Capillary blood self-collection for high-throughput proteomics.

In this study, we sought to compare protein concentrations obtained from a high-throughput proteomics platform (Olink) on samples collected using capillary blood self-collection (with the Tasso+ device) versus standard venipuncture (control). Blood collection was performed on 20 volunteers, including one sample obtained via venipuncture and two via capillary blood using the Tasso+ device. Tasso+ samples were stored at 2°C-8°C for 24-hs (Tasso-24) or 48-h (Tasso-48) prior to processing to simulate shipping times from a study participant's home. Proteomics were analyzed using Olink (384 Inflammatory Panel). Tasso+ blood collection was successful in 37/40 attempts. Of 230 proteins included in our analysis, Pearson correlations (r) and mean coefficient of variation (CV) between Tasso-24 or Tasso-48 versus venipuncture were variable. In the Tasso-24 analysis, 34 proteins (14.8%) had both a correlation r > 0.5 and CV < 0.20. In the Tasso-48 analysis, 68 proteins (29.6%) had a correlation r > 0.5 and CV < 0.20. Combining the Tasso-24 and Tasso-48 analyses, 26 (11.3%) proteins met these thresholds. We concluded that protein concentrations from Tasso+ samples processed 24-48 h after collection demonstrated wide technical variability and variable correlation with a venipuncture gold-standard. Use of home capillary blood self-collection for large-scale proteomics should be limited to select proteins with good agreement with venipuncture.

An Organizational-Level Program of Intervention for AKI: A Pragmatic Stepped Wedge Cluster Randomized Trial.

BACKGROUND: Variable standards of care may contribute to poor outcomes associated with AKI. We evaluated whether a multifaceted intervention (AKI e-alerts, an AKI care bundle, and an education program) would improve delivery of care and patient outcomes at an organizational level. METHODS: A multicenter, pragmatic, stepped-wedge cluster randomized trial was performed in five UK hospitals, involving patients with AKI aged ≥18 years. The intervention was introduced sequentially across fixed three-month periods according to a randomly determined schedule until all hospitals were exposed. The primary outcome was 30-day mortality, with pre-specified secondary endpoints and a nested evaluation of care process delivery. The nature of the intervention precluded blinding, but data collection and analysis were independent of project delivery teams. RESULTS: We studied 24,059 AKI episodes, finding an overall 30-day mortality of 24.5%, with no difference between control and intervention periods. Hospital length of stay was reduced with the intervention (decreases of 0.7, 1.1, and 1.3 days at the 0.5, 0.6, and 0.7 quantiles, respectively). AKI incidence increased and was mirrored by an increase in the proportion of patients with a coded diagnosis of AKI. Our assessment of process measures in 1048 patients showed improvements in several metrics including AKI recognition, medication optimization, and fluid assessment. CONCLUSIONS: A complex, hospital-wide intervention to reduce harm associated with AKI did not reduce 30-day AKI mortality but did result in reductions in hospital length of stay, accompanied by improvements in in quality of care. An increase in AKI incidence likely reflected improved recognition.

Association of Health Literacy and Numeracy with Interest in Research Participation.

BACKGROUND: There is much attention to recruitment of diverse populations in research, but little is known about the influence of health literacy and numeracy skills. OBJECTIVE: To determine if health literacy and numeracy affect individuals' interest to participate in research studies. DESIGN: Cross-sectional survey data were pooled from 3 large studies conducted in the Mid-South Clinical Data Research Network. PARTICIPANTS: Adult patients enrolled in 1 of 3 Mid-South Clinical Data Research Network studies. MAIN MEASURES: The survey domains included demographic items, the 3-item Brief Health Literacy Screen (range 3-15), and the 3-item Subjective Numeracy Scale (range 3-18). The outcome was a sum index measure of a 7-item instrument (range 7-21) assessing individuals' interest in participating in different types of research, including research that involves taking surveys, giving a blood sample, participating via phone or internet, taking an investigational medication, meeting at a local community center or school, including family, or staying overnight at a hospital. KEY RESULTS: Respondents (N = 15,973) were predominately women (65.5%), White (81.4%), and middle aged (M = 52.8 years, SD = 16.5); 32.4% previously participated in research. Self-reported health literacy was relatively high (M = 13.5 out of 15, SD = 2.1), and subjective numeracy skills were somewhat lower (M = 14.3 out of 18, SD = 3.6). After adjustment for age, gender, race, income, education, and other characteristics, lower health literacy and numeracy skills were each independently associated with less interest in research participation (p < 0.001 for each). Prior research participation was associated with greater interest in future research participation (p < 0.001). CONCLUSIONS: After adjustment for factors known to be predictive of interest, individuals with lower health literacy or numeracy scores were less interested in participating in research. Additional work is needed to elucidate reasons for this finding and to determine strategies to engage these populations.

