Lecanemab in Early Alzheimer's Disease.

BACKGROUND: The accumulation of soluble and insoluble aggregated amyloid-beta (Aß) may initiate or potentiate pathologic processes in Alzheimer's disease. Lecanemab, a humanized IgG1 monoclonal antibody that binds with high affinity to Aß soluble protofibrils, is being tested in persons with early Alzheimer's disease. METHODS: We conducted an 18-month, multicenter, double-blind, phase 3 trial involving persons 50 to 90 years of age with early Alzheimer's disease (mild cognitive impairment or mild dementia due to Alzheimer's disease) with evidence of amyloid on positron-emission tomography (PET) or by cerebrospinal fluid testing. Participants were randomly assigned in a 1:1 ratio to receive intravenous lecanemab (10 mg per kilogram of body weight every 2 weeks) or placebo. The primary end point was the change from baseline at 18 months in the score on the Clinical Dementia Rating-Sum of Boxes (CDR-SB; range, 0 to 18, with higher scores indicating greater impairment). Key secondary end points were the change in amyloid burden on PET, the score on the 14-item cognitive subscale of the Alzheimer's Disease Assessment Scale (ADAS-cog14; range, 0 to 90; higher scores indicate greater impairment), the Alzheimer's Disease Composite Score (ADCOMS; range, 0 to 1.97; higher scores indicate greater impairment), and the score on the Alzheimer's Disease Cooperative Study-Activities of Daily Living Scale for Mild Cognitive Impairment (ADCS-MCI-ADL; range, 0 to 53; lower scores indicate greater impairment). RESULTS: A total of 1795 participants were enrolled, with 898 assigned to receive lecanemab and 897 to receive placebo. The mean CDR-SB score at baseline was approximately 3.2 in both groups. The adjusted least-squares mean change from baseline at 18 months was 1.21 with lecanemab and 1.66 with placebo (difference, -0.45; 95% confidence interval [CI], -0.67 to -0.23; P<0.001). In a substudy involving 698 participants, there were greater reductions in brain amyloid burden with lecanemab than with placebo (difference, -59.1 centiloids; 95% CI, -62.6 to -55.6). Other mean differences between the two groups in the change from baseline favoring lecanemab were as follows: for the ADAS-cog14 score, -1.44 (95% CI, -2.27 to -0.61; P<0.001); for the ADCOMS, -0.050 (95% CI, -0.074 to -0.027; P<0.001); and for the ADCS-MCI-ADL score, 2.0 (95% CI, 1.2 to 2.8; P<0.001). Lecanemab resulted in infusion-related reactions in 26.4% of the participants and amyloid-related imaging abnormalities with edema or effusions in 12.6%. CONCLUSIONS: Lecanemab reduced markers of amyloid in early Alzheimer's disease and resulted in moderately less decline on measures of cognition and function than placebo at 18 months but was associated with adverse events. Longer trials are warranted to determine the efficacy and safety of lecanemab in early Alzheimer's disease. (Funded by Eisai and Biogen; Clarity AD ClinicalTrials.gov number, NCT03887455.).

The relationship between patients' kidney stone type and demographics in Israel: analysis of 10 K patients.

PURPOSE: To analyze urinary stone composition in Israel and assess the effects of key demographic parameters (gender, age, socioeconomic status, ethnicity, medical history and geographic region) on stone composition. METHODS: A retrospective review was conducted of stone analysis of 10,633 patients from an HMO Israeli database analyzed by a central laboratory from 2014 to 2019 and subjected to Fourier-transform infrared spectroscopy. Associations between stone composition and different demographic parameters were determined using the Chi-square test. RESULTS: Calcium oxalate (CaOx) monohydrate accounted for 51.9% of the stones. Of the total sample, 5776 stones had one single component (54%), whereas 4857 (46%) had mixed components. Men had a higher frequency of CaOx stones (89.6% vs. 85.6%), whereas women had a higher frequency of calcium phosphate, infection, and cystine stones (27.2%, 17.7%, and 0.9% vs. 17.2%, 7.5%, and 0.5%, respectively). Cystine stones were more abundant in Arabs (1.2% vs. 0.5% in the Jewish population). Lower socioeconomic status was associated with a higher prevalence of calcium phosphate, uric acid, and infection stones and a lower prevalence of CaOx stones. Uric acid stones were associated with medical conditions such as diabetes, hypertension, ischemic heart disease, and obesity (28.3%, 24.9%, 25.7%, and 22.6% vs. 9.6%, 8.4%, 12.3%, and 10.3%, respectively). CONCLUSIONS: Stone types were highly influenced by patients' demographics. COM was the most common stone component in either pure or complex form. UA stone prevalence was found to increase with age and was associated with medical conditions such as diabetes, hypertension, ischemic heart disease, and obesity.

