Oral tryptophan activates duodenal aryl hydrocarbon receptor in healthy subjects: a crossover randomized controlled trial.

Tryptophan is an essential amino acid transformed by host and gut microbial enzymes into metabolites that regulate mucosal homeostasis through aryl hydrocarbon receptor (AhR) activation. Alteration of tryptophan metabolism has been associated with chronic inflammation; however, whether tryptophan supplementation affects the metabolite repertoire and AhR activation under physiological conditions in humans is unknown. We performed a randomized, double blind, placebo-controlled, crossover study in 20 healthy volunteers. Subjects on a low tryptophan background diet were randomly assigned to a 3-wk l-tryptophan supplementation (3 g/day) or placebo, and after a 2-wk washout switched to opposite interventions. We assessed gastrointestinal and psychological symptoms by validated questionnaires, AhR activation by cell reporter assay, tryptophan metabolites by liquid chromatography and high-resolution mass spectrometry, cytokine production in isolated monocytes by ELISA, and microbiota profile by 16S rRNA Illumina technique. Oral tryptophan supplementation was well tolerated, with no changes in gastrointestinal or psychological scores. Compared with placebo, tryptophan increased AhR activation capacity by duodenal contents, but not by feces. This was paralleled by higher urinary and plasma kynurenine metabolites and indoles. Tryptophan had a modest impact on fecal microbiome profiles and no significant effect on cytokine production. At the doses used in this study, oral tryptophan supplementation in humans induces microbial indole and host kynurenine metabolic pathways in the small intestine, known to be immunomodulatory. The results should prompt tryptophan intervention strategies in inflammatory conditions of the small intestine where the AhR pathway is impaired.NEW & NOTEWORTHY We demonstrate that in healthy subjects, orally administered tryptophan activates microbial indole and host kynurenine pathways in the small intestine, the primary metabolic site for dietary components, and the richest source of immune cells along the gut. This study provides novel insights in how to optimally activate immunomodulatory AhR pathways and indole metabolism in the small intestine, serving as basis for future therapeutic trials using l-tryptophan supplementation in chronic inflammatory conditions affecting the small intestine.

Resident Recruitment in a New Era.

ABSTRACT: This chapter focuses on resident recruitment and recent US National Resident Matching Program changes and the impact in the evaluation and ranking of applicants within the specialty of anesthesiology. Recruitment challenges are examined as well as program strategies and potential future directions. Also discussed are DEI initiatives within the recruitment process.

Hidden k-Space Magnetoelectric Multipoles in Nonmagnetic Ferroelectrics.

In condensed matter systems, the electronic degrees of freedom are often entangled to form complex composites, known as hidden orders, which give rise to unusual properties, while escaping detection in conventional experiments. Here we demonstrate the existence of hidden k-space magnetoelectric multipoles in nonmagnetic systems with broken space-inversion symmetry. These k-space magnetoelectric multipoles are reciprocal to the real-space charge dipoles associated with the broken inversion symmetry. Using the prototypical ferroelectric PbTiO_{3} as an example, we show that their origin is a spin asymmetry in momentum space resulting from the broken space inversion symmetry associated with the ferroelectric polarization. In PbTiO_{3}, the k-space spin asymmetry corresponds to a pure k-space magnetoelectric toroidal moment, which can be detected using magnetic Compton scattering, an established tool for probing magnetism in ferromagnets or ferrimagnets with a net spin polarization, which has not been exploited to date for nonmagnetic systems. In particular, the k-space magnetoelectric toroidal moment combined with the spin-orbit interaction manifest in an antisymmetric magnetic Compton profile that can be reversed using an electric field. Our work suggests an experimental route to directly measuring and tuning hidden k-space magnetoelectric multipoles via specially designed magnetic Compton scattering measurements.

REACT: Rapid Evaluation Assessment of Clinical Reasoning Tool.

