Acute exercise alters brain glucose metabolism in aging and Alzheimer's disease.

There is evidence that aerobic exercise improves brain health. Benefits may be modulated by acute physiological responses to exercise, but this has not been well characterized in older or cognitively impaired adults. The randomized controlled trial 'AEROBIC' (NCT04299308) enrolled 60 older adults who were cognitively healthy (n = 30) or cognitively impaired (n = 30) to characterize the acute brain responses to moderate [45-55% heart rate reserve (HRR)] and higher (65-75% HRR) intensity acute exercise. Each participant received two fluorodeoxyglucose positron emission tomography (FDG-PET) scans, one at rest and one following acute exercise. Change in cerebral glucose metabolism from rest to exercise was the primary outcome. Blood biomarker responses were also characterized as secondary outcomes. Whole grey matter FDG-PET standardized uptake value ratio (SUVR) differed between exercise (1.045 ± 0.082) and rest (0.985 ± 0.077) across subjects [Diff = -0.060, t(58) = 13.8, P < 0.001] regardless of diagnosis. Exercise increased lactate area under the curve (AUC) [F(1,56) = 161.99, P < 0.001] more in the higher intensity group [mean difference (MD) = 97.0 ± 50.8] than the moderate intensity group (MD = 40.3 ± 27.5; t = -5.252, P < 0.001). Change in lactate AUC and FDG-PET SUVR correlated significantly (R2 = 0.179, P < 0.001). Acute exercise decreased whole grey matter cerebral glucose metabolism. This effect tracked with the systemic lactate response, suggesting that lactate may serve as a key brain fuel during exercise. Direct measurements of brain lactate metabolism in response to exercise are warranted. KEY POINTS: Acute exercise is associated with a drop in global brain glucose metabolism in both cognitively healthy older adults and those with Alzheimer's disease. Blood lactate levels increase following acute exercise. Change in brain metabolism tracks with blood lactate, suggesting it may be an important brain fuel. Acute exercise stimulates changes in brain-derived neurotrophic factor and other blood biomarkers.

Changes in Cognitive Function After Kidney Transplantation: A Longitudinal Cohort Study.

RATIONALE & OBJECTIVE: Kidney disease negatively affects cognition. We assessed the effect of kidney transplantation (KT) on different cognitive domains. STUDY DESIGN: Prospective cohort study. SETTING & PARTICIPANTS: We examined pre- versus post-KT cognition in patients waitlisted for KT at an academic center. PREDICTORS: Transplant status. We measured cognitive function before KT (n=101), 3 months after KT (n=78), and 1 year after KT (n = 83). OUTCOMES: Our primary outcome was change in cognitive function before versus after KT. We used standard neuropsychological tests to assess global cognition (Mini-Mental State Exam [MMSE]), episodic/declarative memory (Logical Memory), psychomotor speed/visuospatial function (Digit Symbol Substitution Test [DSST], Trail Making Test [TMT] A), working memory/attention (Digit Span), executive function (TMT B), and semantic memory/verbal fluency/language (Category Fluency). ANALYTICAL APPROACH: Using linear mixed model analysis, we evaluated the changes in neuropsychological test scores adjusted for age, sex, race, education, and number of assessments. RESULTS: Before KT, Logical Memory I and II, DSST, MMSE, Category Fluency (animal naming), and Digit Span backward scores were low compared with normative values from the National Alzheimer's Coordinating Center data. Logical Memory I and II scores improved after KT (pre- vs post-KT, estimated group difference [d]=3.3, P<0.001 for Logical Memory I; d=4.27, P<0.001 for Logical Memory II), such that post-KT scores were similar to normative values (post-KT vs normative values, d = -0.37, P=0.06 for Logical Memory I; d = -0.89, P=0.08 for Logical Memory II). Category Fluency (animal naming; d=2.4, P<0.001) and DSST (d=3.12, P=0.01) scores also improved with KT, but post-KT DSST scores remained lower than normative values (post-KT vs normative values, d = -5.17, P<0.001). MMSE, Digit Span, and TMT A and B scores did not change after KT. LIMITATIONS: Single-center study. CONCLUSIONS: Episodic and verbal declarative memory normalize after KT. Semantic memory, verbal fluency, language, psychomotor speed, and visuospatial function show partial improvement. Cognitive impairment in kidney disease is therefore at least partly reversible with KT. PLAIN-LANGUAGE SUMMARY: Cognitive impairment in kidney disease affects self-esteem, vocational abilities, quality of life, health care costs, and mortality. It is not clear whether kidney transplantation (KT) improves cognition and whether the improvement is uniform across cognitive domains. The distinction between reversible and irreversible cognitive impairment has important implications in the clinical care of patients before and after KT. We assessed cognition before KT and 3 months and 12 months after KT and discovered that episodic and verbal declarative memory normalized with KT. Semantic memory, verbal fluency, language, psychomotor speed, and visuospatial function also improved with KT but did not reach normal levels. Cognitive impairment in kidney disease is therefore at least partly reversible.

