Association between cardiorespiratory fitness and cerebrovascular reactivity to a breath-hold stimulus in older adults: influence of aerobic exercise training.

Cerebrovascular reactivity (CVR) to a physiological stimulus is a commonly used surrogate of cerebrovascular health. Cross-sectional studies using blood oxygen level dependent (BOLD) neuroimaging demonstrated lower BOLD-CVR to hypercapnia among adults with high compared with lower cardiorespiratory fitness (CRF) in contrast to transcranial Doppler studies. However, whether BOLD-CVR changes following chronic aerobic exercise in older, cognitively intact adults is unclear. This study evaluated relations between BOLD-CVR with CRF (V̇o2peak) using a cross-sectional and interventional study design. We hypothesized that 1) greater CRF would be associated with lower BOLD-CVR in older adults (n = 114; 65 ± 6.5 yr) with a wide range of CRF and 2) BOLD-CVR would be attenuated after exercise training in a subset (n = 33) randomized to 3-mo of moderate- or light-intensity cycling. CVR was quantified as the change in the BOLD signal in response to acute hypercapnia using a blocked breath-hold design from a region-of-interest analysis for cortical networks. In the cross-sectional analysis, there was a quadratic relation between V̇o2peak (P = 0.03), but not linear (P = 0.87) and cortical BOLD-CVR. BOLD-CVR increased until a V̇o2peak ∼28 mL/kg/min after which BOLD-CVR declined. The nonlinear trend was consistent across all networks (P = 0.04-0.07). In the intervention, both the active and light-intensity exercise groups improved CRF similarly (6% vs. 10.8%, P = 0.28). The percent change in CRF was positively associated with change in BOLD-CVR in the default mode network only. These data suggest that BOLD-CVR is nonlinearly associated with CRF and that in lower-fit adults default mode network may be most sensitive to CRF-related increases in BOLD-CVR.NEW & NOTEWORTHY Earlier studies evaluating associations between cardiorespiratory fitness (CRF) and cerebrovascular reactivity (CVR) have demonstrated conflicting findings dependent on imaging modality or subject characteristics in individuals across a narrow range of CRF. This study demonstrates that CRF is nonlinearly associated with CVR measured by blood oxygen level dependent (BOLD) fMRI in a large sample of middle-aged and older adults across a wide range of CRF, suggesting that conflicting prior findings are related to the range of CRFs studied.

Hippocampal acidity and volume are differentially associated with spatial navigation in older adults.

The hippocampus is negatively affected by aging and is critical for spatial navigation. While there is evidence that wayfinding navigation tasks are especially sensitive to preclinical hippocampal deterioration, these studies have primarily used volumetric hippocampal imaging without considering microstructural properties or anatomical variation within the hippocampus. T1ρ is an MRI measure sensitive to regional pH, with longer relaxation rates reflecting acidosis as a marker of metabolic dysfunction and neuropathological burden. For the first time, we investigate how measures of wayfinding including landmark location learning and delayed memory in cognitively normal older adults (N = 84) relate to both hippocampal volume and T1ρ in the anterior and posterior hippocampus. Regression analyses revealed hippocampal volume was bilaterally related to learning, while right lateralized T1ρ was related to delayed landmark location memory and bilateral T1ρ was related to the delayed use of a cognitive map. Overall, results suggest hippocampal volume and T1ρ relaxation rate tap into distinct mechanisms involved in preclinical cognitive decline as assessed by wayfinding navigation, and laterality influenced these relationships more than the anterior-posterior longitudinal axis of the hippocampus.

Faith in the wake of disaster: A longitudinal qualitative study of religious attachment following a catastrophic flood.