INTRODUCTION: Clinical reasoning encompasses the process of data collection, synthesis, and interpretation to generate a working diagnosis and make management decisions. Situated cognition theory suggests that knowledge is relative to contextual factors, and clinical reasoning in urgent situations is framed by pressure of consequential, time-sensitive decision-making for diagnosis and management. These unique aspects of urgent clinical care may limit the effectiveness of traditional tools to assess, teach, and remediate clinical reasoning. METHODS: Using two validated frameworks, a multidisciplinary group of clinicians trained to remediate clinical reasoning and with experience in urgent clinical care encounters designed the novel Rapid Evaluation Assessment of Clinical Reasoning Tool (REACT). REACT is a behaviorally anchored assessment tool scoring five domains used to provide formative feedback to learners evaluating patients during urgent clinical situations. A pilot study was performed to assess fourth-year medical students during simulated urgent clinical scenarios. Learners were scored using REACT by a separate, multidisciplinary group of clinician educators with no additional training in the clinical reasoning process. REACT scores were analyzed for internal consistency across raters and observations. RESULTS: Overall internal consistency for the 41 patient simulations as measured by Cronbach's alpha was 0.86. A weighted kappa statistic was used to assess the overall score inter-rater reliability. Moderate reliability was observed at 0.56. DISCUSSION: To our knowledge, REACT is the first tool designed specifically for formative assessment of a learner's clinical reasoning performance during simulated urgent clinical situations. With evidence of reliability and content validity, this tool guides feedback to learners during high-risk urgent clinical scenarios, with the goal of reducing diagnostic and management errors to limit patient harm.

Improved adherence to test, treat, and track (T3) malaria strategy among Over-the-Counter Medicine Sellers (OTCMS) through interventions implemented in selected rural communities of Fanteakwa North district, Ghana.

BACKGROUND: Prompt diagnosis and treatment of malaria prevents a mild case from developing into severe disease and death. Unfortunately, parasitological testing of febrile children is greater in the public and formal private sector than in the informal private sector where many patients with malaria-like symptoms first seek treatment. This study was aimed at improving implementation of the T3 policy among OTCMS using some interventions that could be scaled-up easily at the national level. METHODS: Interventions were evaluated using a two-arm, cluster randomized trial across 8 rural communities (4 clusters per arm), in two adjacent districts of Ghana. A total of 7 OTCMS in the intervention arm and 5 OTCMS in the control arm in the selected communities participated in the study. Five interventions were implemented in the intervention arm only. These were acquisition of subsidized malaria rapid diagnostic test (RDT) kits, training of OTCMS, supportive visits to OTCMS, community sensitization on malaria, and introduction of malaria surveillance tool. The primary outcome was the proportion of children under 10 years with fever or suspected to have malaria visiting OTCMS and getting tested (using RDT) before treatment. Secondary outcomes included OTCMS adherence to national malaria treatment guidelines and the recommended RDT retail price. Outcomes were measured using mystery client (an adult who pretends to be a real patient) surveys supplemented by a household survey. Proportions were compared using chi-square test or Fisher exact test. RESULTS: Following deployment of interventions, mystery client survey showed that OTCMS' adherence to malaria protocol in the intervention arm increased significantly (p < 0.05) compared to the control arm. Household surveys in the intervention arm showed that caregivers self-treating their children or visiting drug vendors significantly decreased in favour of visits to OTCMS shops for treatment (p < 0.001). End-line malaria testing rate was higher compared with the baseline rate, though not statistically significant (30.8% vs 10.5%; p = 0.1238). OTCMS in the intervention arm also adhered to the subsidized RDT retail price of GHc2.40. CONCLUSION: Interventions targeting OTCMS in rural communities have the potential of improving adherence to the T3 malaria policy and subsequently improving management of uncomplicated malaria in Ghana. TRIAL REGISTRATION: ISRCTN registry ISRCTN77836926. Registered on 4 November 2019.

Gluten-Free Diet Reduces Symptoms, Particularly Diarrhea, in Patients With Irritable Bowel Syndrome and Antigliadin IgG.

