Proteomic changes induced by longevity-promoting interventions in mice.

Using mouse models and high-throughput proteomics, we conducted an in-depth analysis of the proteome changes induced in response to seven interventions known to increase mouse lifespan. This included two genetic mutations, a growth hormone receptor knockout (GHRKO mice) and a mutation in the Pit-1 locus (Snell dwarf mice), four drug treatments (rapamycin, acarbose, canagliflozin, and 17α-estradiol), and caloric restriction. Each of the interventions studied induced variable changes in the concentrations of proteins across liver, kidney, and gastrocnemius muscle tissue samples, with the strongest responses in the liver and limited concordance in protein responses across tissues. To the extent that these interventions promote longevity through common biological mechanisms, we anticipated that proteins associated with longevity could be identified by characterizing shared responses across all or multiple interventions. Many of the proteome alterations induced by each intervention were distinct, potentially implicating a variety of biological pathways as being related to lifespan extension. While we found no protein that was affected similarly by every intervention, we identified a set of proteins that responded to multiple interventions. These proteins were functionally diverse but tended to be involved in peroxisomal oxidation and metabolism of fatty acids. These results provide candidate proteins and biological mechanisms related to enhancing longevity that can inform research on therapeutic approaches to promote healthy aging.

Melanoma literacy among the general population of three western US states.

Melanoma is a significant cause of cancer death, despite being detectable without specialized or invasive technologies. Understanding barriers to preventive behaviors such as skin self-examination (SSE) could help to define interventions for increasing the frequency of early detection. To determine melanoma knowledge and beliefs across three high-incidence US states, 15,000 surveys were sent to a population-representative sample. We aimed to assess (1) melanoma literacy (i.e., knowledge about melanoma risks, attitudes, and preventive behaviors) and (2) self-reported SSE and its association with melanoma literacy, self-efficacy, and belief in the benefits of SSE. Of 2326 respondents, only 21.2% provided responses indicating high knowledge of melanoma, and 62.8% reported performing an SSE at any time in their lives. Only 38.3% and 7.3% reported being "fairly" or "very" confident about doing SSE, respectively. SSE performance among respondents was most strongly associated with higher melanoma knowledge, higher self-efficacy, and personal history of melanoma. Melanoma literacy among survey respondents was modest, with greater literacy associated with a higher likelihood of reported preventive behavior. This assessment establishes a baseline and provides guidance for public health campaigns designed to increase prevention and early detection of this lethal cancer.

Experimental design considerations for studies of human tear proteins.

PURPOSE: Human tears contain abundant, diverse sets of proteins that may serve as biomarkers of ocular surface health. There is a need for reproducible methods that consider multiple factors influencing the tear proteome, in addition to the variable of interest. Here we examined a workflow for proteomic analysis of tear proteins without the need to pool tear samples from multiple individuals, thus allowing for analyses based on individual factors, and increasing opportunities for protein biomarker discovery. METHODS: Tears were collected by Schirmer strip following topical ocular anesthetic application then individually stored at -80 °C prior to processing for proteomics. Tear proteins were extracted from Schirmer strips, digested using suspension trapping spin columns (S-Trap), and labeled with high multiplicity tandem mass tags (TMT). Peptide digests were then extensively fractionated by two-dimensional chromatography and analyzed by mass spectrometry to identify and measure changes in protein abundance in each sample. Analysis of select samples was performed to test protocols and to compare the impact of clinically relevant parameters. To facilitate comparison of separate TMT experiments, common pool samples were included in each TMT instrument run and internal reference scaling (IRS) was performed. RESULTS: Differences in subsets of tear proteins were noted for: geographic site of tear collection, contact lens use, and differences in tear fluid volume among individuals. CONCLUSION: These findings demonstrate that proteomic analysis of human tear proteins can be performed without the need to pool samples, and that development of analytic workflows must consider factors that may affect outcomes in studies focused on diverse clinical samples.

The Instrumented Stand and Walk (ISAW) test to predict falls in older men.

