Stroke Severity, Caregiver Feedback, and Cognition in the REGARDS-CARES Study.

BACKGROUND: Cognitive impairment after stroke is common and is present in up to 60% of survivors. Stroke severity, indicated by both volume and location, is the most consequential predictor of cognitive impairment, with severe strokes predicting higher chances of cognitive impairment. The current investigation examines the associations of 2 stroke severity ratings and a caregiver-report of poststroke functioning with longitudinal cognitive outcomes. METHODS AND RESULTS: One hundred fifty-seven caregivers and stroke survivor dyads participated in the CARES (Caring for Adults Recovering From the Effects of Stroke) project, an ancillary study of the REGARDS (Reasons for Geographic and Racial Differences in Stroke) national cohort study. The Glasgow Outcome Scale and modified Rankin Scale scores collected at hospitalization discharge were included as 2 primary predictors of cognitive impairment. The number of caregiver-reported problems and impairments at 9 months following stroke were included as a third predictor. Cognition was measured using a biennial telephone battery and included the domains of learning, memory, and executive functioning. Multiple cognitive assessments were analyzed up to 5 years poststroke, controlling for prestroke cognition and demographic variables of the stroke survivor. Separate mixed models showed significant main effects of the Glasgow Outcome Scale (b=0.3380 [95% CI, 0.14-0.5]; P=0.0009), modified Rankin Scale (b=-0.2119 [95% CI, -0.32 to -0.10]; P=0.0002), and caregiver-reported problems (b=-0.0671 [95% CI, -0.09 to -0.04]; P<0.0001) on longitudinal cognitive scores. In a combined model including all 3 predictors, only caregiver-reported problems significantly predicted cognition (b=-0.0480 [95% CI, -0.08 to -0.03]; P<0.0001). CONCLUSIONS: These findings emphasize the importance of caregiver feedback in predicting cognitive consequences of stroke.

Cascading failures in bipartite networks with directional support links.

We study the cascading failures in a system of two interdependent networks whose internetwork supply links are directional. We will show that, by utilizing generating function formalism, the cascading process can be modeled by a set of recursive relations. Most importantly, the functions involved in these relations are solely dependent upon the choice of the degree distribution of ingoing links. Simulation results in the limit of very large networks based on different choices of degree distributions for outgoing links, e.g., Kronecker delta, Poisson and Pareto, are indeed identical and are in excellent agreement with the theory. However, for Pareto distribution with the shape parameter 1<α<2, the convergence is slow. In general, directional networks can be more vulnerable or less vulnerable than their bidirectional counterparts. For three special settings of interdependent networks, we analytically compare their vulnerability. For practical applications it is important to predict if a system responds to the size of the initial attack continuously or if there is catastrophic collapse of the system if the attack exceeds a specific transition size. We analytically show that systems with lower average degrees are more resilient against this abrupt transition. We also establish an equivalence of this transition with the liquid-gas transition in statistical mechanics. In the last section, we derive the set of recursive relation to describe the cascading process where the initial attack is not restricted to a single network.

Assessing Advance Care Planning Fidelity within the Context of Cognitive Impairment: The SHARE Trial.