BACKGROUND & AIMS: Many patients with irritable bowel syndrome (IBS) perceive that their symptoms are triggered by wheat-containing foods. We assessed symptoms and gastrointestinal transit before and after a gluten-free diet (GFD) in unselected patients with IBS and investigated biomarkers associated with symptoms. METHODS: We performed a prospective study of 50 patients with IBS (ROME III, all subtypes), with and without serologic reactivity to gluten (antigliadin IgG and IgA), and 25 healthy subjects (controls) at a university hospital in Hamilton, Ontario, Canada, between 2012 and 2016. Gastrointestinal transit, gut symptoms, anxiety, depression, somatization, dietary habits, and microbiota composition were studied before and after 4 weeks of a GFD. HLA-DQ2/DQ8 status was determined. GFD compliance was assessed by a dietitian and by measuring gluten peptides in stool. RESULTS: There was no difference in symptoms among patients at baseline, but after the GFD, patients with antigliadin IgG and IgA reported less diarrhea than patients without these antibodies (P = .03). Compared with baseline, IBS symptoms improved in 18 of 24 patients (75%) with antigliadin IgG and IgA and in 8 of 21 patients (38%) without the antibodies. Although constipation, diarrhea, and abdominal pain were reduced in patients with antigliadin IgG and IgA, only pain decreased in patients without these antibodies. Gastrointestinal transit normalized in a higher proportion of patients with antigliadin IgG and IgA. Anxiety, depression, somatization, and well-being increased in both groups. The presence of antigliadin IgG was associated with overall reductions in symptoms (adjusted odds ratio compared with patients without this antibody, 128.9; 95% CI, 1.16-1427.8; P = .04). Symptoms were reduced even in patients with antigliadin IgG and IgA who reduced gluten intake but were not strictly compliant with the GFD. In controls, a GFD had no effect on gastrointestinal symptoms or gut function. CONCLUSIONS: Antigliadin IgG can be used as a biomarker to identify patients with IBS who might have reductions in symptoms, particularly diarrhea, on a GFD. Larger studies are needed to validate these findings. ClinicalTrials.gov: NCT03492333.

Anesthesiologist Age and Sex Influence Patient Perceptions of Physician Competence.

BACKGROUND: Uncovering patients' biases toward characteristics of anesthesiologists may inform ways to improve the patient-anesthesiologist relationship. The authors previously demonstrated that patients prefer anesthesiologists displaying confident body language, but did not detect a sex bias. The effect of anesthesiologists' age on patient perceptions has not been studied. In this follow-up study, it was hypothesized that patients would prefer older-appearing anesthesiologists over younger-appearing anesthesiologists and male over female anesthesiologists. METHODS: Three hundred adult, English-speaking patients were recruited in the Preanesthesia Evaluation and Testing Center. Patients were randomized (150 per group) to view a set of four videos in random order. Each 90-s video featured an older female, older male, younger female, or younger male anesthesiologist reciting the same script describing general anesthesia. Patients ranked each anesthesiologist on confidence, intelligence, and likelihood of choosing the anesthesiologist to care for their family member. Patients also chose the one anesthesiologist who seemed most like a leader. RESULTS: Three hundred patients watched the videos and completed the questionnaire. Among patients younger than age 65 yr, the older anesthesiologists had greater odds of being ranked more confident (odds ratio, 1.92; 95% CI, 1.41 to 2.64; P < 0.001) and more intelligent (odds ratio, 2.24; 95% CI, 1.62 to 3.11; P < 0.001), and had greater odds of being considered a leader (odds ratio, 2.62; 95% CI, 1.72 to 4.00; P < 0.001) when compared with younger anesthesiologists. The preference for older anesthesiologists was not observed in patients age 65 and older. Female anesthesiologists had greater odds of being ranked more confident (odds ratio, 1.46; 95% CI, 1.13 to 1.87; P = 0.003) and more likely to be chosen to care for one's family member (odds ratio, 1.80; 95% CI, 1.40 to 2.31; P < 0.001) compared with male anesthesiologists. The ranking preference for female anesthesiologists on these two measures was observed among white patients and not among nonwhite patients. CONCLUSIONS: Patients preferred older anesthesiologists on the measures of confidence, intelligence, and leadership. Patients also preferred female anesthesiologists on the measures of confidence and likelihood of choosing the anesthesiologist to care for one's family member.

Access to Chiral Diamine Derivatives through Stereoselective Cu-Catalyzed Reductive Coupling of Imines and Allenamides.