Remote photonic sensing of action potential in mammalian nerve cells via histogram-based analysis of temporal spatial acoustic vibrations.

Label free and remote action potential detection in neurons can be of great importance in the neuroscience research field. This paper presents a novel label free imaging modality based on the detection of temporal vibrations of speckle patterns illuminating the sample. We demonstrated the feasibility of detecting action potentials originating from spontaneous and stimulated activity in cortical cell culture. The spatiotemporal vibrations of isolated cortical cells were extracted by illuminating the culture with a laser beam while the vibrations of the random back scattered secondary speckle patterns are captured by a camera. The postulated action potentials were estimated following correlation-based analysis on the captured vibrations, where the variance deviation of the signal from a Gaussian distribution is directly associated with the action potential events. The technique was validated in a series of experiments in which the optical signals were acquired concurrently with microelectrode array (MEA) recordings. Our results demonstrate the ability of detecting action potential events in mammalian cells remotely via extraction of acoustic vibrations.

Utilizing Genomically Targeted Molecular Data to Improve Patient-Specific Outcomes in Autism Spectrum Disorder.

Molecular biology combined with genomics can be a powerful tool for developing potential intervention strategies for improving outcomes in children with autism spectrum disorders (ASD). Monogenic etiologies rarely cause autism. Instead, ASD is more frequently due to many polygenic contributing factors interacting with each other, combined with the epigenetic effects of diet, lifestyle, and environment. One limitation of genomics has been identifying ways of responding to each identified gene variant to translate the information to something clinically useful. This paper will illustrate how understanding the function of a gene and the effects of a reported variant on a molecular level can be used to develop actionable and targeted potential interventions for a gene variant or combinations of variants. For illustrative purposes, this communication highlights a specific genomic variant, SHANK3. The steps involved in developing molecularly genomically targeted actionable interventions will be demonstrated. Cases will be shared to support the efficacy of this strategy and to show how clinicians utilized these targeted interventions to improve ASD-related symptoms significantly. The presented approach demonstrates the utility of genomics as a part of clinical decision-making.

Genomics of Detoxification: How Genomics can be Used for Targeting Potential Intervention and Prevention Strategies Including Nutrition for Environmentally Acquired Illness.

Due to their genomic variants, some individuals are more highly affected by toxicants than others. Toxicant metabolizing and activating variants have been linked with a wide variety of health issues including an increased risk of miscarriages, birth defects, Alzheimer's, benzene toxicity, mercury toxicity and cancer. The study of genomics allows a clinician to identify pathways that are less effective and then gives the clinician the opportunity to counsel their patients about diet, supplements and lifestyle modifications that can improve the function of these pathways or compensate to some extent for their deficits. This article will review a few of these critical pathways relating to phase I and phase 2 detox such as GSTP1, GPX1, GSTT1 deletions, PON1 and some of the CYP 450 system as examples of how an individual's genomic vulnerabilities to toxicants can be addressed by upregulating or downregulating specific pathways via genomically targeted use of foods, supplements and lifestyle changes.

Comparing Transcriptome Profiles of Neurons Interfacing Adjacent Cells and Nanopatterned Substrates Reveals Fundamental Neuronal Interactions.

