Association of covert brain infarcts and white matter hyperintensities with risk of hip fracture in older adults: the Cardiovascular Health Study.

Covert brain infarcts and white matter hyperintensities (WMHs), incidental markers of brain microvascular disease commonly seen on brain MRIs in older adults, have been associated with falls and lower bone mineral density. We found covert infarcts and WMHs may also be associated with an increased risk of future hip fracture. INTRODUCTION: To determine whether covert infarcts and white matter hyperintensities (WMHs) are associated with increased risk of incident hip fracture. METHODS: A prospective cohort of 3373 community-dwelling adults aged ≥ 65 years enrolled in the Cardiovascular Health Study with a brain MRI (1992-1993) was analyzed. Covert infarcts were categorized by number of infarcts and largest infarct size. WMH burden was assessed by radiologists and graded qualitatively from 0 (no WMHs) to 9 (extensive). RESULTS: Participants had 465 incident hip fractures during a mean follow-up of 12.8 years. The demographic-adjusted hazard of incident hip fracture was 32% higher among participants with ≥ 1 covert infarct compared to those without infarcts (hazard ratio (HR) 1.32; 95% CI, 1.08-1.62). The hazard of incident hip fracture was similar after further adjustment for medications and medical history (HR = 1.34; 95% CI, 1.08-1.65), but attenuated following additional adjustment for functional status, frailty, and falls (HR = 1.25; 95% CI, 0.99-1.57). Fully adjusted hazard of incident hip fracture per increase in infarct number was 1.10 (95% CI, 0.98-1.23); risk in individuals whose largest infarct was ≥ 20 mm versus 3 to < 20 mm was similar. Compared with WMH grades 0-1, the demographic-adjusted hazard of hip fracture was 1.34 (95% CI, 1.09-1.66) and 1.83 (95% CI, 1.37-2.46), respectively, for WMH grades 2-3 and 4-9. The hazard was similar following adjustment for medications and medical history (grades 2-3: HR = 1.32; 95% CI, 1.05-1.64; grades 4-9: HR = 1.69; 95% CI, 1.23-2.30), but attenuated following additional adjustment for functional status, frailty, and falls (grades 2-3: HR = 1.24; 95% CI, 0.98-1.56; grades 4-9: HR = 1.34; 95% CI, 0.95-1.90). CONCLUSION: Older, community-dwelling adults with covert infarcts or WMHs may be at increased risk of hip fracture.

Differences in Phosphate and Parathyroid Hormone Concentrations over the Day among Patients on Hemodialysis.

BACKGROUND: Elevated serum phosphate and parathyroid hormone (PTH) concentrations are associated with cardiovascular events, bone disease, and mortality in patients on maintenance hemodialysis. Although circadian changes are known in people with CKD, it is unknown whether differences occur in these parameters over the course of a day in people receiving hemodialysis. METHODS: We used clinical data from Fresenius Medical Care US dialysis clinics to determine how the time of day when measurements were collected (hemodialysis treatment start time) may be associated with serum phosphate and PTH concentrations. We used harmonic regression to assess these associations while accounting for demographic data and treatment parameters. RESULTS: A total of 96,319 patients receiving maintenance hemodialysis were included in this analysis. Patients had a mean age of 64±14 years, 43% were women, and dialysis start times ranged from 3:00 am to 7:59 pm. The mean serum phosphate concentration was 5.2±1.5 mg/dl, and the median PTH was 351 pg/ml (interquartile range [IQR], 214-547). In fully adjusted models, serum phosphate had a nadir at 11:00 am of 4.97 (IQR, 4.94-5.01) mg/dl and a peak at 7:00 pm of 5.56 (IQR, 5.50-5.62) mg/dl. Serum PTH had a nadir at 9:00 am of 385 (IQR, 375-395) pg/ml and a peak at 7:00 pm of 530 (IQR, 516-547) pg/ml. CONCLUSIONS: Among patients receiving maintenance hemodialysis, concentrations of PTH and phosphate before a dialysis session vary with the time of day that these values are measured. Consideration of whether these values were obtained at peak or nadir times of the day may be important in treatment decisions.

Plasma amyloid beta, neurofilament light chain, and total tau in the Systolic Blood Pressure Intervention Trial (SPRINT).