Chiral 1,2-diamino compounds are important building blocks in organic chemistry for biological applications and as asymmetric inducers in stereoselective synthesis that are challenging to prepare in a straightforward and stereoselective manner. Herein, we disclose a cost-effective and readily available Cu-catalyzed system for the reductive coupling of a chiral allenamide with N-alkyl substituted aldimines to access chiral 1,2-diamino synthons as single stereoisomers in high yields. The method shows broad reaction scope and high diastereoselectivity and can be easily scaled using standard Schlenk techniques. Mechanistic investigations by density functional theory calculations identified the mechanism and origin of stereoselectivity. In particular, the addition to the imine was shown to be reversible, which has implications toward development of catalyst-controlled stereoselective variants of the identified reductive coupling of imines and allenamides.

The Sphincter of O'Beirne-Part 2: Report of a Case of Chronic Constipation with Autonomous Dyssynergia.

BACKGROUND: Chronic constipation can have one or more of many etiologies, and a diagnosis based on symptoms is not sufficient as a basis for treatment, in particular surgery. AIM: To investigate the cause of chronic constipation in a patient with complete absence of spontaneous bowel movements. METHODS: High-resolution colonic manometry was performed to assess motor functions of the colon, rectum, the sphincter of O'Beirne and the anal sphincters. RESULTS: Normal colonic motor patterns were observed, even at baseline, but a prominent high-pressure zone at the rectosigmoid junction, the sphincter of O'Beirne, was consistently present. In response to high-amplitude propagating pressure waves (HAPWs) that were not consciously perceived, the sphincter and the anal sphincters would not relax and paradoxically contract, identified as autonomous dyssynergia. Rectal bisacodyl evoked marked HAPW activity with complete relaxation of the sphincter of O'Beirne and the anal sphincters, indicating that all neural pathways to generate the coloanal reflex were intact but had low sensitivity to physiological stimuli. A retrograde propagating cyclic motor pattern initiated at the sphincter of O'Beirne, likely contributing to failure of content to move into the rectum. CONCLUSIONS: Chronic constipation without the presence of spontaneous bowel movements can be associated with normal colonic motor patterns but a highly exaggerated pressure at the rectosigmoid junction: the sphincter of O'Beirne, and failure of this sphincter and the anal sphincters to relax associated with propulsive motor patterns. The sphincter of O'Beirne can be an important part of the pathophysiology of chronic constipation.

Lactobacilli Degrade Wheat Amylase Trypsin Inhibitors to Reduce Intestinal Dysfunction Induced by Immunogenic Wheat Proteins.

BACKGROUND & AIMS: Wheat-related disorders, a spectrum of conditions induced by the ingestion of gluten-containing cereals, have been increasing in prevalence. Patients with celiac disease have gluten-specific immune responses, but the contribution of non-gluten proteins to symptoms in patients with celiac disease or other wheat-related disorders is controversial. METHODS: C57BL/6 (control), Myd88-/-, Ticam1-/-, and Il15-/- mice were placed on diets that lacked wheat or gluten, with or without wheat amylase trypsin inhibitors (ATIs), for 1 week. Small intestine tissues were collected and intestinal intraepithelial lymphocytes (IELs) were measured; we also investigated gut permeability and intestinal transit. Control mice fed ATIs for 1 week were gavaged daily with Lactobacillus strains that had high or low ATI-degrading capacity. Nonobese diabetic/DQ8 mice were sensitized to gluten and fed an ATI diet, a gluten-containing diet or a diet with ATIs and gluten for 2 weeks. Mice were also treated with Lactobacillus strains that had high or low ATI-degrading capacity. Intestinal tissues were collected and IELs, gene expression, gut permeability and intestinal microbiota profiles were measured. RESULTS: In intestinal tissues from control mice, ATIs induced an innate immune response by activation of Toll-like receptor 4 signaling to MD2 and CD14, and caused barrier dysfunction in the absence of mucosal damage. Administration of ATIs to gluten-sensitized mice expressing HLA-DQ8 increased intestinal inflammation in response to gluten in the diet. We found ATIs to be degraded by Lactobacillus, which reduced the inflammatory effects of ATIs. CONCLUSIONS: ATIs mediate wheat-induced intestinal dysfunction in wild-type mice and exacerbate inflammation to gluten in susceptible mice. Microbiome-modulating strategies, such as administration of bacteria with ATI-degrading capacity, may be effective in patients with wheat-sensitive disorders.

