Injectable and Dynamically Crosslinked Zwitterionic Hydrogels for Anti-Fouling and Tissue Regeneration Applications.

A zwitterionic injectable and degradable hydrogel based on hydrazide and aldehyde-functionalized [2-(methacryloyloxy)ethyl] dimethyl-(3-sulfopropyl)ammonium hydroxide (DMAPS) precursor polymers that can address practical in vivo needs is reported. Zwitterion fusion interactions between the zwitterionic precursor polymers create a secondary physically crosslinked network to enable much more rapid gelation than previously reported with other synthetic polymers, facilitating rapid gelation at much lower polymer concentrations or degrees of functionalization than previously accessible in addition to promoting zero swelling and long-term degradation responses and significantly stiffer mechanics than are typically accessed with previously reported low-viscosity precursor gelation systems. The hydrogels maintain the highly anti-fouling properties of conventional zwitterionic hydrogels against proteins, mammalian cells, and bacteria while also promoting anti-fibrotic tissue responses in vivo. Furthermore, the use of the hydrogels for effective delivery and subsequent controlled release of viable cells with tunable profiles both in vitro and in vivo is demonstrated, including the delivery of myoblasts in a mouse skeletal muscle defect model for reducing the time between injury and functional mobility recovery. The combination of the injectability, degradability, and tissue compatibility achieved offers the potential to expand the utility of zwitterionic hydrogels in minimally invasive therapeutic applications.

Participation in the Georgia Food for Health programme and CVD risk factors: a longitudinal observational study.

OBJECTIVE: To assess the relationship between programme attendance in a produce prescription (PRx) programme and changes in cardiovascular risk factors. DESIGN: The Georgia Food for Health (GF4H) programme provided six monthly nutrition education sessions, six weekly cooking classes and weekly produce vouchers. Participants became programme graduates attending at least 4 of the 6 of both the weekly cooking classes and monthly education sessions. We used a longitudinal, single-arm approach to estimate the association between the number of monthly programme visits attended and changes in health indicators. SETTING: GF4H was implemented in partnership with a large safety-net health system in Atlanta, GA. PARTICIPANTS: Three hundred thirty-one participants living with or at-risk of chronic disease and food insecurity were recruited from primary care clinics. Over three years, 282 participants graduated from the programme. RESULTS: After adjusting for programme site, year, participant sex, age, race and ethnicity, Supplemental Nutrition Assistance Program participation and household size, we estimated that each additional programme visit attended beyond four visits was associated with a 0·06 kg/m2 reduction in BMI (95 % CI -0·12, -0·01; P = 0·02), a 0·37 inch reduction in waist circumference (95 % CI -0·48, -0·27; P < 0·001), a 1·01 mmHg reduction in systolic blood pressure (95 % CI -1·45, -0·57; P < 0·001) and a 0·43 mmHg reduction in diastolic blood pressure (95 % CI -0·69, -0·17; P = 0·001). CONCLUSIONS: Each additional cooking and nutrition education visit attended beyond the graduation threshold was associated with modest but significant improvements in CVD risk factors, suggesting that increased engagement in educational components of a PRx programme improves health outcomes.

Blood Pressure Variability and Outcome in Traumatic Brain Injury: A Propensity Score Matching Study.

