"I Just Need Proper Treatment": Being Hospitalized for Endocarditis among Individuals Who Inject Drugs Being Hospitalized for Endocarditis.

BACKGROUND: Rates of hospitalization for injection drug use-associated infective endocarditis (IDU-IE) are increasing. Much is known about the poor outcomes of patients with IDU-IE; less is known about the patient experience during hospitalization. OBJECTIVE: To explore the experience of being hospitalized for endocarditis among individuals who inject drugs, providing a foundation on which to develop strategies to improve care for these patients. DESIGN: Qualitative interviews with hospitalized patients undergoing cardiothoracic surgery with a history of injection drug use between February 2021 and May 2022 at the Hospital of the University of Pennsylvania. PARTICIPANTS: Cardiothoracic surgery patients with a documented history of injection drug use and the ability to speak English were recruited during their hospital stay. APPROACH: Thematic analysis of interviews guided by phenomenology and harm reduction theory was used to identify recurrent themes. Interviews were digitally recorded and transcribed and analyzed using NVIVO software. KEY RESULTS: Interviews from 13 participants resulted in four major themes around Hospital Experience: (1) Kindness as an Antidote to Dehumanizing Treatment; (2) Relationships with the Care Team; (3) Withdrawal and Pain Management; and (4) Anticipating and Experiencing the Transition out the Hospital. Participants recounted long histories of dehumanizing care during previous hospitalizations, noted the value of open, sincere, and non-judgmental communication with clinical teams, expressed overall satisfaction with the management of their symptoms during the current hospitalization, reported self-discharging during previous hospitalizations due to undertreated pain and withdrawal, and noted significant challenges around discharge planning and execution. CONCLUSIONS: Participants noted structural (e.g., discharge planning) and interpersonal (e.g., stigma from care team) barriers to quality hospital care. They also noted that expressions of kindness from hospital staff were meaningful and comforting. Patients with IDU-IE face multi-dimensional challenges in the hospital. Their perspectives can meaningfully inform programs and initiatives to improve their outcomes and support recovery.

The effectiveness of financial incentives for COVID-19 vaccination: A systematic review.

Financial incentives are a controversial strategy for increasing vaccination. In this systematic review, we evaluated: 1) the effects of incentives on COVID-19 vaccinations; 2) whether effects differed based on study outcome, study design, incentive type and timing, or sample sociodemographic characteristics; and 3) the cost of incentives per additional vaccine administered. We searched PubMed, EMBASE, Scopus, and Econlit up to March 2022 for terms related to COVID, vaccines, and financial incentives, and identified 38 peer-reviewed, quantitative studies. Independent raters extracted study data and evaluated study quality. Studies examined the impact of financial incentives on COVID-19 vaccine uptake (k = 18), related psychological outcomes (e.g., vaccine intentions, k = 19), or both types of outcomes. For studies of vaccine uptake, none found that financial incentives had a negative effect on uptake, and most rigorous studies found that incentives had a positive effect on uptake. By contrast, studies of vaccine intentions were inconclusive. While three studies concluded that incentives may negatively impact vaccine intentions for some individuals, they had methodological limitations. Study outcomes (uptake versus intentions) and study design (experimental versus observational frameworks) appeared to influence results more than incentive type or timing. Additionally, income and political affiliation may moderate responses to incentives. Most studies evaluating cost per additional vaccine administered found that they ranged from $49-75. Overall, fears about financial incentives decreasing COVID-19 vaccine uptake are not supported by the evidence. Financial incentives likely increase COVID-19 vaccine uptake. While these increases appear to be small, they may be meaningful across populations. Registration: PROSPERO, CRD42022316086 (https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42022316086).

Implementing a resilience coach program to support first year housestaff during the COVID-19 pandemic: early pilot results and comparison with non-housestaff sessions.