INTRODUCTION: Lowering blood pressure (BP) reduces the risk for cognitive impairment and the progression of cerebral white matter lesions. It is unclear whether hypertension control also influences plasma biomarkers related to Alzheimer's disease and non-disease-specific neurodegeneration. METHODS: We examined the effect of intensive (< 120 mm Hg) versus standard (< 140 mm Hg) BP control on longitudinal changes in plasma amyloid beta (Aß)40 and Aß42 , total tau, and neurofilament light chain (NfL) in a subgroup of participants from the Systolic Blood Pressure Intervention Trial (N = 517). RESULTS: Over 3.8 years, there were no significant between-group differences for Aß40, Aß42, Aß42 /Aß40, or total tau. Intensive treatment was associated with larger increases in NfL compared to standard treatment. Adjusting for kidney function, but not BP, attenuated the association between intensive treatment and NfL. DISCUSSION: Intensive BP treatment was associated with changes in NfL, which were correlated with changes in kidney function associated with intensive treatment. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01206062.

Association of Urine Biomarkers of Kidney Tubule Injury and Dysfunction With Frailty Index and Cognitive Function in Persons With CKD in SPRINT.

RATIONALE & OBJECTIVE: The associations of the glomerular markers of kidney disease, estimated glomerular filtration rate (eGFR) and albuminuria, with frailty and cognition are well established. However, the relationship of kidney tubule injury and dysfunction with frailty and cognition is unknown. STUDY DESIGN: Observational cross-sectional study. SETTING & PARTICIPANTS: 2,253 participants with eGFR<60mL/min/1.73m2 in the Systolic Blood Pressure Intervention Trial (SPRINT). EXPOSURE: Eight urine biomarkers: interleukin 18 (IL-18), kidney injury molecule 1 (KIM-1), neutrophil gelatinase-associated lipocalin (NGAL), chitinase-3-like protein 1 (YKL-40), monocyte chemoattractant protein 1 (MCP-1), α1-microglobulin (A1M), ß2-microglobulin (B2M), and uromodulin (Umod). OUTCOME: Frailty was measured using a previously validated frailty index (FI), categorized as fit (FI≤0.10), less fit (0.100.21). Cognitive function was assessed using the Montreal Cognitive Assessment (MoCA). ANALYTICAL APPROACH: Associations between kidney tubule biomarkers with categorical FI were evaluated using multinomial logistic regression with the fit group as the reference. Cognitive function was evaluated using linear regression. Models were adjusted for demographic, behavioral, and clinical variables including eGFR and urine albumin. RESULTS: Three of the 8 urine biomarkers of tubule injury and dysfunction were independently associated with FI. Each 2-fold higher level of urine KIM-1, a marker of tubule injury, was associated with a 1.22 (95% CI, 1.01-1.49) greater odds of being in the frail group. MCP-1, a marker of tubulointerstitial fibrosis, was associated with a 1.30 (95% CI, 1.04-1.64) greater odds of being in the frail group, and A1M, a marker of tubule reabsorptive capacity, was associated with a 1.48 (95% CI, 1.11-1.96) greater odds of being in the frail group. These associations were independent of confounders including eGFR and urine albumin, and were stronger than those of urine albumin with FI (1.15 [95% CI, 0.99-1.34]). Higher urine B2M, another marker of tubule reabsorptive capacity, was associated with worse cognitive scores at baseline (ß: -0.09 [95% CI, -0.17 to-0.01]). Urine albumin was not associated with cognitive function. LIMITATIONS: Cross-sectional design, and FI may not be generalizable in other populations. CONCLUSIONS: Urine biomarkers of tubule injury, fibrosis, and proximal tubule reabsorptive capacity are variably associated with FI and worse cognition, independent of glomerular markers of kidney health. Future studies are needed to validate these results among other patient populations.

The advanced care coordination program: a protocol for improving transitions of care for dual-use veterans from community emergency departments back to the Veterans Health Administration (VA) primary care.