Objective measures of balance and gait have the potential to improve prediction of future fallers because balance and gait impairments are common precursors. We used the Instrumented Stand and Walk Test (ISAW) with wearable, inertial sensors to maximize the domains of balance and gait evaluated in a short test. We hypothesized that ISAW objective measures across a variety of gait and balance domains would improve fall prediction beyond history of falls and better than gait speed or dual-task cost on gait-speed. We recruited 214 high-functioning older men (mean 82 years), of whom 91 participants (42.5%) had one or more falls in the 12 months following the ISAW test. The ISAW test involved 30 s of stance followed by a 7-m walk, turn, and return. We examined regression models for falling using 17 ISAW metrics, with and without age and fall history, and characterize top-performing models by AUC and metrics included. The ISAW test improved distinguishing between future fallers and non-fallers compared to age and history of falls, alone (AUC improved from 0.69 to 0.75). Models with 1 ISAW metric usually included a postural sway measure, models with 2 ISAW measures included a turning measure, models with 3 ISAW measures included a gait variability measure, and models with 4 or 5 measures added a gait initiation measure. Gait speed and dual-task cost did not distinguish between fallers and non-fallers in this high-functioning cohort. The best fall-prediction models support the notion that older people may fall due to a variety of balance and gait impairments.

Guidance for biostatisticians on their essential contributions to clinical and translational research protocol review.

Rigorous scientific review of research protocols is critical to making funding decisions, and to the protection of both human and non-human research participants. Given the increasing complexity of research designs and data analysis methods, quantitative experts, such as biostatisticians, play an essential role in evaluating the rigor and reproducibility of proposed methods. However, there is a common misconception that a statistician's input is relevant only to sample size/power and statistical analysis sections of a protocol. The comprehensive nature of a biostatistical review coupled with limited guidance on key components of protocol review motived this work. Members of the Biostatistics, Epidemiology, and Research Design Special Interest Group of the Association for Clinical and Translational Science used a consensus approach to identify the elements of research protocols that a biostatistician should consider in a review, and provide specific guidance on how each element should be reviewed. We present the resulting review framework as an educational tool and guideline for biostatisticians navigating review boards and panels. We briefly describe the approach to developing the framework, and we provide a comprehensive checklist and guidance on review of each protocol element. We posit that the biostatistical reviewer, through their breadth of engagement across multiple disciplines and experience with a range of research designs, can and should contribute significantly beyond review of the statistical analysis plan and sample size justification. Through careful scientific review, we hope to prevent excess resource expenditure and risk to humans and animals on poorly planned studies.

Cerebrospinal Fluid MicroRNA Changes in Cognitively Normal Veterans With a History of Deployment-Associated Mild Traumatic Brain Injury.

A history of traumatic brain injury (TBI) increases the odds of developing Alzheimer's disease (AD). The long latent period between injury and dementia makes it difficult to study molecular changes initiated by TBI that may increase the risk of developing AD. MicroRNA (miRNA) levels are altered in TBI at acute times post-injury (<4 weeks), and in AD. We hypothesized that miRNA levels in cerebrospinal fluid (CSF) following TBI in veterans may be indicative of increased risk for developing AD. Our population of interest is cognitively normal veterans with a history of one or more mild TBI (mTBI) at a chronic time following TBI. We measured miRNA levels in CSF from three groups of participants: (1) community controls with no lifetime history of TBI (ComC); (2) deployed Iraq/Afghanistan veterans with no lifetime history of TBI (DepC), and (3) deployed Iraq/Afghanistan veterans with a history of repetitive blast mTBI (DepTBI). CSF samples were collected at the baseline visit in a longitudinal, multimodal assessment of Gulf War veterans, and represent a heterogenous group of male veterans and community controls. The average time since the last blast mTBI experienced was 4.7 ± 2.2 years [1.5 - 11.5]. Statistical analysis of TaqManTM miRNA array data revealed 18 miRNAs with significant differential expression in the group comparisons: 10 between DepTBI and ComC, 7 between DepC and ComC, and 8 between DepTBI and DepC. We also identified 8 miRNAs with significant differential detection in the group comparisons: 5 in DepTBI vs. ComC, 3 in DepC vs. ComC, and 2 in DepTBI vs. DepC. When we applied our previously developed multivariable dependence analysis, we found 13 miRNAs (6 of which are altered in levels or detection) that show dependencies with participant phenotypes, e.g., ApoE. Target prediction and pathway analysis with miRNAs differentially expressed in DepTBI vs. either DepC or ComC identified canonical pathways highly relevant to TBI including senescence and ephrin receptor signaling, respectively. This study shows that both TBI and deployment result in persistent changes in CSF miRNA levels that are relevant to known miRNA-mediated AD pathology, and which may reflect early events in AD.

