Eating Around the Clock: Circadian Rhythms of Eating and Metabolism.

The time of day that we eat is increasingly recognized as contributing as importantly to overall health as the amount or quality of the food we eat. The endogenous circadian clock has evolved to promote intake at optimal times when an organism is intended to be awake and active; but electric lights and abundant food allow eating around the clock with deleterious health outcomes. In this review, we highlight literature pertaining to the effects of food timing on health, beginning with animal models and then translation into human experiments. We emphasize the pitfalls and opportunities that technological advances bring in bettering understanding of eating behaviors and their association with health and disease. There is great promise for restricting the timing of food intake both in clinical interventions and in public health campaigns for improving health via nonpharmacological therapies.

A small molecule chaperone rescues keratin-8 mediated trafficking of misfolded podocin to correct genetic Nephrotic Syndrome.

Podocin is a key membrane scaffolding protein of the kidney podocyte essential for intact glomerular filtration. Mutations in NPHS2, the podocin-encoding gene, represent the commonest form of inherited nephrotic syndrome (NS), with early, intractable kidney failure. The most frequent podocin gene mutation in European children is R138Q, causing retention of the misfolded protein in the endoplasmic reticulum. Here, we provide evidence that podocin R138Q (but not wild-type podocin) complexes with the intermediate filament protein keratin 8 (K8) thereby preventing its correct trafficking to the plasma membrane. We have also identified a small molecule (c407), a compound that corrects the Cystic Fibrosis Transmembrane Conductance Regulator protein defect, that interrupts this complex and rescues mutant protein mistrafficking. This results in both the correct localization of podocin at the plasma membrane and functional rescue in both human patient R138Q mutant podocyte cell lines, and in a mouse inducible knock-in model of the R138Q mutation. Importantly, complete rescue of proteinuria and histological changes was seen when c407 was administered both via osmotic minipumps or delivered orally prior to induction of disease or crucially via osmotic minipump two weeks after disease induction. Thus, our data constitute a therapeutic option for patients with NS bearing a podocin mutation, with implications for other misfolding protein disorders. Further studies are necessary to confirm our findings.

Identifying an Acceptable Number of Ambulatory Blood Pressure Measurements for Accuracy of Average Blood Pressure and Nocturnal Dipping Status.

OBJECTIVE: We aimed to identify the minimum number of ABP measures to accurately determine daytime and nighttime systolic BP averages and nocturnal dipping status (i.e., relative daytime:nighttime change). METHODS: Forty-three midlife participants wore an ABP monitor for 24 hours with measurements every 20/30 minutes during the daytime/nighttime, as identified by a sleep diary. We calculated daytime/nighttime systolic BP average and dipping status from all available measurements per participant (i.e., normative data). We then calculated daytime and nighttime BP per participant based on a random selection of 8-20 and 4-10 measurements and replicated random selections 1000 times. We calculated accuracy by checking the proportion from 1000 different randomly selected samples for a particular number of measurements that systolic BP was ±5 mmHg of normative data, and dipping status remained unchanged for each participant compared to the normative value. The best fit for the regression model estimated the minimal number of measurements for an accuracy of 95% in BP averages. RESULTS: For a 95% accuracy in estimating daytime and nighttime systolic BP, 11 daytime and 8 nighttime measurements were required. The highest accuracy for dipping status was 91.6±13.4% using 20 daytime and 10 nighttime measures, while the lowest was (83.4±15.1%) using 8 daytime and 4 nighttime measures. CONCLUSION: Eleven daytime and eight nighttime measurements are likely enough to calculate average systolic BPs accurately. However, no minimum number is suggested to accurately calculate dipping status.

Heparanase inhibition as a systemic approach to protect the endothelial glycocalyx and prevent microvascular complications in diabetes.