BACKGROUND: In response to the COVID-19 pandemic, we launched the Penn Medicine Coping First Aid program to provide psychosocial supports to our health system community. Our approach leveraged lay health worker volunteers trained in principles of Psychological First Aid to deliver coaching services through a centralized virtual platform. METHODS: We emailed all (n = 408) first year housestaff (i.e., residents and fellows) with an invitation to schedule a session with a resilience coach. We compared the mental health concerns, symptoms, and Psychological First Aid techniques recorded in (n = 67) first year housestaff sessions with (n = 91) sessions of other employees in the health system. RESULTS: Between June and November 2020, forty-six first year housestaff attended at least one resilience coaching session. First year housestaff most commonly presented with feelings of anxiety and sadness and shared concerns related to the availability of social support. Resilience coaches most frequently provided practical assistance and ensured safety and comfort to first year housestaff. First year housestaff reported fewer physical or mental health symptoms and held shorter sessions with resilience coaches than non-housestaff. CONCLUSIONS: This work offers insights on how to address psychosocial functioning through low-intensity interventions delivered by lay personnel. More research is needed to understand the efficacy of this program and how best to engage housestaff in wellness and resilience programs throughout training, both during and beyond COVID-19.

"There's absolutely no downside to this, I mean, except community opposition:" A qualitative study of the acceptability of vending machines for harm reduction.

BACKGROUND: Vending machines for harm reduction (VMHR) are an innovative approach to deliver life-saving materials, information, and treatment for hard-to-reach populations, particularly for persons who inject drugs. The current study explores stakeholders' perspectives on the feasibility and acceptability of VMHR in Philadelphia. METHODS: From October 2021 to February 2022, we conducted 31 semi-structured interviews with potential end users, staff, and leadership at a local federally qualified health center, and community members. Trained coders extracted themes from interview transcripts across four key domains: materials and logistics, location, access, and community introduction. RESULTS: Interviewees from all stakeholder groups endorsed using VMHR to provide supplies for wound care, fentanyl test strips, naloxone, and materials to connect individuals to treatment and other services. Dispensing syringes and medications for opioid use disorder were commonly endorsed by health center staff but were more controversial among potential end users. Even within stakeholder groups, views varied with respect to where to locate the machines, but most agreed that the machine should be placed in the highest drug use areas. Across stakeholder groups, interviewees suggested several strategies to introduce and gain community acceptance of VMHR, including community education, one-on-one conversations with community members, and coupling the machine with safe disposal of syringes and information to link individuals to treatment. CONCLUSIONS: Stakeholders were generally receptive to VMHR. The current study findings are consistent with qualitative analyses from outside of the USA and contribute new ideas regarding the anticipated community response and best methods for introducing these machines to a community. With thoughtful planning and design, VMHR could be a feasible and acceptable modality to reduce death and disease transmission associated with the opioid and HIV epidemics in cities like Philadelphia.

Colleague appraisal of Australian general practitioners in training: an analysis of multisource feedback data.

BACKGROUND: Multisource feedback is an evidence-based and validated tool used to provide clinicians, including those in training, feedback on their professional and interpersonal skills. Multisource feedback is mandatory for participants in the Royal Australian College of General Practitioners Practice Experience Program and for some Australian General Practice Training Registrars. Given the recency of the Practice Experience Program, there are currently no benchmarks available for comparison within the program and to other comparable cohorts including doctors in the Australian General Practice Training program. The aim of this study is to evaluate and compare colleague feedback within and across General Practice trainee cohorts. METHODS: Colleague feedback, from multisource feedback of Practice Experience Program participants and Australian General Practice Training Registrars, collected between January 2018 and April 2020, was compared to identify similarities and differences. Analyses entailed descriptive statistics, between and within groups rater consistency and agreement measures, principal component analysis, t-tests, analysis of variance, and psychometric network analysis. RESULTS: Colleague ratings of Practice Experience Program participants (overall average 88.58%) were lower than for Registrars (89.08%), although this difference was not significant. 'Communication with patients' was rated significantly lower for Practice Experience Program participants (2.13%) while this group was rated significantly better for their 'Ability to say no' (1.78%). Psychometric network analyses showed stronger linkages between items making up the behavioural component (compared to the items of the performance and self-management components, as found by principal component analysis) for Practice Experience Program participants as compared to Registrars. Practice Experience Program participants were stronger in clinical knowledge and skills as well as confidentiality, while Registrars were stronger in communicating with patients, managing their own stress, and in their management and leadership skills. CONCLUSIONS: The multisource feedback scores of doctors undertaking the Practice Experience Program suggests that, while all mean values are 'very good' to 'excellent', there are areas for improvement. The linkages between skills suggests that Practice Experience Program doctors' skills are somewhat isolated and have yet to fully synthesise. We now have a better understanding of how different groups of General Practitioners in training compare with respect to professional and interpersonal skills. Based on the demonstrated differences, the Practice Experience Program might benefit from the addition of educational activities to target the less developed skills.