CONTEXT: Advance care planning (ACP) is critical among primary care patients with cognitive impairment, but few interventions have tested ACP with this population. OBJECTIVE: Describe the development and evaluation of a tool for assessing ACP fidelity within the context of cognitive impairment, including inter-rater reliability, convergent validity, and overall fidelity using clinical trial data. DESIGN: SHARE is a multicomponent intervention inclusive of facilitated ACP conversations. From a two group, single blind, randomized controlled trial, recorded ACP conversations were rated for fidelity. 145 primary care patients and their care partners were randomized to receive the intervention. Participating patients were 80+ years, had a care partner, and indications of cognitive impairment. An ACP Fidelity Checklist was developed with three subscales: Meeting Set-Up; ACP Meeting Topics; and Communication Skills. Scores were converted to percentages (100% = perfect fidelity) with a target of ≥80% fidelity. A post-ACP meeting report completed by ACP facilitators was used to assess convergent validity of the checklist. Intra-class correlation (ICC) was to evaluate inter-rater reliability. RESULTS: ACP conversations averaged 33.6 minutes (SD = 14.1). The mean fidelity score across N = 91 rated meetings was 82.9%, with a range of 77.3%-90.6% for subscales. 63.7% of meetings achieved a rating of ≥80%. Cognitive function was positively associated with patient participation (rho = .59, P < 0.001). For checklist items, ICC scores ranged from 0.43-0.96. Post-ACP meeting form scores were correlated with the checklist Meeting Topics subscale (r = 0.36, P = 0.001). CONCLUSIONS: Assessing the fidelity of ACP conversations involving primary care patients living with cognitive impairment and their care partners is feasible.

Efficacy of the residential care transition module: A telehealth intervention for dementia family caregivers of relatives living in residential long-term care settings.

The purpose of this study was to evaluate the efficacy of the Residential Care Transition Module, a six-session, psychosocial, and psychoeducational telehealth intervention for family caregivers of cognitively impaired relatives living in a residential long-term care setting. Eligible participants (including care recipients, regardless of time since admission) were randomized to treatment or usual care control conditions. Survey data were collected at baseline, 4 months, 8 months, and 12 months (N = 240). Primary analytic outcomes included caregiver subjective stress (a stress process mechanism) and depressive symptoms (a measure of global well-being). Secondary analytic outcomes included secondary role strains, residential care stress, caregiver sense of competence, and self-efficacy (additional mechanisms of action). General linear models tested for the main effects of the intervention at 4 months, and longitudinal mixed models examined the 12-month effects of the intervention. Post hoc analyses also examined the influence of moderators. No significant differences between the treatment and control groups for any primary analytic outcome were apparent. Caregivers in the treatment group whose relatives were admitted to residential long-term care in the prior 3 months were more likely to indicate reductions in depressive symptoms over the first 4 months of participation. Over the 12-month study period, caregivers in the treatment group who were employed reported increased self-efficacy over time. The heterogeneity of dementia care requires a broader consideration of key contextual factors that may influence the efficacy of nonpharmacological interventions. Aligning measures with the preferences, goals, and values of dementia caregivers may further demonstrate the direct benefits of interventions such as the Residential Care Transition Module. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Disruption of memory B-cell trafficking by belimumab in patients with systemic lupus erythematosus.

OBJECTIVES: Autoreactive memory B cells contribute to chronic and progressive courses in autoimmune diseases like systemic lupus erythematosus (SLE). The efficacy of belimumab (BEL), the first approved biologic treatment for SLE and lupus nephritis (LN), is generally attributed to depletion of activated naïve B cells and inhibition of B cell activation. BEL's effect on memory B cells (MBCs) is currently unexplained. We performed an in-depth cellular and transcriptomic analysis of BEL's impact on the blood MBC compartment in patients with SLE. METHODS: A retrospective meta-analysis was conducted, pooling flow cytometry data from four randomized trials involving 1245 patients with SLE treated with intravenous BEL or placebo. Then, extensive MBC phenotyping was performed using high-sensitivity flow cytometry in patients with mild/moderate SLE and severe SLE/LN treated with subcutaneous BEL. Finally, transcriptomic characterization of surging MBCs was performed by single-cell RNA sequencing. RESULTS: In BEL-treated patients, a significant increase in circulating MBCs, in a broad range of MBC subsets, was established at week 2, gradually returning to baseline by week 52. The increase was most prominent in patients with higher SLE disease activity, serologically active patients, and patients aged ≤18 years. MBCs had a non-proliferating phenotype with a prominent decrease in activation status and downregulation of numerous migration genes. CONCLUSION: Upon BEL initiation, an increase of MBCs was firmly established. In the small cohort investigated, circulating MBCs were de-activated, non-proliferative, and demonstrated characteristics of disrupted lymphocyte trafficking, expanding on our understanding of the therapeutic mechanism of B cell-activating factor inhibition by BEL. TRIAL REGISTRATION: ClinicalTrials.gov NCT00071487, NCT00410384, NCT01632241, NCT01649765, NCT03312907, NCT03747159.