BACKGROUND: Diabetes mellitus is a chronic disease which is detrimental to cardiovascular health, often leading to secondary microvascular complications, with huge global health implications. Therapeutic interventions that can be applied to multiple vascular beds are urgently needed. Diabetic retinopathy (DR) and diabetic kidney disease (DKD) are characterised by early microvascular permeability changes which, if left untreated, lead to visual impairment and renal failure, respectively. The heparan sulphate cleaving enzyme, heparanase, has previously been shown to contribute to diabetic microvascular complications, but the common underlying mechanism which results in microvascular dysfunction in conditions such as DR and DKD has not been determined. METHODS: In this study, two mouse models of heparan sulphate depletion (enzymatic removal and genetic ablation by endothelial specific Exotosin-1 knock down) were utilized to investigate the impact of endothelial cell surface (i.e., endothelial glycocalyx) heparan sulphate loss on microvascular barrier function. Endothelial glycocalyx changes were measured using fluorescence microscopy or transmission electron microscopy. To measure the impact on barrier function, we used sodium fluorescein angiography in the eye and a glomerular albumin permeability assay in the kidney. A type 2 diabetic (T2D, db/db) mouse model was used to determine the therapeutic potential of preventing heparan sulphate damage using treatment with a novel heparanase inhibitor, OVZ/HS-1638. Endothelial glycocalyx changes were measured as above, and microvascular barrier function assessed by albumin extravasation in the eye and a glomerular permeability assay in the kidney. RESULTS: In both models of heparan sulphate depletion, endothelial glycocalyx depth was reduced and retinal solute flux and glomerular albumin permeability was increased. T2D mice treated with OVZ/HS-1638 had improved endothelial glycocalyx measurements compared to vehicle treated T2D mice and were simultaneously protected from microvascular permeability changes associated with DR and DKD. CONCLUSION: We demonstrate that endothelial glycocalyx heparan sulphate plays a common mechanistic role in microvascular barrier function in the eye and kidney. Protecting the endothelial glycocalyx damage in diabetes, using the novel heparanase inhibitor OVZ/HS-1638, effectively prevents microvascular permeability changes associated with DR and DKD, demonstrating a novel systemic approach to address diabetic microvascular complications.

Development and validation of blood tumor mutational burden reference standards.

Tumor mutational burden (TMB), measured by exome or panel sequencing of tumor tissue or blood (bTMB), is a potential predictive biomarker for treatment benefit in patients with various cancer types receiving immunotherapy targeting checkpoint pathways. However, significant variability in TMB measurement has been observed. We developed contrived bTMB reference materials using DNA from tumor cell lines and donor-matched lymphoblastoid cell lines to support calibration and alignment across laboratories and platforms. Contrived bTMB reference materials were developed using genomic DNA from lung tumor cell lines blended into donor-matched lymphoblastoid cell lines at 0.5% and 2% tumor content, fragmented and size-selected to mirror the size profile of circulating cell-free tumor DNA with TMB scores of 7, 9, 20, and 26 mut/Mb. Variant allele frequency (VAF) and bTMB scores were assessed using PredicineATLAS and GuardantOMNI next-generation sequencing assays. DNA fragment sizes in the contrived reference samples were similar to those found within patient plasma-derived cell-free DNA, and mutational patterns aligned with those in the parental tumor lines. For the 7, 20, and 26 mut/Mb contrived reference samples with 2% tumor content, bTMB scores estimated using either assay aligned with expected scores from the parental tumor cell lines and showed good reproducibility. A bioinformatic filtration step was required to account for low-VAF artifact variants. We demonstrate the feasibility and challenges of producing and using bTMB reference standards across a range of bTMB levels, and how such standards could support the calibration and validation of bTMB platforms and help harmonization between panels and laboratories.

Chronological distribution of readings in ambulatory blood pressure monitoring exams affects the nighttime average and the magnitude of blood pressure dipping.

STUDY OBJECTIVES: Averaged nighttime blood pressure (BP) is superior to daytime BP for cardiovascular risk stratification, and the relative change between daytime/nighttime BP (dipping%) significantly predicts cardiovascular risk. Newer reports suggest that 4 measurements at night may be enough for cardiovascular risk stratification. Since BP oscillates across the night, the temporal distribution of measurements across the night may impact nighttime BP and dipping%. Therefore, we compared average nighttime BP and dipping% when using measurements in the first half (1st-half), second (2nd-half), and a combination of both (combined). METHODS: Forty-three (17 females and twenty-six males) midlife adults aged 50±10 years old wore an ambulatory BP monitor for 24 hours at home, programmed to measure BP every 20 minutes when scheduled for daytime and every 30 minutes during a self-selected 8-hour nighttime for time-in-bed. We compared the nighttime BP averages and dipping% when using either the first four measurements from the 1st-half or 2nd-half of the nighttime and combined. RESULTS: Nighttime Systolic BP was significantly different across 1st-half, 2nd-half, and combined (111±9 vs.107±11 vs. 109±9 mmHg, p<0.01), respectively, with significant pairwise differences across all categories (p<0.01 for each). Systolic BP dipping% was significantly different across 1st-half, 2nd-half, and combined (9.9±5.5 vs.13.5±6.4 vs. 11.7±5.0 %, p<0.01), respectively, with significant pairwise differences across all categories (p<0.01 for each. Diastolic BP and diastolic dipping% were similar across the three different bins. CONCLUSION: In midlife adults, systolic nighttime BP and dipping% may depend upon when BP measurements are taken during the night.