Relationships Between Sensorimotor Inhibition and Mobility in Older Adults With and Without Parkinson's Disease.

BACKGROUND: Reduced cortical sensorimotor inhibition is associated with mobility and cognitive impairments in people with Parkinson's disease (PD) and older adults (OAs). However, there is a lack of clarity regarding the relationships among sensorimotor, cognitive, and mobility impairments. The purpose of this study was to determine how cortical sensorimotor inhibition relates to impairments in mobility and cognition in people with PD and OAs. METHOD: Cortical sensorimotor inhibition was characterized with short-latency afferent inhibition (SAI) in 81 people with PD and 69 OAs. Six inertial sensors recorded single- and dual-task gait and postural sway characteristics during a 2-minute walk and a 1-minute quiet stance. Cognition was assessed across the memory, visuospatial, executive function, attention, and language domains. RESULTS: SAI was significantly impaired in the PD compared to the OA group. The PD group preformed significantly worse across all gait and postural sway tasks. In PD, SAI significantly correlated with single-task foot strike angle and stride length variability, sway area, and jerkiness of sway in the coronal and sagittal planes. In OAs, SAI significantly related to single-task gait speed and stride length, dual-task stride length, and immediate recall (memory domain). No relationship among mobility, cognition, and SAI was observed. CONCLUSIONS: Impaired SAI related to slower gait in OA and to increased gait variability and postural sway in people with PD, all of which have been shown to be related to increased fall risk.

Sensorimotor Inhibition and Mobility in Genetic Subgroups of Parkinson's Disease.

Background: Mobility and sensorimotor inhibition impairments are heterogeneous in Parkinson's disease (PD). Genetics may contribute to this heterogeneity since the apolipoprotein (APOE) ε4 allele and glucocerebrosidase (GBA) gene variants have been related to mobility impairments in otherwise healthy older adult (OA) and PD cohorts. The purpose of this study is to determine if APOE or GBA genetic status affects sensorimotor inhibition and whether the relationship between sensorimotor inhibition and mobility differs in genetic sub-groups of PD. Methods: Ninety-three participants with idiopathic PD (53 non-carriers; 23 ε4 carriers; 17 GBA variants) and 72 OA (45 non-carriers; 27 ε4 carriers) had sensorimotor inhibition characterized by short-latency afferent inhibition. Mobility was assessed in four gait domains (pace/turning, rhythm, trunk, variability) and two postural sway domains (area/jerkiness and velocity) using inertial sensors. Results: Sensorimotor inhibition was worse in the PD than OA group, with no effect of genetic status. Gait pace/turning was slower and variability was higher (p < 0.01) in PD compared to OA. Postural sway area/jerkiness (p < 0.01) and velocity (p < 0.01) were also worse in the PD than OA group. Genetic status was not significantly related to any gait or postural sway domain. Sensorimotor inhibition was significantly correlated with gait variability (r = 0.27; p = 0.02) and trunk movement (r = 0.23; p = 0.045) in the PD group. In PD non-carriers, sensorimotor inhibition related to variability (r = 0.35; p = 0.010) and trunk movement (r = 0.31; p = 0.025). In the PD ε4 group, sensorimotor inhibition only related to rhythm (r = 0.47; p = 0.024), while sensorimotor inhibition related to pace/turning (r = -0.49; p = 0.046) and rhythm (r = 0.59; p = 0.013) in the PD GBA group. Sensorimotor inhibition was significantly correlated with gait pace/turning (r = -0.27; p = 0.04) in the OA group. There was no relationship between sensorimotor inhibition and postural sway. Conclusion: ε4 and GBA genetic status did not affect sensorimotor inhibition or mobility impairments in this PD cohort. However, worse sensorimotor inhibition was associated with gait variability in PD non-carriers, but with gait rhythm in PD ε4 carriers and with gait rhythm and pace in PD with GBA variants. Impaired sensorimotor inhibition had a larger effect on mobility in people with PD than OA and affected different domains of mobility depending on genetic status.

