Cu, Fe, and Zn isotope ratios in murine Alzheimer's disease models suggest specific signatures of amyloidogenesis and tauopathy.

Alzheimer's disease (AD) is characterized by accumulation of tau and amyloid-beta in the brain, and recent evidence suggests a correlation between associated protein aggregates and trace elements, such as copper, iron, and zinc. In AD, a distorted brain redox homeostasis and complexation by amyloid-beta and hyperphosphorylated tau may alter the isotopic composition of essential mineral elements. Therefore, high-precision isotopic analysis may reveal changes in the homeostasis of these elements. We used inductively coupled plasma-mass spectrometry (ICP-MS)-based techniques to determine the total Cu, Fe, and Zn contents in the brain, as well as their isotopic compositions in both mouse brain and serum. Results for male transgenic tau (Line 66, L66) and amyloid/presenilin (5xFAD) mice were compared with those for the corresponding age- and sex-matched wild-type control mice (WT). Our data show that L66 brains showed significantly higher Fe levels than did those from the corresponding WT. Significantly less Cu, but more Zn was found in 5xFAD brains. We observed significantly lighter isotopic compositions of Fe (enrichment in the lighter isotopes) in the brain and serum of L66 mice compared with WT. For 5xFAD mice, Zn exhibited a trend toward a lighter isotopic composition in the brain and a heavier isotopic composition in serum compared with WT. Neither mouse model yielded differences in the isotopic composition of Cu. Our findings indicate significant pathology-specific alterations of Fe and Zn brain homeostasis in mouse models of AD. The associated changes in isotopic composition may serve as a marker for proteinopathies underlying AD and other types of dementia.

Fidelity Assessment of a Social Work-Led Intervention Among Patients with Firearm Injuries.

PURPOSE: To support future development and refinement of social work-led intervention programs among patients with firearm injuries and to demonstrate how a fidelity assessment can be used to adjust and refine intervention delivery in an ongoing trial. METHODS: We conducted a fidelity assessment of a randomized controlled trial of a social work-led intervention among patients with a firearm injury. RESULTS: We found that our study intervention was well implemented, meeting 70% of the fidelity assessment score items, however noted lower fidelity with client-based items. DISCUSSION: As a result of fidelity assessment findings, we refined intervention delivery to improve implementation fidelity including beginning to review cases of all patients each month, rather than focusing on patients in crisis. Our fidelity assessment process and findings offer insight into the challenges of implementing an intervention among patients with firearm injuries and highlights the value of monitoring intervention fidelity during an ongoing trial.

The specificity and role of microglia in epileptogenesis in mouse models of tuberous sclerosis complex.

OBJECTIVE: Microglial abnormalities have been reported in pathologic specimens from patients with tuberous sclerosis complex (TSC), a genetic disorder characterized by epilepsy, intellectual disability, and autism. However, the pathogenic role of microglia in epilepsy in TSC is poorly understood, particularly whether microglia defects may be a primary contributor to epileptogenesis or are secondary to seizures or simply epiphenomena. In this study, we tested the hypothesis that Tsc1 gene inactivation in microglia is sufficient to cause epilepsy in mouse models of TSC. METHODS: Using a chemokine receptor, Cx3cr1, to target microglia, conventional Tsc1Cx3cr1-Cre CKO (conditional knockout) mice and postnatal-inducible Tsc1Cx3cr1-CreER CKO mice were generated and assessed for molecular and histopathologic evidence of microglial abnormalities, mechanistic target of rapamycin 1 (mTORC1) pathway activation, and epilepsy. RESULTS: Tsc1Cx3cr1-Cre CKO mice exhibited a high efficiency of microglia Tsc1 inactivation, mTORC1 activation, increased microglial size and number, and robust epilepsy, which were rapamycin-dependent. However, Cre reporter studies demonstrated that constitutive Cx3cr1 expression affected not only microglia, but also a large percentage of cortical neurons, confounding the role of microglia in epileptogenesis in Tsc1 Cx3cr1-Cre CKO mice. In contrast, postnatal inactivation of Tsc1 utilizing a tamoxifen-inducible Cx3cr1-CreER resulted in a more-selective microglia Tsc1 inactivation with high efficiency, mTORC1 activation, and increased microglial size and number, but no documented epilepsy. SIGNIFICANCE: Microglia abnormalities may contribute to epileptogenesis in the context of neuronal involvement in TSC mouse models, but selective Tsc1 gene inactivation in microglia alone may not be sufficient to cause epilepsy, suggesting that microglia have more supportive roles in the pathogenesis of seizures in TSC.