Views on Using Psychoactive Substances to Self-Manage Functional Neurological Disorder: Online Patient Survey Results.

Objective: Functional neurological disorder (FND) causes a high burden of disability and distress. Although it is a common disorder, there is a pressing need for improved access to evidence-based treatments. With difficulties in finding effective treatment, some people with FND may seek alternative means of symptom relief, such as legal and illicit psychoactive substances, although the prevalence and nature of such self-management strategies are currently unclear. Additionally, psychoactive substances may represent novel treatment research opportunities, particularly for those with suboptimal improvement. The investigators examined the use of self-management techniques, as well as perspectives on novel therapies, in this patient population. Methods: An online survey was created to assess self-management strategies and views on novel treatments for FND, including psychedelic therapy. The survey was accessible for 1 month, and respondents were recruited internationally through social media and patient groups. A total of 1,048 respondents from 16 countries completed the survey. Results: Almost half (46%) of 980 respondents reported having tried legal psychoactive substances for the management of their FND symptoms and, on average, nicotine, alcohol, and cannabidiol were reported as modestly effective. Additionally, 15% of respondents reported having used illicit substances, mostly cannabis, to manage FND, with the majority reporting moderate effectiveness and experiencing no or minimal physical (90%) and psychological (95%) sequelae. Many respondents (46%) reported that they would be willing to try medically supervised psychedelic therapy (with 19% of respondents ambivalent) if it were found to be safe and effective. Conclusions: Many people with FND seek alternative means of symptom management outside usual medical care, including legal and illicit psychoactive substances. Further research exploring novel treatment options, such as psychedelics, in FND may be warranted.

A New Class of Single-Material, Non-Reciprocal Microactuators.

A crucial component in designing soft actuating structures with controllable shape changes is programming internal, mismatching stresses. In this work, a new paradigm for achieving anisotropic dynamics between isotropic end-states-yielding a non-reciprocal shrinking/swelling response over a full actuation cycle-in a microscale actuator made of a single material, purely through microscale design is demonstrated. Anisotropic dynamics is achieved by incorporating micro-sized pores into certain segments of the structures; by arranging porous and non-porous segments (specifically, struts) into a 2D hexagonally-shaped microscopic poly(N-isopropyl acrylamide) hydrogel particle, the rate of isotropic shrinking/swelling in the structure is locally modulated, generating global anisotropic, non-reciprocal, dynamics. A simple mathematical model is introduced that reveals the physics that underlies these dynamics. This design has the potential to be used as a foundational tool for inducing non-reciprocal actuation cycles with a single material structure, and enables new possibilities in producing customized soft actuators and modular anisotropic metamaterials for a range of real-world applications, such as artificial cilia.

A role for NPY-NPY2R signaling in albuminuric kidney disease.

Albuminuria is an independent risk factor for the progression to end-stage kidney failure, cardiovascular morbidity, and premature death. As such, discovering signaling pathways that modulate albuminuria is desirable. Here, we studied the transcriptomes of podocytes, key cells in the prevention of albuminuria, under diabetic conditions. We found that Neuropeptide Y (NPY) was significantly down-regulated in insulin-resistant vs. insulin-sensitive mouse podocytes and in human glomeruli of patients with early and late-stage diabetic nephropathy, as well as other nondiabetic glomerular diseases. This contrasts with the increased plasma and urinary levels of NPY that are observed in such conditions. Studying NPY-knockout mice, we found that NPY deficiency in vivo surprisingly reduced the level of albuminuria and podocyte injury in models of both diabetic and nondiabetic kidney disease. In vitro, podocyte NPY signaling occurred via the NPY2 receptor (NPY2R), stimulating PI3K, MAPK, and NFAT activation. Additional unbiased proteomic analysis revealed that glomerular NPY-NPY2R signaling predicted nephrotoxicity, modulated RNA processing, and inhibited cell migration. Furthermore, pharmacologically inhibiting the NPY2R in vivo significantly reduced albuminuria in adriamycin-treated glomerulosclerotic mice. Our findings suggest a pathogenic role of excessive NPY-NPY2R signaling in the glomerulus and that inhibiting NPY-NPY2R signaling in albuminuric kidney disease has therapeutic potential.

