"Being careful": How much caution is enough? The relational context of fear of older adult falling in older adult-family caregiver dyads.

Family caregivers play an important role in coping with older adult falls; however, their perspectives on fear of older adult falling are lacking from the falls prevention literature. A mixed-method design (N=25 dyads) with interview and survey data examined linguistic characteristics and coping strategies used by older adult and family caregiver dyads to manage fear of older adult falling. Fear of older adult falling consisted of both affective (e.g., worry) and cognitive (e.g., cautious) properties. Family caregivers more frequently used affective words and first-person plural pronouns ("we" language) when talking about fear of older adult falling, while older adults more frequently used cognitive and first-and-second person singular pronouns ("I", "you"). The concept of "being careful" was shared within dyads. However, dyad partners differed in their perspectives of what constituted "being careful" and the possibilities of future falling. Findings suggest that the need for family-centered interventions to prevent falls are needed.

Acceptability, feasibility, and utility of a safety aid reduction treatment in underserved veterans: a pilot investigation.

Access to mental health services, particularly for veterans residing in underserved communities, remain scarce. One approach to addressing availability barriers is through the use of group-based transdiagnostic or unified treatment protocols. One such protocol, Safety Aid Reduction Treatment (START), previously termed False Safety Behavior Elimination Treatment (FSET), has received increasing empirical support. However, prior research has only examined this treatment among civilians with a primary anxiety diagnosis. Thus, the purpose of the current study was to replicate and extend prior research by examining the acceptability, feasibility, and utility of START among veterans, particularly those living in underserved communities, and across a wider array of diagnoses. Veterans (n = 22) were assessed prior to, immediately after, and one month following the 8-week treatment. The majority of veterans found START useful and acceptable. Additionally, recruitment and retention rates suggest that the treatment was feasible. Notably, results revealed reductions in overall anxiety, depression, and safety aid usage, which were maintained throughout the brief follow-up period. These findings add to a growing body of literature highlighting the utility of transdiagnostic approaches in the amelioration of various anxiety and related disorders. Limitations include the small sample size and uncontrolled design.

Fear of older adult falling questionnaire for caregivers (FOAFQ-CG): Evidence from content validity and item-response theory graded-response modelling.

AIMS: (1) Determine the content validity of the Fear of Older Adult Falling Questionnaire-Caregivers using a panel of gerontological experts and a target sample of family caregivers (Stage 1) and (2) Examine the response patterns of the Fear of Older Adult Falling Questionnaire-Caregivers and compare it with older adult version of Fear of Falling Questionnaire Revised using graded-response modelling (Stage 2). DESIGN: Cross-sectional mixed-method design. METHODS: Five content experts and 10 family caregivers were involved in the Stage 1 study and 53 family caregiver-older adult dyads (N = 106) were included in the Stage 2 study. The content-validity index and graded-response modelling were used to analyse data. RESULTS: Among experts, the Fear of Older Adult Falling Questionnaire-Caregivers content-validity index for relevancy, importance, and clarity of individual items and total scale ranged from 0.60-1.00 and from 0.77-0.87, respectively. Among family caregivers, the ratings of the item and scale level content-validity index for relevancy, importance, and clarity ranged from 0.90-1.00 and from 0.95-0.97, respectively. Combining feedback from both groups, we revised one item. Subsequently, the graded-response modelling revealed that a 1-factor, 3-item version of the Fear of Older Adult Falling Questionnaire-Caregivers had acceptable psychometric properties. CONCLUSIONS: The brief 3-item version of the Fear of Older Adult Falling Questionnaire-Caregivers is promising for assessing caregivers' fear of their older adult care recipient falling. IMPACT: A significant concern for family caregivers is fearing that older adult care recipients will fall, but a lack of validated measures limits the study of this phenomena. A 3-item version of the Fear of Older Adult Falling Questionnaire-Caregivers has the potential to identify family caregivers with high fear of older adult falling so that fall risk can be appropriately assessed and addressed.

TNF-α-driven inflammation and mitochondrial dysfunction define the platelet hyperreactivity of aging.