BACKGROUND: Veterans who access both the Veterans Health Administration (VA) and non-VA health care systems require effective care coordination to avoid adverse health care outcomes. These dual-use Veterans have diverse and complex needs. Gaps in transitions of care between VA and non-VA systems are common. The Advanced Care Coordination (ACC) quality improvement program aims to address these gaps by implementing a comprehensive longitudinal care coordination intervention with a focus on Veterans' social determinants of health (SDOH) to facilitate Veterans' transitions of care back to the Eastern Colorado Health Care System (ECHCS) for follow-up care. METHODS: The ACC program is an ongoing quality improvement study that will enroll dual-use Veterans after discharge from non-VA emergency department (EDs), and will provide Veterans with social worker-led longitudinal care coordination addressing SDOH and providing linkage to resources. The ACC social worker will complete biopsychosocial assessments to identify Veteran needs, conduct regular in-person and phone visits, and connect Veterans back to their VA care teams. We will identify non-VA EDs in the Denver, Colorado metro area that will provide the most effective partnership based on location and Veteran need. Veterans will be enrolled into the ACC program when they visit one of our selected non-VA EDs without being hospitalized. We will develop a program database to allow for continuous evaluation. Continuing education and outreach including the development of a resource guide, Veteran Care Cards, and program newsletters will generate program buy-in and bridge communication. We will evaluate our program using the Reach, Effectiveness, Adoption, Implementation, and Maintenance framework, supported by the Practical, Robust Implementation and Sustainability Model, Theoretical Domains Framework, and process mapping. DISCUSSION: The ACC program will improve care coordination for dual-use Veterans by implementing social-work led longitudinal care coordination addressing Veterans' SDOH. This intervention will provide an essential service for effective care coordination.

Cognitive impairment in older adults with epilepsy: Characterization and risk factor analysis.

OBJECTIVE: Cognitive deficits are common in epilepsy, though the impact of epilepsy on cognition in older adults is understudied. This study aimed to characterize cognition in older adults with epilepsy compared with healthy older adults and identify potential risk factors for impairment. METHODS: Thirty-eight older adults with epilepsy and 29 healthy controls completed a comprehensive neuropsychological battery, as well as measures of depression and anxiety. Chart review for current medications, seizure history, and neuroimaging was also completed. To compare cognitive performance between groups, ANOVA was used, and linear regression identified predictors of impairment among the group with epilepsy. RESULTS: Patients with epilepsy performed worse across nearly all cognitive domains, and were clinically impaired (i.e., ≥ 1.5 SD below mean) on more individual tests when compared with controls, including a subset of patients with epilepsy with normal MRIs. For all patients with epilepsy, taking a greater number of antiepileptic drugs was associated with poorer language and visuospatial abilities, and higher anxiety was associated with poorer visual memory. CONCLUSIONS: Older adults with epilepsy demonstrated greater cognitive deficits than matched controls. Polytherapy and anxiety heightened the risk for cognitive impairment in some cognitive domains, but not in others. Understanding the nature of cognitive decline in this population, as well as associated risk factors, may assist in the differential diagnosis of cognitive complaints and improve the design of treatment studies for older patients with epilepsy. Replication in larger, longitudinal studies is warranted to generalize these findings.

Glenoid version and its relationship to glenohumeral instability and labral tears.

BACKGROUND: Evidence suggests a relationship between glenoid retroversion and posterior instability, but no literature exists comparing glenoid version referencing the scapular body versus the endosteal vault. This study evaluated glenoid version and its relationship to unidirectional instability and labral tears. METHODS: Glenoid version in patients with unidirectional instability or labral tears was measured with magnetic resonance imaging by either the Friedman method or the Poon and Ting method. Analyses of variance followed by independent t tests were used to compare 3 groups: anterior instability or labral tears (anterior pathology group, n = 33); posterior instability or labral tears (posterior pathology group, n = 34); and stable controls (n = 30). The referencing error for 2-dimensional axial images was evaluated for variance by imaging facility. Interobserver and intraobserver reliability scores were calculated. RESULTS: With the Friedman method, the posterior pathology group (-9°) was more retroverted than the control group (-4°) (P = .0005) and the anterior pathology group (-5°) (P = .0104) but there was no difference between the control group and anterior pathology group (P = .38). The referencing error in the sagittal plane averaged 23° and varied by facility (P = .0365). The coronal-plane error averaged 1° and did not vary by facility (P = .7180). Intraclass correlation coefficient scores showed good to excellent intrarater and inter-rater reliability. CONCLUSION: The posterior pathology group had 5° more retroversion than controls using the Friedman method. Glenoid version using the Poon and Ting method or the Friedman method did not predict anterior instability or labral tears. Axial magnetic resonance images were constructed with a referencing error in the sagittal plane that varied by magnetic resonance imaging facility and has implications for improving 2-dimensional axial imaging protocols.