Developing neuronal axons are directed by chemical and physical signals toward a myriad of target cells. According to current dogma, the resulting network architecture is critically shaped by electrical interconnections, the synapses; however, key mechanisms translating neuronal interactions into neuronal growth behavior during network formation are still unresolved. To elucidate these mechanisms, we examined neurons interfacing nanopatterned substrates and compared them to natural interneuron interactions. We grew similar neuronal populations under three connectivity conditions, (1) the neurons are isolated, (2) the neurons are interconnected, and (3) the neurons are connected only to artificial substrates, then quantitatively compared both the cell morphologies and the transcriptome-expression profiles. Our analysis shows that whereas axon-guidance signaling pathways in isolated neurons are predominant, in isolated neurons interfacing nanotopography, these pathways are downregulated, similar to the interconnected neurons. Moreover, in nanotopography, interfacing neuron genes related to synaptogenesis and synaptic regulation are highly expressed, that is, again resembling the behavior of interconnected neurons. These molecular findings demonstrate that interactions with nanotopographies, although not leading to electrical coupling, play a comparable functional role in two major routes, neuronal guidance and network formation, with high relevance to the design of regenerative interfaces.

Personalized Nutrition: Translating the Science of NutriGenomics Into Practice: Proceedings From the 2018 American College of Nutrition Meeting.

Adverse reactions to foods and adverse drug reactions are inherent in product defects, medication errors, and differences in individual drug exposure. Pharmacogenetics is the study of genetic causes of individual variations in drug response and pharmacogenomics more broadly involves genome-wide analysis of the genetic determinants of drug efficacy and toxicity. The similarity of nutritional genomics and pharmacogenomics stems from the innate goal to identify genetic variants associated with metabolism and disease. Thus, nutrigenomics can be thought of as encompassing gene-diet interactions involving diverse compounds that are present in even the simplest foods. The advances in the knowledge base of the complex interactions among genotype, diet, lifestyle, and environment is the cornerstone that continues to elicit changes in current medical practice to ultimately yield personalized nutrition recommendations for health and risk assessment. This information could be used to understand how foods and dietary supplements uniquely affect the health of individuals and, hence, wellness. The individual's gut microbiota is not only paramount but pivotal in embracing the multiple-functional relationships with complex metabolic mechanisms involved in maintaining cellular homeostasis. The genetic revolution has ushered in an exciting era, one in which many new opportunities are expected for nutrition professionals with expertise in nutritional genomics. The American College of Nutrition's conference focused on "Personalized Nutrition: Translating the Science of NutriGenomics Into Practice" was designed to help to provide the education needed for the professional engagement of providers in the personalized medicine era.

Associations Between Prematurity, Birthweight, and Adolescence Blood Pressure in a Nationwide Cohort.

Introduction: Prematurity is associated with incomplete nephrogenesis and an increased incidence of acute kidney injury, that may increase the risk of future kidney disease, including hypertension, proteinuria and reduced glomerular filtration rate. The aim of this study was to evaluate the risk of hypertension or proteinuria in adolescents born prematurely or small for gestational age, in a nationwide cohort. Methods: The study cohort included potential recruits examined in the Israel Defense Forces (IDF) medical facilities, between November 2005 and October 2018. Clinical and anthropometric data, including blood pressure (BP) measurement, were retrieved from the IDF medical files. Adolescents born between January 1993 and December 2000 had additional data on gestational age at birth, retrieved from the Israeli Ministry of Health database. Results: The study cohort included 513,802 participants, aged 17.3 ± 0.9 years, of whom 48,994 had gestational age data. Adolescents born as very preterm, as extremely preterm infants, those born with very low birthweight (VLBW), or with extremely low birthweight (ELBW) had higher incidence of hypertensive-range BP (55%, 47%, 19% and 12%, respectively). No significant association between birthweight (BW) adjusted to gestational age and hypertension was observed. Within the overweight and obese adolescents, those born with VLBW and ELBW, had further increased hypertensive-range BP rate. Proteinuria was diagnosed in 0.33% of the study cohort, with no significant difference between BW or gestational age categories. Conclusion: Adolescents born with VLBW or as significant preterm were associated with high BP and should be monitored for hypertension development and its potential complications.