Responsiveness of Objective vs. Clinical Balance Domain Outcomes for Exercise Intervention in Parkinson's Disease.

Background: Balance deficits in people with Parkinson's disease (PD) are often not helped by pharmacological or surgical treatment. Although balance exercise intervention has been shown to improve clinical measures of balance, the efficacy of exercise on different, objective balance domains is still unknown. Objective: To compare the sensitivity to change in objective and clinical measures of several different domains of balance and gait following an Agility Boot Camp with Cognitive Challenges (ABC-C) intervention. Methods: In this cross-over, randomized design, 86 individuals with PD participated in 6-week (3×/week) ABC-C exercise classes and 6-week education classes, consisting of 3-6 individuals. Blinded examiners tested people in their practical off state. Objective outcome measures from wearable sensors quantified four domains of balance: sway in standing balance, anticipatory postural adjustments (APAs) during step initiation, postural responses to the push-and-release test, and a 2-min natural speed walk with and without a cognitive task. Clinical outcome measures included the Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Part III, the Mini Balance Evaluation Systems Test (Mini-BESTest), the Activities of Balance Confidence (ABC), and the Parkinson's Disease Questionnaire (PDQ-39). The standardized response means (SRM) of the differences between before and after each intervention compared responsiveness of outcomes to intervention. A linear mixed model compared effects of exercise with the active control-education intervention. Results: The most responsive outcome measures to exercise intervention with an SRM > 0.5 were objective measures of gait and APAs, specifically arm range of motion, gait speed during a dual-task walk, trunk coronal range of motion, foot strike angle, and first-step length at step initiation. The most responsive clinical outcome measure was the patient-reported PDQ-39 activities daily living subscore, but all clinical measures had SRMs <0.5. Conclusions: The objective measures were more sensitive to change after exercise intervention compared to the clinical measures. Spatiotemporal parameters of gait, including gait speed with a dual task, and APAs were the most sensitive objective measures, and perceived functional independence was the most sensitive clinical measure to change after the ABC-C exercise intervention. Future exercise intervention to improve gait and balance in PD should include objective outcome measures.

Performance of Validated MicroRNA Biomarkers for Alzheimer's Disease in Mild Cognitive Impairment.

BACKGROUND: Cerebrospinal fluid (CSF) microRNA (miRNA) biomarkers of Alzheimer's disease (AD) have been identified, but have not been evaluated in prodromal AD, including mild cognitive impairment (MCI). OBJECTIVE: To assess whether a set of validated AD miRNA biomarkers in CSF are also sensitive to early-stage pathology as exemplified by MCI diagnosis. METHODS: We measured the expression of 17 miRNA biomarkers for AD in CSF samples from AD, MCI, and cognitively normal controls (NC). We then examined classification performance of the miRNAs individually and in combination. For each miRNA, we assessed median expression in each diagnostic group and classified markers as trending linearly, nonlinearly, or lacking any trend across the three groups. For trending miRNAs, we assessed multimarker classification performance alone and in combination with apolipoprotein E ɛ4 allele (APOEɛ4) genotype and amyloid-ß42 to total tau ratio (Aß42:T-Tau). We identified predicted targets of trending miRNAs using pathway analysis. RESULTS: Five miRNAs showed a linear trend of decreasing median expression across the ordered diagnoses (control to MCI to AD). The trending miRNAs jointly predicted AD with area under the curve (AUC) of 0.770, and MCI with AUC of 0.705. Aß42:T-Tau alone predicted MCI with AUC of 0.758 and the AUC improved to 0.813 (p = 0.051) after adding the trending miRNAs. Multivariate correlation of the five trending miRNAs with Aß42:T-Tau was weak. CONCLUSION: Selected miRNAs combined with Aß42:T-Tau improved classification performance (relative to protein biomarkers alone) for MCI, despite a weak correlation with Aß42:T-Tau. Together these data suggest that that these miRNAs carry novel information relevant to AD, even at the MCI stage. Preliminary target prediction analysis suggests novel roles for these biomarkers.

