Citations

Abstract BACKGROUND We compared the ability of several plasma biomarkers versus amyloid positron emission tomography (PET) to predict rates of memory decline among cognitively unimpaired individuals. METHODS We studied 645 Mayo Clinic Study of Aging participants. Predictor variables were age, sex, education, apolipoprotein E ( APOE ) ε 4 genotype, amyloid PET, and plasma amyloid beta (Aβ)42/40, phosphorylated tau (p‐tau)181, neurofilament light (NfL), glial fibrillary acidic protein (GFAP), and p‐tau217. The outcome was a change in a memory composite measure. RESULTS All plasma biomarkers, except NfL, were associated with mean memory decline in models with individual biomarkers. However, amyloid PET and plasma p‐tau217, along with age, were key variables independently associated with mean memory decline in models combining all predictors. Confidence intervals were narrow for estimates of population mean prediction, but person‐level prediction intervals were wide. DISCUSSION Plasma p‐tau217 and amyloid PET provide useful information about predicting rates of future cognitive decline in cognitively unimpaired individuals at the population mean level, but not at the individual person level.

Fibrodysplasia ossificans progressiva (FOP; MIM# 135100) is an ultra-rare congenital disorder caused by gain-of-function point mutations in the Activin receptor A type I (ACVR1, also known as ALK2) gene. FOP is characterized by episodic heterotopic ossification (HO) in skeletal muscles, tendons, ligaments, or other soft tissues that progressively causes irreversible loss of mobility. FOP mutations cause mild ligand-independent constitutive activation as well as ligand-dependent bone morphogenetic protein (BMP) pathway hypersensitivity of mutant ACVR1. BMP signaling is also a key pathway for mediating acquired HO. However, HO is a highly complex biological process involving multiple interacting signaling pathways. Among them, the hypoxia-inducible factor (HIF) and mechanistic target of rapamycin (mTOR) pathways are intimately involved in both genetic and acquired HO formation. HIF-1α inhibition or mTOR inhibition reduces HO formation in mouse models of FOP or acquired HO in part by de-amplifying the BMP pathway signaling. Here, we review the recent progress on the mechanisms of the HIF-1α and mTOR pathways in the amplification of HO lesions and discuss the future directions and strategies to translate the targeting of HIF-1α and the mTOR pathways into clinical interventions for FOP and other forms of HO.

AbstractDespite its high prevalence among dementias, Lewy body dementia (LBD) remains poorly understood with a limited, albeit growing, evidence base. The public‐health burden that LBD imposes is worsened by overlapping pathologies, which contribute to misdiagnosis, and lack of treatments. For this report, we gathered and analyzed public‐domain information on advocacy, funding, research outputs, and the therapeutic pipeline to identify gaps in each of these key elements. To further understand the current gaps, we also conducted interviews with leading experts in regulatory/governmental agencies, LBD advocacy, academic research, and biopharmaceutical research, as well as with funding sources. We identified wide gaps across the entire landscape, the most critical being in research. Many of the experts participated in a workshop to discuss the prioritization of research areas with a view to accelerating therapeutic development and improving patient care. This white paper outlines the opportunities for bridging the major LBD gaps and creates the framework for collaboration in that endeavor.Highlights A group representing academia, government, industry, and consulting expertise was convened to discuss current progress in Dementia with Lewy Body care and research. Consideration of expert opinion,natural language processing of the literature as well as publicly available data bases, and Delphi inspired discussion led to a proposed consensus document of priorities for the field.

We aimed to assess the prognostic role of the neutrophil/lymphocyte ratio (NLR) in community-acquired pneumonia (CAP) via a single-center retrospective cohort of hospitalized adult patients from 1/2009 to 12/2019. Patients were dichotomized into lower NLR (≤12) and higher NLR (>12). The primary outcome was mortality. ICU admission and hospital- and ICU-free days were secondary outcomes. The pneumonia severity index (PSI) and the NLR’s ability to predict outcomes was also tested. An NLR ≤12 was observed in 2513 (62.2%) patients and >12 in 1526 (37.8%). After adjusting for PSI, the NLR was not associated with hospital mortality (odds ratio [OR] 1.115; 95% confidence interval [CI] 0.774, 1.606; p = 0.559), but it was associated with a higher risk of ICU admission (OR 1.405; 95% CI 1.216, 1.624; p < 0.001). The PSI demonstrated acceptable discrimination for mortality (area under the receiver operating characteristic curve [AUC] 0.78; 95% CI 0.75, 0.82) which was not improved by adding the NLR (AUC 0.78; 95% CI 0.75, 0.82, p = 0.4476). The PSI’s performance in predicting ICU admission was also acceptable (AUC 0.75; 95% CI 0.74, 0.77) and improved by including the NLR (AUC 0.76, 95% CI 0.74, 0.77, p = 0.008), although with limited clinical significance. The NLR was not superior to the PSI for predicting mortality in hospitalized CAP patients.

Epstein-Barr virus (EBV) belongs to the group of human herpes virus and can cause clinical and subclinical infections. Although EBV-related disease presentations are similar, they can lead to oncogenic transformation with various clinical manifestations. A thorough workup with morphology, immunohistochemistry, and molecular studies is crucial for the diagnosis of EBV-positive polymorphic B-cell lymphoproliferative disorder, not otherwise specified (NOS), which is a new entity introduced by International Consensus Classification in 2022. We describe an interesting presentation of EBV-positive polymorphic B-cell lymphoproliferative disorder with laryngeal involvement to bring awareness to this entity and we would like to address the need for more accessible treatment options.