Dynamic Prediction of Mortality Using Longitudinally Measured Pediatric Sequential Organ Failure Assessment Scores: A Joint Modeling Approach.

OBJECTIVES: The pediatric Sequential Organ Failure Assessment (pSOFA) score was designed to track illness severity and predict mortality in critically ill children. Most commonly, pSOFA at a point in time is used to assess a static patient condition. However, this approach has a significant drawback because it fails to consider any changes in a patients' condition during their PICU stay and, especially, their response to initial critical care treatment. We aimed to evaluate the performance of longitudinal pSOFA scores for predicting mortality. DESIGN: Single-center, retrospective cohort study. SETTING: Quaternary 40-bed PICU. PATIENTS: All patients admitted to the PICU between 2015 and 2021 with at least 24 hours of ICU stay. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We calculated daily pSOFA scores up to 30 days, or until death or discharge from the PICU, if earlier. We used the joint longitudinal and time-to-event data model for the dynamic prediction of 30-day in-hospital mortality. The dataset, which included 9146 patients with a 30-day in-hospital mortality of 2.6%, was divided randomly into training (75%) and validation (25%) subsets, and subjected to 40 repeated stratified cross-validations. We used dynamic area under the curve (AUC) to evaluate the discriminative performance of the model. Compared with the admission-day pSOFA score, AUC for predicting mortality between days 5 and 30 was improved on average by 6.4% (95% CI, 6.3-6.6%) using longitudinal pSOFA scores from the first 3 days and 9.2% (95% CI, 9.0-9.5%) using scores from the first 5 days. CONCLUSIONS: Compared with admission-day pSOFA score, longitudinal pSOFA scores improved the accuracy of mortality prediction in PICU patients at a single center. The pSOFA score has the potential to be used dynamically for the evaluation of patient conditions.

Pediatric Burn Care for Burn Injury: Outcomes by Timing of Referral Using a U.S. Single-Center Retrospective Cohort, 2005-2019.

OBJECTIVES: Burn centers offer specialized care to pediatric patients with burn injuries. However, data about outcome in relation to timing of transfer are limited. We examined these timings and outcomes among burn-injured pediatric patients. DESIGN: Single-center, retrospective cohort study of U.S. national and international practice. SETTING: Shriners ESO Trauma Burn Registry, 2005-2019. PATIENTS: Patients 0-17 years old admitted to a pediatric burn center with 10-80% total body surface area (TBSA) burn between 2005 and 2019. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The cohort of 761 patients was subcategorized according to timing of referral: early presentation (EP) (0-7 d), delayed presentation (DP) (8-60 d), and very delayed presentation (VDP) (> 60 d). Primary outcomes included hospital length of stay (LOS), ICU LOS, percent TBSA (%TBSA)/LOS ratio, mortality, and disposition. Dichotomous outcomes were analyzed using logistic regression and continuous outcomes were compared using median regression, both utilizing multivariable analysis adjusting for a priori confounders and presented as adjusted coefficients (ACs) with 95% CI. Delayed referral (DP and VDP) was associated with higher %TBSA burn and with fewer referrals from high-income countries. Compared with EP, VDP was associated with higher LOS/%TBSA (AC, 0.2 [0.01-0.4]). On univariate analysis, in comparison with EP, DP and VDP were associated with higher ICU (DP 16 [6-29]; VDP 8 [0-18]) and hospital LOS (DP 34 [21-55]; VDP 32 [18-58]). Overall, ten of 761 patients died (1.3%), and we found no association between timing of referral and mortality. Also, in 751 survivors, 635 patients (84.6%) were discharged home without home health, and we found no association with timing of referral on multivariable analysis. CONCLUSIONS: In this report, we have reviewed our single-center, international burn-injured pediatric cohort, operating in the United States (2005-2019). We find that referral with VDP as opposed to EP was associated with increased LOS/%TBSA.

Comparing the Quality of Domain-Specific Versus General Language Models for Artificial Intelligence-Generated Differential Diagnoses in PICU Patients.