Reduced Glomerular Filtration in Diabetes Is Attributable to Loss of Density and Increased Resistance of Glomerular Endothelial Cell Fenestrations.

BACKGROUND: Glomerular endothelial cell (GEnC) fenestrations are recognized as an essential component of the glomerular filtration barrier, yet little is known about how they are regulated and their role in disease. METHODS: We comprehensively characterized GEnC fenestral and functional renal filtration changes including measurement of glomerular Kf and GFR in diabetic mice (BTBR ob-/ob- ). We also examined and compared human samples. We evaluated Eps homology domain protein-3 (EHD3) and its association with GEnC fenestrations in diabetes in disease samples and further explored its role as a potential regulator of fenestrations in an in vitro model of fenestration formation using b.End5 cells. RESULTS: Loss of GEnC fenestration density was associated with decreased filtration function in diabetic nephropathy. We identified increased diaphragmed fenestrations in diabetes, which are posited to increase resistance to filtration and further contribute to decreased GFR. We identified decreased glomerular EHD3 expression in diabetes, which was significantly correlated with decreased fenestration density. Reduced fenestrations in EHD3 knockdown b.End5 cells in vitro further suggested a mechanistic role for EHD3 in fenestration formation. CONCLUSIONS: This study demonstrates the critical role of GEnC fenestrations in renal filtration function and suggests EHD3 may be a key regulator, loss of which may contribute to declining glomerular filtration function through aberrant GEnC fenestration regulation. This points to EHD3 as a novel therapeutic target to restore filtration function in disease.

Integrating community health workers within a pharmacy to address health-related social needs.

BACKGROUND: Community pharmacies in the United States are beginning to serve as patient care service destinations addressing both clinical and health-related social needs (HRSN). Although there is support for integrating social determinant of health (SDoH) activities into community pharmacy practice, the literature remains sparse on optimal pharmacy roles and practice models. OBJECTIVE: To assess the feasibility of a community pharmacy HRSN screening and referral program adapted from a community health worker (CHW) model and evaluate participant perceptions and attitudes toward the program. METHODS: This feasibility study was conducted from January 2022 to April 2022 at an independent pharmacy in Buffalo, NY. Collaborative relationships were developed with 3 community-based organizations including one experienced in implementing CHW programs. An HRSN screening and referral intervention was developed and implemented applying a CHW practice model. Pharmacy staff screened subjects for social needs and referred to an embedded CHW, who assessed and referred subjects to community resources with as-needed follow-up. Post intervention, subjects completed a survey regarding their program experience. Descriptive statistics were used to report demographics, screening form, and survey responses. RESULTS: Eighty-six subjects completed screening and 21 (24.4%) an intervention and referral. Most participants utilized Medicaid (57%) and lived within a ZIP Code associated with the lowest estimated quartile for median household income (66%). Eighty-seven social needs were identified among the intervention subjects, with neighborhood and built environment (31%) and economic stability challenges (30%) being the most common SDoH domains. The CHW spent an average of 33 minutes per patient from initial case review through follow-up. All respondents had a positive perception of the program, and the majority agreed that community pharmacies should help patients with their social needs (70%). CONCLUSIONS: This feasibility study demonstrated that embedding a CHW into a community pharmacy setting can successfully address HRSN and that participants have a positive perception toward these activities.

In vivo dissection of Rhoa function in vascular development using zebrafish.

The small monomeric GTPase RHOA acts as a master regulator of signal transduction cascades by activating effectors of cellular signaling, including the Rho-associated protein kinases ROCK1/2. Previous in vitro cell culture studies suggest that RHOA can regulate many critical aspects of vascular endothelial cell (EC) biology, including focal adhesion, stress fiber formation, and angiogenesis. However, the specific in vivo roles of RHOA during vascular development and homeostasis are still not well understood. In this study, we examine the in vivo functions of RHOA in regulating vascular development and integrity in zebrafish. We use zebrafish RHOA-ortholog (rhoaa) mutants, transgenic embryos expressing wild type, dominant negative, or constitutively active forms of rhoaa in ECs, pharmacological inhibitors of RHOA and ROCK1/2, and Rock1 and Rock2a/b dgRNP-injected zebrafish embryos to study the in vivo consequences of RHOA gain- and loss-of-function in the vascular endothelium. Our findings document roles for RHOA in vascular integrity, developmental angiogenesis, and vascular morphogenesis in vivo, showing that either too much or too little RHOA activity leads to vascular dysfunction.

