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Abstract Introduction Introduction: Jazz DUET (Develop hypersomnia Understanding by Evaluating low-sodium oxybate Treatment) is a phase 4, prospective, multicenter, single-arm, multiple-cohort, open-label study (NCT05875974) evaluating the effectiveness of low-sodium oxybate (LXB, Xywav®) treatment on daytime and nighttime symptoms, including excessive daytime sleepiness (EDS) and polysomnography in participants with idiopathic hypersomnia (IH) or narcolepsy. Data presented are from the IH cohort. Methods DUET included screening (with 2-week washout for oxybate users), 8-day baseline (BL), 2- to 8-week LXB titration, 2-week stable-dose, 8-day end-of-treatment (EOT), and 2-week safety follow-up periods. The primary endpoint was change in Epworth Sleepiness Scale (ESS) score from BL to EOT. Secondary endpoints for the IH cohort included change in Idiopathic Hypersomnia Severity Scale (IHSS) total score, Patient Global Impression of Change (PGIc)−overall IH disease, PGIc−sleep inertia, and Patient Global Impression of Severity (PGIs)−sleep inertia. Exploratory endpoints included IHSS component scores (daytime functioning, sleep inertia). Primary and key secondary (IHSS total score) endpoints were controlled for multiplicity with sequential testing; all other P-values are considered nominal. Results Forty-six people with IH enrolled and were dosed with LXB; 40 were completers. Enrolled participants were mostly female (80.4%) and White (84.8%), with a mean (SD) age of 38.1 (11.8) years. For completers, BL mean (SD) ESS score and IHSS total score were 16.5 (2.7) and 32.9 (7.1), respectively; least-squares mean (LSM) (SE) changes from BL to EOT were −8.4 (0.7), P<.0001 and −15.5 (1.5), P<.0001. BL mean (SD) IHSS component scores for daytime functioning and sleep inertia were 17.7 (4.2) and 10.7 (3.1), respectively; LSM (SE) changes from BL to EOT were −8.8 (1.0), P<.0001 and −4.8 (0.4), P<.0001. At EOT, most participants reported improvement (very much, much, minimally) on PGIc−overall IH disease (94.6%) and PGIc−sleep inertia (81.1%). At BL, 25.0% of participants reported sleep inertia severity as very mild/mild/not present on PGIs–sleep inertia vs 59.0% at EOT. Treatment-emergent adverse events were consistent with the known safety profile of LXB. Conclusion People with IH taking open-label LXB showed improvements in EDS and sleep inertia (decreased ESS and IHSS component scores) and reported reduced multi-symptom burden (decreased IHSS total scores and improved PGIc/PGIs ratings). Support (if any) Jazz Pharmaceuticals

Nonspecific symptoms and other diagnostic challenges lead to underdiagnosis of cardiac amyloidosis (CA). Artificial intelligence (AI) could help address these challenges, but a summary of the performance of these tools is lacking. This narrative review of published literature describes the performance of AI tools that use data from ECGs and echocardiography to improve identification of CA and challenges that hinder adoption of these tools. Thirteen studies met inclusion criteria with sample sizes ranging from 50 to 2451 patients. Four studies used ECG data, 8 used echocardiography data, and 1 used both. The CA gold standard was typically defined as a CA diagnosis in an institutional or other database but the requirements for these diagnoses were heterogenous across studies, and many did not distinguish among CA subtypes. AI model development varied considerably, and only 4 studies included external validation. The ability of models to predict CA ranged from 0.71 to 1.00, sensitivity ranged from 16% to 100%, and specificity from 75% to 100%. Only 1 study reported model performance across strata of sex, age, race, and CA type. Persistent challenges to AI adoption include usability, cost, value added, electronic health record/information technology interoperability, patient‐related factors, regulation, and privacy and liability. Published studies on AI for improved identification of CA show favorable performance measures but numerous methodologic and other challenges must be addressed before these tools are more widely adopted.