The dose of behavioral interventions to prevent and treat childhood obesity: a systematic review and meta-regression.

BACKGROUND: A better understanding of the optimal "dose" of behavioral interventions to affect change in weight-related outcomes is a critical topic for childhood obesity intervention research. The objective of this review was to quantify the relationship between dose and outcome in behavioral trials targeting childhood obesity to guide future intervention development. METHODS: A systematic review and meta-regression included randomized controlled trials published between 1990 and June 2017 that tested a behavioral intervention for obesity among children 2-18 years old. Searches were conducted among PubMed (Web-based), Cumulative Index to Nursing and Allied Health Literature (EBSCO platform), PsycINFO (Ovid platform) and EMBASE (Ovid Platform). Two coders independently reviewed and abstracted each included study. Dose was extracted as intended intervention duration, number of sessions, and length of sessions. Standardized effect sizes were calculated from change in weight-related outcome (e.g., BMI-Z score). RESULTS: Of the 258 studies identified, 133 had sufficient data to be included in the meta-regression. Average intended total contact (# sessions x length of sessions) was 27.7 (SD 32.2) hours and average duration was 26.0 (SD 23.4) weeks. When controlling for study covariates, a random-effects meta-regression revealed no significant association between contact hours, intended duration or their interaction and effect size. CONCLUSIONS: This systematic review identified wide variation in the dose of behavioral interventions to prevent and treat pediatric obesity, but was unable to detect a clear relationship between dose and weight-related outcomes. There is insufficient evidence to provide quantitative guidance for future intervention development. One limitation of this review was the ability to uniformly quantify dose due to a wide range of reporting strategies. Future trials should report dose intended, delivered, and received to facilitate quantitative evaluation of optimal dose. TRIAL REGISTRATIONS: The protocol was registered on PROSPERO (Registration # CRD42016036124 ).

Factors associated with placement of rural primary care physicians in North Carolina.

OBJECTIVES: The objective of this study was to determine what factors influence primary care physicians to choose rural practice locations to better develop the rural workforce in North Carolina. To better recruit and retain physicians, residents, and medical students for rural practice, we must understand what factors positively influence their choice of practice location. METHODS: A survey was sent to all primary care physicians licensed in the state of North Carolina (N = 2829), with 975 usable (return rate 34.5%). Results were analyzed using basic descriptive statistics and χ(2) automatic interaction detection analysis. RESULTS: Findings indicated that solo practice, critical access hospital, community health center, or federally qualified health center sites were strongly associated with rural practice. Pay as a factor in choosing a work site, financial support from a hospital, and medical school loan repayment also was correlated with rural practice. Seventy-two percent of rural physicians reported being raised in a town of ≤11,000, which was found to be highly associated with working in a rural area. This single point is highly indicative of rural practice and by defining this new level it roughly doubles the predictive value previously defined by other researchers. CONCLUSIONS: Incentives such as loan repayment, salary guarantees, and practice assistance for rural physicians currently provided under several federal and state programs should continue to assist in attracting primary care physicians to rural areas. Having been raised in an area of ≤11,000 was highly predictive of future rural medical practice and could be used in the recruitment of physicians and residents to increase the ultimate yield for rural areas. With these new data, North Carolina medical schools and practices serving rural areas may be able to better recruit and retain physicians with a predilection to rural practice.

Perceptions of community health center impact on private primary care physician practice.