Evaluation of satisfaction and durability after hemiarthroplasty and total shoulder arthroplasty in a cohort of patients aged 50 years or younger: an analysis of discordance of patient satisfaction and implant survival.

BACKGROUND: Shoulder arthroplasty in individuals aged 50 years or younger reportedly leads to worse outcomes than in older patients. Current methods of determining survivorship may be inadequate and may not reflect actual patient definitions of satisfaction. The purpose of this study is to evaluate and contrast the survival of patient satisfaction and implant survival in the youngest reported patients undergoing either a primary hemiarthroplasty (HA) or total shoulder arthroplasty (TSA) using a third-generation stemmed prosthesis. METHODS: Outcomes in 71 patients aged 50 years or younger who were treated with primary HA or TSA were evaluated for patient satisfaction and implant survival rates. Patient satisfaction survival was based on yes or no answers to 2 binary questions regarding willingness to undergo surgery again and whether surgery improved the patient's shoulder. RESULTS: The Kaplan-Meier patient satisfaction survival rates at 5 years were 71.6% (95% confidence interval [CI], 46%-87%) for HAs and 95% (95% CI, 81%-99%) for TSAs. Multivariable regression analysis implicated postoperative pain as the primary causative factor for failure of patient satisfaction in all patients. In contrast, the implant survival rates at 5 years were 89% (95% CI, 69%-96%) for HAs and 95% (CI, 85%-100%) for TSAs. CONCLUSIONS: Patients aged 50 years or younger who undergo shoulder arthroplasty have declining rates of self-reported satisfaction despite high implant survival rates, and this finding highlights the discordance between patient satisfaction and implant survival. Primary TSA outperforms HA in both implant survival and patient satisfaction survival rates at short-term follow-up. Future studies and registries must incorporate measurements of patient satisfaction and not just revision rates to truly interpret outcomes.

Neurocognitive Effects of Obesity and Bariatric Surgery.

This review paper will discuss the recent literature examining the relationship between obesity and neurocognitive outcomes, with a particular focus on cognitive changes after bariatric surgery. Obesity is now recognized as an independent risk factor for adverse neurocognitive outcomes, and severely obese persons appear to be at even greater risk. Bariatric surgery is associated with rapid improvements in cognitive function that persist for at least several years, although the mechanisms underlying these improvements are incompletely understood. Assessment of cognitive impairment in bariatric surgery patients is challenging, and improved methods are needed, as poorer performance on neuropsychological tests of memory and executive function leads to poorer clinical weight outcomes. In addition to its clinical importance, further study in this area will provide key insight into obesity-related cognitive dysfunction and clarify the possibility of an obesity paradox for neurological outcomes.

Complex proteinopathy with accumulations of prion protein, hyperphosphorylated tau, α-synuclein and ubiquitin in experimental bovine spongiform encephalopathy of monkeys.

Proteins aggregate in several slowly progressive neurodegenerative diseases called 'proteinopathies'. Studies with cell cultures and transgenic mice overexpressing mutated proteins suggested that aggregates of one protein induced misfolding and aggregation of other proteins as well - a possible common mechanism for some neurodegenerative diseases. However, most proteinopathies are 'sporadic', without gene mutation or overexpression. Thus, proteinopathies in WT animals genetically close to humans might be informative. Squirrel monkeys infected with the classical bovine spongiform encephalopathy agent developed an encephalopathy resembling variant Creutzfeldt-Jakob disease with accumulations not only of abnormal prion protein (PrP(TSE)), but also three other proteins: hyperphosphorylated tau (p-tau), α-synuclein and ubiquitin; ß-amyloid protein (Aß) did not accumulate. Severity of brain lesions correlated with spongiform degeneration. No amyloid was detected. These results suggested that PrP(TSE) enhanced formation of p-tau and aggregation of α-synuclein and ubiquitin, but not Aß, providing a new experimental model for neurodegenerative diseases associated with complex proteinopathies.