Abstract Background: Flash glucose monitoring (FGM) can improve diabetes management, but no randomised controlled trials (RCTs) of FGM have been undertaken in Indigenous Australian populations. This study aimed to assess the feasibility of performing a RCT of FGM in Indigenous Australians with type 2 diabetes. Methods: In this open-labelled pilot RCT, Indigenous adults with type 2 diabetes were randomised to FGM or standard care for 6 months. Eligible participants were being treated with injectable diabetes medications and had a glycosylated haemoglobin (HbA1c) ≥ 7.0%. The feasibility outcome was the proportion of participants completing the trial. The preliminary effective outcome was the change in HbA1c. Secondary effectiveness outcomes included a change in time spent in target blood glucose; safety (hypoglycaemic episodes); and quality of life (EuroQol 5-Dimension 3-Level (EQ-5D-3L) score). Results: Of 126 screened individuals, 74 were eligible, 40 (31.7%) were randomised and 39 (97.5%) completed the study. Participants’ baseline characteristics were similar between the FGM and usual care groups, except for sex and body mass index. There were no between-group differences for: change in HbA1c; percentage of time spent in target blood glucose, low glucose and high glucose; or EQ-5D-3L scores. No severe hypoglycaemic episodes occurred. Conclusions: This is the first pilot RCT of FGM in Indigenous Australians with type 2 diabetes. The results support a larger RCT, which is currently in progress. Trial registration: Australian New Zealand Clinical Trials Registry (ANZCTR12621000021875), retrospectively registered on 14 January 2021.

AbstractINTRODUCTIONAmyloid beta and tau pathology are the hallmarks of sporadic Alzheimer's disease (AD) and autosomal dominant AD (ADAD). However, Lewy body pathology (LBP) is found in ≈ 50% of AD and ADAD brains.METHODSUsing an α‐synuclein seed amplification assay (SAA) in cerebrospinal fluid (CSF) from asymptomatic (n = 26) and symptomatic (n = 27) ADAD mutation carriers, including 12 with known neuropathology, we investigated the timing of occurrence and prevalence of SAA positive reactivity in ADAD in vivo.RESULTSNo asymptomatic participant and only 11% (3/27) of the symptomatic patients tested SAA positive. Neuropathology revealed LBP in 10/12 cases, primarily affecting the amygdala or the olfactory areas. In the latter group, only the individual with diffuse LBP reaching the neocortex showed α‐synuclein seeding activity in CSF in vivo.DISCUSSIONResults suggest that in ADAD LBP occurs later than AD pathology and often as amygdala‐ or olfactory‐predominant LBP, for which CSF α‐synuclein SAA has low sensitivity.Highlights Cerebrospinal fluid (CSF) real‐time quaking‐induced conversion (RT‐QuIC) detects misfolded α‐synuclein in ≈ 10% of symptomatic autosomal dominant Alzheimer's disease (ADAD) patients. CSF RT‐QuIC does not detect α‐synuclein seeding activity in asymptomatic mutation carriers. Lewy body pathology (LBP) in ADAD mainly occurs as olfactory only or amygdala‐predominant variants. LBP develops late in the disease course in ADAD. CSF α‐synuclein RT‐QuIC has low sensitivity for focal, low‐burden LBP.

