve conduction F-wave studies contain crucial information about subclinical motor dysfunction that can be used to diagnose patients with amyotrophic lateral sclerosis (ALS). However, F-wave responses are highly variable in morphology, making waveform interpretation challenging. Artificial intelligence techniques can extract time–frequency features to provide new insights into ALS diagnosis and prognosis. A retrospective analysis was performed on F-wave responses from 46 802 patients. Discrete wavelet transforms were applied to time-series waveform responses after stimulating ulnar, median, fibular and tibial nerves. Wavelet coefficient statistics, onset age, sex and body mass index were features for training a Gradient Boosting Machine model on 40 095 patients (5329 diagnosed with motor neuron disease). Model performance was tested on responses from 689 ALS patients meeting Gold Coast criteria and 689 age- and sex-matched controls. An exploratory analysis examined model performance on cohorts of patients with inclusion body myositis, cervical radiculopathy, lumbar radiculopathy or peripheral neuropathy, which can mimic ALS symptoms. Factors affecting survival were estimated through Cox proportional hazards regression. The model trained using wavelet features on the full waveform had 90% recall, 87% precision and 88% accuracy. Similar model performance was measured using features from only the M-wave or F-wave. Classification probabilities for ALS patients were statistically different from the diagnoses mimicking ALS symptoms (P &lt; 0.001, ANOVA, Tukey’s post hoc test). Higher model classification probabilities of ALS, older age at onset, and family history of ALS alone or with frontotemporal dementia were factors decreasing survival. Longer diagnostic delay and upper limb onset site were factors increasing survival. Model scores two standard deviations below the mean had 4 months increased survival (two standard deviations below had 3 months decreased survival). Artificial intelligence techniques extracted important information from F-wave responses to estimate a patient’s likelihood of ALS and their survival risks. Although the model can make predictions at a specific decision threshold as presented here, the true strength of such a model lies in its ability to provide probabilities about whether a patient is likely to have ALS in comparison to other mimicking diagnoses, such as inclusion body myositis, cervical or lumbar radiculopathy or peripheral neuropathy. These probabilities provide clinicians with additional information that they can use to make the final diagnosis with greater confidence and precision. Integrating such a model into the clinical workflow could help clinicians to diagnose ALS sooner and manage treatment based on estimated survival, which might improve outcomes and the quality of life of patients.

Abstract The largest risk factor for dementia is age. Heterochronic blood exchange studies have uncovered age-related blood factors that demonstrate ‘pro-aging’ or ‘pro-youthful’ effects on the mouse brain. The clinical relevance and combined effects of these factors for humans is unclear. We examined five previously identified brain rejuvenation factors in cerebrospinal fluid of adults with autosomal dominant forms of frontotemporal dementia and sporadic Alzheimer’s disease. Our frontotemporal dementia cohort included 100 observationally followed adults carrying autosomal dominant frontotemporal dementia mutations (Mage = 49.6; 50% female; 43% C9orf72, 24% GRN, 33% MAPT) and 62 non-carriers (Mage = 52.6; 45% female) with cerebrospinal fluid analysed on Somascan, and longitudinal (Mvisits = 3 years, range 1–7 years) neuropsychological and functional assessments and plasma neurofilament light chain. Our Alzheimer’s disease cohort included 35 adults with sporadic Alzheimer’s disease (Mage = 69.4; 60% female) and 56 controls (Mage = 68.8, 50% female) who completed the same cerebrospinal fluid and clinical outcome measures cross-sectionally. Levels of C-C motif chemokine ligand 11, C-C motif chemokine ligand 2, beta-2-micorglobulin, bone gamma-carboxyglutamate protein (aka Osteocalcin) and colony stimulating factor 2 in cerebrospinal fluid were linearly combined into a composite score, with higher values reflecting ‘pro-youthful’ levels. In genetic frontotemporal dementia, higher baseline cerebrospinal fluid rejuvenation proteins predicted slower decline across cognitive, functional, and neurofilament light chain trajectories; estimates were similar across genotypes. In transdiagnostic analyses, higher cerebrospinal fluid rejuvenation proteins associated with better functional, cognitive, and neurofilament light chain outcomes in adults with sporadic Alzheimer’s disease. Proteins with pre-clinical evidence for brain rejuvenation show translational clinical relevance in adults with Alzheimer’s disease and related dementias and warrant further investigation.