Aging and chronic inflammation are independent risk factors for the development of atherothrombosis and cardiovascular disease. We hypothesized that aging-associated inflammation promotes the development of platelet hyperreactivity and increases thrombotic risk during aging. Functional platelet studies in aged-frail adults and old mice demonstrated that their platelets are hyperreactive and form larger thrombi. We identified tumor necrosis factor α (TNF-α) as the key aging-associated proinflammatory cytokine responsible for platelet hyperreactivity. We further showed that platelet hyperreactivity is neutralized by abrogating signaling through TNF-α receptors in vivo in a mouse model of aging. Analysis of the bone marrow compartments showed significant platelet-biased hematopoiesis in old mice reflected by increased megakaryocyte-committed progenitor cells, megakaryocyte ploidy status, and thrombocytosis. Single-cell RNA-sequencing analysis of native mouse megakaryocytes showed significant reprogramming of inflammatory, metabolic, and mitochondrial gene pathways in old mice that appeared to play a significant role in determining platelet hyperreactivity. Platelets from old mice (where TNF-α was endogenously increased) and from young mice exposed to exogenous TNF-α exhibited significant mitochondrial changes characterized by elevated mitochondrial mass and increased oxygen consumption during activation. These mitochondrial changes were mitigated upon TNF-α blockade. Similar increases in platelet mitochondrial mass were seen in platelets from patients with myeloproliferative neoplasms, where TNF-α levels are also increased. Furthermore, metabolomics studies of platelets from young and old mice demonstrated age-dependent metabolic profiles that may differentially poise platelets for activation. Altogether, we present previously unrecognized evidence that TNF-α critically regulates megakaryocytes resident in the bone marrow niche and aging-associated platelet hyperreactivity and thrombosis.

The frailty syndrome and outcomes in the TOPCAT trial.

AIMS: The impact of frailty on outcomes in randomized heart failure with preserved ejection fraction (HFpEF) trials has not been previously reported. This analysis sought to characterize frailty in a large contemporary HFpEF clinical trial cohort and to evaluate its impact on patient relevant outcomes. METHODS AND RESULTS: Using data from the Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist (TOPCAT) trial, a frailty index (FI) was constructed at baseline using 39 clinical, laboratory, and self-reported variables. The relationship between frailty and outcomes and the role of frailty in modulating the benefits of spironolactone were examined in a subset of 1767 TOPCAT patients. For the cohort as a whole (mean age 71.5 years, 49% female), the mean FI at baseline was 0.37 ± 0.11. Four frailty classes were defined ranging from FI < 0.3 to FI ≥ 0.5. Overall, 94% of subjects were considered frail (defined as a FI > 0.21). Mean age was lowest for the most frail class (69 ± 9 years for Class 4; 73 ± 10 years for Class 1; P < 0.001). Body mass index, systolic blood pressure, and pulse pressure all increased as FI increased. Both primary and secondary outcomes increased as frailty severity increased. There was no interaction between frailty class and treatment effect of spironolactone. CONCLUSIONS: Frailty was very common in TOPCAT HFpEF participants. Greater frailty was associated with a higher risk of cardiovascular outcomes and mortality. The benefit of spironolactone on outcomes in TOPCAT was not attenuated by frailty class.

Gametocytocidal screen identifies novel chemical classes with Plasmodium falciparum transmission blocking activity.

Discovery of transmission blocking compounds is an important intervention strategy necessary to eliminate and eradicate malaria. To date only a small number of drugs that inhibit gametocyte development and thereby transmission from the mosquito to the human host exist. This limitation is largely due to a lack of screening assays easily adaptable to high throughput because of multiple incubation steps or the requirement for high gametocytemia. Here we report the discovery of new compounds with gametocytocidal activity using a simple and robust SYBR Green I- based DNA assay. Our assay utilizes the exflagellation step in male gametocytes and a background suppressor, which masks the staining of dead cells to achieve healthy signal to noise ratio by increasing signal of viable parasites and subtracting signal from dead parasites. By determining the contribution of exflagellation to fluorescent signal and using appropriate cutoff values, we were able to screen for gametocytocidal compounds. After assay validation and optimization, we screened an FDA approved drug library of approximately 1500 compounds, as well as the 400 compound MMV malaria box and identified 44 gametocytocidal compounds with sub to low micromolar IC50s. Major classes of compounds with gametocytocidal activity included quaternary ammonium compounds with structural similarity to choline, acridine-like compounds similar to quinacrine and pyronaridine, as well as antidepressant, antineoplastic, and anthelminthic compounds. Top drug candidates showed near complete transmission blocking in membrane feeding assays. This assay is simple, reproducible and demonstrated robust Z-factor values at low gametocytemia levels, making it amenable to HTS for identification of novel and potent gametocytocidal compounds.