INTRODUCTION: Patients with tIPH (used here to refer to traumatic intraparenchymal hemorrhagic contusion) or intraparenchymal hemorrhage face high rates of mortality and persistent functional deficits. Prior studies have found an association between blood pressure variability (BPV) and neurologic outcomes in patients with spontaneous IPH. Our study investigated the association between BPV and discharge destination (a proxy for functional outcome) in patients with tIPH. METHODS: We retrospectively reviewed the charts of patients admitted to a Level I trauma center for ≥ 24 hours with tIPH. We examined variability in hourly BP measurements over the first 24 hours of hospitalization. Our outcome of interest was discharge destination (home vs facility). We performed 1:1 propensity score matching and multivariate regressions to identify demographic and clinical factors predictive of discharge home. RESULTS: We included 354 patients; 91 were discharged home and 263 to a location other than home. The mean age was 56 (SD 21), 260 (73%) were male, 22 (6%) were on anticoagulation, and 54 (15%) on antiplatelet therapy. Our propensity-matched cohorts included 76 patients who were discharged home and 76 who were discharged to a location other than home. One measure of BPV (successive variation in systolic BP) was identified as an independent predictor of discharge location in our propensity-matched cohorts (odds ratio 0.89, 95% confidence interval 0.8-0.98; P = 0.02). Our model demonstrated good goodness of fit (P-value for Hosmer-Lemeshow test = 0.88) and very good discriminatory capability (AUROC = 0.81). High Glasgow Coma Scale score at 24 hours and treatment with fresh frozen plasma were also associated with discharge home. CONCLUSION: Our study suggests that increased BPV is associated with lower rates of discharge home after initial hospitalization among patients with tIPH. Additional research is needed to evaluate the impact of BP control on patient outcomes.

Luminal mucus plugs are spatially associated with airway wall thickening in severe COPD and asthma: A single-centered, retrospective, observational study.

BACKGROUND: Airway wall thickening and excess airway mucus occur in asthma and chronic obstructive pulmonary disease (COPD), but few studies have investigated the relationship between them. Our objective was to determine the association between computed tomography (CT) airway wall thickening in segmental airways proximal to airways with or without mucus plugging in patients with asthma and COPD. METHODS: Mucus plugging was scored using a CT bronchopulmonary segment-based scoring system in asthma and COPD patients. For each of the 19 segmental airways, a mucus plug was defined as complete occlusion of one or more of the daughter branches (sub-segmental airways) by mucus. CT airway measurements were generated for each of the 19 segmental airways: wall-area-percentage (WA%), lumen area (LA), and total airway count (TAC) (VIDA Diagnostics Inc.). Multivariable logistic regression models were constructed for the presence of mucus plugs with corresponding CT measurement and adjusted by covariates; each of the 19 segments was treated as a nested variable. RESULTS: A total of 33 participants were evaluated. Participants had a mean age of 60 ± 15yrs and there were n = 14 (42%) males. There were 16 (48%) participants with a diagnosis of asthma and 17 (52%) with a COPD diagnosis. The mean FEV1 was 53 ± 21%pred and FEV1/FVC was 54 ± 15%. The mean mucus score in all participants was 15 ± 4 (min = 0, max = 19). Multivariable logistic regression analysis showed the presence of airway mucus was significantly associated with increased CT WA% (ß = 7.30, p = 0.004) and reduced TAC (ß = -0.06, p = 0.045). CONCLUSIONS: There was increased airway wall thickness and reduced airway counts on CT in segments where there was a distal mucus plug compared to segments without mucus plugs in asthma and COPD.

Traumatic brain injury and intraparenchymal hemorrhage progression: Blood pressure variability matters.

INTRODUCTION: Blood pressure variability (BPV) has been shown to correlate with intraparenchymal hematoma progression (HP) and worse outcomes in patients with spontaneous intracerebral hemorrhage (sICH). However, this association has not been elucidated in patients with traumatic intraparenchymal hemorrhage or contusion (tIPH). We hypothesized that 24 h-BPV from time of admission is associated with hemorrhagic progression of contusion or intraparenchymal hemorrhage (HPC), and worse outcomes in patients with tIPH. METHOD: We performed a retrospective observational analysis of adult patients treated at an academic regional Level 1 trauma center between 01/2018-12/2019. We included patients who had tIPH and ≥ 2 computer tomography (CT) scans within 24 h of admission. HP, defined as ≥30% of admission hematoma volume, was calculated by the ABC/2 method. We performed stepwise multivariable logistic regressions for the association between clinical factors and outcomes. RESULTS: We analyzed 354 patients' charts. Mean age (Standard Deviation [SD]) was 56 (SD = 21) years, 260 (73%) were male. Mean admission hematoma volume was 7 (SD =19) cubic centimeters (cm3), 160 (45%) had HP. Coefficient of variation in systolic blood pressure (SBPCV) (OR 1.03, 95%CI 1.02-1.3, p = 0.026) was significantly associated with HPC among patients requiring external ventricular drain (EVD). Difference between highest and lowest systolic blood pressure (SBPmax-min) (OR 1.02, 95%CI 1.004-1.03, p = 0.007) was associated with hospital mortality. CONCLUSION: SBPCV was significantly associated with HP among patients who required EVD. Additionally, increased SBPmax-min was associated with an increase in mortality. Clinicians should be cautious with patients' blood pressure until further studies confirm these observations.