An electroencephalogram microdisplay to visualize neuronal activity on the brain surface.

Functional mapping during brain surgery is applied to define brain areas that control critical functions and cannot be removed. Currently, these procedures rely on verbal interactions between the neurosurgeon and electrophysiologist, which can be time-consuming. In addition, the electrode grids that are used to measure brain activity and to identify the boundaries of pathological versus functional brain regions have low resolution and limited conformity to the brain surface. Here, we present the development of an intracranial electroencephalogram (iEEG)-microdisplay that consists of freestanding arrays of 2048 GaN light-emitting diodes laminated on the back of micro-electrocorticography electrode grids. With a series of proof-of-concept experiments in rats and pigs, we demonstrate that these iEEG-microdisplays allowed us to perform real-time iEEG recordings and display cortical activities by spatially corresponding light patterns on the surface of the brain in the surgical field. Furthermore, iEEG-microdisplays allowed us to identify and display cortical landmarks and pathological activities from rat and pig models. Using a dual-color iEEG-microdisplay, we demonstrated coregistration of the functional cortical boundaries with one color and displayed the evolution of electrical potentials associated with epileptiform activity with another color. The iEEG-microdisplay holds promise to facilitate monitoring of pathological brain activity in clinical settings.

Transplantation: platform to study recurrence of disease.

Beyond the direct benefit that a transplanted organ provides to an individual recipient, the study of the transplant process has the potential to create a better understanding of the pathogenesis, etiology, progression and possible therapy for recurrence of disease after transplantation while at the same time providing insight into the original disease. Specific examples of this include: 1) recurrence of focal segmental glomerulosclerosis (FSGS) after kidney transplantation, 2) recurrent autoimmunity after pancreas transplantation, and 3) recurrence of disease after orthotopic liver transplantation (OLT) for cirrhosis related to progressive steatosis secondary to jejuno-ileal bypass (JIB) surgery. Our team has been studying these phenomena and their immunologic underpinnings, and we suggest that expanding the concept to other pathologic processes and/or transplanted organs that harbor the risk for recurrent disease may provide novel insight into the pathogenesis of a host of other disease processes that lead to organ failure.

Wildland-urban interface wildfire increases metal contributions to stormwater runoff in Paradise, California.

The 2018 Camp Fire was a large late-year (November) wildfire that produced an urban firestorm in the Town of Paradise, California, USA, and destroyed more than 18 000 structures. Runoff from burned wildland areas is known to contain ash, which can transport contaminants including metals into nearby watersheds. However, due to historically infrequent occurrences, the effect of wildland-urban interface (WUI) fires, such as the Camp Fire, on surface water quality has not been well-characterized. Therefore, this study investigated the effects of widespread urban burning on surface water quality in major watersheds of the Camp Fire area. Between November 2018 and May 2019, 140 surface water samples were collected, including baseflow and stormflow, from burned and unburned watersheds with varying extent of urban development. Samples were analyzed for total and filter-passing metals, dissolved organic carbon, major anions, and total suspended solids. Ash and debris from the Camp Fire contributed metals to downstream watersheds via runoff throughout the storm season. Increases in concentration up to 200-fold were found for metals Cr, Cu, Ni, Pb, and Zn in burned watersheds compared to pre-fire values. Total concentrations of Al, Cd, Cu, Pb, and Zn exceeded EPA aquatic habitat acute criteria by up to 16-fold for up to five months after the fire. To assess possible transport mechanisms and bioavailability, a subset of 18 samples was analyzed using four filters with nominal pore sizes ranging from 0.22 to 1.2 µm to determine the particulate size distribution of metals. Trace and major metals (Al, Ba, Co, Cr, Cu, Fe, Hg, Mn, Ni, Pb, and Zn) were found mostly associated with larger grain sizes (>0.45 µm), and some metals (Al, Cr, Fe, and Pb) also included a substantial colloidal phase (0.22 to 0.45 µm). This study suggests that fires in the wildland-urban interface increase metal concentrations, mainly through particulate driven transport. The metals with the largest increases are likely from anthropogenic disaster materials, though biomass ash also is a major contributor to water quality. The increase in metals following WUI burning may have adverse ecological impacts.