A matched-cohort study of pediatric head injuries: collecting data to inform an evidence-based triage assessment.

UNLABELLED: Triage nurses are the "first stop" for patients who present to the emergency department for care. The assessment of pediatric head injuries is especially challenging because signs and symptoms of head trauma in children do not correlate well with the risk of closed head injury (CHI). METHODS: A retrospective matched cohort study was conducted to compare 2 groups of patients who presented to a pediatric emergency department for evaluation of a head injury: a CHI-positive cohort and a CHI-negative cohort as identified by computed tomography scan. The purpose of the chart review was to collect specific information from both cohorts which could be used to inform a nurse-driven pediatric head injury assessment tool. RESULTS: The younger the child, the more likely they were to be asymptomatic. Scalp hematomas in infants <3 months were associated with CHI even if the infants were otherwise asymptomatic. Injuries to the temporal-parietal region were associated with CHI at every age. Frequency of caregiver report of loss of consciousness (LOC) was almost identical in both cohorts. Children in every age category sustained CHIs as the result of minor falls based on standard age-related fall criteria. DISCUSSION: The infants and children at highest risk for CHI are often the most difficult to assess. The results of this study reinforce the need for a nurse-driven, evidence-based risk scoring system that could be used to aid with early identification of infants and children who are at high risk for CHI.

Simplified homology-assisted CRISPR for gene editing in Drosophila.

In vivo genome editing with clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 generates powerful tools to study gene regulation and function. We revised the homology-assisted CRISPR knock-in method to convert Drosophila GAL4 lines to LexA lines using a new universal knock-in donor strain. A balancer chromosome-linked donor strain with both body color (yellow) and eye red fluorescent protein (RFP) expression markers simplified the identification of LexA knock-in using light or fluorescence microscopy. A second balancer chromosome-linked donor strain readily converted the second chromosome-linked GAL4 lines regardless of target location in the cis-chromosome but showed limited success for the third chromosome-linked GAL4 lines. We observed a consistent and robust expression of the yellow transgene in progeny harboring a LexA knock-in at diverse genomic locations. Unexpectedly, the expression of the 3xP3-RFP transgene in the "dual transgene" cassette was significantly increased compared with that of the original single 3xP3-RFP transgene cassette in all tested genomic locations. Using this improved screening approach, we generated 16 novel LexA lines; tissue expression by the derived LexA and originating GAL4 lines was similar or indistinguishable. In collaboration with 2 secondary school classes, we also established a systematic workflow to generate a collection of LexA lines from frequently used GAL4 lines.

Comparing a recommendation for self-paced versus moderate intensity physical activity for midlife adults: Rationale and design.

Current U.S. guidelines recommend that adults obtain 150 min per week of moderate intensity physical activity (PA), 75 min of vigorous intensity PA, or some equivalent combination. However, less than half of U.S. adults reach this goal, with the proportion even smaller among adults with overweight or obesity. Moreover, regular PA declines after age 45-50. Previous research suggests a shift in national guidelines to emphasize PA of a self-selected intensity (i.e., self-paced), instead of prescribed moderate intensity PA, may result in better adherence to PA programs, particularly among midlife adults with overweight or obesity. The present paper presents the protocol for a field-based RCT testing the hypothesis that adherence to PA programs is improved when PA is explicitly recommended to be self-paced rather than prescribed at moderate intensity among midlife (ages 50-64) adults (N = 240) with overweight or obesity. All participants receive a 12-month intervention designed to help them overcome barriers to regular PA and are randomly assigned to either self-paced or prescribed moderate intensity PA. The primary outcome is total volume of PA (minutes by intensity) as measured by accelerometry. Secondary outcomes include self-reported min/week of PA and changes in bodyweight. Additionally, using ecological momentary assessment, we examine putative mediators of treatment effects. We hypothesize self-paced PA will lead to a more positive affective response to PA, more perceived autonomy, and lower perceived exertion during PA, and thus greater increases in PA behavior. Findings will have direct implications for PA intensity recommendations among midlife adults with overweight or obesity.