The HOPE4MCI study: A randomized double-blind assessment of AGB101 for the treatment of MCI due to AD.

INTRODUCTION: In addition to the accumulation of amyloid plaques and neurofibrillary tangles, the presence of excess neural activity is a pathological hallmark of Alzheimer's disease (AD) and a prognostic indicator for progression of AD pathology and clinical/cognitive worsening in mild cognitive impairment due to Alzheimer's disease (MCI due to AD). The HOPE4MCI clinical study tested the efficacy of a therapeutic with demonstrated ability to normalize heightened neural activity in the hippocampus in a randomized controlled trial of 78 weeks duration in patients with MCI due to AD. METHODS: One hundred and sixty-four participants were randomized to placebo (n = 83) or AGB101 (n = 81), an extended-release formulation of low dose (220 mg) levetiracetam. The primary endpoint was the change in Clinical Dementia Rating Scale Sum of Boxes score (CDR-SB) comparing follow up at 18 months to baseline. The goal of the primary efficacy analysis was to estimate the difference between the AGB101 and placebo arms in the mean change of the primary endpoint. RESULTS: The mean change in CDR-SB was estimated to be 1.12 (95% confidence interval [CI]: 0.66, 1.69) for the AGB101 arm and 1.22 (95% CI: 0.75, 1.78) for the placebo arm. The estimated difference between arms is -0.10 (95% CI: -0.85, 0.58), which was not statistically significant. In a prespecified analysis, the difference was -0.45 (95% CI: -1.43, 0.53) for ApoE-4 noncarriers and -0.10 (95% CI: -0.92, 0.72) for apolipoprotein E (ApoE)-4 carriers. DISCUSSION: The possibility that ApoE-4 carriers and noncarriers will respond differently to therapeutic intervention is consistent with recently reported findings from biologics and the present results show further testing of AGB101 in patients with MCI due to AD who are noncarriers of the ApoeE-4 allele is warranted. Conclusions from the HOPE4MCI study are limited primarily due to the small sample size and results can only be regarded as a guide to future research.

Health care reform: implications for employers after the 2012 election.

While the regulatory landscape of the Affordable Care Act (ACA) continues to evolve, employers must focus on implementing upcoming group health plan mandates. This article provides a high-level checklist of the most common long-term requirements facing employers and some strategic considerations, outlining the three possible health care strategies employers generally should consider for 2014 and later. Although specific implementation will depend on each employer's particular situation, group health plan design, and regulatory guidance, the complexity involved means that employers are well advised to begin this process sooner rather than later.

Postal Delivery of Sleep Monitoring Devices: Research Implications.

The purpose of this article is to describe the protocol development, feasibility, and lessons learned in the postal mail delivery of sleep monitoring devices to study participants. The original study protocol included four in-person visits with distribution of a sleep monitoring device (Actiwatch) and return of the Actiwatch via the postal service in a self-addressed, stamped envelope. The COVID-19 pandemic limited in-person research contact thus requiring a remote study protocol for application and return of the Actiwatches using postal delivery. While there were postal delivery and return challenges, the overall return rate of 94.4% confirmed remote protocol feasibility. Key lessons learned were: consistent and frequent communication via telephone calls and/or text; confirming required postage; and use of package tracking labels. All these strategies contributed to successful postal delivery/return and concomitantly decreased the potential loss of data and valuable research equipment.

Evaluating the mental health of international students in the U.S. during the COVID-19 outbreak: The case of University of Florida.