Protocol for a mechanistic study of mindfulness based cognitive therapy during pregnancy.

OBJECTIVE: Preventive interventions for postpartum depression (PPD) are critical for women at elevated risk of PPD. Mindfulness based cognitive therapy - perinatal depression (MBCT-PD) is a preventive intervention that has been shown to reduce risk for PPD in women with a prior history of depression. The objective of this clinical trial is to examine two potential mechanisms of action of MBCT-PD, emotion regulation and cognitive control, using behavioral and neuroimaging methods. METHOD: This baseline protocol describes a randomized control trial (RCT) with two arms, MBCT-PD and treatment as usual (TAU). We plan on enrolling 74 females with a prior history of a major depressive episode, with 37 participants randomized to each arm. Participants in the MBCT-PD arm will receive MBCT-PD during pregnancy, and the TAU group will receive standard prenatal care. All participants will complete the Center for Epidemiological Studies Depression Scale - Revised (CESD-R), Emotion Regulation Questionnaire (ERQ), and classic Stroop task at multiple points from pregnancy through six months postpartum. Participants will also complete an fMRI scan at six weeks postpartum. RESULTS: All primary outcomes are collected at six weeks postpartum. Primary behavioral outcomes include: depressive symptoms on the CESD-R, cognitive reappraisal on the ERQ, and Stroop task performance. In parallel, the primary neurobiological outcomes include whole-brain activation during fMRI tasks when participants 1) regulate emotional responding and 2) engage cognitive control. CONCLUSIONS: This results of this innovative RCT will help identify potential behavioral and neurobiological mechanisms of action of preventive interventions for PPD for in-depth examination in larger scale RCTs. (PsycInfo Database Record (c) 2020 APA, all rights reserved).

Association of Palliative Care Use and Setting With Health-care Utilization and Quality of Care at the End of Life Among Patients With Advanced Lung Cancer.

BACKGROUND: Palliative care is associated with improved survival and quality of life among patients with lung cancer; however, its influence on health-care utilization and quality of care is unclear. RESEARCH QUESTION: Is palliative care, and the setting in which it occurs, associated with health-care resource utilization and quality of care among patients with advanced lung cancer? STUDY DESIGN AND METHODS: This was a retrospective cohort study of 23,142 patients with stage IIIB/IV lung cancer in the Veterans Affairs HealthCare System between 2007 and 2013. Exposures included the receipt of specialist-delivered palliative care, and the setting of the initial palliative care encounter (inpatient or outpatient) received after cancer diagnosis. Primary outcomes included rates of ED visits, along with rates of hospitalization and odds of ICU admission within the last 30 days of life. Secondary outcomes included any health-care utilization (ED, hospital, or ICU) related to chemotherapy toxicity. We used propensity score methods to perform Poisson and logistic regression modeling. RESULTS: Among the 23,142 patients, 57% received palliative care, and 36% of initial palliative care encounters were outpatient. Compared with no palliative care, initial palliative care encounter in the outpatient setting was associated with reduced rates of ED visits (adjusted incidence rate ratio [aIRR], 0.86; 95% CI, 0.77-0.96) and hospitalizations in the last 30 days of life (aIRR, 0.64; 95% CI, 0.59-0.70). Initial palliative care encounters in both inpatient (adjusted OR [aOR], 0.63; 95% CI, 0.53-0.75) and outpatient (aOR, 0.42; 95% CI, 0.35-0.52) settings were associated with reduced odds of ICU admission in the last 30 days of life. Palliative care was also associated with reduced health-care utilization related to chemotherapy toxicity (aOR, 0.88; 95% CI, 0.82-0.95). INTERPRETATION: Palliative care (particularly in outpatient settings) is associated with reduced health-care utilization at the end of life and may improve the quality of care among patients with advanced lung cancer. These findings support the role of palliative care as an important component of comprehensive cancer care and highlight the potential benefits of outpatient palliative care services.