ABSTRACT Introduction Despite the emergence of drugs to treat irritable bowel syndrome (IBS), improving abdominal pain can still be challenging. α 2 δ ligands, such as gabapentin and pregabalin, are sometimes used off‐label to tackle this problem. However, evidence for efficacy is limited, and no large‐scale studies have been published. Aim To study the efficacy of the α 2 δ ligand PD‐217,014 in IBS. Methods This multi‐centre, double‐blind, randomised, placebo‐controlled, parallel group study randomised participants with Rome II‐defined IBS to 150 or 300 mg b.d. of PD‐217,014 or placebo b.d. for 4 weeks. The primary efficacy endpoint was responder, defined as having adequate relief of abdominal pain/discomfort for ≥ 50% of the active treatment period. Key secondary endpoints were change from baseline in abdominal pain, bloating, stool frequency/consistency, and global assessment of IBS symptoms. Results We randomised 330 participants [aged 19–73 years; 209 (65%) female] satisfying Rome II criteria, 322 (98%) were treated, and of whom 271 (84%) completed the study. In this study, 321 satisfied Rome IV criteria. Neither dose of PD‐217,014 improved the percentage of participants reporting adequate relief of abdominal pain/discomfort compared with placebo, either using the Rome II‐defined total cohort or Rome II and IV IBS bowel habit sub‐types. There were similar observations for secondary endpoints, and no association between abdominal pain or anxiety levels at baseline with participant improvement. PD‐217,014 was generally well tolerated. Conclusion This first large, dose‐ranging trial examining the efficacy of PD‐217,014 showed no significant efficacy in participants with IBS or bowel habit sub‐types, irrespective of their pain and anxiety levels.

AbstractEUS-guided gallbladder drainage (EUS-GBD) using lumen apposing metal stents (LAMS) has excellent technical and short-term clinical success for acute cholecystitis (AC). The goals of this study were to determine the long-term clinical outcomes and adverse events (AEs) of EUS-GBD with LAMS.A multicenter, retrospective study was conducted at 18 US tertiary care institutions. Inclusion criteria: any AC patient with attempted EUS-GBD with LAMS and minimum 30-day post-procedure follow-up. Long-term clinical success was defined as absence of recurrent acute cholecystitis (RAC) > 30 days and long-term AE was defined as occurring > 30 days from the index procedure.A total of 109 patients were included. Technical success was achieved in 108 of 109 (99.1%) and initial clinical success in 106 of 109 (97.2%). Long-term clinical success was achieved in 98 of 109 (89.9%) over a median follow-up of 140 days (range 30–1188). On multivariable analysis (MVA), acalculous cholecystitis (odds ratio [OR] 15.93, 95% confidence interval [CI] 1.22–208.52, P = 0.04) and the occurrence of a LAMS-specific AE (OR 63.60, 95% CI 5.08–799.29, P <0.01) were associated with RAC. AEs occurred in 38 of 109 patients (34.9%) at any time, and in 10 of 109 (9.17%) > 30 days from the index procedure. Most long-term AEs (7 of 109; 6.42%) were LAMS-specific. No technical or clinical factors were associated with occurrence of AEs. LAMS were removed in 24 of 109 patients (22%). There was no difference in RAC or AEs whether LAMS was removed or not.EUS-GBD with LAMS has a high rate of long-term clinical success and modest AE rates in patients with AC and is a reasonable destination therapy for high-risk surgical candidates.