OBJECTIVE: This longitudinal qualitative study explores the impact of natural disasters on religious attachment (perceived relationship with God). We sought to validate and conceptually extend the religion-as-attachment model in a postdisaster context. METHOD: At 4 weeks (T1; n = 36) and 6 months postdisaster (T2; n = 29), survivors of the 2016 Louisiana flood completed a disaster-adapted version of the Religious Attachment Interview (Granqvist & Main, 2017). RESULTS: At T1 and T2, survivors emphasized God being a safe haven (source of protection, comfort, or nurturance). This emphasis was especially pronounced for survivors who were directly affected (their home or business flooded) or had previous disaster exposure to Hurricane Katrina. Overall, survivors consistently emphasized God serving as a stronger and wiser attachment figure, and it was rare for them to report experiencing perceived separation or loss of intimacy from God. At T1 and T2, around 85% of survivors described their current religious attachment as either having a positive affective quality (e.g., closer, stronger) or as no different from before the disaster; around 15% said it had a negative affective quality (e.g., disappointed, strained). In describing their postdisaster religion/spirituality, survivors highlighted (a) God being a source of love, comfort, strength, and hope; (b) actively putting trust/faith in God; and (c) experiencing God through family/community. CONCLUSION: Results support and conceptually extend the religion-as-attachment model in a postdisaster context. Findings suggest disasters activate the attachment system, and survivors commonly view and relate with God as an attachment figure, especially one who serves as a safe haven. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

Emergency department management of patients with rib fracture based on a clinical practice guideline.

BACKGROUND: Clinical practice guidelines (CPGs) have the ability to increase efficiency and standardize care. A CPG based on forced vital capacity (FVC) for rib fractures was developed as a tool for triage of these patients. The objectives of this study were to assess the efficacy and compliance of physicians with this rib fracture CPG. METHODS: Patients >18 that were discharged from an urban level 2 trauma center emergency department (ED) between the dates of January 1, 2014, to December 31, 2016, were eligible for the study. Demographics, mechanism, outcomes and FVC were abstracted by review of the electronic medical record. Compliance with the CPG was examined, and comparisons were made between patients successfully discharged and patients who returned. RESULTS: 455 patients met were identified during the study period. 233 were eligible after exclusions. 64% of the cohort was male with median age of 53 years. Falls were the most common mechanism (59.6%). The median number of rib fractures was 2 and median FVC 2500 mL. 28 (12.0%) of the 233 returned to the ED after discharge. The groups were well matched with no significant differences. The most common reason for return was pain (95%). Adjusted analysis showed that increasing age (adjusted OR (AOR) 0.968) and FVC (AOR 0.999) were independent predictors. Adherence with the CPG was good for hemothorax/pneumothorax and bilateral fractures (96%), but lagged with the number of fractures (74%). CONCLUSIONS: This study confirms that the rib fracture CPG is safe and an FVC of 1500 mL is a safe criterion for discharging patients with rib fractures. Interestingly, it appears that older age is protective. More work needs to be done on effective pain control to decrease return to ED visits using this CPG. LEVEL OF EVIDENCE: IV. TYPE OF STUDY: Therapeutic.

Mitigation of Tumor-Associated Fibroblast-Facilitated Head and Neck Cancer Progression With Anti-Hepatocyte Growth Factor Antibody Ficlatuzumab.