A comparison of patient appraisal of professional skills for GPs in training participating in differing education programs.

BACKGROUND: Medical boards and healthcare providers internationally are coming under increasing pressure to attract international medical graduates (IMGs) and overseas trained doctors (OTDs) to cope with predicted general practice (GP) doctor shortages. Various pathways to registration are made available for this purpose. There is very little understanding of the effects of different training pathways to licensing and registration on the ability of IMGs and OTDs, as well as locally trained doctors, to acquire the desirable professional skills deemed necessary for working effectively in the primary care sector. METHODS: Feedback from patients was collected at the end of their scheduled consultation with their doctor using a questionnaire consisting of 13 Likert scale items that asked them to rate their experience of the consultation. Feedback was obtained for doctors going through the Royal Australian College of General Practice (RACGP) Practice Experience Program (PEP) and the Australian General Practice Training Program (AGPT), with the former intended primarily for IMGs and OTDs, and the latter for local medical graduates including from New Zealand. Patient feedback was also obtained for patients visiting already Fellowed and experienced GPs for comparative purposes, resulting in data for three groups of doctors (two trainee, one already Fellowed). Rater consistency and agreement measures, analysis of variance, principal component analysis, t-tests and psychometric network analysis were undertaken between and within groups to identify similarities and differences in patient experience and professionalism of doctors. RESULTS: There was a small but significant difference in average patient raw scores given to PEP and AGPT doctors (90.25, 90.97%), with the highest scores for 'Respect shown' (92.24, 93.15%) and the lowest for 'Reassurance' 89.38, 89.84%). Male patients gave lower scores (89.56%) than female patients (91.23%) for both groups of doctors. In comparison, patients gave experienced GPs an average 91.38% score, with male patients giving a lower average score than female patients (90.62, 91.93%). Two components were found in the patient data (interpersonal communication, caring/empathy) that account for over 80% of the variance. When patient scores were aggregated by doctor, the average PEP and AGPT doctor scores received were 90.27 and 90.99%, in comparison to the average experienced GP score of 91.43%. Network analysis revealed differences in the connectedness of items between these two groups as well as in comparison with experienced GPs, suggesting that PEP doctors' skills are less cohesively developed in the areas of listening ability, explaining and providing reassurance. CONCLUSIONS: The small but statistically significant differences between doctor groups reported in this preliminary study are supplemented by percentile analysis, network analysis and principal component analysis to identify areas for further exploration and study. There is scope for improving the integration of interpersonal communication skills of GPs in Training with their caring and empathy skills, when compared with experienced GPs as a benchmark. Suggestions are made for enhancing professional skills from a patients' perspective in future training programs.

It's all in the name: why exposure therapy could benefit from a new one.