Objective: The study aims to capture the emotional challenges faced by international students due to the changes in U.S. visa regulations during the COVID-19 outbreak. Participants: 165 international students from University of Florida participated in the study. Methods: We conducted a cross-sectional online survey using previously validated questionnaire tools (PHQ-9 and GAD-7). The collected data was quantitatively analyzed through different statistical approaches, including ANOVA, Independent Sample t-Test, and Binary Logistic Regression. Results: 18.8% of our study sample had a moderately severe to severe depressive status, and 20.6% of the study sample had severe anxiety. Additionally, there was a statistically significant difference in the depression and anxiety scores based on gender. Conclusions: Our findings addressed the importance of taking serious measures when emotionally impactful political issues arise to prevent the development of mental illnesses among international students at U.S. institutions of higher education.

Lead Poisoning From Home-Prepared Indian Spices in 3 Families.

Spice consumption, along with other environmental factors, can contribute to pediatric lead poisoning. Although public health efforts have increased awareness of contamination of spices, false assumptions regarding the safety of home-prepared spices have emerged. Here, we present the clinical features, family beliefs, and environmental toxicology of 3 spice-associated pediatric lead poisoning cases.

Suspected Non-ST-elevation acute coronary syndrome meeting rapid rule-out criteria: resource utilization, diagnostic yield, and clinical outcomes of hospital admission.

AIMS: Many patients with suspected non-ST-elevation (NSTE) acute coronary syndromes (ACS) are admitted, even those with initial high-sensitivity cardiac troponins (hs-cTn) values who meet rapid rule-out criteria for myocardial infarction (MI). We examined the clinical outcomes, resource utilization, and diagnostic yield of suspected NSTE-ACS patients, who presented with hs-cTnT values meeting these criteria but were nevertheless hospitalized. METHODS AND RESULTS: Applying the 2020 European Society of Cardiology (ESC) rapid rule-out MI criteria, we identified consecutive patients with an initial value of hs-cTnT <5 ng/L or an initial value of ≥5 ng/L but <14 ng/L (99th percentile) and a small increment in a subsequent test, who were nevertheless admitted. The majority (85.4%) of patients presented to the emergency department (ED) with suspected NSTE-ACS had an initial hs-cTnT <99th percentile. We examined 3775 admitted patients out of 11 477 patients who were triaged and met MI rule-out criteria. Only 0.32% (12 patients) of admitted patients experienced index MI or overall death within 30 days. Resource utilization in terms of ED stay, hospital stay, noninvasive and invasive tests was substantial, yet revascularization was uncommon (2.5%). Multivariate adjustment for age, gender, and baseline cardiovascular risk factors demonstrates similar survival of admitted vs. discharged patients (P = 0.88). Initial hs-cTnT even below the 99th percentile provided a prognostic stratification for long term mortality. CONCLUSION: Our findings support a policy of ED discharge of suspected NSTE-ACS patients meeting rapid MI rule-out criteria and subsequent ambulatory evaluation, sparing resource-consuming admissions. In-hospital and ensuing prognosis were better with lower initial hs-cTnT values.

Longitudinal White and Gray Matter Response to Precision Medicine-Guided Intervention for Alzheimer's Disease.

BACKGROUND: Alzheimer's disease (AD) is a debilitating condition that is widely known to adversely affect gray matter (GM) and white matter (WM) tracts within the brain. Recently, precision medicine has shown promise in alleviating the clinical and gross morphological trajectories of patients with AD. However, regional morphological changes have not yet been adequately characterized. OBJECTIVE: Investigate regional morphological responses to a precision medicine-guided intervention with regards to white and gray matter in AD and mild cognitive impairment (MCI). METHODS: Clinical and neuroimaging data were compiled over a 9-month period from 25 individuals who were diagnosed with AD or MCI receiving individualized treatment plans. Structural T1-weighted MRI scans underwent segmentation and volumetric quantifications via Neuroreader. Longitudinal changes were calculated via annualized percent change of WM or GM ratios. RESULTS: Montreal Cognitive Assessment scores (p < 0.001) and various domains of the Computerized Neurocognitive Screening Vital Signs significantly improved from baseline to 9-month follow-up. There was regional variability in WM and GM atrophy or hypertrophy, but none of these observed changes were statistically significant after correction for multiple comparisons.