Embedding Caregiver Support Within Adult Day Services: Outcomes of a Multisite Trial.

BACKGROUND AND OBJECTIVES: Adult day services (ADS) provide quality-of-life benefits to people with dementia, but few provide systematic caregiver support. We report outcomes of a multisite, national trial testing a staff-delivered caregiver program, ADS Plus. RESEARCH DESIGN AND METHODS: Cluster-randomized trial involving 34 ADS: 18 sites provided ADS (controls) and 16 provided ADS and ADS Plus (intervention). Trained staff met with caregivers to provide dementia education, support/validation, referrals/linkages, and strategies for care challenges and self-care over 12 months. Main outcomes included depressive symptoms (Center for Epidemiological Studies Depression Scale [CES-D]) and well-being at 6 and 12 months, and client attendance over 12 months. RESULTS: Of 203 caregivers (Intervention = 102; Control = 101), 5.9% at 3 months, 12.8% at 6 months, and 22.7% at 12 months were lost to follow-up. Caregivers were predominantly female (80.3%), with 76.4% identifying as White/Caucasian, 14.8% Black/African American, and 12.3% Hispanic/Latino. Most (88.2%) had ≥college education and were 65.0 years old (SD = 13.46). For those with 6-month data, 40.4% control and 40.2% ADS Plus caregivers had depressed symptoms (≥16 CES-D) at baseline. By 6 months, 43.6% control versus 34.2% ADS Plus caregivers had ≥16 scores (odds ratio = 0.38, p = .072). By 12 months, after covariate adjustments, ADS Plus caregivers reported reduced total depression scores versus controls (p = .013) and lower depressed affect scores (p = .015). Of 18 sites providing 12-month client attendance data, 9 intervention sites reported 126.05 days attended versus 78.49 days for 9 control sites (p = .079). DISCUSSION AND IMPLICATIONS: Compared with ADS alone, by 12 months, ADS Plus improved caregiver mood and increased ADS utilization by 60.6%. Results support ADS staff delivering evidence-based caregiver support to enhance ADS benefits. CLINICAL TRIAL REGISTRATION: NCT02927821.

Stroke Severity, Caregiver Feedback, and Cognition in the REGARDS-CARES Study.

Objective: Cognitive impairment after stroke is common, present up to 60% of survivors. Stroke severity, indicated by both volume and location, is the most consequential predictor of cognitive impairment, with severe strokes predicting higher chances of cognitive impairment. The current investigation examines the associations of two stroke severity ratings and a caregiver-report of post-stroke functioning with longitudinal cognitive outcomes. Methods: The analysis was conducted on 157 caregivers and stroke survivor dyads who participated in the Caring for Adults Recovering from the Effects of Stroke (CARES) project, an ancillary study of the REasons for Geographic and Racial Differences in Stroke (REGARDS) national cohort study. Glasgow Outcome Scale (GOS) and modified Rankin Scale (mRS) collected at hospitalization discharge were included as two primary predictors of cognitive impairment. The number of caregiver-reported problems and impairments at nine months following stroke were included as a third predictor. Cognition was assessed using a biennial telephone battery, incorporating multiple cognitive assessments to assess learning, memory, and executive functioning. Longitudinal cognitive scores were analyzed up to five years post-stroke, controlling for baseline (pre-stroke) cognitive scores and demographic variables of each stroke survivor collected at CARES baseline. Results: Separate mixed models showed significant main effects of GOS (b=0.3280, p=0.0009), mRS (b=-0.2119, p=0.0002), and caregiver-reported impairments (b=-0.0671, p<0.0001) on longitudinal cognitive scores. In a combined model including all three predictors, only caregiver-reported problems significantly predicted cognitive outcomes (b=-0.0480, p<0.0001). Impact: These findings underscore the importance of incorporating caregivers feedback in understanding cognitive consequences of stroke.