Pyloric interventions are surgical procedures employed to increase the gastric emptying rate in gastroparesis patients. In this study, we use an in silico model to investigate the consequences of pyloric intervention on gastric flow and emptying for two phenotypes of gastroparesis: antral hypomotility and decreased gastric tone. The transpyloric pressure gradient predicted by the in silico model, based on viscous fluid flow equations, is compared against in vivo measurements. Both phenotypes exhibit a similar pre-procedural emptying rate reduction, but after pyloric surgery, antral hypomotility case with preserved gastric tone shows significant improvements in emptying rates, up to 131%, accompanied by bile reflux from the duodenum into the stomach. Conversely, severely reduced gastric tone cases exhibited a post-procedural reduction in the net emptying rate due to the relatively larger bile reflux. In cases with a combination of antral hypomotility and reduced gastric tone, post-procedural improvements were observed only when both conditions were mild. Our findings highlight the pivotal role of the relative increase in pyloric orifice diameter in determining post-operative emptying rates. The study suggests a possible explanation for the selective response of patients toward these procedures and underscores the potential of in silico modelling to generate valuable insights to inform gastric surgery.

Abstract Aims The determinants and relevance of right ventricular (RV) mechanical dyssynchrony in heart failure with reduced ejection fraction (HFrEF) are poorly understood. We hypothesized that increased afterload may adversely affect the synchrony of RV contraction. Methods and results A total of 148 patients with HFrEF and 36 controls underwent echocardiography, right heart catheterization, and gated single-photon emission computed tomography to measure RV chamber volumes and mechanical dyssynchrony (phase standard deviation of systolic displacement timing). Exams were repeated after preload (N = 135) and afterload (N = 15) modulation. Patients with HFrEF showed higher RV dyssynchrony compared with controls (40.6 ± 17.5° vs. 27.8 ± 9.1°, P &lt; 0.001). The magnitude of RV dyssynchrony in HFrEF correlated with larger RV and left ventricular (LV) volumes, lower RV ejection fraction (RVEF) and LV ejection fraction, reduced intrinsic contractility, increased heart rate, higher pulmonary artery (PA) load, and impaired RV–PA coupling (all P ≤ 0.01). Low RVEF was the strongest predictor of RV dyssynchrony. Left bundle branch block (BBB) was associated with greater RV dyssynchrony than right BBB, regardless of QRS duration. RV afterload reduction by sildenafil improved RV dyssynchrony (P = 0.004), whereas preload change with passive leg raise had modest effect. Patients in the highest tertiles of RV dyssynchrony had an increased risk of adverse clinical events compared with those in the lower tertile [T2/T3 vs. T1: hazard ratio 1.98 (95% confidence interval 1.20–3.24), P = 0.007]. Conclusions RV dyssynchrony is associated with RV remodelling, dysfunction, adverse haemodynamics, and greater risk for adverse clinical events. RV dyssynchrony is mitigated by acute RV afterload reduction and could be a potential therapeutic target to improve RV performance in HFrEF.

AbstractBackground and AimUp to 40% of gastroesophageal reflux disease (GERD) patients experience inadequate symptom relief with a proton pump inhibitor (PPI), termed PPI‐resistant or refractory GERD. Vonoprazan, a potassium‐competitive acid blocker, has better efficacy than PPI in suppressing gastric acid secretion. This meta‐analysis summarizes the efficacy and safety of vonoprazan for treating PPI‐resistant GERD (both erosive esophagitis [EE] and non‐erosive reflux disease [NERD]).MethodsFour electronic databases (Medline, Embase, SCOPUS, and CENTRAL) were searched for studies indexed until August 1, 2023. Both observational studies and clinical trials assessing the efficacy and safety of vonoprazan in PPI‐resistant GERD were included. Efficacy outcomes included healing and maintenance rates of EE and improvement of the Frequency Scale for Symptoms of GERD (FSSG) scores. Serious adverse events (SAEs) were considered a safety outcome. The modified Newcastle‐Ottawa Scale (NOS) was used to assess study quality.ResultsTwelve studies were included in this meta‐analysis. Healing rates of PPI‐resistant EE with vonoprazan 20 mg were 91.7% (95% CI 86.8–94.8%) and 88.5% (95% CI 69.7–96.2%) at weeks 4 and 8, respectively. For healed PPI‐resistant EE, the overall maintenance rates with vonoprazan 10 mg were 82.6% (95% 61.2–95.0%) at week 8, 86.0% (95% CI 72.1–94.7%) at week 24, and 93.8% (95% CI 69.8–99.8%) at week 48. FSSG scores were improved in 74.6% (95% CI 65.8–81.7%) and 51.9% (95% CI 37.8–65.7%) of patients at weeks 4 and 8. Overall, no SAE was reported.ConclusionVonoprazan demonstrated high efficacy in the healing and maintenance of PPI‐resistant EE and moderate efficacy for the improvement of FSSG score. Vonoprazan was well tolerated in PPI‐resistant GERD patients.