Mistimed restricted feeding disrupts circadian rhythms of male mating behavior and female preovulatory LH surges in mice.

In rodents, eating at atypical circadian times, such as during the biological rest phase when feeding is normally minimal, reduces fertility. Prior findings suggest this fertility impairment is due, at least in part, to reduced mating success. However, the physiological and behavioral mechanisms underlying this reproductive suppression are not known. In the present study, we tested the hypothesis that mistimed feeding-induced infertility is due to a disruption in the normal circadian timing of mating behavior and/or the generation of pre-ovulatory luteinizing hormone (LH) surges (estrogen positive feedback). In the first experiment, male+female mouse pairs, acclimated to be food restricted to either the light (mistimed feeding) or dark (control feeding) phase, were scored for mounting frequency and ejaculations over 96 h. Male mounting behavior and ejaculations were distributed much more widely across the day in light-fed mice than in dark-fed controls and fewer light-fed males ejaculated. In the second experiment, the timing of the LH surge, a well characterized circadian event driven by estradiol (E2) and the SCN, was analyzed from serial blood samples taken from ovariectomized and E2-primed female mice that were light-, dark-, or ad-lib-fed. LH concentrations peaked 2 h after lights-off in both dark-fed and ad-lib control females, as expected, but not in light-fed females. Instead, the normally clustered LH surges were distributed widely with high inter-mouse variability in the light-fed group. These data indicate that mistimed feeding disrupts the temporal control of the neural processes underlying both ovulation and mating behavior, contributing to infertility.

Chemically active filaments: analysis and extensions of slender phoretic theory.

Autophoretic microswimmers self-propel via surface interactions with a surrounding solute fuel. Chemically-active filaments are an exciting new microswimmer design that augments traditional autophoretic microswimmers, such as spherical Janus particles, with extra functionality inherent to their slender filament geometry. Slender Phoretic Theory (SPT) was developed by Katsamba et al. to analyse the dynamics of chemically-active filaments with arbitrary three-dimensional shape and chemical patterning. SPT provides a line integral solution for the solute concentration field and slip velocity on the filament surface. In this work, we exploit the generality of SPT to calculate a number of new, non-trivial analytical solutions for slender autophoretic microswimmers, including a general series solution for phoretic filaments with arbitrary geometry and surface chemistry, a universal solution for filaments with a straight centreline, and explicit solutions for some canonical shapes useful for practical applications and benchmarking numerical code. Many common autophoretic particle designs include discrete jumps in surface chemistry; here we extend our SPT to handle such discontinuities, showing that they are regularised by a boundary layer around the jump. Since our underlying framework is linear, combinations of our results provide a library of analytic solutions that will allow researchers to probe the interplay of activity patterning and shape.

Non-REM Apnea and Hypopnea Duration Varies across Population Groups and Physiologic Traits.

Rationale: Symptoms and morbidities associated with obstructive sleep apnea (OSA) vary across individuals and are not predicted by the apnea-hypopnea index (AHI). Respiratory event duration is a heritable trait associated with mortality that may further characterize OSA.Objectives: We evaluated how hypopnea and apnea durations in non-REM (NREM) sleep vary across demographic groups and quantified their associations with physiological traits (loop gain, arousal threshold, circulatory delay, and pharyngeal collapsibility).Methods: Data were analyzed from 1,546 participants from the Multi-Ethnic Study of Atherosclerosis with an AHI ≥5. Physiological traits were derived using a validated model fit to the polysomnographic airflow signal. Multiple linear regression models were used to evaluate associations of event duration with demographic and physiological factors.Measurements and Main Results: Participants had a mean age ± SD of 68.9 ± 9.2 years, mean NREM hypopnea duration of 21.73 ± 5.60, and mean NREM apnea duration of 23.87 ± 7.44 seconds. In adjusted analyses, shorter events were associated with younger age, female sex, higher body mass index (P < 0.01, all), and Black race (P < 0.05). Longer events were associated with Asian race (P < 0.01). Shorter event durations were associated with lower circulatory delay (2.53 ± 0.13 s, P < 0.01), lower arousal threshold (1.39 ± 0.15 s, P < 0.01), reduced collapsibility (-0.71 ± 0.16 s, P < 0.01), and higher loop gain (-0.27 ± 0.11 s, P < 0.05) per SD change. Adjustment for physiological traits attenuated age, sex, and obesity associations and eliminated racial differences in event duration.Conclusions: Average event duration varies across population groups and provides information on ventilatory features and airway collapsibility not captured by the AHI.