Fetal bladder morphology as a predictor of outcome in fetal lower urinary tract obstruction.

OBJECTIVE: We evaluate survival of fetuses with severe Lower Urinary Tract Obstruction (LUTO) based on bladder morphology. We hypothesize that fetuses with a "floppy" appearing bladder on initial prenatal ultrasound will have worse infant outcomes than fetuses with full/rounded bladders. METHOD: We retrospectively reviewed all cases of LUTO evaluated in our fetal center between January 2013 and December 2021. Ultrasonographic assessment, renal biochemistry, and bladder refilling contributed to a "favorable" or "unfavorable" evaluation. Bladder morphology on initial ultrasound was classified as "floppy" or "full/rounded." Vesicoamniotic shunting was offered for favorably evaluated fetuses. Baseline demographics, ultrasound parameters, prenatal evaluations of fetal renal function, and infant outcomes were collected. Fetuses diagnosed with severe LUTO were included in analysis using descriptive statistics. The primary outcome measured was survival at 6 months of life. RESULTS: 104 LUTO patients were evaluated; 24 were included in analysis. Infant survival rate at 6 months was 60% for rounded bladders and 0% for floppy bladders (p = 0.003). Bladder refill adequacy was lower in fetuses with floppy bladders compared with rounded bladders (p value < 0.00001). CONCLUSION: We propose that bladder morphology in fetuses with severe LUTO may be a prognostication factor for predicting infant outcomes and provides a valuable, noninvasive assessment tool.

Subtypes of Transitions into a Family Caregiving Role: A Latent Class Analysis.

This paper groups persons who have transitioned into family caregiving using a latent class analysis and examines class differences on measures of well-being. Latent classes were identified for a sample of 251 participants who became family caregivers while participating in a longitudinal national study, and linear regression analyses compared average well-being change scores across classes. Fit indices supported a four-class solution dispersed along two conceptual dimensions: caregiving intensity and caregiving stain. The largest class (35.5%) was characterized as low intensity, low strain. The smallest class (12.7%) was characterized as high intensity, high strain, and these caregivers had significantly worse well-being change scores compared to the other caregiving classes. Categorizing caregivers by differing levels of care intensity and caregiving strain helps identify caregivers who are at most risk for poor psychosocial outcomes, determines which caregivers might benefit from specific caregiver support programs, and informs investigators on possible refinements to interventions.

Modeling and Phenotyping Acute and Chronic Type 2 Diabetes Mellitus In Vitro in Rodent Heart and Skeletal Muscle Cells.