OBJECTIVES: Generative language models (LMs) are being evaluated in a variety of tasks in healthcare, but pediatric critical care studies are scant. Our objective was to evaluate the utility of generative LMs in the pediatric critical care setting and to determine whether domain-adapted LMs can outperform much larger general-domain LMs in generating a differential diagnosis from the admission notes of PICU patients. DESIGN: Single-center retrospective cohort study. SETTING: Quaternary 40-bed PICU. PATIENTS: Notes from all patients admitted to the PICU between January 2012 and April 2023 were used for model development. One hundred thirty randomly selected admission notes were used for evaluation. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Five experts in critical care used a 5-point Likert scale to independently evaluate the overall quality of differential diagnoses: 1) written by the clinician in the original notes, 2) generated by two general LMs (BioGPT-Large and LLaMa-65B), and 3) generated by two fine-tuned models (fine-tuned BioGPT-Large and fine-tuned LLaMa-7B). Differences among differential diagnoses were compared using mixed methods regression models. We used 1,916,538 notes from 32,454 unique patients for model development and validation. The mean quality scores of the differential diagnoses generated by the clinicians and fine-tuned LLaMa-7B, the best-performing LM, were 3.43 and 2.88, respectively (absolute difference 0.54 units [95% CI, 0.37-0.72], p < 0.001). Fine-tuned LLaMa-7B performed better than LLaMa-65B (absolute difference 0.23 unit [95% CI, 0.06-0.41], p = 0.009) and BioGPT-Large (absolute difference 0.86 unit [95% CI, 0.69-1.0], p < 0.001). The differential diagnosis generated by clinicians and fine-tuned LLaMa-7B were ranked as the highest quality in 144 (55%) and 74 cases (29%), respectively. CONCLUSIONS: A smaller LM fine-tuned using notes of PICU patients outperformed much larger models trained on general-domain data. Currently, LMs remain inferior but may serve as an adjunct to human clinicians in real-world tasks using real-world data.

LEAP! Rx: A randomized trial of a pragmatic approach to lifestyle medicine.

INTRODUCTION: Clinicians lack the tools to incorporate physical activity into clinical care for Alzheimer's disease prevention. We tested a 52-week exercise and health education program (Lifestyle Empowerment for Alzheimer's Prevention [LEAP! Rx]) that integrates clinician referrals and community-based fitness resources. METHODS: We randomized 219 participants to the LEAP! Rx (ie, exercise and monthly brain health education) or a standard-of-care control group and tested the effects on cardiorespiratory fitness, insulin resistance, body composition, lipids, and cognitive performance. RESULTS: Physicians were able to connect their patients to a community lifestyle intervention. The intervention group increased in cardiorespiratory fitness at 12 and 52 weeks (p = 0.005). We observed no effects on secondary measures. Participants meeting 80% of weekly goals (150 min, moderate to vigorous activity) saw greater fitness improvements than those with less than 80% (p < 0.001). DISCUSSION: These results hold promise for broad implementation of exercise interventions into larger healthcare systems and have implications for improved research recruitment strategies. TRIAL REGISTRATION: NCT No. NCT03253341. HIGHLIGHTS: Our community-based exercise program increased cardiorespiratory fitness. Our digital physician referral method increased the diversity of the participant sample. Our findings have implications for personalized dementia risk reduction strategies.

Reversibility of cognitive worsening observed with BACE inhibitor umibecestat in the Alzheimer's Prevention Initiative (API) Generation Studies.

INTRODUCTION: The Alzheimer's Prevention Initiative (API) Generation Studies evaluated the BACE inhibitor umibecestat for Alzheimer's disease (AD) prevention. The studies were terminated early, and the reversibility of umibecestat's side effects was assessed. METHODS: Cognitively unimpaired 60- to 75-year-old apolipoprotein E (APOE) Îµ4 homozygotes and heterozygotes (the latter with elevated brain amyloid deposition) (n = 1556) received umibecestat (50 or 15 mg daily) or placebo for 7 months on average and were followed for a median (interquartile range) of 4 (3 to 6) months after washout. RESULTS: Compared to placebo, umibecestat-treated participants had small, non-progressive, but statistically significant decline in performance on certain cognitive batteries including Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) and API Preclinical Composite Cognitive test, but not Clinical Dementia Rating-Sum of Boxes. RBANS differences were no longer significant at the end of follow-up. DISCUSSION: In people at genetic risk for AD, high-dose beta-site amyloid precursor protein cleaving enzyme (BACE) inhibition was associated with early mild cognitive worsening, which reversed shortly after washout, suggesting a symptomatic side effect not associated with neurodegeneration. Fully anonymized data, images, and samples are available upon request for further research on BACE inhibition. HIGHLIGHTS: This is the first trial with blinded assessment of reversibility of BACE inhibitor side effects. Umibecestat was tested in cognitively unimpaired persons at genetic risk for AD. Umibecestat led to early mild cognitive decline that reversed shortly after washout. This suggests a potentially manageable effect not associated with neurodegeneration. Further research may determine the future of BACE inhibition in AD prevention.