Testing an insurance-based monetary incentive program for exercise: RCT design and rationale.

Participation in regular physical activity (PA) has numerous health benefits; however, as few as 10% of U.S. adults meet guidelines when device-based assessments of PA are used. The present paper presents the design and rationale for an RCT examining the efficacy of an exercise incentive program currently offered by at least three major US insurance companies, in which participants must attend a YMCA fitness facility at least 50 times within 6 months to receive an incentive. In a factorial design, incentive amount ($200, $100, $0) is crossed with a comparison of the standard gain-framed incentive program and a loss-framed incentive condition in which participants are told their membership fee is being held and will be returned or forfeited depending on their fitness facility attendance. Participants (N = 330) are randomized to gain-framed $100 incentive (n = 55), gain-framed $200 incentive (n = 55), loss-framed $100 incentive (n = 55), loss-framed $200 incentive (n = 55), or control (n = 110). Each participant is enrolled in the same condition for two consecutive 6-month periods for a total of 12 months per participant. The primary outcome is number of visits to the fitness facility over each 6-month period, verified by objective swipe-card data. Secondary outcomes include total moderate-to-vigorous PA (MVPA) over 7-day periods assessed at 3-month intervals through accelerometers (Actigraph wGT3x-BT) and self-report. Habit formation and anticipated regret are putative mediators and household income is a putative moderator of the incentive-based programs. A payer-perspective, within-trial cost-utility analysis will quantify the incremental costs per (a) quality-adjusted life year gained, (b) YMCA attendance, and (c) change in MVPA.

Generation of LexA enhancer-trap lines in Drosophila by an international scholastic network.

Conditional gene regulation in Drosophila through binary expression systems like the LexA-LexAop system provides a superb tool for investigating gene and tissue function. To increase the availability of defined LexA enhancer trap insertions, we present molecular, genetic, and tissue expression studies of 301 novel Stan-X LexA enhancer traps derived from mobilization of the index SX4 line. This includes insertions into distinct loci on the X, II, and III chromosomes that were not previously associated with enhancer traps or targeted LexA constructs, an insertion into ptc, and seventeen insertions into natural transposons. A subset of enhancer traps was expressed in CNS neurons known to produce and secrete insulin, an essential regulator of growth, development, and metabolism. Fly lines described here were generated and characterized through studies by students and teachers in an international network of genetics classes at public, independent high schools, and universities serving a diversity of students, including those underrepresented in science. Thus, a unique partnership between secondary schools and university-based programs has produced and characterized novel resources in Drosophila, establishing instructional paradigms devoted to unscripted experimental science.

Syringes must be prioritized globally to ensure equitable access to COVID-19 and other essential vaccines and to sustain safe injection practices.

Supply of autodisable (AD) syringes has been a key component of global COVID-19 vaccination campaigns, and it is critical to maintaining safe injection practices for routine immunization as well as pandemic response. AD syringe production increased significantly in response to demand, but distribution challenges have included the need to coordinate syringes to meet the specific delivery requirements of various COVID-19 vaccines, shipping bottlenecks, and syringe export restrictions. Stockpiling syringes, ensuring standardization of future vaccine dose volumes, and geographical diversification of syringe production would improve syringe logistics in the future. Balancing syringe supply and demand and stabilizing the market over the long term is essential to ensure that the world is prepared for possible new variants of COVID-19 or a new global outbreak. This will require concerted action on the part of public, nonprofit, and private partners.

Testing the Feasibility and Acceptability of an Acceptance and Commitment Therapy Intervention to Increase Physical Activity among Individuals with Depression: A Protocol Paper.