Targeted interleukin-10 plasmid DNA therapy in the treatment of osteoarthritis: Toxicology and pain efficacy assessments.

Osteoarthritis results in chronic pain and loss of function. Proinflammatory cytokines create both osteoarthritis pathology and pain. Current treatments are poorly effective, have significant side effects, and have not targeted the cytokines central to osteoarthritis development and maintenance. Interleukin-10 is an anti-inflammatory cytokine that potently and broadly suppresses proinflammatory cytokine activity. However, interleukin-10 protein has a short half-life in vivo and poor joint permeability. For sustained IL-10 activity, we developed a plasmid DNA-based therapy that expresses a long-acting human interleukin-10 variant (hIL-10var). Here, we describe the 6-month GLP toxicology study of this therapy. Intra-articular injections of hIL-10var pDNA into canine stifle joints up to 1.5 mg bilaterally were well-tolerated and without pathologic findings. This represents the first long-term toxicologic assessment of intra-articular pDNA therapy. We also report results of a small double-blind, placebo-controlled study of the effect of intra-articular hIL-10var pDNA on pain measures in companion (pet) dogs with naturally occurring osteoarthritis. This human IL-10-based targeted therapy reduced pain measures in the dogs, based on veterinary and owner ratings, without any adverse findings. These results with hIL-10var pDNA therapy, well-tolerated and without toxicologic effects, establish the basis for clinical trials of a new class of safe and effective therapies for OA.

Anesthesiology Resident Night Float Duty Alters Sleep Patterns: An Observational Study.

BACKGROUND: Residency programs utilize night float systems to adhere to duty hour restrictions; however, the influence of night float on resident sleep has not been described. The study aim was to determine the influence of night float on resident sleep patterns and quality of sleep. We hypothesized that total sleep time decreases during night float, increases as residents acclimate to night shift work, and returns to baseline during recovery. METHODS: This was a single-center observational study of 30 anesthesia residents scheduled to complete six consecutive night float shifts. Electroencephalography sleep patterns were recorded during baseline (three nights), night float (six nights), and recovery (three nights) using the ZMachine Insight monitor (General Sleep Corporation, USA). Total sleep time; light, deep, and rapid eye movement sleep; sleep efficiency; latency to persistent sleep; and wake after sleep onset were observed. RESULTS: Mean total sleep time ± SD was 5.9 ± 1.9 h (3.0 ± 1.2.1 h light; 1.4 ± 0.6 h deep; 1.6 ± 0.7 h rapid eye movement) at baseline. During night float, mean total sleep time was 4.5 ± 1.8 h (1.4-h decrease, 95% CI: 0.9 to 1.9, Cohen's d = -1.1, P < 0.001) with decreases in light (2.2 ± 1.1 h, 0.7-h decrease, 95% CI: 0.4 to 1.1, d = -1.0, P < 0.001), deep (1.1 ± 0.7 h, 0.3-h decrease, 95% CI: 0.1 to 0.4, d = -0.5, P = 0.005), and rapid eye movement sleep (1.2 ± 0.6 h, 0.4-h decrease, 95% CI: 0.3 to 0.6, d = -0.9, P < 0.001). Mean total sleep time during recovery was 5.4 ± 2.2 h, which did not differ significantly from baseline; however, deep (1.0 ± 0.6 h, 0.4-h decrease, 95% CI: 0.2 to 0.6, d = -0.6, P = 0.001 *, P = 0.001) and rapid eye movement sleep (1.2 ± 0.8 h, 0.4-h decrease, 95% CI: 0.2 to 0.6, d = -0.9, P < 0.001 P < 0.001) were significantly decreased. CONCLUSIONS: Electroencephalography monitoring demonstrates that sleep quantity is decreased during six consecutive night float shifts. A 3-day period of recovery is insufficient for restorative sleep (rapid eye movement and deep sleep) levels to return to baseline.

Influence of Sex and Body Language on Patient Perceptions of Anesthesiologists.