A text message intervention to support latino dementia family caregivers (CuidaTEXT): feasibility study.

OBJECTIVES: To test the feasibility, acceptability, and preliminary efficacy of CuidaTEXT: a bidirectional text message intervention to support Latino dementia family caregivers. METHODS: CuidaTEXT is a six-month, bilingual intervention tailored to caregiver needs (e.g., education, problem-solving, resources). We used convenience sampling and reached 31 potential participants via clinics, registries, community promotion, and online advertising. We enrolled 24 Latino caregivers in a one-arm trial and assessed feasibility, acceptability, and preliminary efficacy within six months. RESULTS: None of the participants unsubscribed from CuidaTEXT and 83.3% completed the follow up survey. Most participants (85.7%) reported reading most text messages thoroughly. All participants reported being very or extremely satisfied with the intervention. Participants reported that CuidaTEXT helped a lot (vs not at all, a little, or somehow) in caring for their care recipient (71.4%; n = 15), for themselves (66.7%; n = 14), and understanding more about dementia (85.7%; n = 18). Compared to baseline, at six months caregiver behavioral symptom distress (0-60) decreased from 19.8 to 12.0 and depression (0-30) from 8.8 to 5.4 (p < .05). CONCLUSIONS: CuidaTEXT demonstrated high levels of feasibility, acceptability, and preliminary efficacy among Latino caregivers. CLINICAL IMPLICATIONS: CuidaTEXT's feasibility and potential for widespread implementation holds promise in supporting Latino caregivers of people with dementia.

GCN2 is required to maintain core body temperature in mice during acute cold.

Nonshivering thermogenesis in rodents requires macronutrients to fuel the generation of heat during hypothermic conditions. In this study, we examined the role of the nutrient sensing kinase, general control nonderepressible 2 (GCN2) in directing adaptive thermogenesis during acute cold exposure in mice. We hypothesized that GCN2 is required for adaptation to acute cold stress via activation of the integrated stress response (ISR) resulting in liver production of FGF21 and increased amino acid transport to support nonshivering thermogenesis. In alignment with our hypothesis, female and male mice lacking GCN2 failed to adequately increase energy expenditure and veered into torpor. Mice administered a small molecule inhibitor of GCN2 were also profoundly intolerant to acute cold stress. Gcn2 deletion also impeded liver-derived FGF21 but in males only. Within the brown adipose tissue (BAT), acute cold exposure increased ISR activation and its transcriptional execution in males and females. RNA sequencing in BAT identified transcripts that encode actomyosin mechanics and transmembrane transport as requiring GCN2 during cold exposure. These transcripts included class II myosin heavy chain and amino acid transporters, critical for maximal thermogenesis during cold stress. Importantly, Gcn2 deletion corresponded with higher circulating amino acids and lower intracellular amino acids in the BAT during cold stress. In conclusion, we identify a sex-independent role for GCN2 activation to support adaptive thermogenesis via uptake of amino acids into brown adipose.NEW & NOTEWORTHY This paper details the discovery that GCN2 activation is required in both male and female mice to maintain core body temperature during acute cold exposure. The results point to a novel role for GCN2 in supporting adaptive thermogenesis via amino acid transport and actomyosin mechanics in brown adipose tissue.

Implementing a home-based virtual hypertension programme-a pilot feasibility study.