Exposure therapy for anxiety and related disorders is the psychological intervention with the strongest support for its efficacy and effectiveness to date. Yet, it is the least used evidence-based intervention in routine clinical practice, with a long-acknowledged public relations problem. Despite a wealth of research aimed at improving uptake of exposure, exposure's marketing and branding remains an untapped target. We first introduce principles from the marketing literature to propose that the field take steps toward a rebranding and repackaging of exposure therapy to support efforts to implement it widely. Second, we present preliminary data on clinician preferences for the use of alternative terminology developed to be more palatable and marketable - "Supported Approach of Feared Experiences - Cognitive Behavioral Therapy (SAFE-CBT)" - compared to traditional terminology. This initial survey indicated that most clinicians preferred use of the SAFE-CBT term when talking to patients, whereas only a minority preferred it for use among training clinicians. We conclude by discussing implications of these results for future efforts to implement exposure therapy more widely and set an agenda for future research in this space.

Protein kinase A negatively regulates Ca2+ signalling in Toxoplasma gondii.

The phylum Apicomplexa comprises a group of obligate intracellular parasites that alternate between intracellular replicating stages and actively motile extracellular forms that move through tissue. Parasite cytosolic Ca2+ signalling activates motility, but how this is switched off after invasion is complete to allow for replication to begin is not understood. Here, we show that the cyclic adenosine monophosphate (cAMP)-dependent protein kinase A catalytic subunit 1 (PKAc1) of Toxoplasma is responsible for suppression of Ca2+ signalling upon host cell invasion. We demonstrate that PKAc1 is sequestered to the parasite periphery by dual acylation of PKA regulatory subunit 1 (PKAr1). Upon genetic depletion of PKAc1 we show that newly invaded parasites exit host cells shortly thereafter, in a perforin-like protein 1 (PLP-1)-dependent fashion. Furthermore, we demonstrate that loss of PKAc1 prevents rapid down-regulation of cytosolic [Ca2+] levels shortly after invasion. We also provide evidence that loss of PKAc1 sensitises parasites to cyclic GMP (cGMP)-induced Ca2+ signalling, thus demonstrating a functional link between cAMP and these other signalling modalities. Together, this work provides a new paradigm in understanding how Toxoplasma and related apicomplexan parasites regulate infectivity.

Heat Waves Alter Macrophyte-Derived Detrital Nutrients Release under Future Climate Warming Scenarios.

In addition to a rise in global air and water mean temperatures, extreme climate events such as heat waves are increasing in frequency, intensity, and duration in many regions of the globe. Developing a mechanistic understanding of the impacts of heat waves on key ecosystem processes and how they differ from just an increase in mean temperatures is therefore of utmost importance for adaptive management against effects of global change. However, little is known about the impact of extreme events on freshwater ecosystem processes, particularly the decomposition of macrophyte detritus. We performed a mesocosm experiment to evaluate the impact of warming and heat waves on macrophyte detrital decomposition, applied as a fixed increment (+4 °C) above ambient and a fluctuating treatment with similar energy input, ranging from 0 to 6 °C above ambient (i.e., simulating heat waves). We showed that both warming and heat waves significantly accelerate dry mass loss of the detritus and carbon (C) release but found no significant differences between the two heated treatments on the effects on detritus dry mass loss and C release amount. This suggests that moderate warming indirectly enhanced macrophyte detritus dry mass loss and C release mainly by the amount of energy input rather than by the way in which warming was provided (i.e., by a fixed increment or in heat waves). However, we found significantly different amounts of nitrogen (N) and phosphorus (P) released between the two warming treatments, and there was an asymmetric response of N and P release patterns to the two warming treatments, possibly due to species-specific responses of decomposers to short-term temperature fluctuations and litter quality. Our results conclude that future climate scenarios can significantly accelerate organic matter decomposition and C, N, and P release from decaying macrophytes, and more importantly, there are asymmetric alterations in macrophyte-derived detrital N and P release dynamic. Therefore, future climate change scenarios could lead to alterations in N/P ratios in the water column via macrophyte decomposition processes and ultimately affect the structure and function of aquatic ecosystems, especially in the plankton community.

Community stakeholder preferences for evidence-based practice implementation strategies in behavioral health: a best-worst scaling choice experiment.