BACKGROUND: Patient perception of physician competence is important. The role of body language and physician sex on patient perceptions has not been investigated. The authors hypothesized that patients perceive anesthesiologists displaying confident body language as more competent and that patients would prefer male anesthesiologists. METHODS: Two hundred adult patients presenting to the Preanesthesia Evaluation and Testing Center at the University of Virginia Health System were recruited to participate using consecutive sampling. Patients viewed four 90-s videos in random order. Each video featured a male or female actor displaying confident, high-power poses or unconfident, low-power poses. Each actor recited the same script describing general anesthesia. Patients were randomized (100 per group) to view one of two sets of videos to account for any actor preferences. Participants ranked each actor anesthesiologist on perceived confidence, intelligence, and likelihood of choosing that anesthesiologist to care for their family member. Participants also chose the one actor anesthesiologist who seemed most like a leader. RESULTS: Two hundred patients watched the videos and completed the questionnaire. Actor anesthesiologists displaying confident, high-power body language had greater odds of being ranked as more confident (odds ratio, 2.27; 95% CI, 1.76 to 2.92; P < 0.0001), more intelligent (odds ratio, 1.69; 95% CI, 1.13 to 2.18; P < 0.0001), more likely chosen to care for one's family member (odds ratio, 2.34; 95% CI, 1.82 to 3.02; P < 0.0001), and more likely to be considered a leader (odds ratio, 2.60; 95% CI, 1.86 to 3.65; P < 0.0001). Actor anesthesiologist sex was not associated with ranking for any response measures. CONCLUSIONS: Patients perceive anesthesiologists displaying confident body language as more confident, more intelligent, more like a leader, and are more likely to choose that anesthesiologist to care for their family member. Differences in patient perceptions based on sex of the anesthesiologist were not detected.

Understanding the gap between access and use: a qualitative study on barriers and facilitators to insecticide-treated net use in Ghana.

BACKGROUND: Mass and continuous distribution channels have significantly increased access to insecticide-treated nets (ITNs) in Ghana since 2000. Despite these gains, a large gap remains between ITN access and use. METHODS: A qualitative research study was carried out to explore the individual and contextual factors influencing ITN use among those with access in three sites in Ghana. Eighteen focus group discussions, and free listing and ranking activities were carried out with 174 participants; seven of those participants were selected for in-depth case study. Focus group discussions and case study interviews were audio-recorded, transcribed verbatim, and analysed thematically. RESULTS: ITN use, as described by study participants, was not binary; it varied throughout the night, across seasons, and over time. Heat was the most commonly cited barrier to consistent ITN use and contributed to low reported ITN use during the dry season. Barriers to ITN use throughout the year included skin irritation; lack of airflow in the sleeping space; and, in some cases, a lack of information on the connection between the use of ITNs and malaria prevention. Falling ill or losing a loved one to malaria was the most powerful motivator for consistent ITN use. Participants also discussed developing a habit of ITN use and the economic benefit of prevention over treatment as facilitating factors. Participants reported gender differences in ITN use, noting that men were more likely than women and children to stay outdoors late at night and more likely to sleep outdoors without an ITN. CONCLUSION: The study results suggest the greatest gains in ITN use among those with access could be made by promoting consistent use throughout the year among occasional and seasonal users. Opportunities for improving communication messages, such as increasing the time ITNs are aired before first use, as well as structural approaches to enhance the usability of ITNs in challenging contexts, such as promoting solutions for outdoor ITN use, were identified from this work. The information from this study can be used to inform social and behaviour change messaging and innovative approaches to closing the ITN use gap in Ghana.

Prevalence of asymptomatic malaria parasitaemia following mass testing and treatment in Pakro sub-district of Ghana.