Muller glia in retinal innate immunity: a perspective on their roles in endophthalmitis.

Muller cells are the predominant glial cell type in the retina and have a unique anatomy, with processes that span the entire retinal thickness. Although extensive morphological and physiological studies of Muller glia have been performed, much less is known about their role in retinal innate immunity, specifically in infectious endophthalmitis. They were found to express toll-like receptors (TLRs), a major family of pattern recognition receptors that mediate innate responses and provide an important mechanism by which Muller glia are able to sense both pathogen- and host-derived ligands in the vitreous and the retina. An increasing body of evidence suggests that TLR-signaling mediates beneficial effects in the retina via production of proinflammatory cytokines/chemokines, antimicrobial peptides, and neuroprotective growth factors to restore tissue homeostasis. In this review, we discussed retinal innate immunity in general with emphasis on the role of Muller glia in initiating retinal innate defense.

Imaging characteristics of lesser tuberosity osteotomy after total shoulder replacement: a study of 220 patients.

BACKGROUND: The lesser tuberosity osteotomy (LTO) has been gaining popularity as a method of exposing the glenohumeral joint during total shoulder replacement, whereby a small fragment of bone is removed from the lesser tuberosity, thus preserving the subscapularis tendon. To date, no large, randomized studies have reported evaluations of LTO healing and healing rates. METHODS: We reviewed the radiographs and available computed tomography images of 362 patients who underwent a total shoulder arthroplasty by the same surgeon between 2006 and 2012. The integrity of the LTO site was graded as not seen, bony union, nondisplaced nonunion, and displaced nonunion. The smoking status of patients was also assessed. RESULTS: Of 362 patients investigated, 220 had a minimum of 6 months of radiographic follow-up. The LTO site was not seen in 37 patients; of the remaining 183, 159 patients (86.89%) demonstrated bony union, 8.80% of whom were smokers; 16 patients (8.74%) demonstrated nondisplaced nonunion, 6.3% of whom were smokers; and 8 patients (4.3%) demonstrated displaced nonunion, 25.0% of whom were smokers. Overall, 19 of the 24 nonunions were in male patients (79.1%) and 5 were in female patients (20.8%). CONCLUSIONS: This is the first large-scale study to report the healing rate of LTOs. LTO healing is best assessed on radiographs; if nondisplaced or displaced nonunions are suspected, computed tomography can be a helpful additional examination. The number of radiographs where there is a lack of adequate visualization of the LTO site raises important questions about definitive radiographic evaluation using current techniques.

(Mis)matched direct and moderating relationships among pro-environmental attitudes, environmental efficacy, and pro-environmental behaviors across and within 11 countries.

Pro-environmental behaviors are influenced by individuals' pro-environmental attitudes and environmental efficacy, among many other factors. However, attitude-behavior models are inconsistent on whether and how attitudes, efficacy, and behaviors should match in specificity or generality, and on the moderation effect of efficacy. This study first tests a simple model including direct and moderating relationships between pro-environmental attitudes, environmental efficacy, and pro-environmental behaviors. Then it examines relationships among subscales matched or mismatched in their respective specific or general domain of environmental attitudes (concern, values), environmental efficacy (self, collective), and pro-environmental behaviors (private, public). Secondary data come from an overall sample of 11,000 respondents across 11 countries, with n = 1,000 from each country. Pro-environmental attitudes and efficacy have direct relationships with pro-environmental behavior, but efficacy has little moderation effect. Different combinations of (mis)matched measures produce slightly different results, with the most variance explained, counter to hypotheses, by two mismatched models. Results are generally consistent across countries.

Ability to regulate emotion is predicted by depressive symptoms and cognitive function in a cardiac sample.