Highly potent anti-proliferative effects of a gallium(III) complex with 7-chloroquinoline thiosemicarbazone as a ligand: synthesis, cytotoxic and antimalarial evaluation.

A gallium(III) complex with 7-chloroquinoline thiosemicarbazone was synthesized and characterized. The complex proved to be thirty-one times more potent on colon cancer cell line, HCT-116, with considerably less cytotoxicity on non-cancerous colon fibroblast, CCD-18Co, when compared to etoposide. Its anti-malarial potential on 3D7 isolate of Plasmodium falciparum was better than lumefantrine.

Erythrocyte lysis and Xenopus laevis oocyte rupture by recombinant Plasmodium falciparum hemolysin III.

Malaria kills more than 1 million people per year worldwide, with severe malaria anemia accounting for the majority of the deaths. Malaria anemia is multifactorial in etiology, including infected erythrocyte destruction and decrease in erythrocyte production, as well as destruction or clearance of noninfected erythrocytes. We identified a panspecies Plasmodium hemolysin type III related to bacterial hemolysins. The identification of a hemolysin III homologue in Plasmodium suggests a potential role in host erythrocyte lysis. Here, we report the first characterization of Plasmodium falciparum hemolysin III, showing that the soluble recombinant P. falciparum hemolysin III is a pore-forming protein capable of lysing human erythrocytes in a dose-, time-, and temperature-dependent fashion. The recombinant P. falciparum hemolysin III-induced hemolysis was partially inhibited by glibenclamide, a known channel antagonist. Studies with polyethylene glycol molecules of different molecular weights indicated a pore size of approximately 3.2 nm. Heterologous expression of recombinant P. falciparum hemolysin III in Xenopus oocytes demonstrated early hypotonic lysis similar to that of the pore-forming aquaporin control. Live fluorescence microscopy localized transfected recombinant green fluorescent protein (GFP)-tagged P. falciparum hemolysin III to the essential digestive vacuole of the P. falciparum parasite. These transfected trophozoites also possessed a swollen digestive vacuole phenotype. Native Plasmodium hemolysin III in the digestive vacuole may contribute to lysis of the parasitophorous vacuole membrane derived from the host erythrocyte. After merozoite egress from infected erythrocytes, remnant P. falciparum hemolysin III released from digestive vacuoles could potentially contribute to lysis of uninfected erythrocytes to contribute to severe life-threatening anemia.

Identification of an Atg8-Atg3 protein-protein interaction inhibitor from the medicines for Malaria Venture Malaria Box active in blood and liver stage Plasmodium falciparum parasites.

Atg8 is a ubiquitin-like autophagy protein in eukaryotes that is covalently attached (lipidated) to the elongating autophagosomal membrane. Autophagy is increasingly appreciated as a target in diverse diseases from cancer to eukaryotic parasitic infections. Some of the autophagy machinery is conserved in the malaria parasite, Plasmodium. Although Atg8's function in the parasite is not well understood, it is essential for Plasmodium growth and survival and partially localizes to the apicoplast, an indispensable organelle in apicomplexans. Here, we describe the identification of inhibitors from the Malaria Medicine Venture Malaria Box against the interaction of PfAtg8 with its E2-conjugating enzyme, PfAtg3, by surface plasmon resonance. Inhibition of this protein-protein interaction prevents PfAtg8 lipidation with phosphatidylethanolamine. These small molecule inhibitors share a common scaffold and have activity against both blood and liver stages of infection by Plasmodium falciparum. We have derivatized this scaffold into a functional platform for further optimization.

Antimalarial efficacy of hydroxyethylapoquinine (SN-119) and its derivatives.