CONTEXT: Community health centers (CHCs) were created in the mid-1960s to expand access to care in impoverished and underserved areas. The number of CHC sites has more than tripled in eastern North Carolina from 28 primary care centers in 2000 to 89 in 2010. OBJECTIVE: This study determined the perceptions of physicians on the impact of CHC expansion on the local practice environment. DESIGN: Descriptive statistics and correlations were used to compare responses regarding perceptions and differences between practice characteristics as well as physician ratios by year. Both CHC and private practice physician addresses were mapped using ArcGIS. SETTING AND PARTICIPANTS: Surveys were sent to 1422 (461 returns/32.5% response rate) primary care physicians residing in 43 predominantly rural eastern North Carolina counties. RESULTS: A large percentage of the respondents (82.7%) affirmed that they felt neutral or did not view CHCs to be competitors, whereas a minority (17%) did view them to be difficult to compete against. Forty-two percent of private practice respondents disagreed that CHCs offer a wider range of services despite significantly more CHC physicians than private practice respondents indicating that their facility provided basic services. CONCLUSION: The CHCs were perceived to offer a wider range of services, employ more staff, and have more practice locations than private practices. However, private practice physicians did not perceive CHCs to have a competitive advantage or to unfairly impact their practices, possibly due to inconsistent population growth in relation to the physician retention during the last 10 years.

Controlling the Expression Level of the Neuronal Reprogramming Factors for a Successful Reprogramming Outcome.

Neuronal reprogramming is a promising approach for making major advancement in regenerative medicine. Distinct from the approach of induced pluripotent stem cells, neuronal reprogramming converts non-neuronal cells to neurons without going through a primitive stem cell stage. In vivo neuronal reprogramming brings this approach to a higher level by changing the cell fate of glial cells to neurons in neural tissue through overexpressing reprogramming factors. Despite the ongoing debate over the validation and interpretation of newly generated neurons, in vivo neuronal reprogramming is still a feasible approach and has the potential to become clinical treatment with further optimization and refinement. Here, we discuss the major neuronal reprogramming factors (mostly pro-neurogenic transcription factors during development), especially the significance of their expression levels during neurogenesis and the reprogramming process focusing on NeuroD1. In the developing central nervous system, these pro-neurogenic transcription factors usually elicit distinct spatiotemporal expression patterns that are critical to their function in generating mature neurons. We argue that these dynamic expression patterns may be similarly needed in the process of reprogramming adult cells into neurons and further into mature neurons with subtype identities. We also summarize the existing approaches and propose new ones that control gene expression levels for a successful reprogramming outcome.

Examining the utility of near infrared light as pre-exposure therapy to mitigate temporary noise-induced hearing loss in humans.

Introduction: This study sought to determine the effect of Occupational Safety and Health Administration (OSHA) compliant noise on auditory health and assess whether pre-noise near infrared (NIR) light therapy can mitigate the effects of noise exposure. Methods: Over four visits, participants (n = 30, NCT#: 03834714) with normal hearing completed baseline hearing health assessments followed by exposure to open ear, continuous pink noise at 94 dBA for 15 min. Immediately thereafter, post-noise hearing tests at 3000, 4000, and 6000 Hz and distortion product otoacoustic emissions (DPOAEs) were conducted along with the Modified Rhyme Test (MRT), Masking Level Difference Test (MLD), and Fixed Level Frequency Tests (FLFT) [collectively referred to as the Central and Peripheral Auditory Test Battery (CPATB)] to acquire baseline noise sensitivity profiles. Participants were then randomized to either Active or Sham NIR light therapy for 30 min binaurally to conclude Visit 1. Visit 2 (≥24 and ≤ 48 h from Visit 1) began with an additional 30-min session of Active NIR light therapy or Sham followed by repeat CPATB testing and noise exposure. Post-noise testing was again conducted immediately after noise exposure to assess the effect of NIR light therapy. The remaining visits were conducted following ≥2 weeks of noise rest in a cross-over design (i.e., those who had received Active NIR light therapy in Visits 1 and 2 received Sham therapy in Visits 3 and 4). Results: Recovery hearing tests and DPOAEs were completed at the end of each visit. Participants experienced temporary threshold shifts (TTS) immediately following noise exposure, with a mean shift of 6.79 dB HL (±6.25), 10.61 dB HL (±6.89), and 7.30 dB HL (±7.25) at 3000, 4000, and 6000 Hz, respectively, though all thresholds returned to baseline at 3000, 4000, and 6000 Hz within 75 min of noise exposure. Paradoxically, Active NIR light therapy threshold shifts were statistically higher than Sham therapy at 3000 Hz (p = 0.04), but no other differences were observed at the other frequencies tested. An age sub-analysis demonstrated that TTS among younger adults were generally larger in the Sham therapy group versus Active therapy, though this was not statistically different. There were no differences in CPATB test results across Active or Sham groups. Finally, we observed no changes in auditory function or central processing following noise exposure, suggestive of healthy and resilient inner ears. Conclusion: In this study, locally administered NIR prior to noise exposure did not induce a significant protective effect in mitigating noise-induced TTS. Further exploration is needed to implement effective dosage and administration for this promising otoprotective therapy.