Precision Medicine Approach to Alzheimer's Disease: Rationale and Implications.

The neurodegenerative disease field has enjoyed extremely limited success in the development of effective therapeutics. One potential reason is the lack of disease models that yield accurate predictions and optimal therapeutic targets. Standard clinical trials have pre-determined a single treatment modality, which may be unrelated to the primary drivers of neurodegeneration. Recent proof-of-concept clinical trials using a precision medicine approach suggest a new model of Alzheimer's disease (AD) as a chronic innate encephalitis that creates a network insufficiency. Identifying and addressing the multiple potential contributors to cognitive decline for each patient may represent a more effective strategy. Here we review the rationale for a precision medicine approach in prevention and treatment of cognitive decline associated with AD. Results and implications from recent proof-of-concept clinical trials are presented. Randomized controlled trials, with much larger patient numbers, are likely to be significant to establishing precision medicine protocols as a standard of care for prevention and treatment of cognitive decline. Furthermore, combining this approach with the pharmaceutical approach offers the potential for enhanced outcomes. However, incorporating precision medicine approaches into everyday evaluation and care, as well as future clinical trials, would require fundamental changes in trial design, IRB considerations, funding considerations, laboratory evaluation, personalized treatment plans, treatment teams, and ultimately in reimbursement guidelines. Nonetheless, precision medicine approaches to AD, based on a novel model of AD pathophysiology, offer promise that has not been realized to date with monotherapeutic approaches.

Stress and strain patterns of 1-piece and 2-piece implant systems in bone: a 3-dimensional finite element analysis.

STATEMENT OF PROBLEM: The transition from implant to abutment is solid in 1-piece (1P) and broken in 2-piece (2P) implant designs. This difference may affect occlusal load distribution and marginal bone response. PURPOSE: To determine whether 1P and 2P implants with equivalent geometries exhibited stresses and strains differently under applied loading conditions. MATERIALS AND METHODS: Design software simulated 1P and 2P implants restored with metal copings and embedded in 3 cylindrical bone block models that varied in dimensions, density, and percentage of bone-to-implant contact. Three-dimensional, finite element analysis simulated occlusal loading. Experiments evaluated stresses and strains relative to implant design and (1) periimplant bone thickness, (2) cortical bone thickness, (3) magnitude and direction of occlusal loading, and (4) % bone-to-implant contact. RESULTS: Implants with equivalent dimensions exhibited comparable stresses and strains in all experimental conditions. Implant diameter and periimplant bone thickness influenced stress levels. Only small-diameter (3.0 mm) 1P implants in low-density bone exhibited stress levels that might adversely affect marginal bone stability. CONCLUSIONS: Implant diameter and periimplant bone thickness influenced load distribution in bone, but the type of implant-abutment transition had no significant effect. Small-diameter 1P implants should be limited to dense bone to minimize stress concentrations.

Esrrb is a cell-cycle-dependent associated factor balancing pluripotency and XEN differentiation.

Cell cycle and differentiation decisions are linked; however, the underlying principles that drive these decisions are unclear. Here, we combined cell-cycle reporter system and single-cell RNA sequencing (scRNA-seq) profiling to study the transcriptomes of embryonic stem cells (ESCs) in the context of cell-cycle states and differentiation. By applying retinoic acid, to G1 and G2/M ESCs, we show that, while both populations can differentiate toward epiblast stem cells (EpiSCs), only G2/M ESCs could differentiate into extraembryonic endoderm cells. We identified Esrrb, a pluripotency factor that is upregulated during G2/M, as a driver of extraembryonic endoderm stem cell (XEN) differentiation. Furthermore, enhancer chromatin states based on wild-type (WT) and ESRRB knockout (KO) ESCs show association of ESRRB with XEN poised enhancers. G1 cells overexpressing Esrrb allow ESCs to produce XENs, while ESRRB-KO ESCs lost their potential to differentiate into XEN. Overall, this study reveals a vital link between Esrrb and cell-cycle states during the exit from pluripotency.