Digital Biomarkers of Mobility in Parkinson's Disease During Daily Living.

BACKGROUND: Identifying digital biomarkers of mobility is important for clinical trials in Parkinson's disease (PD). OBJECTIVE: To determine which digital outcome measures of mobility discriminate mobility in people with PD from healthy control (HC) subjects over a week of continuous monitoring. METHODS: We recruited 29 people with PD, and 27 age-matched HC subjects. Subjects were asked to wear three inertial sensors (Opal by APDM) attached to both feet and to the lumbar region, and a subset of subjects also wore two wrist sensors, for a week of continuous monitoring. We derived 43 digital outcome measures of mobility grouped into five domains. An Area Under Curve (AUC) was calculated for each digital outcome measures of mobility, and logistic regression employing a 'best subsets selection strategy' was used to find combinations of measures that discriminated mobility in PD from HC. RESULTS: Duration of recordings was 66±14 hours in the PD and 59±16 hours in the HC. Out of a total of 43 digital outcome measures of mobility, we found six digital outcome measures of mobility with AUC > 0.80. Turn angle (AUC = 0.89, 95% CI: 0.79-0.97) and swing time variability (AUC = 0.87, 95% CI: 0.75-0.96) were the most discriminative individual measures. Turning measures were most consistently selected via the best subsets strategy to discriminate people with PD from HC, followed by gait variability measures. CONCLUSION: Clinical studies and clinical practice with digital biomarkers of daily life mobility in PD should include turning and variability measures.

Improving Smoking Cessation Outcomes Through Tailored-Risk Patient Messages at a University Hospital Tobacco Cessation Service.

BACKGROUND: Postdischarge follow-up is a critical step for increasing effectiveness of hospital smoking cessation treatment. A quality improvement project was undertaken at an academic medical center tobacco cessation consult service to evaluate whether a tailored message (TM) linking immediate risks of continued smoking-particularly carbon monoxide exposure-to hospital recovery would stimulate more patient interest in the hospital's cessation treatment, including agreement to postdischarge follow-up, compared to patients receiving the usual treatment protocol with a standard message (SM) regarding more general health benefits of abstinence. METHODS: Data from 697 smokers ordered/referred for smoking cessation treatment in 2013 who received either the SM (January-April; n = 323) or the TM (April-November; n =374) were analyzed. RESULTS: Multivariate regression analysis showed that the TM was associated with significantly greater agreement for follow-up (odds ratio [OR] = 10.83, 95% confidence interval [CI] = 3.66-32.04, p < 0.0001) than the SM. Those patients who received the TM were more willing to try to remain abstinent postdischarge (willingness score = 10, p = 0.0052) and engaged in longer consults (consult time > 10 minutes, p = 0.0075) than SM patients. TM patients also self-reported a higher continuous abstinence rate (OR = 2.07, 95% CI = 1.17-3.66, p = 0.0130] at follow-up than SM. CONCLUSION: Linking risks of continued smoking, particularly carbon monoxide exposure, to hospital patients' immediate recovery following discharge in a treatment protocol resulted in longer consult times and increased agreement to follow-up compared to the usual protocol message. The TM was integrated into the hospital tobacco cessation intervention as standard of care.

Cognitively Challenging Agility Boot Camp Program for Freezing of Gait in Parkinson Disease.