Type 2 diabetes (T2D) has a complex pathophysiology which makes modeling the disease difficult. We aimed to develop a novel model for simulating T2D in vitro, including hyperglycemia, hyperlipidemia, and variably elevated insulin levels targeting muscle cells. We investigated insulin resistance (IR), cellular respiration, mitochondrial morphometry, and the associated function in different T2D-mimicking conditions in rodent skeletal (C2C12) and cardiac (H9C2) myotubes. The physiological controls included 5 mM of glucose with 20 mM of mannitol as osmotic controls. To mimic hyperglycemia, cells were exposed to 25 mM of glucose. Further treatments included insulin, palmitate, or both. After short-term (24 h) or long-term (96 h) exposure, we performed radioactive glucose uptake and mitochondrial function assays. The mitochondrial size and relative frequencies were assessed with morphometric analyses using electron micrographs. C2C12 and H9C2 cells that were treated short- or long-term with insulin and/or palmitate and HG showed IR. C2C12 myotubes exposed to T2D-mimicking conditions showed significantly decreased ATP-linked respiration and spare respiratory capacity and less cytoplasmic area occupied by mitochondria, implying mitochondrial dysfunction. In contrast, the H9C2 myotubes showed elevated ATP-linked and maximal respiration and increased cytoplasmic area occupied by mitochondria, indicating a better adaptation to stress and compensatory lipid oxidation in a T2D environment. Both cell lines displayed elevated fractions of swollen/vacuolated mitochondria after T2D-mimicking treatments. Our stable and reproducible in vitro model of T2D rapidly induced IR, changes in the ATP-linked respiration, shifts in energetic phenotypes, and mitochondrial morphology, which are comparable to the muscles of patients suffering from T2D. Thus, our model should allow for the study of disease mechanisms and potential new targets and allow for the screening of candidate therapeutic compounds.

Long-term effects of average calcineurin inhibitor trough levels (over time) on renal function in a prospectively followed cohort of 150 kidney transplant recipients.

More favorable clinical outcomes with medium-term follow-up have been reported among kidney transplant recipients receiving maintenance therapy consisting of "reduced-tacrolimus (TAC) dosing," mycophenolate mofetil (MMF), and low-dose corticosteroids. However, it is not clear whether long-term maintenance therapy with reduced-calcineurin inhibitor (CNI) dosing still leads to reduced renal function. A prospectively followed cohort of 150 kidney transplant recipients randomized to receive TAC/sirolimus (SRL) versus TAC/MMF versus cyclosporine microemulsion (CSA)/SRL, plus low-dose maintenance corticosteroids, now has 20 years of post-transplant follow-up. Average CNI trough levels over time among patients who were still alive with functioning grafts at 60, 120, and 180 months post-transplant were determined and ranked from smallest-to-largest for both TAC and CSA. Stepwise linear regression was used to determine whether these ranked average trough levels were associated with the patient's estimated glomerular filtration rate (eGFR) at those times, particularly after controlling for other significant multivariable predictors. Experiencing biopsy-proven acute rejection (BPAR) and older donor age were the two most significant multivariable predictors of poorer eGFR at 60, 120, and 180 months post-transplant (p < 000001 and 0.000003 for older donor age at 60 and 120 months; p = 0.00008 and <0.000001 for previous BPAR at 60 and 120 months). Assignment to CSA also implied a significantly poorer eGFR (but with less magnitudes of effect) in multivariable analysis at 60 and 120 months (p = 0.01 and 0.002). Higher ranked average CNI trough levels had no association with eGFR at any timepoint in either univariable or multivariable analysis (p > 0.70). Long-term maintenance therapy with reduced-CNI dosing does not appear to cause reduced renal function.

The Efficiency of Bacterial Vaccines on Mortality during the 'Spanish' Influenza Pandemic of 1918-19.

The worldwide 'Spanish' influenza pandemic of 1918-19, which extended into the 1920s, infected more than a third of the world's population and killed an estimated 50-100 million people, more than the civilian and military casualties of World War I. Present-day medical scholars, journalists, and other commentators have often ignored, downplayed or treated with scepticism the role of bacterial vaccines in reducing mortality during the pandemic. There have been repeated claims in this century that these vaccines were 'useless', 'concocted', and possibly harmful. Focussing on the Australian scene, I show that bacterial vaccines from reputable sources did indeed reduce mortality, perhaps to a greater extent in some cases than modern anti-viral influenza vaccines.

Examining the Malleability of Negative Views of Aging, Self-Efficacy Beliefs, and Behavioral Intentions in Middle-Aged and Older Adults.