Sterol and oxysterol synthases near the ciliary base activate the Hedgehog pathway.

Vertebrate Hedgehog signals are transduced through the primary cilium, a specialized lipid microdomain that is required for Smoothened activation. Cilia-associated sterol and oxysterol lipids bind to Smoothened to activate the Hedgehog pathway, but how ciliary lipids are regulated is incompletely understood. Here we identified DHCR7, an enzyme that produces cholesterol, activates the Hedgehog pathway, and localizes near the ciliary base. We found that Hedgehog stimulation negatively regulates DHCR7 activity and removes DHCR7 from the ciliary microenvironment, suggesting that DHCR7 primes cilia for Hedgehog pathway activation. In contrast, we found that Hedgehog stimulation positively regulates the oxysterol synthase CYP7A1, which accumulates near the ciliary base and produces oxysterols that promote Hedgehog signaling in response to pathway activation. Our results reveal that enzymes involved in lipid biosynthesis in the ciliary microenvironment promote Hedgehog signaling, shedding light on how ciliary lipids are established and regulated to transduce Hedgehog signals.

My Quest, a Community-Based mHealth Intervention to Increase Physical Activity and Promote Weight Loss in Predominantly Rural-Dwelling, Low-Income, Alabama Women.

Rural-dwelling, overweight/obese, limited-resource individuals and women have the lowest leisure-time physical activity rates among Americans. This community-based, single-group pre- posttest study sought to increase physical activity, step counts, and promote weight loss in 104 low-income women (84% rural). Analyses included nonparametric and repeated-measures analyses of variance to determine physical activity behaviors, step counts, and weight loss. Results show, from pre- to postintervention, participants improved self-reported step counts, physical activity goal setting and behaviors, and body weight. This study adds support that text message programs can reach a high-risk, limited-resource, predominantly rural population to promote physical activity and weight loss.

Human kidney on a chip assessment of polymyxin antibiotic nephrotoxicity.

Drug-induced kidney injury, largely caused by proximal tubular intoxicants, limits development and clinical use of new and approved drugs. Assessing preclinical nephrotoxicity relies on animal models that are frequently insensitive; thus, potentially novel techniques - including human microphysiological systems, or "organs on chips" - are proposed to accelerate drug development and predict safety. Polymyxins are potent antibiotics against multidrug-resistant microorganisms; however, clinical use remains restricted because of high risk of nephrotoxicity and limited understanding of toxicological mechanisms. To mitigate risks, structural analogs of polymyxins (NAB739 and NAB741) are currently in clinical development. Using a microphysiological system to model human kidney proximal tubule, we exposed cells to polymyxin B (PMB) and observed significant increases of injury signals, including kidney injury molecule-1 KIM-1and a panel of injury-associated miRNAs (each P < 0.001). Surprisingly, transcriptional profiling identified cholesterol biosynthesis as the primary cellular pathway induced by PMB (P = 1.22 ×10-16), and effluent cholesterol concentrations were significantly increased after exposure (P < 0.01). Additionally, we observed no upregulation of the nuclear factor (erythroid derived-2)-like 2 pathway, despite this being a common pathway upregulated in response to proximal tubule toxicants. In contrast with PMB exposure, minimal changes in gene expression, injury biomarkers, and cholesterol concentrations were observed in response to NAB739 and NAB741. Our findings demonstrate the preclinical safety of NAB739 and NAB741 and reveal cholesterol biosynthesis as a potentially novel pathway for PMB-induced injury. To our knowledge, this is the first demonstration of a human-on-chip platform used for simultaneous safety testing of new chemical entities and defining unique toxicological pathway responses of an FDA-approved molecule.