BACKGROUND: Reduced ability to regulate emotion is exhibited in depressed individuals as well as patients with neurocognitive change. Given that patients with cardiovascular disease (CVD) often exhibit both cognitive and mood changes, these could, in combination, lead to increased volatility of emotion. OBJECTIVE: The current study examined the association between ability to regulate emotion, depressive symptoms, and cognitive function in a sample of patients with CVD. METHODS: Ninety-one CVD patients referred for outpatient stress testing completed brief cognitive testing and self-report measures of emotion regulation and depressive symptoms. RESULTS: Hierarchical multiple regression analyses revealed that depressive symptoms (P < .001) and executive function (P < .05) independently contribute to emotion regulation. The interaction between these variables demonstrates that elevated depressive symptoms and decreased executive function predict increased emotion dysregulation. CONCLUSION: Findings suggest that in combination, elevated depressive symptoms and executive dysfunction contribute to poorer ability to regulate emotion in patients with CVD. Given the prevalence of depression and cognitive change in this population, these findings underscore the importance of clinician awareness of these issues in this population and suggest clinical implications for treatment of mental health issues, especially emotion regulation, in this population.

Higher serum insulin-like growth factor-1 is associated with better cognitive performance in persons with mild cognitive impairment.

BACKGROUND: Serum insulin-like growth factor-1 (IGF-1) is a mitogenic peptide involved in the regulation of cell proliferation, differentiation, and apoptosis in a wide variety of cells and tissues. Recent research suggests higher circulating levels of IGF-1 are associated with better cognitive performance in healthy older adults and in early stages of Alzheimer's disease, although the cognitive profile associated with elevated IGF-1 has not been examined in persons with mild cognitive impairment. METHODS: Thirty-one participants (age: 83.71 ± 3.59 years; 58% women) with mild cognitive impairment completed neuropsychological testing and 12-hour fasting blood draw to assess serum IGF-1. RESULTS: Partial correlations between serum IGF-1 and neuropsychological measures were conducted, adjusting for insulin, body mass index, and age. Higher IGF-1-values were associated with better global cognition (Modified Mini Mental State Exam: r = 0.39, P = 0.04) and verbal list learning (Hopkins Verbal Learning Test learning: r = 0.38, P = 0.05), Hopkins Verbal Learning Test free recall (r = 0.41, P = 0.03), and Hopkins Verbal Learning Test recognition discriminability (r = 0.46, P = 0.01). A similar trend emerged for executive function as tested by the Frontal Assessment Battery (r = 0.33, P = 0.09). CONCLUSION: Results suggest higher levels of serum IGF-1 are associated with better cognitive performance in persons with mild cognitive impairment, particularly on tests of learning and memory. These findings suggest IGF-1 may be neuroprotective not only in healthy older adults, but also in adults in the earliest stages of Alzheimer's disease. Further investigation is needed to clarify the nature of this relationship, particularly prospective studies.

Brain-derived neurotrophic factor Val66Met polymorphism and cognitive function in persons with cardiovascular disease.

AIM: Cognitive impairment is common among persons with cardiovascular disease (CVD), and several potential aetiological mechanisms have been described, including contributions of genetic markers such as variations in the brain-derived neurotrophic (BDNF) gene. This current study examined the associations of BDNF genotype with cognitive function among individuals with CVD. METHODS: This study included 110 participants with CVD who completed a comprehensive neuropsychological battery that assessed global cognitive function, attention/executive function, memory, language, and visuospatial abilities. All participants also underwent blood draw to provide a DNA sample that was used to determine BDNF genotype. Carriers of either one or two copies of the methionine allele of BDNF were categorized into one group (n = 33); non-carriers were categorized into a second group (n = 77). RESULTS: After adjustment for demographic and medical characteristics, hierarchical regression analyses revealed persons with one or more methionine alleles displayed better performance than valine/valine individuals for attention/executive function (ß = 0.22, P = 0.047) and memory (ß = 0.25, P = 0.03), as well as a trend for language (ß = 0.19, P = 0.08) and visuospatial abilities (ß = 0.21, P = 0.06). CONCLUSIONS: BDNF Val66Met had little impact on cognitive functioning in a sample of older adults with CVD, and significant findings contradicted that predicted by past work. Future work is much needed to clarify the mechanisms of these findings, particularly studies examining both circulating BDNF levels and genetic variation in the BDNF gene and cognitive function over time.

Proinflammatory Responses in SARS-CoV-2 and Soluble Spike Glycoprotein S1 Subunit Activated Human Macrophages.