OBJECTIVES: This study examined the malleability of a tripartite cluster of purported mechanistic variables targeted in a 4-week intervention program designed to improve adults' engagement in physical activity. The targeted cluster of purported mechanisms consisted of negative views of aging (NVOA), self-efficacy beliefs, and behavioral intentions. METHODS: A randomized single-blind control group design was used to implement the AgingPLUS program in a sample of middle-aged and older adults (N = 335; Mage = 60.1 years; SDage = 8.3 years; age range 45-75 years). RESULTS: Using an intention-to-treat approach and analyses of covariance adjusting for participants' baseline scores, findings showed significant improvements in the purported mechanistic variables both at the immediate (Week 4) and delayed posttest (Week 8) in the treatment group but not in the control group. These improvements were for the most part maintained until 8-month postrandomization, although to a smaller extent. Specifically, participants in the AgingPLUS group showed significant improvements in NVOA, self-efficacy beliefs, and behavioral intentions compared to the Health Education control group. Standardized effect sizes for statistically significant effects were variable and ranged from small (d = -0.23) to large (d = 0.80). Effect sizes showed some decay of the intervention at the 8-month posttest. DISCUSSION: Taken together, the findings supported the efficacy of the AgingPLUS program and showed that variables representing the purported mechanisms of the intervention were significantly moved in a positive direction. In doing so, the AgingPLUS program met a major requirement of the experimental medicine approach to behavior change interventions. CLINICAL TRIALS REGISTRATION NUMBER: NCT0329948.

Hierarchical Development of Physical Frailty and Cognitive Impairment and Their Association With Incident Cardiovascular Disease.

BACKGROUND: Frailty and cognitive impairment (CI) are geriatric conditions that lead to poor health outcomes among older adults with cardiovascular disease. The association between their temporal patterns of development and cardiovascular risk is unknown. OBJECTIVES: This study aims to examine the 5-year cardiovascular outcomes by the pattern of development of frailty and CI in older adults without a history of coronary artery disease. METHODS: We used the National Health and Aging Trends Study, linked to Medicare data. Frailty was measured using the physical frailty phenotype. CI was measured using the AD8 Dementia Screening Interview, measured cognitive performance, or self-report by patient or caregiver for a diagnosis given by a physician. The primary outcome was incident major adverse cardiovascular event at 5 years. RESULTS: Of a total 2,189 study participants aged 65 and older, 38.5% were male. In this study population, 154 (7%) participants developed frailty first, 829 (38%) developed CI first, and 195 (9%) participants developed both simultaneously (frail-CI group). Those who developed frailty and CI simultaneously were older, more likely to be female, and had multiple chronic conditions. The frail-CI group had the highest risk of major adverse cardiovascular event (hazard ratio [HR]: 1.81; 95% CI: 1.47-2.23) followed by frail first (HR: 1.46; 95% CI: 1.17-1.81) and CI first (HR: 1.31; 95% CI: 1.15-1.50). Frailty first was associated with the greater risk of stroke (HR: 1.49; 95% CI: 1.06-2.09) compared to the intact group. CONCLUSIONS: The simultaneous development of frailty and CI is associated with an increased risk of adverse cardiovascular outcomes including death compared with the development of each syndrome alone. Diagnostics to detect frailty and CI are critical in assessment of cardiovascular risk in the older population.

Use of tamibarotene, a potent and selective RARα agonist, in combination with azacitidine in patients with relapsed and refractory AML with RARA gene overexpression.

Tamibarotene-based therapy is a novel targeted approach for the treatment of relapsed/refractory (R/R) acute myeloid leukemia (AML) with retinoic acid receptor alpha (RARA) gene overexpression. Approximately, 50% of higher-risk myelodysplastic syndrome (MDS) patients and approximately 30% of AML patients are positive for RARA overexpression using a blood-based biomarker test that measures RARA expression in peripheral blasts. A phase 2 study investigating the activity of tamibarotene in patients with RARA overexpression was conducted in patients with AML and MDS (NCT02807558). In 28 patients with R/R AML and RARA overexpression treated with tamibarotene in combination with azacitidine, the median overall survival was 5.9 months. In 21 response-evaluable patients, the complete remission/complete remission with incomplete hematologic recovery (CR/CRi) rate was 19%, and median time to initial CR/CRi was 1.2 months. The favorable safety profile and preliminary clinical activity support the development of combination therapies with tamibarotene in myeloid malignancies with RARA overexpression.