Quinine and other cinchona-derived alkaloids, although recently supplanted by the artemisinins (ARTs), continue to be important for treatment of severe malaria. Quinine and quinidine have narrow therapeutic indices, and a safer quinine analog is desirable, particularly with the continued threat of antimalarial drug resistance. Hydroxyethylapoquinine (HEAQ), used at 8 g a day for dosing in humans in the 1930s and halving mortality from bacterial pneumonias, was shown to cure bird malaria in the 1940s and was also reported as treatment for human malaria cases. Here we describe synthesis of HEAQ and its novel stereoisomer hydroxyethylapoquinidine (HEAQD) along with two intermediates, hydroxyethylquinine (HEQ) and hydroxyethylquinidine (HEQD), and demonstrate comparable but elevated antimalarial 50% inhibitory concentrations (IC50) of 100 to 200 nM against Plasmodium falciparum quinine-sensitive strain 3D7 (IC50, 56 nM). Only HEAQD demonstrated activity against quinine-tolerant P. falciparum strains Dd2 and INDO with IC50s of 300 to 700 nM. HEQD had activity only against Dd2 with an IC50 of 313 nM. In the lethal mouse malaria model Plasmodium berghei ANKA, only HEQD had activity at 20 mg/kg of body weight comparable to that of the parent quinine or quinidine drugs measured by parasite inhibition and 30-day survival. In addition, HEQ, HEQD, and HEAQ (IC50 ≥ 90 µM) have little to no human ether-à-go-go-related gene (hERG) channel inhibition expressed in CHO cells compared to HEAQD, quinine, and quinidine (hERG IC50s of 27, 42, and 4 µM, respectively). HEQD more closely resembled quinine in vitro and in vivo for Plasmodium inhibition and demonstrated little hERG channel inhibition, suggesting that further optimization and preclinical studies are warranted for this molecule.

Standardized care pathway versus conventional approach in the management of patients presenting with faint at the University of Utah.

BACKGROUND: Despite the availability of guidelines, the evaluation of patients with faint continues to be inconsistent. The purpose of this study was to test the hypothesis that utilization of a new standardized-care pathway (Faint-Algorithm) reduces hospital admissions and improves diagnostic yield when compared to the conventional approach in the evaluation of patients with faint. METHODS: We reviewed the data of 154 consecutive patients presenting with faint to the Faint and Fall Clinic at the University of Utah (standardized group) and 100 patients previously evaluated for faint using the conventional approach (conventional group). RESULTS: Using a standardized approach, only 4% of patients were admitted when compared to 20% in the conventional group (P < 0.001). The rate of diagnosis at initial evaluation was similar between the groups; however, at 45 days, it was greater in the standardized group when compared to the conventional group (57% vs 45% in the total population, P = 0.09; 57% vs 39% in the outpatient subgroups, P = 0.02). The number of tests or consultations associated with additional charges was significantly lower in the standardized group when compared to the conventional group (1.9 ± 1.0 vs 2.6 ± 1.2, P = 0.001). CONCLUSIONS: The use of a standardized approach in the evaluation of patients with faint decreased the number of hospital admissions and increased the rate of diagnosis at 45 days. This was achieved with less utilization of costly tests and consultations.

The effects of radio-frequency ablation on blood pressure control in patients with atrial fibrillation and hypertension.

PURPOSE: The effects of radio-frequency ablation (RFA) on blood pressure (BP) regulation in patients with atrial fibrillation (AF) and hypertension remain unknown. We hypothesized that patients with successful ablation had a lower BP and/or lesser utilization of antihypertensive drug therapy during follow-up when compared to patients with failed ablation. METHODS AND RESULTS: This was a retrospective evaluation of patients with AF and hypertension treated with ablation at the University of Utah between July 2006 and June 2010. BP and use of antihypertensive medications were assessed at baseline and 1 year follow-up. A total of 167 patients were identified. Eight patients were excluded due to the need for AAD therapy beyond the blanking period thus leaving 80 patients in the success group and 79 patients in the failure group. The mean BP and HR at baseline were not significant between the groups. In the success group, the mean systolic BP decreased from a baseline value of 129 ± 17 to 125 ± 14 mmHg at 1 year (p = 0.075). In contrast, in the failure group, the mean systolic BP increased from a baseline value of 124 ± 16 to 127 ± 14 mmHg at 1 year (p = 0.176). Between-group comparison revealed a p value of 0.026. Minimal changes in diastolic BP were noted in both groups. No significant changes in antihypertensive therapy were noted. CONCLUSION: We have shown that successful catheter ablation in patients with AF and hypertension is associated with a decrease in systolic BP when compared to an increase in patients with failed ablation. Our findings suggest that restoring sinus rhythm could have an antihypertensive effect in patients with AF and hypertension.