Background: Engaging in regular physical activity (PA) is particularly important among individuals with depression, who are at heightened risk for a host of negative health outcomes. However, people with depression are 50% less likely to meet national guidelines for PA and face unique barriers to PA adherence, including lower distress tolerance and motivation for exercise. Acceptance and Commitment Therapy (ACT) may offer promise for increasing PA among adults with depressive symptoms due to its effects on distress tolerance and motivation. Therefore, we developed ACTivity, an ACT-based intervention designed to promote PA among low-active adults with elevated depressive symptoms. Prior to testing the efficacy of ACTivity in an RCT, an important first step is to conduct a preliminary trial to establish feasibility of study procedures for the ACTivity and comparison intervention programs, as well as to establish the credibility/acceptability of the intervention. The purpose of this paper is to describe the ACTivity intervention and the design of this feasibility trial. Method/Design: We will conduct a feasibility RCT with two parallel groups and a 1:1 allocation ratio comparing ACTivity to a comparison intervention (relaxation training + PA promotion) among 60 low-active adults with elevated depressive symptoms. All study procedures will be conducted remotely. Discussion: Results of this feasibility study will inform a subsequent RCT designed to test the efficacy of ACTivity. If shown to be efficacious, ACTivity will provide a treatment that can be widely disseminated to increase PA among adults with depressive symptoms and thereby decrease their risk for chronic disease.

Helping individuals with firearm injuries: A cluster randomized trial.

BACKGROUND: Patients with firearm injuries are at high risk of subsequent arrest and injury following hospital discharge. We sought to evaluate the effect of a 6-month joint hospital- and community-based low-intensity intervention on risk of arrest and injury among patients with firearm injuries. METHODS: We conducted a cluster randomized controlled trial, enrolling patients with firearm injuries who received treatment at Harborview Medical Center, the level 1 trauma center in Seattle, Washington, were 18 years or older at the time of injury, spoke English, were able to provide consent and a method of contact, and lived in one of the five study counties. The intervention consisted of hospital-based motivational interviewing, followed by a 6-month community-based intervention, and multiagency support. The primary outcome was the risk of subsequent arrest. The main secondary outcome was the risk of death or subsequent injury requiring treatment in the emergency department or hospitalization. RESULTS: Neither assignment to or engagement with the intervention, defined as having at least 1 contact point with the support specialist, was associated with risk of arrest at 2 years post-hospital discharge (relative risk for intervention assignment, 1.15; 95% confidence interval, 0.90-1.48; relative risk for intervention engagement, 1.07; 95% confidence interval, 0.74-2.19). There was similarly no association observed for subsequent injury. CONCLUSIONS: This study represents one of the first randomized controlled trials of a joint hospital- and community-based intervention delivered exclusively among patients with firearm injuries. The intervention was not associated with changes in risk of arrest or injury, a finding most likely due to the low intensity of the program. LEVEL OF EVIDENCE: Care management, level II.

Click synthesis and biologic evaluation of (R)- and (S)-2-amino-3-[1-(2-[18F]fluoroethyl)-1H-[1,2,3]triazol-4-yl]propanoic acid for brain tumor imaging with positron emission tomography.

The (R)- and (S)-enantiomers of 2-amino-3-[1-(2-[18F]fluoroethyl)-1H-[1,2,3]triazol-4-yl]propanoic acid (4) were synthesized and evaluated in the rat 9L gliosarcoma brain tumor model using cell uptake assays, biodistribution studies, and micro-positron emission tomography (microPET). The (R)- and (S)-enantiomers of [18F]4 were radiolabeled separately using the click reaction in 57% and 51% decay-corrected yields, respectively. (S)-[18F]4 was a substrate for cationic amino acid transport and, to a lesser extent, system L transport in vitro. In vivo biodistribution studies demonstrated that (S)-[18F]4 provided higher tumor uptake and higher tumor to brain ratios (15:1 at the 30- and 60-minute time points) compared to the (R)-enantiomer (7:1 at the 30- and 60-minute time points). MicroPET studies with (S)-[18F]4 confirmed that this tracer provides good target to background ratios for both subcutaneous and intracranial 9L gliosarcoma tumors. Based on these results, the 1H-[1,2,3]triazole-substituted amino acid (S)-[18F]4 has promising PET properties for brain tumors and represents a novel class of radiolabeled amino acids for tumor imaging.