IMPORTANCE: Ficlatuzumab can be used to treat head and neck squamous cell carcinoma (HNSCC) by inhibiting c-Met receptor-mediated cell proliferation, migration, and invasion. OBJECTIVE: To understand the effect of ficlatuzumab on HNSCC proliferation, migration, and invasion. DESIGN, SETTING, AND PARTICIPANTS: The effects of ficlatuzumab on HNSCC proliferation, invasion, and migration were tested. Mitigation of c-Met and downstream signaling was assessed by immunoblotting. The tumor microenvironment has emerged as an important factor in HNSCC tumor progression. The most abundant stromal cells in HNSCC tumor microenvironment are tumor-associated fibroblasts (TAFs). We previously reported that TAFs facilitate HNSCC growth and metastasis. Furthermore, activation of the c-Met tyrosine kinase receptor by TAF-secreted hepatocyte growth factor (HGF) facilitates tumor invasion. Ficlatuzumab is a humanized monoclonal antibody that sequesters HGF, preventing it from binding to and activating c-Met. We hypothesized that targeting the c-Met pathway with ficlatuzumab will mitigate TAF-mediated HNSCC proliferation, migration, and invasion. Representative HNSCC cell lines HN5, UM-SCC-1, and OSC-19 were used in these studies. EXPOSURES FOR OBSERVATIONAL STUDIES: The HNSCC cell lines were treated with ficlatuzumab, 0 to 100 µg/mL, for 24 to 72 hours. MAIN OUTCOMES AND MEASURES: Ficlatuzumab inhibited HNSCC progression through c-Met and mitogen-activated protein kinase (MAPK) signaling pathway. RESULTS: Ficlatuzumab significantly reduced TAF-facilitated HNSCC cell proliferation (HN5, P < .001; UM-SCC-1, P < .001), migration (HN5, P = .002; UM-SCC-1, P = .01; and OSC-19, P = .04), and invasion (HN5, P = .047; UM-SCC-1, P = .03; and OSC-19, P = .04) through a 3-dimensional peptide-based hydrogel (PGmatrix). In addition, ficlatuzumab also inhibited the phosphorylation of c-Met at Tyr1234/1235 and p44/42 MAPK in HNSCC cells exposed to recombinant HGF. CONCLUSIONS AND RELEVANCE: We demonstrate that neutralizing TAF-derived HGF with ficlatuzumab effectively mitigates c-Met signaling and decreases HNSCC proliferation, migration, and invasion. Thus, ficlatuzumab effectively mitigates stromal influences on HNSCC progression.

Radiation-induced fibrosis: mechanisms and implications for therapy.

PURPOSE: Radiation-induced fibrosis (RIF) is a long-term side effect of external beam radiation therapy for the treatment of cancer. It results in a multitude of symptoms that significantly impact quality of life. Understanding the mechanisms of RIF-induced changes is essential to developing effective strategies to prevent long-term disability and discomfort following radiation therapy. In this review, we describe the current understanding of the etiology, clinical presentation, pathogenesis, treatment, and directions of future therapy for this condition. METHODS: A literature review of publications describing mechanisms or treatments of RIF was performed. Specific databases utilized included PubMed and clinicaltrials.gov, using keywords "Radiation-Induced Fibrosis," "Radiotherapy Complications," "Fibrosis Therapy," and other closely related terms. RESULTS: RIF is the result of a misguided wound healing response. In addition to causing direct DNA damage, ionizing radiation generates reactive oxygen and nitrogen species that lead to localized inflammation. This inflammatory process ultimately evolves into a fibrotic one characterized by increased collagen deposition, poor vascularity, and scarring. Tumor growth factor beta serves as the primary mediator in this response along with a host of other cytokines and growth factors. Current therapies have largely been directed toward these molecular targets and their associated signaling pathways. CONCLUSION: Although RIF is widely prevalent among patients undergoing radiation therapy and significantly impacts quality of life, there is still much to learn about its pathogenesis and mechanisms. Current treatments have stemmed from this understanding, and it is anticipated that further elucidation will be essential for the development of more effective therapies.

Toward self-adjuvanting subunit vaccines: model peptide and protein antigens incorporating covalently bound toll-like receptor-7 agonistic imidazoquinolines.

Toll-like receptor (TLR)-7 agonists show prominent Th1-biased immunostimulatory activities. A TLR7-active N(1)-(4-aminomethyl)benzyl substituted imidazoquinoline 1 served as a convenient precursor for the syntheses of isothiocyanate and maleimide derivatives for covalent attachment to free amine and thiol groups of peptides and proteins. 1 was also amenable to direct reductive amination with maltoheptaose without significant loss of activity. Covalent conjugation of the isothiocyanate derivative 2 to α-lactalbumin could be achieved under mild, non-denaturing conditions, in a controlled manner and with full preservation of antigenicity. The self-adjuvanting α-lactalbumin construct induced robust, high-affinity immunoglobulin titers in murine models. The premise of covalently decorating protein antigens with adjuvants offers the possibility of drastically reducing systemic exposure of the adjuvant, and yet eliciting strong, Th1-biased immune responses.