BACKGROUND: Community behavioral health clinicians, supervisors, and administrators play an essential role in implementing new psychosocial evidence-based practices (EBP) for patients receiving psychiatric care; however, little is known about these stakeholders' values and preferences for implementation strategies that support EBP use, nor how best to elicit, quantify, or segment their preferences. This study sought to quantify these stakeholders' preferences for implementation strategies and to identify segments of stakeholders with distinct preferences using a rigorous choice experiment method called best-worst scaling. METHODS: A total of 240 clinicians, 74 clinical supervisors, and 29 administrators employed within clinics delivering publicly-funded behavioral health services in a large metropolitan behavioral health system participated in a best-worst scaling choice experiment. Participants evaluated 14 implementation strategies developed through extensive elicitation and pilot work within the target system. Preference weights were generated for each strategy using hierarchical Bayesian estimation. Latent class analysis identified segments of stakeholders with unique preference profiles. RESULTS: On average, stakeholders preferred two strategies significantly more than all others-compensation for use of EBP per session and compensation for preparation time to use the EBP (P < .05); two strategies were preferred significantly less than all others-performance feedback via email and performance feedback via leaderboard (P < .05). However, latent class analysis identified four distinct segments of stakeholders with unique preferences: Segment 1 (n = 121, 35%) strongly preferred financial incentives over all other approaches and included more administrators; Segment 2 (n = 80, 23%) preferred technology-based strategies and was younger, on average; Segment 3 (n = 52, 15%) preferred an improved waiting room to enhance client readiness, strongly disliked any type of clinical consultation, and had the lowest participation in local EBP training initiatives; Segment 4 (n = 90, 26%) strongly preferred clinical consultation strategies and included more clinicians in substance use clinics. CONCLUSIONS: The presence of four heterogeneous subpopulations within this large group of clinicians, supervisors, and administrators suggests optimal implementation may be achieved through targeted strategies derived via elicitation of stakeholder preferences. Best-worst scaling is a feasible and rigorous method for eliciting stakeholders' implementation preferences and identifying subpopulations with unique preferences in behavioral health settings.

A pilot study of participatory and rapid implementation approaches to increase depression screening in primary care.

BACKGROUND: Most individuals with depression go unidentified and untreated. In 2016 the US Preventive Services Task Force released guidelines recommending universal screening in primary care to identify patients with depression and to link them to treatment. Feasible, acceptable, and effective strategies to implement these guidelines are needed. METHODS: This three-phased study employed rapid participatory methods to design and test strategies to increase depression screening at Penn Medicine, a large health system with 90 primary care practices. First, researchers solicited ideas and barriers from stakeholders to increase screening using an innovation tournament-a crowdsourcing method that invites stakeholders to submit ideas to address a workplace challenge. Second, a panel of stakeholders and scientists deliberated over and ranked the tournament ideas. An instant runoff election was held to select the winning idea. Third, the research team piloted the winning idea in a primary care practice using rapid prototyping, an approach that quickly refines and iterates strategy designs. RESULTS: The innovation tournament yielded 31 ideas and 32 barriers from diverse stakeholders (12 primary care physicians, 10 medical assistants, 4 nurse practitioners, 2 practice managers, and 4 patient support assistants). A panel of 6 stakeholders and scientists deliberated on the ideas and voted for patient self-report (i.e., through tablet computers, text message, or an online patient portal) as the winning idea. The research team rapid prototyped tablets in one primary care practice with one physician over 5 five-hour shifts to examine the feasibility, acceptability, and effectiveness of the strategy. Most patients, the physician, and medical assistants found the tablets acceptable and feasible. However, patient support assistants struggled to incorporate them in their workflow and expressed concerns about scaling up the process. Depression screening rates were higher using tablets compared to usual care; follow-up was comparable between tablets and usual care. CONCLUSIONS: Rapid participatory methods engaged and amplified the voices of diverse stakeholders in primary care. These methods helped design an acceptable and feasible implementation strategy that showed promise for increasing depression screening in a primary care setting. The next step is to evaluate the strategy in a randomized controlled trial across primary care practices.