Atrial fibrillation: an independent risk factor for nonaccidental falls in older patients.

BACKGROUND: Nonaccidental falls are often the result of a combination of factors including cardiovascular disorders such as orthostatic hypotension and unspecified cardiac arrhythmias. The objective of this study was to determine if there is an association between atrial fibrillation (AF) and nonaccidental falls. METHODS: We reviewed the records of 442 consecutive patients >65 years old who presented to the Emergency Department at the University of Utah Medical Center with a complaint of fall. RESULTS: Two-hundred eleven patients presented with nonaccidental fall, 231 patients with accidental fall. Patients with nonaccidental fall were more likely to be older, have a history of hypertension and neurological disorders, and taking five or more medications when compared to patients with accidental fall. Despite a similar prevalence of sinus rhythm at presentation, the prevalence of a history of AF was significantly higher in patients with nonaccidental fall compared to patients with accidental fall (26% vs 15%; P = 0.003). After adjusting for clinically and statistically significant predictors with a multivariate logistic regression analysis, AF, neurological disorders, and age ≤81 years were independent predictors of nonaccidental fall. In patients ≤81 years old (median age), the risk of nonaccidental falls was 2.5 times greater in patients with a history of AF when compared to those without a history of AF (odds ratio = 2.53 [confidence interval 95% 1.3-5], P = 0.007). CONCLUSION: AF is an independent risk factor for nonaccidental falls. Our results emphasize the need to screen for AF in patients presenting with nonaccidental fall.

Restoring sinus rhythm results in blood pressure reduction in patients with persistent atrial fibrillation and a history of hypertension.

INTRODUCTION: The long-term effects of atrial fibrillation (AF) on blood pressure (BP) in patients with hypertension (HTN) remain unclear. We hypothesized that restoration of normal sinus rhythm (NSR) results in a decrease in BP despite the expected increase in cardiac output. METHODS AND RESULTS: Twenty-four-hour BP measurements were obtained during AF, and on Day 1 and Day 30 post-successful cardioversion in 18 patients with AF and HTN (cardioversion group), and another 22 patients with AF and HTN with no immediate plans for cardioversion (control group). Except for the duration of AF, the clinical characteristics and use of medications were similar between the groups. In the cardioversion group, a significant decrease in diastolic blood pressure (DBP) and mean blood pressure (MBP) were noted on Day 1 post-cardioversion with no significant change in systolic blood pressure (SBP): 117/74/88 ± 13/9/9 mmHg during AF and 116/70/85 ± 13/9/10 mmHg during Day 1 post-cardioversion (P = 0.68; <0.01 and 0.04 for SBP, DBP, and MBP, respectively). In the 13 subjects who remained in NSR at Day 30, DBP and MBP decreased further on Day 30 when compared to Day 1 with no significant change in SBP: 118/76/90 ± 13/7/8 mmHg during AF; 119/72/88 ± 12/8/9 mmHg during Day 1; and 118/69/86 ± 10/8/7 mmHg during Day 30 post-cardioversion (P = 0.97; <0.001 and 0.03 for SBP, DBP, and MBP, respectively). In the control group, no significant changes in BP were noted. CONCLUSION: Restoring NSR in patients with AF and HTN resulted in a sustained decrease in DBP and MBP. To our knowledge, this is the first study to show that maintenance of NSR improves BP control in patients with AF and HTN.

Irregular ventricular activation results in QT prolongation and increased QT dispersion: a new insight into the mechanism of AF-induced ventricular arrhythmogenesis.