INTRODUCTION: Implementing a health system-based hypertension programme may lower blood pressure (BP). METHODS: We performed a randomized, controlled pilot study to assess feasibility, acceptability, and safety of a home-based virtual hypertension programme integrating evidence-based strategies to overcome current barriers to BP control. Trained clinical pharmacists staffed the virtual collaborative care clinic (vCCC) to remotely manage hypertension using a BP dashboard and phone "visits" to monitor BP, adherence, side effects of medications, and prescribe anti-hypertensives. Patients with uncontrolled hypertension were identified via electronic health records. Enrolled patients were randomized to either vCCC or usual care for 3 months. We assessed patients' home BP monitoring behaviour, and patients', physicians', and pharmacists' perspectives on feasibility and acceptability of individual programme components. RESULTS: Thirty-one patients (vCCC = 17, usual care = 14) from six physician clinics completed the pilot study. After 3 months, average BP decreased in the vCCC arm (P = 0.01), but not in the control arm (P = 0.45). The vCCC participants measured BP more (9.9 vs. 1.2 per week, P < 0.001). There were no intervention-related adverse events. Participating physicians (n = 6), pharmacists (n = 5), and patients (n = 31) rated all programme components with average scores of >4.0, a pre-specified benchmark. Nine adaptations in vCCC design and delivery were made based on potential barriers to implementing the programme and suggestions. CONCLUSION: A home-based virtual hypertension programme using team-based care, technology, and a logical integration of evidence-based strategies is safe, acceptable, and feasible to intended users. These pilot data support studies to assess the effectiveness of this programme at a larger scale.

Driving Automation for Older Adults with Preclinical Alzheimer's Disease.

INTRODUCTION: Older adults with preclinical Alzheimer's disease (AD) show changes in on-road driving performance. The impact of preclinical AD on using automated vehicle (AV) technology is unknown. The aim was to evaluate safety and cognitive workload while operating AV technology in drivers with preclinical AD. INTRODUCTION: This cross-sectional study included 40 participants: 19 older adults (age 74.16 ± 4.78; MOCA scores 26.42 ± 2.52) with preclinical AD, evidenced by elevated cortical beta-amyloid; and 21 controls (age 73.81 ± 5.62; MOCA scores 28.24 ± 1.67). All participants completed two scenarios in a driving simulator. Scenario 1 included conditional automation with an emergency event that required a manual take-over maneuver. Scenario 2 was identical but with a cognitive distractor task. Emergency response time was the main safety outcome measure. Cognitive workload was calculated using moment-to-moment changes in pupillary size and converted into an Index of Cognitive Activity (ICA). Mann-Whitney U and independent t tests were used to compare group differences. RESULTS: Emergency response times were similar between drivers with preclinical AD and controls in scenario 1 (20.85 s ± 1.08 vs. 20.52 s ± 3.18; p = 0.83) and scenario 2 (14.83 s ± 7.37 vs. 13.45 s ± 10.43; p = 0.92). Likewise, no differences were found in ICA between drivers with preclinical AD and controls in scenario 1 (0.34 ± 0.08 vs. 0.33 ± 0.17; p = 0.74) or scenario 2 (0.30 ± 0.07 vs. 0.29 ± 0.17; p = 0.93). CONCLUSIONS: Older drivers with preclinical AD may safely operate AV technology, without increased response times or cognitive workload. Future on-road studies with AV technology should confirm these preliminary results in drivers with preclinical AD.

Trends in Disease Severity Among Critically Ill Children With Severe Acute Respiratory Syndrome Coronavirus 2: A Retrospective Multicenter Cohort Study in the United States.

OBJECTIVES: To describe trends in critical illness from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in children over the course of the COVID-19 pandemic. We hypothesized that PICU admission rates were higher in the Omicron period compared with the original outbreak but that fewer patients needed endotracheal intubation. DESIGN: Retrospective cohort study. SETTING: This study took place in nine U.S. PICUs over 3 weeks in January 2022 (Omicron period) compared with 3 weeks in March 2020 (original period). PATIENTS: Patients less than or equal to 21 years old who screened positive for SARS-CoV-2 infection by polymerase chain reaction or hospital-based rapid antigen test and were admitted to a PICU or intermediate care unit were included. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: A total of 267 patients (239 Omicron and 28 original) were reviewed. Forty-five patients in the Omicron cohort had incidental SARS-CoV-2 and were excluded from analysis. The Omicron cohort patients were younger compared with the original cohort patients (median [interquartile range], 6 yr [1.3-13.3 yr] vs 14 yr [8.3-17.3 yr]; p = 0.001). The Omicron period, compared with the original period, was associated with an average increase in COVID-19-related PICU admissions of 13 patients per institution (95% CI, 6-36; p = 0.008), which represents a seven-fold increase in the absolute number admissions. We failed to identify an association between cohort period (Omicron vs original) and odds of intubation (odds ratio, 0.7; 95% CI, 0.3-1.7). However, we cannot exclude the possibility of up to 70% reduction in intubation. CONCLUSIONS: COVID-19-related PICU admissions were seven times higher in the Omicron wave compared with the original outbreak. We could not exclude the possibility of up to 70% reduction in use of intubation in the Omicron versus original epoch, which may represent differences in PICU/hospital admission policy in the later period, or pattern of disease, or possibly the impact of vaccination.