Community health worker intervention improves early childhood vaccination rates: results from a propensity-score matching evaluation.

BACKGROUND: Arizona's Health Start Program is a statewide community health worker (CHW) maternal and child health home visiting intervention. The objective of this study was to test if participation in Health Start during 2006-2016 improved early childhood vaccination completion rates. METHODS: This retrospective study used 11 years of administrative, birth certificate, and immunization records. Propensity score matching was used to identify control groups, based on demographic, socioeconomic, and geographic characteristics. Results are reported by historically disadvantaged subgroups and/or with a history of low vaccine uptake, including Hispanic/Latinx and American Indian children, and children of low socioeconomic status and from rural areas, children with teen mothers and first-born children. The average treatment-on-the-treated (ATT) effect estimated the impact of Health Start on timely completion of seven early childhood vaccine series: diphtheria/tetanus toxoids and acellular/whole-cell pertussis (DTaP/DTP), Haemophilus influenzae type b (Hib), hepatitis B (Hep. B), measles-mumps-rubella (MMR), pneumococcal conjugate vaccine (PCV13), poliovirus, and varicella. RESULTS: Vaccination completion rates (by age five) were 5.0% points higher for Health Start children as a group, and on average 5.0% points higher for several subgroups of mothers: women from rural border counties (ATT 5.8), Hispanic/Latinx women (ATT 4.8), American Indian women (ATT 4.8), women with less than high school education (ATT 5.0), teen mothers (ATT 6.1), and primipara women (ATT 4.5), compared to matched control groups (p-value ≤ 0.05). Time-to-event analyses show Health Start children complete vaccination sooner, with a hazard rate for full vaccination 13% higher than their matches. CONCLUSION: A state-operated home visiting intervention with CHWs as the primary interventionist can effectively promote early childhood vaccine completion, which may reduce the incidence of preventable diseases and subsequently improve children's health. Effects of CHW interventions on vaccination uptake is particularly relevant given the rise in vaccine-preventable diseases in the US and globally. TRIAL REGISTRATION: Approved by the University of Arizona Research Institutional Review Board (Protocol 1701128802), 25 January 2017.

Impact of a Community Health Worker (CHW) Home Visiting Intervention on Any and Adequate Prenatal Care Among Ethno-Racially Diverse Pregnant Women of the US Southwest.

OBJECTIVES: Social and structural barriers drive disparities in prenatal care utilization among minoritized women in the United States. This study examined the impact of Arizona's Health Start Program, a community health worker (CHW) home visiting intervention, on prenatal care utilization among an ethno-racially and geographically diverse cohort of women. METHODS: We used Health Start administrative and state birth certificate data to identify women enrolled in the program during 2006-2016 (n = 7,117). Propensity score matching was used to generate a statistically-similar comparison group (n = 53,213) of women who did not participate in the program. Odds ratios were used to compare rates of prenatal care utilization. The process was repeated for select subgroups, with post-match regression adjustments applied where necessary. RESULTS: Health Start participants were more likely to report any (OR 1.24, 95%CI 1.02-1.50) and adequate (OR 1.08, 95%CI 1.01-1.16) prenatal care, compared to controls. Additional specific subgroups were significantly more likely to receive any prenatal care: American Indian women (OR 2.22, 95%CI 1.07-4.60), primipara women (OR 1.64, 95%CI 1.13-2.38), teens (OR 1.58, 95%CI 1.02-2.45), women in rural border counties (OR 1.45, 95%CI 1.05-1.98); and adequate prenatal care: teens (OR 1.31, 95%CI 1.11-1.55), women in rural border counties (OR 1.18, 95%CI 1.05-1.33), primipara women (OR 1.18, 95%CI 1.05-1.32), women with less than high school education (OR 1.13, 95%CI 1.00-1.27). CONCLUSIONS FOR PRACTICE: A CHW-led perinatal home visiting intervention operated through a state health department can improve prenatal care utilization among demographically and socioeconomically disadvantaged women and reduce maternal and child health inequity.