Applying NUDGE to Inform Design of EBP Implementation Strategies in Community Mental Health Settings.

We demonstrate the application of NUDGE (Narrow, Understand, Discover, Generate, Evaluate), a behavioral economics approach to systematically identifying behavioral barriers that impede behavior enactment, to the challenge of evidence-based practice (EBP) use in community behavioral health. Drawing on 65 clinician responses to a system-wide crowdsourcing challenge about EBP underutilization, we applied NUDGE to discover, synthesize and validate specific behavioral barriers to EBP utilization that directly inform the design of tailored implementation strategies. To our knowledge, this is the first study to apply behavioral economic insights to clinician-proposed solutions to implementation challenges in order to design implementation strategies. The study demonstrates the successful application of NUDGE to implementation strategy design and provides novel targets for intervention.

Protein O-fucosyltransferase 2-mediated O-glycosylation of the adhesin MIC2 is dispensable for Toxoplasma gondii tachyzoite infection.

Toxoplasma gondii is a ubiquitous, obligate intracellular eukaryotic parasite that causes congenital birth defects, disease in immunocompromised individuals, and blindness. Protein glycosylation plays an important role in the infectivity and evasion of immune responses of many eukaryotic parasites and is also of great relevance to vaccine design. Here we demonstrate that micronemal protein 2 (MIC2), a motility-associated adhesin of T. gondii, has highly glycosylated thrombospondin repeat (TSR) domains. Using affinity-purified MIC2 and MS/MS analysis along with enzymatic digestion assays, we observed that at least seven C-linked and three O-linked glycosylation sites exist within MIC2, with >95% occupancy at these O-glycosylation sites. We found that addition of O-glycans to MIC2 is mediated by a protein O-fucosyltransferase 2 homolog (TgPOFUT2) encoded by the TGGT1_273550 gene. Even though POFUT2 homologs are important for stabilizing motility-associated adhesins and for host infection in other apicomplexan parasites, loss of TgPOFUT2 in T. gondii had only a modest impact on MIC2 levels and the wider parasite proteome. Consistent with this, both plaque formation and tachyzoite invasion were broadly similar in the presence or absence of TgPOFUT2. These findings indicate that TgPOFUT2 O-glycosylates MIC2 and that this glycan, in contrast to previous findings in another study, is dispensable in T. gondii tachyzoites and for T. gondii infectivity.

An apically located hybrid guanylate cyclase-ATPase is critical for the initiation of Ca2+ signaling and motility in Toxoplasma gondii.

Protozoan parasites of the phylum Apicomplexa actively move through tissue to initiate and perpetuate infection. The regulation of parasite motility relies on cyclic nucleotide-dependent kinases, but how these kinases are activated remains unknown. Here, using an array of biochemical and cell biology approaches, we show that the apicomplexan parasite Toxoplasma gondii expresses a large guanylate cyclase (TgGC) protein, which contains several upstream ATPase transporter-like domains. We show that TgGC has a dynamic localization, being concentrated at the apical tip in extracellular parasites, which then relocates to a more cytosolic distribution during intracellular replication. Conditional TgGC knockdown revealed that this protein is essential for acute-stage tachyzoite growth, as TgGC-deficient parasites were defective in motility, host cell attachment, invasion, and subsequent host cell egress. We show that TgGC is critical for a rapid rise in cytosolic [Ca2+] and for secretion of microneme organelles upon stimulation with a cGMP agonist, but these deficiencies can be bypassed by direct activation of signaling by a Ca2+ ionophore. Furthermore, we found that TgGC is required for transducing changes in extracellular pH and [K+] to activate cytosolic [Ca2+] flux. Together, the results of our work implicate TgGC as a putative signal transducer that activates Ca2+ signaling and motility in Toxoplasma.

Evidence Base Update for Brief, Free, and Accessible Youth Mental Health Measures.