Cybersex and the E-teen: what marriage and family therapists should know.

Adolescents who use the Internet regularly (the "e-teen") present a new set of challenges for marriage and family therapists. This article introduces marriage and family therapists to (a) the basic technological concepts and unique psychological characteristics of the Internet important in understanding and addressing adolescent online sexual behavior, (b) the appropriate developmental expectations for teens online, including risk-taking behaviors and critical decision-making skills, and (c) suggested strategies for assessment, prevention, and intervention when dealing with problematic online sexual behavior in adolescents. Marriage and family therapists cannot ignore the role the Internet plays in adolescent sexual development and its implication for the family. This article will serve as a primer for the marriage and family therapist when presented with adolescents who engage in online sexual behaviors.

Comparison of standing balance between female collegiate dancers and soccer players.

STUDY DESIGN: This study was designed as a comparison study of two cohorts. OBJECTIVES: The hypothesis of this study was that soccer players and dancers have different balance abilities and that these differences could be objectively measured using center of pressure measurements. BACKGROUND: Center of pressure (COP) measurements are reproducible and have been validated in the literature for assessing standing balance. The literature does not provide sensitive enough techniques for discriminating between two groups of athletes with excellent standing balance. METHODS AND MEASURES: A Matscan pressure mat (Tekscan, Boston, MA) was used to compare COP change variability between 32 female collegiate soccer players and 32 dancers. COP was used to calculate sway index, center acquisition time, sway path length and sway velocity as measures of standing balance. RESULTS: The dancers had significantly better balance scores (p<0.05) in 5 of 20 balance tests. Results for the remaining 15 balance tests were not significantly different. CONCLUSION: These data show that standing balance characteristics of dancers and soccer players can be objectively measured using COP data. Dancers have certain standing balance abilities that are better than those of soccer players. The COP measurements in this study can be used as a tool in future studies investigating standing balance in different groups of athletes.

Posttraumatic Growth in Relationally Betrayed Women.

The research literature on relational betrayal in a committed relationship has focused on the resulting trauma from the betrayal; however, few studies investigated the potential for posttraumatic growth following a relational betrayal. This study investigated the presence of posttraumatic growth in relationally betrayed women. The research focused on women's perceptions of the relational betrayal, and factors that facilitated posttraumatic growth. Results indicated relationally betrayed women perceived the betrayal as a traumatic event, to the extent that some met criteria for PTSD diagnosis. The passage of time was significant corollary to posttraumatic growth when moderated by a PTSD diagnosis. Finally, certain resources were reported to be more helpful than others in the development of posttraumatic growth. Clinical implications are presented.

Patellofemoral pain syndrome: evaluation of location and intensity of pain.

OBJECTIVES: To identify the sites and intensity of pain in patients with patellofemoral pain syndrome. METHOD: A prospective cohort study was conducted at an academic sports medicine practice in Boston, Massachusetts. All patients met inclusion criteria and were enrolled and evaluated during the study time frame. A single sports medicine orthopaedic surgeon examined a consecutive sample of patients with patellofemoral pain not explained by one of several well-defined anterior knee pain diagnoses. The study group consisted of 100 patients (75 females, 25 males) with median age of 14 years. Eleven discrete locations were palpated for tenderness. Hamstring tightness was evaluated by measuring the popliteal angle. Patients reported intensity of pain using a 0- to 9-point ordinal scale. Regression and nonparametric statistical methods were used. RESULTS: The most common site of pain was the patella during anterior-posterior compression (90 patients), followed by the distal pole of the patella, the medial plica, and the nonarticular medial femoral condyle. Median "worst pain" intensity was 6 out of a possible 9. The most common site of "worst pain" was also the patella in compression (63 patients). Median duration of symptoms was 10 months, with an interquartile range of 3 to 20 months. Pain intensity was inversely correlated with duration of symptoms (P < 0.01). CONCLUSIONS: In these patients with patellofemoral pain syndrome, the major source of pain was the patella subchondral bone.