Inflammatory and blood gas markers of COVID-19 delirium compared to non-COVID-19 delirium: a cross-sectional study.

OBJECTIVES: We aimed to find the association of inflammation and respiratory failure with delirium in COVID-19 patients. We compare the inflammatory and arterial blood gas markers between patients with COVID-19 delirium and delirium in other medical disorders. METHODS: This cross-sectional study used the CHART-DEL, a validated research tool, to screen patients for delirium retrospectively from clinical notes. Inflammatory markers C-reactive protein (CRP) and white cell count (WBC), and the partial pressures of oxygen (PO2) and carbon dioxide (PCO2) were compared between patients with COVID-19 delirium and delirium in other medical disorders. RESULTS: In bivariate analysis, CRP (mg/L) was significantly higher in the COVID-19 group, (81.7 ± 80.0 vs. 58.8 ± 87.7, p = 0.04), and WBC (109/L) was significantly lower (7.44 ± 3.42 vs. 9.71 ± 5.45, p = 0.04). The geometric mean of CRP in the COVID-19 group was 140% higher in multiple linear regression (95% CI = 7-439%, p = 0.03) with age and sex as covariates. There were no significant differences in pO2 or pCO2 across groups. CONCLUSION: The association between higher CRP and COVID-19 in patients with delirium may suggest an inflammatory basis for delirium in COVID-19. Our findings may assist clinicians in establishing whether delirium is due to COVID-19, which may improve management and outcomes of infected patients.

Oxidatively modified low-density lipoproteins are potential mediators of proteasome inhibitor resistance in multiple myeloma.

Proteasome inhibitor (PI) therapy has improved the survival of multiple myeloma (MM) patients. However, inevitably, primary or acquired resistance to PIs leads to disease progression; resistance mechanisms are unclear. Obesity is a risk factor for MM mortality. Oxidized LDL (OxLDL), a central mediator of atherosclerosis that is elevated in metabolic syndrome (co-occurrence of obesity, insulin resistance, dyslipidemia and hypertension), has been linked to an increased risk of solid cancers and shown to stimulate pro-oncogenic/survival signaling. We hypothesized that OxLDL is a mediator of chemoresistance and evaluated its effects on MM cell killing by PIs. OxLDL potently suppressed the ability of the boronic acid-based PIs bortezomib (BTZ) and ixazomib, but not the epoxyketone-based PI carfilzomib, to kill human MM cell lines and primary cells. OxLDL suppressed BTZ-induced inhibition of proteasome activity and induction of pro-apoptotic signaling. These cytoprotective effects were abrogated when lipid hydroperoxides (LOOHs) associated with OxLDL were enzymatically reduced. We also demonstrated the presence of OxLDL in the MM bone marrow microenvironment as well as numerous granulocytes and monocytes capable of cell-mediated LDL oxidation through myeloperoxidase. Our findings suggest that OxLDL may be a potent mediator of boronic acid-based PI resistance, particularly for MM patients with metabolic syndrome, given their elevated systemic levels of OxLDL. LDL cholesterol-lowering therapy to reduce circulating OxLDL, and pharmacologic targeting of LOOH levels or resistance pathways induced by the modified lipoprotein, could deepen the response to these important agents and offer clinical benefit to MM patients with metabolic syndrome.

The Pathological Relevance of Increased Endothelial Glycocalyx Permeability.

The endothelial glycocalyx is a vital regulator of vascular permeability. Damage to this delicate layer can result in increased protein and water transit. The clinical importance of albuminuria as a predictor of kidney disease progression and vascular disease has driven research in this area. This review outlines how research to date has attempted to measure the contribution of the endothelial glycocalyx to vessel wall permeability. We discuss the evidence for the role of the endothelial glycocalyx in regulating permeability in discrete areas of the vasculature and highlight the inherent limitations of the data that have been produced to date. In particular, this review emphasizes the difficulties in interpreting urinary albumin levels in early disease models. In addition, the research that supports the view that glycocalyx damage is a key pathologic step in a diverse array of clinical conditions, including diabetic complications, sepsis, preeclampsia, and atherosclerosis, is summarized. Finally, novel methods are discussed, including an ex vivo glomerular permeability assay that enhances the understanding of permeability changes in disease.