Lipid peroxidation biomarkers for evaluating oxidative stress in equine neuroaxonal dystrophy.

BACKGROUND: Equine neuroaxonal dystrophy/equine degenerative myeloencephalopathy (eNAD/EDM) is a neurodegenerative disorder affecting genetically predisposed foals maintained on an α-tocopherol (α-TOH) deficient diet. Currently no antemortem diagnostic test for eNAD/EDM is available. HYPOTHESIS: Because α-TOH deficiency is associated with increased lipid peroxidation, it was hypothesized that F2 -isoprostanes (F2 IsoP), F4 -neuroprostanes (F4 NP) and oxysterols derived from free radical oxidation would be increased in the cerebrospinal fluid (CSF) and neural tissue of eNAD/EDM affected horses and could serve as potential biomarkers for disease. ANIMALS: Isoprostane Study A: 14 Quarter horse foals (10 healthy foals and 4 eNAD/EDM affected foals) at 1 and 6 months of age. Isoprostane Study B: 17 eNAD/EDM affected and 10 unaffected horses ≥ 1-4 years of age. Oxysterol study: eNAD/EDM affected (n = 14, serum; n = 11, CSF; n = 10, spinal cord [SC]) and unaffected horses 1-4 years of age (n = 12, serum; n = 10, CSF; n = 7, SC). PROCEDURES: Cerebrospinal fluid [F2 IsoP] and [F4 NP] were assessed using gas chromatography-negative ion chemical ionization mass spectrometry. Serum, CSF, and cervical SC [oxysterols] were quantified using high performance liquid chromatography mass spectrometry. Results were compared with respective α-TOH concentrations. RESULTS: Spinal cord [7-ketocholesterol], [7-hydroxycholesterol], and [7-keto-27-hydrocholesterol] were higher in eNAD/EDM horses whereas [24-ketocholesterol] was lower. No significant difference was found in CSF [F2 IsoP] and [F4 NP], serum [oxysterols] and CSF [oxysterols] between eNAD/EDM affected and unaffected horses. No correlation was found between [F2 IsoP], [F4 NP], or [oxysterols] and respective [α-TOH]. CONCLUSIONS AND CLINICAL IMPORTANCE: In the SC, targeted markers of cholesterol oxidation were significantly increased in horses with eNAD/EDM.

An innate immune response and altered nuclear receptor activation defines the spinal cord transcriptome during alpha-tocopherol deficiency in Ttpa-null mice.

Mice with deficiency in tocopherol (alpha) transfer protein gene develop peripheral tocopherol deficiency and sensory neurodegeneration. Ttpa-/- mice maintained on diets with deficient α-tocopherol (α-TOH) had proprioceptive deficits by six months of age, axonal degeneration and neuronal chromatolysis within the dorsal column of the spinal cord and its projections into the medulla. Transmission electron microscopy revealed degeneration of dorsal column axons. We addressed the potential pathomechanism of α-TOH deficient neurodegeneration by global transcriptome sequencing within the spinal cord and cerebellum. RNA-sequencing of the spinal cord in Ttpa-/- mice revealed upregulation of genes associated with the innate immune response, indicating a molecular signature of microglial activation as a result of tocopherol deficiency. For the first time, low level Ttpa expression was identified in the murine spinal cord. Further, the transcription factor liver X receptor (LXR) was strongly activated by α-TOH deficiency, triggering dysregulation of cholesterol biosynthesis. The aberrant activation of transcription factor LXR suppressed the normal induction of the transcription factor retinoic-related orphan receptor-α (RORA), which is required for neural homeostasis. Thus we find that α-TOH deficiency induces LXR, which may lead to a molecular signature of microglial activation and contribute to sensory neurodegeneration.