Associations of Sarcopenia and Body Composition Measures With Mortality After Transcatheter Aortic Valve Replacement.

BACKGROUND: Frailty associates with worse outcomes after transcatheter aortic valve replacement (TAVR). Sarcopenia underlies frailty, but the association between a comprehensive assessment of sarcopenia-muscle mass, strength, and performance-and outcomes after TAVR has not been examined. METHODS: From a multicenter prospective registry of patients with symptomatic severe aortic stenosis undergoing TAVR, 445 who had a preprocedure computed tomography and clinical assessment of frailty were included. Cross-sectional muscle (psoas and paraspinal) areas were measured on computed tomography and indexed to height. Gait speed and handgrip strength were obtained, and patients were dichotomized into fast versus slow; strong versus weak; and normal versus low muscle mass. As measures of body composition, cross-sectional fat (subcutaneous and visceral) was measured and indexed to height. RESULTS: The frequency of patients who were slow, weak, and had low muscle mass was 56%, 59%, and 42%, respectively. Among the 3 components of sarcopenia, only slower gait speed (muscle performance) was independently associated with increased post-TAVR mortality (adjusted hazard ratio, 1.12 per 0.1 m/s decrease [95% CI, 1.04-1.21]; P=0.004; adjusted hazard ratio, 1.38 per 1 SD decrease [95% CI, 1.11-1.72]; P=0.004). Meeting multiple sarcopenia criteria was not associated with higher mortality risk than fewer. Lower indexed visceral fat area (adjusted hazard ratio, 1.48 per 1 SD decrease [95% CI, 1.15-1.89]; P=0.002) was associated with mortality but indexed subcutaneous fat was not. Death occurred in 169 (38%) patients. CONCLUSIONS: Among patients with symptomatic severe aortic stenosis and comprehensive sarcopenia and body composition phenotyping, gait speed was the only sarcopenia measure associated with post-TAVR mortality. Lower visceral fat was also associated with increased risk pointing to an obesity paradox also observed in other patient populations. These findings reinforce the clinical utility of gait speed as a measure of risk and a potential target for adjunctive interventions alongside TAVR to optimize clinical outcomes.

Airway and Systemic Immune Responses Following the Third COVID-19 Vaccination in COPD Patients.

Introduction: Booster vaccinations are required to maintain protection against COVID-19. COPD patients are at higher risk of developing severe illness following SARS-CoV-2 infection. Previous cross-sectional analysis after the second COVID-19 booster showed similar immune responses in COPD patients and controls, but pre-vaccination samples were not available. This longitudinal study evaluated systemic and airway immune responses in COPD patients using samples obtained pre- and post-third COVID-19 vaccination. Methods: Twelve COPD patients were recruited, with plasma, nasal and sputum (n = 10) samples collected pre-vaccination and 4- and 14-weeks post vaccination. Samples were analyzed for anti-spike IgA and IgG and cellular immunity. The ability of plasma and nasal samples to block ACE2-spike protein interaction was assessed for Wild type, Delta, and Omicron spike variants. Results: Vaccinations increased anti-spike IgG in plasma (p < 0.001), nasal (IgG p < 0.001) and sputum (p = 0.002) samples, IgA in plasma (p < 0.001) and blood cellular immunity (p = 0.001). Plasma and nasal anti-spike IgA levels correlated (rho: 0.6, p = 0.02), with similar results for IgG (rho: 0.79, p = 0.003). Post-vaccination nasal (p = 0.002) and plasma (p < 0.001) samples were less effective at blocking Omicron spike binding to ACE2 compared to the Wild type spike variant. Discussion: Airway and systemic immune responses against SARS-CoV-2 increased in COPD patients following a third COVID-19 vaccination. Nasal and systemic responses in COPD patients were less effective against Omicron variant compared to previous variants.