Association between the Estimated Glomerular Filtration Rate and Brain Atrophy in Older Adults.

End-stage kidney disease has been associated with cognitive impairment and brain atrophy. It remains unclear if mild to moderate kidney dysfunction is associated with brain atrophy, especially in older adults. We used cross-sectional data from the Alzheimer's Disease Neuroimaging Initiative (ADNI), an NIH-funded multicenter longitudinal cohort study, to better understand the association between estimated glomerular filtration rate (eGFR) and brain volumes. We included all ADNI participants with both baseline serum creatinine values and MRI brain volume assessments. We used multiple linear regression modeling to assess cross-sectional associations between eGFR and whole-brain gray matter, hippocampus, entorhinal, fusiform, and middle temporal brain volumes. Participants (n = 1,596) were 74 ± 7 years old with a mean eGFR of 69.4 ± 14.8 mL/min/1.73 m2; 53% had mild cognitive impairment, and 19% had dementia. Unadjusted analysis showed an association between lower eGFR and smaller brain volumes. After adjusting for age, sex, and education, there was no association between eGFR brain volumes (p > 0.05 for all). These results remained consistent after subgroup analysis by age stratification and baseline cognitive status. Age was a confounding variable in the unadjusted association between the eGFR and brain volumes. Thus, a mild to moderately reduced eGFR was not associated with brain atrophy in ADNI participants.

Mild to moderate decrease in eGFR and cognitive decline in older adults.

BACKGROUND: Whether mild to moderately low estimated glomerular filtration rate (eGFR) is associated with cognitive decline in older adults is not clear. We evaluated changes in cognition in relation to baseline eGFR in older adults participating in the Alzheimer's Disease Neuroimaging Initiative (ADNI). METHODS: This is a longitudinal secondary analysis of an established observational cohort. We used data from the ADNI, an National Institutes of Health-funded, multicenter longitudinal observational study that includes participants with and without cognitive impairment who were administered a comprehensive battery of neuropsychological tests every 6 months. We related the Chronic Kidney Disease Epidemiology Collaboration eGFR with previously validated cognition composite scores for memory (ADNI-Mem) and executive function (ADNI-EF) in multivariable linear regression analysis adjusted for age, sex, race and level of education. RESULTS: A total of 1127 ADNI participants (mean age 74 ± 7 years, 57% men, 97% Caucasian, mean follow-up 6 ± 2.6 years) were included in the analysis. The mean baseline eGFR was 76 ± 19 mL/min/1.73 m2, with 6% with eGFR <45, 22% with eGFR 45-<60, 51% with eGFR 60-90 and 21% with eGFR >90 mL/min/1.73 m2 at baseline. Both ADNI-Mem and ADNI-EF scores declined over time. In the multivariable linear regression model, older age (ß = -0.117, P = 0.01), female sex (ß = 0.312, P < 0.001) and lower education (ß = 0.079, P < 0.001) were associated with a decline in ADNI-Mem scores, whereas baseline eGFR (each 10 mL/min/1.73 m2 change) was not {ß = -0.03 [confidence interval (CI) -0.06-0.001], P = 0.11}. Similarly, older age (ß = -0.278, P < 0.001) and lower education (ß = 0.099, P < 0.001) were associated with a decline in ADNI-EF scores, whereas baseline eGFR was not [ß = 0.004 (95% CI -0.04-0.04), P = 0.84]. CONCLUSIONS: In this cohort from the ADNI study, there was no association between baseline eGFR and cognitive decline in older adults with mild to moderately low eGFR.

Factors Associated With Mechanical Ventilation Duration in Pediatric Burn Patients in a Regional Burn Center in the United States.