Critically ill COVID-19 patients display signs of generalized hyperinflammation. Macrophages trigger inflammation to eliminate pathogens and repair tissue, but this process can also lead to hyperinflammation and resulting exaggerated disease. The role of macrophages in dysregulated inflammation during SARS-CoV-2 infection is poorly understood. We inoculated and treated human macrophage cell line THP-1 with SARS-CoV-2 and purified, glycosylated, soluble SARS-CoV-2 spike protein S1 subunit (S1) to clarify the role of macrophages in pro-inflammatory responses. Soluble S1 upregulated TNF-α and CXCL10 mRNAs, and induced secretion of TNF-α from THP-1 macrophages. While THP-1 macrophages did not support productive SARS-CoV-2 replication or viral entry, virus exposure resulted in upregulation of both TNF-α and CXCL10 genes. Our study shows that extracellular soluble S1 protein is a key viral component inducing pro-inflammatory responses in macrophages, independent of virus replication. Thus, virus- or soluble S1-activated macrophages may become sources of pro-inflammatory mediators contributing to hyperinflammation in COVID-19 patients.

Reprogramming Cancer into Antigen-Presenting Cells as a Novel Immunotherapy.

Therapeutic cancer vaccination seeks to elicit activation of tumor-reactive T cells capable of recognizing tumor-associated antigens (TAA) and eradicating malignant cells. Here, we present a cancer vaccination approach utilizing myeloid-lineage reprogramming to directly convert cancer cells into tumor-reprogrammed antigen-presenting cells (TR-APC). Using syngeneic murine leukemia models, we demonstrate that TR-APCs acquire both myeloid phenotype and function, process and present endogenous TAAs, and potently stimulate TAA-specific CD4+ and CD8+ T cells. In vivo TR-APC induction elicits clonal expansion of cancer-specific T cells, establishes cancer-specific immune memory, and ultimately promotes leukemia eradication. We further show that both hematologic cancers and solid tumors, including sarcomas and carcinomas, are amenable to myeloid-lineage reprogramming into TR-APCs. Finally, we demonstrate the clinical applicability of this approach by generating TR-APCs from primary clinical specimens and stimulating autologous patient-derived T cells. Thus, TR-APCs represent a cancer vaccination therapeutic strategy with broad implications for clinical immuno-oncology. SIGNIFICANCE: Despite recent advances, the clinical benefit provided by cancer vaccination remains limited. We present a cancer vaccination approach leveraging myeloid-lineage reprogramming of cancer cells into APCs, which subsequently activate anticancer immunity through presentation of self-derived cancer antigens. Both hematologic and solid malignancies derive significant therapeutic benefit from reprogramming-based immunotherapy. This article is highlighted in the In This Issue feature, p. 1027.

Acute cold exposure and cognitive function: evidence for sustained impairment.

Several industries experience periods of cold exposure and rewarming throughout the workday but mental performance under these conditions is unknown. A better understanding of cognition during the rewarming phase after cold exposure may help reduce accidents and improve performance. Ten young men (wearing ~0.1 clo) underwent three consecutive mornings trials where they were exposed to cold air (10°C) and then subsequently rewarmed (25°C air). A computerised test battery was administered during each stage of the protocol to determine working memory, choice reaction time, executive function and maze navigation. Rectal and skin temperature, oxygen consumption and thermal sensation were also measured throughout and showed a typical response. Relative to baseline performance, working memory, choice reaction time and executive function declined during exposure to 10°C, and these impairments persisted 60 min into the recovery period (i.e. once physiological parameters had returned to baseline). Further work is needed to develop countermeasures to this predicament. PRACTITIONER SUMMARY: This study showed that working memory, choice reaction time and executive function declined during exposure to 10°C air, and these impairments persisted 60 min into the rewarming period (i.e. once measurable physiological parameters had returned to normal). Individuals may be at risk for injury after removal from a cold environment.

The Relationship of Kidney Tubule Biomarkers with Brain Imaging in CKD Patients in SPRINT.

Urine biomarker concentrations reflecting kidney tubule injury and dysfunction were not associated with brain MRI measures.Higher eGFR was associated with lower total brain cerebral blood flow.This is the first evaluation of the relationship of kidney tubule biomarkers with brain imaging by MRI in patients with CKD.