A Retrospective Analysis of Clinical Utilization Between Patients Who Used Telemedicine and Office Visits in Outpatient Physical Medicine and Rehabilitation Clinics During the COVID-19 Pandemic.

OBJECTIVE: To describe the demographic characteristics of patients who used telemedicine and office visits in physical medicine and rehabilitation during the COVID-19 pandemic and to quantify differences in clinical utilization between groups. Clinical utilization was defined as emergency department, urgent care, and hospital visits. DESIGN: This was a retrospective cohort study of 1096 patients who used telemedicine and 1171 patients who used office visits from April to June 2020 in the outpatient physical medicine and rehabilitation clinics at University of Pittsburgh Medical Center for musculoskeletal-related complaints. RESULTS: The telemedicine groups contained proportionally more people of color and higher comorbidities than the office visit groups. Patients who were seen in the telemedicine groups were more likely to be prescribed opioids than the office visit group. There were no differences in clinical utilizations between the telemedicine and office visit groups. CONCLUSIONS: The higher use of telemedicine in patients of color suggests a need for studying long-term outcomes to evaluate differences in care standards. There is an urgent need to understand how telemedicine affects opioid prescribing practices. Lastly, future studies are needed to understand why there were no differences in clinical utilization between the telemedicine and office visit groups.

Dyadic versus individual delivery of a yoga program for family caregivers of glioma patients undergoing radiotherapy: Results of a 3-arm randomized controlled trial.

BACKGROUND: Despite their significant distress, supportive care interventions for caregivers of glioma patients are generally lacking. And, whether caregivers are more likely to benefit from interventions targeting patient-caregiver dyads or caregivers individually is unknown. This pilot randomized controlled trial compared the feasibility and preliminary efficacy of a dyadic yoga (DY) versus an individual caregiver yoga (CY) intervention as a supportive care strategy for family caregivers. METHODS: Patient-caregiver dyads were randomized to a DY, CY or usual care (UC) arm. DY and CY interventions were delivered over 15 sessions. Caregivers completed assessments of their depressive symptoms, quality of life (QOL), and caregiving reactions at baseline, 6 weeks, and 12 weeks, and a subset completed qualitative interviews at 12 weeks. RESULTS: With a consent rate of 63%, 67 dyads were randomized. Attendance in the DY was higher than in the CY group (session means, DY = 12.23, CY = 9.00; p = 0.06). Caregivers (79% female; 78% non-Hispanic White; mean age, 53 years) reported significantly more subjective benefit in the CY arm than in the DY arm (d = 2.1; p < .01), which was consistent with the qualitative assessment. There were medium effect sizes for improved mental QOL (d = 0.46) and financial burden (d = 0.53) in favor of the CY over the UC group. Caregivers in the CY group reported more caregiving esteem (d = 0.56) and less health decline (d = 0.60) than those in the DY group. CONCLUSION: Individual rather than dyadic delivery may be a superior supportive care approach for this vulnerable caregiver population. A larger, adequately powered efficacy trial is warranted.

Association of Depression and Cognitive Dysfunction With Patient-Centered Outcomes After Transcatheter Aortic Valve Replacement.

BACKGROUND: Depression and cognitive dysfunction (CD) are not routinely screened for in patients before transcatheter aortic valve replacement (TAVR) and their association with postprocedural outcomes is poorly understood. The objectives of this study are to determine the prevalence of depression and CD in patients with aortic stenosis undergoing TAVR and evaluate their association with mortality and quality of life. METHODS: We analyzed a prospective, multicenter TAVR registry that systematically screened patients for preexisting depression and CD with the Patient Health Questionnaire-2 and Mini-Cog, respectively. The associations with mortality were assessed with Cox proportional hazard models and quality of life (Kansas City Cardiomyopathy Questionnaire and EuroQol visual analogue scale) were evaluated using multivariable ordinal regression models. RESULTS: A total of 884 patients were included; median follow-up was 2.88 years (interquartile range=1.2-3.7). At baseline, depression was observed in 19.6% and CD in 31.8%. In separate models, after adjustment, depression (HR, 1.45 [95% CI, 1.13-1.86]; P<0.01) and CD (HR, 1.27 [95% CI, 1.02-1.59]; P=0.04) were each associated with increased mortality. Combining depression and CD into a single model, mortality was greatest among those with both depression and CD (n=62; HR, 2.06 [CI, 1.44-2.96]; P<0.01). After adjustment, depression was associated with 6.6 (0.3-13.6) points lower on the Kansas City Cardiomyopathy Questionnaire 1-year post-TAVR and 6.7 (0.5-12.7) points lower on the EuroQol visual analogue scale. CD was only associated with lower EuroQol visual analogue scale. CONCLUSIONS: Depression and CD are common in patients that undergo TAVR and are associated with increased mortality and worse quality of life. Depression may be a modifiable therapeutic target to improve outcomes after TAVR.