Introduction. It is well documented that freezing of gait (FoG) episodes occur in situations that are mentally challenging, such as dual tasks, consistent with less automatic control of gait in people with Parkinson disease (PD) and FoG. However, most physical rehabilitation does not include such challenges. The purpose was to determine (1) feasibility of a cognitively challenging Agility Boot Camp-Cognitive (ABC-C) program and (2) effects of this intervention on FoG, dual-task cost, balance, executive function, and functional connectivity. Methods. A total of 46 people with PD and FoG enrolled in this randomized crossover trial. Each participant had 6 weeks of ABC-C and Education interventions. Outcome measures were the following: FoG, perceived and objective measures; dual-task cost on gait; balance; executive function; and right supplementary motor area (SMA)-pedunculopontine nucleus (PPN) functional connectivity. Effect sizes were calculated. Results. ABC-C had high compliance (90%), with a 24% dropout rate. Improvements after exercise, revealed by moderate and large effect sizes, were observed for subject perception of FoG after exercise, dual-task cost on gait speed, balance, cognition (Scales for Outcomes in Parkinson's disease-Cognition), and SMA-PPN connectivity. Conclusions. The ABC-C for people with PD and FoG is a feasible exercise program that has potential to improve FoG, balance, dual-task cost, executive function, and brain connectivity. The study provided effect sizes to help design future studies with more participants and longer duration to fully determine the potential to improve FoG.

Association of Early Palliative Care Use With Survival and Place of Death Among Patients With Advanced Lung Cancer Receiving Care in the Veterans Health Administration.

Importance: Palliative care is a patient-centered approach associated with improvements in quality of life; however, results regarding its association with a survival benefit have been mixed, which may be a factor in its underuse. Objective: To assess whether early palliative care is associated with a survival benefit among patients with advanced lung cancer. Design, Setting, and Participants: This retrospective population-based cohort study was conducted among patients with lung cancer who were diagnosed with cancer between January 1, 2007, and December 31, 2013, with follow-up until January 23, 2017. Participants comprised 23 154 patients with advanced lung cancer (stage IIIB and stage IV) who received care in the Veterans Affairs health care system. Data were analyzed from February 15, 2019, to April 28, 2019. Exposure: Palliative care defined as a specialist-delivered palliative care encounter received after lung cancer diagnosis. Main Outcomes and Measures: The primary outcome was survival. The association between palliative care and place of death was also examined. Propensity score and time-varying covariate methods were used to calculate Cox proportional hazards and to perform regression modeling. Results: Of the 23 154 patients enrolled in the study, 57% received palliative care. The mean (SD) age of participants was 68 (9.5) years, and 98% of participants were men. An examination of the timing of palliative care receipt relative to cancer diagnosis found that palliative care received 0 to 30 days after diagnosis was associated with decreases in survival (adjusted hazard ratio [aHR], 2.13; 95% CI, 1.97-2.30), palliative care received 31 to 365 days after diagnosis was associated with increases in survival (aHR, 0.47; 95% CI, 0.45-0.49), and palliative care received more than 365 days after diagnosis was associated with no difference in survival (aHR, 1.00; 95% CI, 0.94-1.07) compared with nonreceipt of palliative care. Receipt of palliative care was also associated with a reduced risk of death in an acute care setting (adjusted odds ratio, 0.57; 95% CI, 0.52-0.64) compared with nonreceipt of palliative care. Conclusions and Relevance: The results suggest that palliative care was associated with a survival benefit among patients with advanced lung cancer. Palliative care should be considered a complementary approach to disease-modifying therapy in patients with advanced lung cancer.

Healthcare-associated urinary tract infections with onset post hospital discharge.