OBJECTIVES: Among burned children who arrive at a burn center and require invasive mechanical ventilation (IMV), some may have prolonged IMV needs. This has implications for patient-centered outcomes as well as triage and resource allocation decisions. Our objective was to identify factors associated with the duration of mechanical ventilation in pediatric patients with acute burn injury in this setting. DESIGN: Single-center, retrospective cohort study. SETTING: Registry data from a regional, pediatric burn center in the United States. PATIENTS: Children less than or equal to 18 years old admitted with acute burn injury who received IMV between January 2005 and December 2020. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Ventilator days were defined as any full or partial day having received IMV via an endotracheal tube or tracheostomy, not inclusive of time spent ventilated for procedures. Of 5,766 admissions for acute burn care, 4.3% ( n = 249) required IMV with a median duration of 10 days. A multivariable model for freedom from mechanical ventilation showed that the presence of inhalational injury (subhazard ratio [sHR], 0.62; 95% CI, 0.46-0.85) and burns to the head and neck region (sHR, 0.94; 95% CI, 0.90-0.98) were associated with increased risk of remaining mechanically ventilated at any time point. Older (sHR, 1.03; 95% CI, 1.01-1.04) and male children (sHR, 1.39; 95% CI, 1.05-1.84) were more likely to discontinue mechanical ventilation. A majority of children (94.8%) survived to hospital discharge. CONCLUSIONS: The presence of inhalational injury and burns to the head and neck region were associated with a longer duration of mechanical ventilation. Older age and male gender were associated with a shorter duration of mechanical ventilation. These factors should help clinicians better estimate a burned child's expected trajectory and resource-intensive needs upon arrival to a burn center.

Statin contribution to middle cerebral artery blood flow velocity in older adults at risk for dementia.

PURPOSE: It is plausible that statins could improve cerebral blood flow through pleiotropic mechanisms. The purpose of this investigation was to assess the contribution of statins to cerebrovascular variables in older adults with dyslipidemia and familial history of dementia. Furthermore, we explored the interaction between statin use and sex due to prevalent bias in statin trials. METHODS: Middle cerebral artery blood flow velocity (MCAv) was measured using transcranial Doppler ultrasound. Continuous supine rest recordings lasted 8 min. Participants included in analyses were statin (n = 100) or non-statin users (n = 112). RESULTS: MCAv and cerebrovascular conductance were significantly higher in statin users (p = 0.047; p = 0.04), and pulsatility index (PI) was significantly lower in statin users (p < 0.01). An interaction effect between statin use and sex was present for PI (p = 0.02); female statin users had significantly lower cerebrovascular resistance than the other three groups. CONCLUSION: In this cross-sectional analysis, statin use was positively associated with cerebrovascular variables in older adults at risk for dementia. Female statin users had significantly higher resting MCAv and cerebrovascular conductance than female non-statin users. The greatest contribution of statin use was the association with reduced cerebrovascular resistance. Given that cerebrovascular dysregulation is one of the earliest changes in Alzheimer's disease and related dementia pathology, targeting the cerebrovasculature with statins may be a promising prevention strategy.

Normalization of Cerebral Blood Flow, Neurochemicals, and White Matter Integrity after Kidney Transplantation.

BACKGROUND: CKD is associated with abnormalities in cerebral blood flow, cerebral neurochemical concentrations, and white matter integrity. Each of these is associated with adverse clinical consequences in the non-CKD population, which may explain the high prevalence of dementia and stroke in ESKD. Because cognition improves after kidney transplantation, comparing these brain abnormalities before and after kidney transplantation may identify potential reversibility in ESKD-associated brain abnormalities. METHODS: In this study of patients with ESKD and age-matched healthy controls, we used arterial spin labeling to assess the effects of kidney transplantation on cerebral blood flow and magnetic resonance spectroscopic imaging to measure cerebral neurochemical concentrations (N-acetylaspartate, choline, glutamate, glutamine, myo-inositol, and total creatine). We also assessed white matter integrity measured by fractional anisotropy (FA) and mean diffusivity (MD) with diffusion tensor imaging. We used a linear mixed model analysis to compare longitudinal, repeated brain magnetic resonance imaging measurements before, 3 months after, and 12 months after transplantation and compared these findings with those of healthy controls. RESULTS: Study participants included 29 patients with ESKD and 19 controls; 22 patients completed post-transplant magnetic resonance imaging. Cerebral blood flow, which was higher in patients pretransplant compared with controls (P=0.003), decreased post-transplant (P<0.001) to values in controls. Concentrations of neurochemicals choline and myo-inositol that were higher pretransplant compared with controls (P=0.001 and P<0.001, respectively) also normalized post-transplant (P<0.001 and P<0.001, respectively). FA increased (P=0.001) and MD decreased (P<0.001) post-transplant. CONCLUSIONS: Certain brain abnormalities in CKD are reversible and normalize with kidney transplantation. Further studies are needed to understand the mechanisms underlying these brain abnormalities and to explore interventions to mitigate them even in patients who cannot be transplanted. CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER: Cognitive Impairment and Imaging Correlates in End Stage Renal Disease, NCT01883349.