BACKGROUND: Global efforts to scale-up malaria control interventions are gaining steam. These include the use of Long-Lasting Insecticide Nets, Indoor Residual Spraying, Intermittent Preventive Treatment and Test, Treat and Track. Despite these, the drive for malaria elimination is far from being realistic in endemic communities in Africa. This is partly due to the fact that asymptomatic parasite carriage, not specifically targeted by most interventions, remains the bedrock that fuels transmission. This has led to mass testing, treatment and tracking (MTTT) as an alternative strategy to target asymptomatic individuals. We report the impact of MTTT on the prevalence of asymptomatic malaria parasitaemia over a one-year period in Ghana, hypothesizing that implementing MTTT could reduce the rate of asymptomatic parasitaemia. METHODS: A population of about 5000 individuals in seven communities in the Pakro sub-district of Ghana participated in this study. A register was developed for each community following a census. MTTT engaged trained community-based health volunteers who conducted house-to-house testing using RDTs every 4 months and treated positive cases with Artemisinin-based Combination Therapy. Between interventions, community-based management of malaria was implemented for symptomatic cases. RESULTS: MTTT Coverage was 98.8% in July 2017 and 79.3% in July 2018. Of those tested, asymptomatic infection with malaria parasites reduced from 36.3% (1795/4941) in July 2017 to 32.9% (1303/3966) in July 2018 (p = 0.001). Prevalence of asymptomatic parasitaemia among children under 15 years declined from 52.6% (1043/1984) in July 2017 to 47.5% (820/1728) in July 2018 (p = 0.002). Implementing MTTT significantly reduced asymptomatic parasitaemia by 24% from July 2017 to July 2018 after adjusting for age, ITN use and axillary temperature (OR = 0.76, CI = 0.67, 0.85 p ≤ 0.001). CONCLUSION: This study has demonstrated that implementing MTTT is feasible and could reduce the prevalence of asymptomatic malaria parasitaemia in children under 15 years of age. Furthermore, the use of community-based health volunteers could ensure high coverage at lower cost of implementation. TRIAL REGISTRATION: NCT04167566, Date 14/11/2019. Retrospective registration.

Generative retrieval results in positive academic emotions and long-term retention of cardiovascular anatomy using transthoracic echocardiography.

With increasing medical knowledge, procedural, and diagnostic skills to learn, it is vital for educators to make the limited amount of teaching time available to students effective and efficient. Generative retrieval is an effective and efficient learning tool, improving long-term retention through the practice of retrieval from memory. Forty medical students were randomized to learn normal cardiovascular anatomy using transthoracic echocardiography video clips in a generative retrieval (GR) or standard practice (SP) group. GR participants were required to verbally identify each unlabeled cardiovascular structure after viewing the video. After answering, participants viewed the correctly labeled video. SP participants viewed the same video clips labeled with the correct cardiovascular structure for the same amount of total time without verbally generating an answer. All participants were tested for intermediate (1-wk), late (1-mo), and long-term (6- to 9-mo) retention of cardiovascular anatomy. Additionally, a three-question survey was incorporated to assess perceptions of the learning method. There was no difference in pretest scores. The GR group demonstrated a trend toward improvement in recall at 1 wk [GR = 74.3 (SD 12.3); SP = 65.4 (SD 16.7); P = 0.10] and 1 mo [GR = 69.9 (SD15.6); SP = 64.3 (SD 15.4); P = 0.33]. At the 6- to 9-mo time point, there was a statistically significant difference in scores [GR = 74.3 (SD 9.9); SP = 65.0 (SD 14.1); P = 0.042]. At nearly every time point, learners had a statistically significantly higher perception of effectiveness, enjoyment, and satisfaction with GR. In addition to improved recall, GR is associated with increased perceptions of effectiveness, enjoyment, and satisfaction, which may lead to increased engagement, time spent studying, and improved retention.

Compassionate communities and collective memory: a conceptual framework to address the epidemic of loneliness.

In recent years, tackling loneliness has become the focus of increased scholarly debate, social intervention and the development of international policy. One response to the 'epidemic of loneliness' has been the development of the compassionate communities model. The diversity of compassionate communities approaches has led to scholars such as Allan Kellehear (2005; 2017) to highlight a lack of a cohesive underpinning theory to support and drive policy development. In this paper, we propose the use of 'collective memory' as a novel approach to linking loneliness, memory and identity in a way that draws out conceptual links between the role compassionate communities play in tackling social isolation and loneliness. We suggest that the service-led approach that seeks to identify and transpose strategies from one community to another is ineffective; instead, we emphasise the need to develop bespoke community-centred models that can be used by community nurses.

Identification of a Water-Coordinating HER2 Inhibitor by Virtual Screening Using Similarity-Based Scoring.