My Quest, an Intervention Using Text Messaging to Improve Dietary and Physical Activity Behaviors and Promote Weight Loss in Low-Income Women.

OBJECTIVE: To evaluate changes in dietary and physical activity behaviors and weight after implementation of a 12-week text messaging initiative (My Quest). DESIGN: The researchers conducted a 1-group, pre- to posttest study design to determine changes after implementation of a text messaging initiative developed using the tenets of the Social Cognitive Theory. SETTING: A total of 55 Alabama counties (84% rural) with high rates of poverty, overweight/obesity, and chronic diseases. PARTICIPANTS: Convenience sample of low-income, primarily overweight/obese women (n = 104). INTERVENTION: Short texts (n = 2-3/d) provided health tips, reminders, and goal-setting prompts. Weekly electronic newsletters provided tips and recipes. Participant self-monitored body weight weekly. MAIN OUTCOME MEASURE: Outcomes included goal setting, self-efficacy, behavioral and environmental factors, self-monitoring, and body weight; data collection occurred through text message response and online surveys. ANALYSIS: Analyses were conducted using McNemar test (dichotomous data), Wilcoxon signed rank test (ordinal data), or paired t test (continuous data). RESULTS: Participants significantly (P < .05) improved dietary and physical activity behaviors and food environment; increased dietary and physical activity goal setting; and reduced body weight. CONCLUSIONS AND IMPLICATIONS: A low-cost, text messaging initiative particularly targeting women residing in rural communities with high rates of poverty and obesity can promote weight loss and improve dietary and physical activity behaviors. Future studies may include a control group and social support component such as group text messaging.

Improving Medical Oncology Quality Through Peer-to-Peer Consultation.

PURPOSE: This study describes how the use of peer-to-peer (P2P) physician consultation improves medical oncology care quality by preventing non-evidence-based and potentially morbid chemotherapy treatments. New Century Health (NCH) has adapted a physician audit and feedback model to strengthen adherence to clinical guidelines. In the NCH oncology program, P2P consultation complements clinical pathways and an online prior authorization platform. Payers are adopting the use of clinical pathways as a management strategy for managing costs and improving quality. Managing medical oncology is a complex process, because evidence evolves rapidly, and almost one third of chemotherapy is prescribed off label. The use of prior authorization, combined with standardized protocols for patients with specific cancer diagnoses, is one way for payers to reduce unnecessary treatment variation. [Table: see text] Methods: NCH completed a retrospective analysis of the chemotherapy treatment requests (CTRs) submitted by payers' oncologists for prior authorization between January and December 2012. The objectives of the clinical impact analysis were to measure the CTR disposition rate, identify the CTR intervention rate resulting from P2P consultation, and identify the types of drug triggering the interventions. RESULTS: Analysis of the 13,078 CTRs associated with the 1,116 unique Medicare and commercial patients of a national health plan determined that CTRs voluntarily withdrawn or recommended adverse determination (RAD; ie, NCH recommendation to member's health plan to not authorize treatment as requested; after review of health plan policy and compendia, NCH was not able to resolve provider's request through P2P consultation and could not recommend approval of treatment plan as requested, therefore recommending denial of request) by the submitting physician as a result of a P2P consultation with an NCH board-certified oncologist comprised 11.6% of all CTRs. Further analysis identified the types of medication associated with the 1,521 CTRs withdrawn/RAD as a consequence of P2P consultation. Interventions on chemotherapeutic medications and supportive care were evenly distributed at 51.2% and 48.8%, respectively. Interventions on medications that had received US Food and Drug Administration approval within the last 2 years (initial approval or for new indications) represented 12.1%. [Table: see text] Conclusion: Using P2P consultation to complement a pathway-driven prior authorization process improves medical oncology quality. In addition, P2P consultation can be an effective collaborative physician engagement strategy by supporting oncologists with critical clinical information and mitigating concerns about pathway implementation and about payer involvement in drug use management.