The podocyte: glomerular sentinel at the crossroads of innate and adaptive immunity.

Focal segmental glomerulosclerosis (FSGS) is a common glomerular disorder that manifests clinically with the nephrotic syndrome and has a propensity to recur following kidney transplantation. The pathophysiology and therapies available to treat FSGS currently remain elusive. Since the podocyte appears to be the target of apparent circulating factor(s) that lead to recurrence of proteinuria following kidney transplantation, this article is focused on the podocyte. In the context of kidney transplantation, the performance of pre- and post-reperfusion biopsies, and the establishment of in vitro podocyte liquid biopsies/assays allow for the development of clinically relevant studies of podocyte biology. This has given insight into new pathways, involving novel targets in innate and adaptive immunity, such as SMPDL3b, cGAS-STING, and B7-1. Elegant experimental studies suggest that the successful clinical use of rituximab and abatacept, two immunomodulating agents, in our case series, may be due to direct effects on the podocyte, in addition to, or perhaps distinct from their immunosuppressive functions. Thus, tissue biomarker-directed therapy may provide a rational approach to validate the mechanism of disease and allow for the development of new therapeutics for FSGS. This report highlights recent progress in the field and emphasizes the importance of kidney transplantation and recurrent FSGS (rFSGS) as a platform for the study of primary FSGS.

The Brain Electroencephalogram Microdisplay for Precision Neurosurgery.

Brain surgeries are among the most delicate clinical procedures and must be performed with the most technologically robust and advanced tools. When such surgical procedures are performed in functionally critical regions of the brain, functional mapping is applied as a standard practice that involves direct coordinated interactions between the neurosurgeon and the clinical neurology electrophysiology team. However, information flow during these interactions is commonly verbal as well as time consuming which in turn increases the duration and cost of the surgery, possibly compromising the patient outcomes. Additionally, the grids that measure brain activity and identify the boundaries of pathological versus functional brain regions suffer from low resolution (3-10 mm contact to contact spacing) with limited conformity to the brain surface. Here, we introduce a brain intracranial electroencephalogram microdisplay (Brain-iEEG-microdisplay) which conforms to the brain to measure the brain activity and display changes in near real-time (40 Hz refresh rate) on the surface of the brain in the surgical field. We used scalable engineered gallium nitride (GaN) substrates with 6" diameter to fabricate, encapsulate, and release free-standing arrays of up to 2048 GaN light emitting diodes (µLEDs) in polyimide substrates. We then laminated the µLED arrays on the back of micro-electrocorticography (µECoG) platinum nanorod grids (PtNRGrids) and developed hardware and software to perform near real-time intracranial EEG analysis and activation of light patterns that correspond to specific cortical activities. Using the Brain-iEEG-microdisplay, we precisely ideFSntified and displayed important cortical landmarks and pharmacologically induced pathological activities. In the rat model, we identified and displayed individual cortical columns corresponding to individual whiskers and the near real-time evolution of epileptic discharges. In the pig animal model, we demonstrated near real-time mapping and display of cortical functional boundaries using somatosensory evoked potentials (SSEP) and display of responses to direct electrical stimulation (DES) from the surface or within the brain tissue. Using a dual-color Brain-iEEG-microdisplay, we demonstrated co-registration of the functional cortical boundaries with one color and displayed the evolution of electrical potentials associated with epileptiform activity with another color. The Brain-iEEG-microdisplay holds the promise of increasing the efficiency of diagnosis and possibly surgical treatment, thereby reducing the cost and improving patient outcomes which would mark a major advancement in neurosurgery. These advances can also be translated to broader applications in neuro-oncology and neurophysiology.