Metabolic Signatures of Cardiac Dysfunction, Multimorbidity, and Post-Transcatheter Aortic Valve Implantation Death.

Background Studies in mice and small patient subsets implicate metabolic dysfunction in cardiac remodeling in aortic stenosis, but no large comprehensive studies of human metabolism in aortic stenosis with long-term follow-up and characterization currently exist. Methods and Results Within a multicenter prospective cohort study, we used principal components analysis to summarize 12 echocardiographic measures of left ventricular structure and function pre-transcatheter aortic valve implantation in 519 subjects (derivation). We used least absolute shrinkage and selection operator regression across 221 metabolites to define metabolic signatures for each structural pattern and measured their relation to death and multimorbidity in the original cohort and up to 2 validation cohorts (N=543 for overall validation). In the derivation cohort (519 individuals; median age, 84 years, 45% women, 95% White individuals), we identified 3 axes of left ventricular remodeling, broadly specifying systolic function, diastolic function, and chamber volumes. Metabolite signatures of each axis specified both known and novel pathways in hypertrophy and cardiac dysfunction. Over a median of 3.1 years (205 deaths), a metabolite score for diastolic function was independently associated with post-transcatheter aortic valve implantation death (adjusted hazard ratio per 1 SD increase in score, 1.54 [95% CI, 1.25-1.90]; P<0.001), with similar effects in each validation cohort. This metabolite score of diastolic function was simultaneously associated with measures of multimorbidity, suggesting a metabolic link between cardiac and noncardiac state in aortic stenosis. Conclusions Metabolite profiles of cardiac structure identify individuals at high risk for death following transcatheter aortic valve implantation and concurrent multimorbidity. These results call for efforts to address potentially reversible metabolic biology associated with risk to optimize post-transcatheter aortic valve implantation recovery, rehabilitation, and survival.

MicroRNA-375 Is Induced during Astrocyte-to-Neuron Reprogramming and Promotes Survival of Reprogrammed Neurons when Overexpressed.

While astrocyte-to-neuron (AtN) reprogramming holds great promise in regenerative medicine, the molecular mechanisms that govern this unique biological process remain elusive. To understand the function of miRNAs during the AtN reprogramming process, we performed RNA-seq of both mRNAs and miRNAs on human astrocyte (HA) cultures upon NeuroD1 overexpression. Bioinformatics analyses showed that NeuroD1 not only activated essential neuronal genes to initiate the reprogramming process but also induced miRNA changes in HA. Among the upregulated miRNAs, we identified miR-375 and its targets, neuronal ELAVL genes (nELAVLs), which encode a family of RNA-binding proteins and were also upregulated by NeuroD1. We further showed that manipulating the miR-375 level regulated nELAVLs' expression during NeuroD1-mediated reprogramming. Interestingly, miR-375/nELAVLs were also induced by the reprogramming factors Neurog2 and ASCL1 in HA, suggesting a conserved function to neuronal reprogramming, and by NeuroD1 in the mouse astrocyte culture and spinal cord. Functionally, we showed that miR-375 overexpression improved NeuroD1-mediated reprogramming efficiency by promoting cell survival at early stages in HA and did not appear to compromise the maturation of the reprogrammed neurons. Lastly, overexpression of miR-375-refractory ELAVL4 induced apoptosis and reversed the cell survival-promoting effect of miR-375 during AtN reprogramming. Together, we demonstrated a neuroprotective role of miR-375 during NeuroD1-mediated AtN reprogramming.