Apolipoprotein E4 Moderates the Association Between Vascular Risk Factors and Brain Pathology.

BACKGROUND: The strongest genetic risk factor for late-onset Alzheimer disease (AD), Apolipoprotein E4 (APOE4), increases cardiovascular disease risk and may also act synergistically with vascular risk factors to contribute to AD pathogenesis. Here, we assess the interaction between APOE4 and vascular risk on cerebrovascular dysfunction and brain pathology. METHODS: This is an observational study of cognitively normal older adults, which included positron emission tomography imaging and vascular risk factors. We measured beat-to-beat blood pressure and middle cerebral artery velocity at rest and during moderate-intensity exercise. Cerebrovascular measures included cerebrovascular conductance index and the cerebrovascular response to exercise. RESULTS: There was a significant interaction between resting cerebrovascular conductance index and APOE4 carrier status on ß-amyloid deposition (P=0.026), with poor conductance in the cerebrovasculature associated with elevated ß-amyloid for the APOE4 carriers only. There was a significant interaction between non-high-density lipoprotein cholesterol and APOE4 carrier status (P=0.014), with elevated non-high-density lipoprotein cholesterol predicting a blunted cerebrovascular response to exercise in APOE4 carriers and the opposite relationship in noncarriers. CONCLUSIONS: Both cerebral and peripheral vascular risk factors are preferentially associated with brain pathology in APOE4 carriers. These findings provide insight into pathogenic vascular risk mechanisms and target strategies to potentially delay AD onset.

Safety and target engagement profile of two oxaloacetate doses in Alzheimer's patients.

INTRODUCTION: Brain bioenergetics are defective in Alzheimer's disease (AD). Preclinical studies find oxaloacetate (OAA) enhances bioenergetics, but human safety and target engagement data are lacking. METHODS: We orally administered 500 or 1000 mg OAA, twice daily for 1 month, to AD participants (n = 15 each group) and monitored safety and tolerability. To assess brain metabolism engagement, we performed fluorodeoxyglucose positron emission tomography (FDG PET) and magnetic resonance spectroscopy before and after the intervention. We also assessed pharmacokinetics and cognitive performance. RESULTS: Both doses were safe and tolerated. Compared to the lower dose, the higher dose benefited FDG PET glucose uptake across multiple brain regions (P < .05), and the higher dose increased parietal and frontoparietal glutathione (P < .05). We did not demonstrate consistent blood level changes and cognitive scores did not improve. CONCLUSIONS: 1000 mg OAA, taken twice daily for 1 month, is safe in AD patients and engages brain energy metabolism.

Clinical Documentation for Intensivists: The Impact of Diagnosis Documentation.

OBJECTIVES: The aim of this review is to describe the interaction of clinical documentation with patient care, measures of patient acuity, quality metrics, research database accuracy, and healthcare reimbursement in order to highlight potential areas of improvement for intensivists. DATA SOURCES: An online search of PubMed was undertaken as well as review of resources published by the American Academy of Pediatrics, the Society of Critical Care Medicine, the American Medical Association, and the Association of Clinical Documentation Improvement Specialists. STUDY SELECTION: Selected publications included those that described coding, medical record documentation, healthcare reimbursement, quality metrics, administrative databases, Clinical Documentation Improvement programs, medical scribe programs, and various payment models. DATA EXTRACTION: Relevant information was extracted to highlight the impact of diagnosis documentation on patient care, perceived patient severity of illness, quality metrics, and healthcare reimbursement. Query data from our hospital's Clinical Documentation Improvement program were reviewed to highlight areas of improvement within our own Division of Critical Care Medicine. Additionally, interventions to improve clinical documentation were incorporated into this review. DATA SYNTHESIS: Available data in the literature indicate that documentation of precise diagnoses in the medical record has a positive impact on quality metrics, accuracy of administrative databases, hospital reimbursement, and perceived patient complexity. However, there is insufficient data to make conclusions regarding documentation of specific diagnoses and effects on patient care. Administrative responsibilities associated with documentation have been increasing, especially with the introduction of electronic medical records. CONCLUSIONS: Documentation of specific diagnoses in the medical record is important in the broad context of our existing medical system but there is an associated burden in doing so. Widespread implementation of electronic medical record systems has inadvertently led to clinician dissatisfaction and burnout. Research is needed to further evaluate the impact of documentation on patient care as well as steps to decrease the associated burden.