OBJECTIVE: Current surveillance for healthcare-associated (HA) urinary tract infection (UTI) is focused on catheter-associated infection with hospital onset (HO-CAUTI), yet this surveillance does not represent the full burden of HA-UTI to patients. Our objective was to measure the incidence of potentially HA, community-onset (CO) UTI in a retrospective cohort of hospitalized patients. DESIGN: Retrospective cohort study. SETTING: Academic, quaternary care, referral center. PATIENTS: Hospitalized adults at risk for HA-UTI from May 2009 to December 2011 were included. METHODS: Patients who did not experience a UTI during the index hospitalization were followed for 30 days post discharge to identify cases of potentially HA-CO UTI. RESULTS: We identified 3,273 patients at risk for potentially HA-CO UTI. The incidence of HA-CO UTI in the 30 days post discharge was 29.8 per 1,000 patients. Independent risk factors of HA-CO UTI included paraplegia or quadriplegia (adjusted odds ratio [aOR], 4.6; 95% confidence interval [CI], 1.2-18.0), indwelling catheter during index hospitalization (aOR, 1.5; 95% CI, 1.0-2.3), prior piperacillin-tazobactam prescription (aOR, 2.3; 95% CI, 1.1-4.5), prior penicillin class prescription (aOR, 1.7; 95% CI, 1.0-2.8), and private insurance (aOR, 0.6; 95% CI, 0.4-0.9). CONCLUSIONS: HA-CO UTI may be common within 30 days following hospital discharge. These data suggest that surveillance efforts may need to be expanded to capture the full burden to patients and better inform antibiotic prescribing decisions for patients with a history of hospitalization.

Validation of MicroRNA Biomarkers for Alzheimer's Disease in Human Cerebrospinal Fluid.

We previously discovered microRNAs (miRNAs) in cerebrospinal fluid (CSF) that differentiate Alzheimer's disease (AD) patients from Controls. Here we examined the performance of 37 candidate AD miRNA biomarkers in a new and independent cohort of CSF from 47 AD patients and 71 Controls on custom TaqMan arrays. We employed a consensus ranking approach to provide an overall priority score for each miRNA, then used multimarker models to assess the relative contributions of the top-ranking miRNAs to differentiate AD from Controls. We assessed classification performance of the top-ranking miRNAs when combined with apolipoprotein E4 (APOE4) genotype status or CSF amyloid-ß42 (Aß42):total tau (T-tau) measures. We also assessed whether miRNAs that ranked higher as AD markers correlate with Mini-Mental State Examination (MMSE) scores. We show that of 37 miRNAs brought forth from the discovery study, 26 miRNAs remained viable as candidate biomarkers for AD in the validation study. We found that combinations of 6-7 miRNAs work better to identify AD than subsets of fewer miRNAs. Of 26 miRNAs that contribute most to the multimarker models, 14 have higher potential than the others to predict AD. Addition of these 14 miRNAs to APOE4 status or CSF Aß42:T-tau measures significantly improved classification performance for AD. We further show that individual miRNAs that ranked higher as AD markers correlate more strongly with changes in MMSE scores. Our studies validate that a set of CSF miRNAs serve as biomarkers for AD, and support their advancement toward development as biomarkers in the clinical setting.

Analytics of Cerebrospinal Fluid MicroRNA Quantitative PCR Studies.

MicroRNAs (miRNAs) are small non-coding RNAs that regulate post-transcriptional gene expression. Recent studies have shown that human disease states correlate with measurable differences in the level of circulating miRNAs relative to healthy controls. Thus, there is great interest in developing clinical miRNA assays as diagnostic or prognostic biomarkers for diseases, and as surrogate measures for therapeutic outcomes. Our studies have focused on miRNAs in human cerebral spinal fluid (CSF) as biomarkers for central nervous system (CNS) diseases. Our objective here was to examine factors that may affect the outcome of quantitative PCR (qPCR) studies on CSF miRNAs, in order to guide planning and interpretation of future CSF miRNA TaqMan® low-density array (TLDA) studies. We obtained CSF from neurologically normal (control) donors and used TLDAs to measure miRNA expression. We examined sources of error in the TLDA outcomes due to (1) nonspecific amplification of products in total RNA, (2) variations in RNA isolations performed on different days, (3) miRNA primer probe efficiency, and (4) variations in individual TLDA cards. We also examined the utility of card-to-card TLDA corrections and use of an unchanged "reference standard" to remove batch processing effects in large-scale studies.