INTRODUCTION: Atrial fibrillation (AF) has been shown to be associated with increased risk of ventricular arrhythmias. We have previously shown reverse electrical remodeling of the ventricles following successful restoration of sinus rhythm in patients with persistent AF. The purpose of this study was to assess the relative role of irregular ventricular activation in mediating the previously observed changes. METHODS AND RESULTS: Twenty-two patients referred for an invasive electrophysiologic study were randomized to 30 minutes of regular or irregular atrioventricular (AV) sequential pacing at 100 beats per minute (bpm) with a programmed AV interval of 100 ms. Irregular pacing was triggered from prerecorded digital signal with a mean rate of 100 bpm, and a standard deviation of 150 ms (25% of the mean rate). In the regular pacing group, QT and QTc decreased from 448 ± 102 ms and 453 ± 105 ms to 428 ± 109 ms and 442 ± 104 ms, respectively (P < 0.001 for QT interval and P < 0.001 for QTc interval). There was no significant change in QT dispersion. In the irregular pacing group, QT and QTc increased from 477 ± 104 ms and 486 ± 78 ms to 489 ± 106 ms and 500 ± 106 ms (P < 0.01 for QT interval and P = 0.03 for QTc interval). In addition, there was a significant increase in QT dispersion from 50 ± 22 ms to 66 ± 22 ms (P = 0.001). Since the rate and pacing sites were similar between the groups, we attribute the repolarization changes in the irregular pacing group to the irregular activation of the ventricles. CONCLUSION: The detrimental effects of irregular pacing go beyond the hemodynamic changes and include electrical remodeling that favors an arrhythmogenic substrate.

Rotavirus infection accelerates type 1 diabetes in mice with established insulitis.

Infection modulates type 1 diabetes, a common autoimmune disease characterized by the destruction of insulin-producing islet beta cells in the pancreas. Childhood rotavirus infections have been associated with exacerbations in islet autoimmunity. Nonobese diabetic (NOD) mice develop lymphocytic islet infiltration (insulitis) and then clinical diabetes, whereas NOD8.3 TCR mice, transgenic for a T-cell receptor (TCR) specific for an important islet autoantigen, show more rapid diabetes onset. Oral infection of infant NOD mice with the monkey rotavirus strain RRV delays diabetes development. Here, the effect of RRV infection on diabetes development once insulitis is established was determined. NOD and NOD8.3 TCR mice were inoculated with RRV aged > or = 12 and 5 weeks, respectively. Diabetes onset was significantly accelerated in both models (P < 0.024), although RRV infection was asymptomatic and confined to the intestine. The degree of diabetes acceleration was related to the serum antibody titer to RRV. RRV-infected NOD mice showed a possible trend toward increased insulitis development. Infected males showed increased CD8(+) T-cell proportions in islets. Levels of beta-cell major histocompatibility complex class I expression and islet tumor necrosis factor alpha mRNA were elevated in at least one model. NOD mouse exposure to mouse rotavirus in a natural experiment also accelerated diabetes. Thus, rotavirus infection after beta-cell autoimmunity is established affects insulitis and exacerbates diabetes. A possible mechanism involves increased exposure of beta cells to immune recognition and activation of autoreactive T cells by proinflammatory cytokines. The timing of infection relative to mouse age and degree of insulitis determines whether diabetes onset is delayed, unaltered, or accelerated.

Rotavirus infection of infant and young adult nonobese diabetic mice involves extraintestinal spread and delays diabetes onset.

Rotaviruses have been implicated as a possible viral trigger for exacerbations in islet autoimmunity, suggesting they might modulate type 1 diabetes development. In this study, the ability of rotavirus strain RRV to infect the pancreas and affect insulitis and diabetes was examined in nonobese diabetic (NOD) mice, an experimental model of type 1 diabetes. Mice were inoculated either orally or intraperitoneally as infants or young adults. In infant mice inoculated orally, rotavirus antigen was detected in pancreatic macrophages outside islets and infectious virus was found in blood cells, pancreas, spleen, and liver. Extraintestinal RRV spread and pancreatic presence of infectious virus also occurred in intraperitoneally inoculated infant and adult mice. The initiation of insulitis was unaltered by infection. The onset of diabetes was delayed in infant mice inoculated orally and infant and adult mice inoculated intraperitoneally. In contrast, adult mice inoculated orally showed no evidence of pancreatic RRV, the lowest rate of detectable RRV replication, and no diabetes modulation. Thus, the ability of RRV infection to modulate diabetes development in infant and young adult NOD mice was related to the overall extent of detectable virus replication and the presence of infectious virus extraintestinally, including in the pancreas. These studies show that RRV infection of infant and young adult NOD mice provides significant protection against diabetes. As these findings do not support the hypothesis that rotavirus triggers autoimmunity related to type 1 diabetes, further research is needed to resolve this issue.