ImportanceIncreased white matter hyperintensity (WMH) volume is a common magnetic resonance imaging (MRI) finding in both autosomal dominant Alzheimer disease (ADAD) and late-onset Alzheimer disease (LOAD), but it remains unclear whether increased WMH along the AD continuum is reflective of AD-intrinsic processes or secondary to elevated systemic vascular risk factors.ObjectiveTo estimate the associations of neurodegeneration and parenchymal and vessel amyloidosis with WMH accumulation and investigate whether systemic vascular risk is associated with WMH beyond these AD-intrinsic processes.Design, Setting, and ParticipantsThis cohort study used data from 3 longitudinal cohort studies conducted in tertiary and community-based medical centers—the Dominantly Inherited Alzheimer Network (DIAN; February 2010 to March 2020), the Alzheimer’s Disease Neuroimaging Initiative (ADNI; July 2007 to September 2021), and the Harvard Aging Brain Study (HABS; September 2010 to December 2019).Main Outcome and MeasuresThe main outcomes were the independent associations of neurodegeneration (decreases in gray matter volume), parenchymal amyloidosis (assessed by amyloid positron emission tomography), and vessel amyloidosis (evidenced by cerebral microbleeds [CMBs]) with cross-sectional and longitudinal WMH.ResultsData from 3960 MRI sessions among 1141 participants were included: 252 pathogenic variant carriers from DIAN (mean [SD] age, 38.4 [11.2] years; 137 [54%] female), 571 older adults from ADNI (mean [SD] age, 72.8 [7.3] years; 274 [48%] female), and 318 older adults from HABS (mean [SD] age, 72.4 [7.6] years; 194 [61%] female). Longitudinal increases in WMH volume were greater in individuals with CMBs compared with those without (DIAN: t = 3.2 [P = .001]; ADNI: t = 2.7 [P = .008]), associated with longitudinal decreases in gray matter volume (DIAN: t = −3.1 [P = .002]; ADNI: t = −5.6 [P < .001]; HABS: t = −2.2 [P = .03]), greater in older individuals (DIAN: t = 6.8 [P < .001]; ADNI: t = 9.1 [P < .001]; HABS: t = 5.4 [P < .001]), and not associated with systemic vascular risk (DIAN: t = 0.7 [P = .40]; ADNI: t = 0.6 [P = .50]; HABS: t = 1.8 [P = .06]) in individuals with ADAD and LOAD after accounting for age, gray matter volume, CMB presence, and amyloid burden. In older adults without CMBs at baseline, greater WMH volume was associated with CMB development during longitudinal follow-up (Cox proportional hazards regression model hazard ratio, 2.63; 95% CI, 1.72-4.03; P < .001).Conclusions and RelevanceThe findings suggest that increased WMH volume in AD is associated with neurodegeneration and parenchymal and vessel amyloidosis but not with elevated systemic vascular risk. Additionally, increased WMH volume may represent an early sign of vessel amyloidosis preceding the emergence of CMBs.

Background: Mortality remains high in patients with ST-segment–elevation myocardial infarction (STEMI) complicated by cardiogenic shock (CS), and early reperfusion has been shown to improve outcomes. We analyzed the association between first medical contact (FMC)-to-percutaneous coronary angiography time with mortality and major adverse cardiovascular events among patients with STEMI with and without CS. Methods: We performed a retrospective analysis of the Vancouver Coastal Health Authority STEMI registry, including all patients with STEMI who received primary percutaneous coronary angiography between January 1, 2010, and December 31, 2020, and stratified them by presence or absence of CS at hospital arrival. The primary outcome was in-hospital mortality, the secondary outcome was in-hospital major adverse cardiovascular events, defined as a composite of the first occurrence of mortality, cardiac arrest, heart failure, intracerebral hemorrhage, cerebrovascular accident, or reinfarction. Mixed effects logistic regression with restricted cubic splines was used to estimate the relationships between FMC-to-device time and the outcomes in the CS and non-CS groups. Results: 2929 patients were included, 9.4% (n=275) had CS. Median FMC-to-device time was 113.5 (interquartile range, 93.0–145.0) and 103.0 (interquartile range, 85.0–130.0) minutes for patients with CS and without CS, respectively. More patients with CS had FMC-to-device times above guideline recommendations (76.6% versus 54.1%, P <0.001). Between 60 and 90 minutes, for each 10-minute increase in FMC-to-device time, absolute mortality for patients with CS increased by 4% to 7%, whereas for patients without CS, it increased by <0.5%. Conclusions: Among patients with STEMI undergoing primary percutaneous coronary angiography, reperfusion delays among patients with CS are associated with significantly worse outcomes. Strategies to reduce FMC-to-device times for patients with STEMI presenting with CS are required.