Evidence-based assessment (EBA) is foundational to high-quality mental health care for youth and is a critical component of evidence-based practice delivery, yet is underused in the community. Administration time and measure cost are barriers to use; thus, identifying and disseminating brief, free, and accessible measures are critical. This Evidence Base Update evaluates the empirical literature for brief, free, and accessible measures with psychometric support to inform research and practice with youth. A systematic review using PubMed and PsycINFO identified measures in the following domains: overall mental health, anxiety, depression, disruptive behavior, traumatic stress, disordered eating, suicidality, bipolar/mania, psychosis, and substance use. To be eligible for inclusion, measures needed to be brief (50 items or less), free, accessible, and have psychometric support for their use with youth. Eligible measures were evaluated using adapted criteria established by De Los Reyes and Langer (2018) and were classified as having excellent, good, or adequate psychometric properties. A total of 672 measures were identified; 95 (14%) met inclusion criteria. Of those, 21 (22%) were "excellent," 34 (36%) were "good," and 40 (42%) were "adequate." Few measures had support for their use to routinely monitor progress in therapy. Few measures with excellent psychometric support were identified for disordered eating, suicidality, psychosis, and substance use. Future research should evaluate existing measures for use with routine progress monitoring and ease of implementation in community settings. Measure development is needed for disordered eating, suicidality, psychosis, and substance use to increase availability of brief, free, accessible, and validated measures.

Evaluation of 4-Amino 2-Anilinoquinazolines against Plasmodium and Other Apicomplexan Parasites In Vitro and in a P. falciparum Humanized NOD-scid IL2Rγnull Mouse Model of Malaria.

A series of 4-amino 2-anilinoquinazolines optimized for activity against the most lethal malaria parasite of humans, Plasmodium falciparum, was evaluated for activity against other human Plasmodium parasites and related apicomplexans that infect humans and animals. Four of the most promising compounds from the 4-amino 2-anilinoquinazoline series were equally as effective against the asexual blood stages of the zoonotic P. knowlesi, suggesting that they could also be effective against the closely related P. vivax, another important human pathogen. The 2-anilinoquinazoline compounds were also potent against an array of P. falciparum parasites resistant to clinically available antimalarial compounds, although slightly less so than against the drug-sensitive 3D7 parasite line. The apicomplexan parasites Toxoplasma gondii, Babesia bovis, and Cryptosporidium parvum were less sensitive to the 2-anilinoquinazoline series with a 50% effective concentration generally in the low micromolar range, suggesting that the yet to be discovered target of these compounds is absent or highly divergent in non-Plasmodium parasites. The 2-anilinoquinazoline compounds act as rapidly as chloroquine in vitro and when tested in rodents displayed a half-life that contributed to the compound's capacity to clear P. falciparum blood stages in a humanized mouse model. At a dose of 50 mg/kg of body weight, adverse effects to the humanized mice were noted, and evaluation against a panel of experimental high-risk off targets indicated some potential off-target activity. Further optimization of the 2-anilinoquinazoline antimalarial class will concentrate on improving in vivo efficacy and addressing adverse risk.

Analysis of Sensitivity, Linearity, Hysteresis, Responsiveness, and Fatigue of Textile Knit Stretch Sensors.

Wearable technology is widely used for collecting information about the human body and its movement by placing sensors on the body. This paper presents research into electronic textile strain sensors designed specifically for wearable applications which need to be lightweight, robust, and comfortable. In this paper, sixteen stretch sensors, each with different conductive stretch fabrics, are evaluated: EeonTex (Eeonyx Corporation), knitted silver-plated yarn, and knitted spun stainless steel yarn. The sensors' performance is tested using a tensile tester while monitoring their resistance with a microcontroller. Each sensor was analyzed for its sensitivity, linearity, hysteresis, responsiveness, and fatigue through a series of dynamic and static tests. The findings show that for wearable applications a subset of the silver-plated yarn sensors had better ranked performance in terms of sensitivity, linearity, and steady state. EeonTex was found to be the most responsive, and the stainless steel yarn performed the worst, which may be due to the characteristics of the knit samples under test.