Human epidermal growth factor receptor 2 (HER2) is a validated breast cancer drug target for small molecule inhibitors that target the ATP-binding pocket of the kinase domain. In this work, a large-scale virtual screen was performed to a novel homology model of HER2, in a hypothesized "fully active" state, that considered water-mediated interactions during the prioritization of compounds for experimental testing. This screen led to the identification of a new inhibitor with micro molar affinity and potency ( Kd = 7.0 µM, IC50 = 4.6 µM). Accompanying molecular dynamics simulations showed that inhibitor binding likely involves water coordination through an important water-mediated network previously identified in our laboratory. The predicted binding geometry also showed a remarkable overlap with the crystallographic poses for two previously reported inhibitors of the related Chk1 kinase. Concurrent with the HER2 studies, we developed formalized computational protocols that leverage solvated footprints (per-residue interaction maps that include bridging waters) to identify ligands that can "coordinate" or "displace" key binding site waters. Proof-of-concept screens targeting HIVPR and PARP1 demonstrate that molecules with high footprint overlap can be effectively identified in terms of their coordination or displacement patterns relative to a known reference. Overall, the procedures developed as a result of this study should be useful for researchers targeting HER2 and, more generally, for any protein in which the identification of compounds that exploit binding site waters is desirable.

Probiotic Bifidobacterium longum NCC3001 Reduces Depression Scores and Alters Brain Activity: A Pilot Study in Patients With Irritable Bowel Syndrome.

BACKGROUND & AIMS: Probiotics can reduce symptoms of irritable bowel syndrome (IBS), but little is known about their effects on psychiatric comorbidities. We performed a prospective study to evaluate the effects of Bifidobacterium longum NCC3001 (BL) on anxiety and depression in patients with IBS. METHODS: We performed a randomized, double-blind, placebo-controlled study of 44 adults with IBS and diarrhea or a mixed-stool pattern (based on Rome III criteria) and mild to moderate anxiety and/or depression (based on the Hospital Anxiety and Depression scale) at McMaster University in Canada, from March 2011 to May 2014. At the screening visit, clinical history and symptoms were assessed and blood samples were collected. Patients were then randomly assigned to groups and given daily BL (n = 22) or placebo (n = 22) for 6 weeks. At weeks 0, 6, and 10, we determined patients' levels of anxiety and depression, IBS symptoms, quality of life, and somatization using validated questionnaires. At weeks 0 and 6, stool, urine and blood samples were collected, and functional magnetic resonance imaging (fMRI) test was performed. We assessed brain activation patterns, fecal microbiota, urine metabolome profiles, serum markers of inflammation, neurotransmitters, and neurotrophin levels. RESULTS: At week 6, 14 of 22 patients in the BL group had reduction in depression scores of 2 points or more on the Hospital Anxiety and Depression scale, vs 7 of 22 patients in the placebo group (P = .04). BL had no significant effect on anxiety or IBS symptoms. Patients in the BL group had a mean increase in quality of life score compared with the placebo group. The fMRI analysis showed that BL reduced responses to negative emotional stimuli in multiple brain areas, including amygdala and fronto-limbic regions, compared with placebo. The groups had similar fecal microbiota profiles, serum markers of inflammation, and levels of neurotrophins and neurotransmitters, but the BL group had reduced urine levels of methylamines and aromatic amino acids metabolites. At week 10, depression scores were reduced in patients given BL vs placebo. CONCLUSION: In a placebo-controlled trial, we found that the probiotic BL reduces depression but not anxiety scores and increases quality of life in patients with IBS. These improvements were associated with changes in brain activation patterns that indicate that this probiotic reduces limbic reactivity. ClinicalTrials.gov no. NCT01276626.

Lung Isolation in the Patient With a Difficult Airway.

One-lung ventilation is routinely used to facilitate exposure for thoracic surgical procedures and can be achieved via several lung isolation techniques. The optimal method for lung isolation depends on a number of factors that include (1) the indication for lung isolation, (2) anatomic features of the upper and lower airway, (3) availability of equipment and devices, and (4) the anesthesiologist's proficiency and preferences. Though double-lumen endobronchial tubes (DLTs) are most commonly utilized to achieve lung isolation, the use of endobronchial blockers offer advantages in patients with challenging airway anatomy. Anesthesiologists should be familiar with existing alternatives to the DLT for lung isolation and alternative techniques for DLT placement in the patient with a difficult airway. Newer technologies such as videolaryngoscopy with or without adjunctive fiberoptic bronchoscopy may facilitate intubation and lung isolation in difficult airway management.