Phosphorylation of αSNAP is Required for Secretory Organelle Biogenesis in Toxoplasma gondii.

Upon infection, apicomplexan parasites quickly invade host cells and begin a replicative cycle rapidly increasing in number over a short period of time, leading to tissue lysis and disease. The secretory pathway of these highly polarized protozoan parasites tightly controls, in time and space, the biogenesis of specialized structures and organelles required for invasion and intracellular survival. In other systems, regulation of protein trafficking can occur by phosphorylation of vesicle fusion machinery. Previously, we have shown that Toxoplasma gondii αSNAP - a protein that controls the disassembly of cis-SNARE complexes--is phosphorylated. Here, we show that this post-translational modification is required for the correct function of αSNAP in controlling secretory traffic. We demonstrate that during intracellular development conditional expression of a non-phosphorylatable form of αSNAP results in Golgi fragmentation and vesiculation of all downstream secretory organelles. In addition, we show that the vestigial plastid (termed apicoplast), although reported not to be reliant on Golgi trafficking for biogenesis, is also affected upon overexpression of αSNAP and is much more sensitive to the levels of this protein than targeting to other organelles. This work highlights the importance of αSNAP and its phosphorylation in Toxoplasma organelle biogenesis and exposes a hereto fore-unexplored mechanism of regulation of vesicle fusion during secretory pathway trafficking in apicomplexan parasites.

A forward genetic screen identifies a negative regulator of rapid Ca2+-dependent cell egress (MS1) in the intracellular parasite Toxoplasma gondii.

Toxoplasma gondii, like all apicomplexan parasites, uses Ca2+ signaling pathways to activate gliding motility to power tissue dissemination and host cell invasion and egress. A group of "plant-like" Ca2+-dependent protein kinases (CDPKs) transduces cytosolic Ca2+ flux into enzymatic activity, but how they function is poorly understood. To investigate how Ca2+ signaling activates egress through CDPKs, we performed a forward genetic screen to isolate gain-of-function mutants from an egress-deficient cdpk3 knockout strain. We recovered mutants that regained the ability to egress from host cells that harbored mutations in the gene Suppressor of Ca2+-dependent Egress 1 (SCE1). Global phosphoproteomic analysis showed that SCE1 deletion restored many Δcdpk3-dependent phosphorylation events to near wild-type levels. We also show that CDPK3-dependent SCE1 phosphorylation is required to relieve its suppressive activity to potentiate egress. In summary, our work has uncovered a novel component and suppressor of Ca2+-dependent cell egress during Toxoplasma lytic growth.

Identifying High-Risk Individuals for Chronic Kidney Disease: Results of the CHERISH Community Demonstration Project.

BACKGROUND: Most people with chronic kidney disease (CKD) are not aware of their condition. OBJECTIVES: To assess screening criteria in identifying a population with or at high risk for CKD and to determine their level of control of CKD risk factors. METHOD: CKD Health Evaluation Risk Information Sharing (CHERISH), a demonstration project of the Centers for Disease Control and Prevention, hosted screenings at 2 community locations in each of 4 states. People with diabetes, hypertension, or aged ≥50 years were eligible to participate. In addition to CKD, screening included testing and measures of hemoglobin A1C, blood pressure, and lipids. -Results: In this targeted population, among 894 people screened, CKD prevalence was 34%. Of participants with diabetes, 61% had A1C < 7%; of those with hypertension, 23% had blood pressure < 130/80 mm Hg; and of those with high cholesterol, 22% had low-density lipoprotein < 100 mg/dL. CONCLUSIONS: Using targeted selection criteria and simple clinical measures, CHERISH successfully identified a population with a high CKD prevalence and with poor control of CKD risk factors. CHERISH may prove helpful to state and local programs in implementing CKD detection programs in their communities.