Search

Objective: Although extant research points to NonVerbal Learning Disability (NVLD) as a distinct disorder, it is not included in the diagnostic nomenclatures, and there is heterogeneity in how it is defined. We formed a working group to gain consensus on a standard DSM type definition for NVLD, a necessary first step for proposing its inclusion in future DSMs and renamed the disorder to better reflect the core deficit - visual-spatial problems., Method: An iterative process was used to reach consensus on a DSM style criteria set that reconceptualizes NVLD as Developmental Visual-Spatial Disorder (DVSD). This process, similar to that used during the DSM-5 revision, included working with an advisory group of NVLD experts and obtaining feedback from experts in youth psychiatric diagnosis and child mental health practitioners. Data on stakeholder acceptance of the new name were collected from adults who self-identify as having NVLD and parents of youth with NVLD., Results: During the iterative process, the criteria set shifted from syndromic, multi-area, and quantitative to singly-focused and more clinically oriented, conceptualizing individuals with the disorder as having persistent deficits in a single area: processing or integrating visual and spatial information. This fills a gap in the DSM system, which includes diagnoses underpinned by problems in other cognitive domains. Data indicate stakeholder acceptance of the name., Conclusion: A standard definition for NVLD, reconceptualized as DVSD, and included in the DSM will lead to improved identification of individuals with clinically significant visual-spatial deficits and associated functional impairment and improve research in the area., (Copyright © 2025. Published by Elsevier Inc.)

The current study examines the role of pediatric PCPs in bridging treatment for youth who have experienced mental health crises and the characteristics of these patients for whom PCPs sought psychiatric consultation and referral support from a child psychiatry access program, Maryland Behavioral Health Integration in Pediatric Primary Care. Psychiatric consultation and referral calls between 2012 and 2021 were included if a) the patient was recently seen in a higher level of care and b) the PCP was bridging treatment following the patient's discharge; 208 calls met criteria. The most common mental health concerns included depressed mood, suicidal thoughts/gestures, and anxiety. Acute concerns of aggression, suicide attempts, and hallucinations were also reported. Over half of the patients had two or more mental health diagnoses. At the time of the call, only one quarter of these patients had outpatient therapy services while about half were receiving medication treatment. Most of these patients were discharged from the higher level of care without a care plan. Pediatric PCPs are managing their patients' complex mental health concerns following receipt of higher levels of care. Improvements in collaboration and care coordination between pediatric PCPs and emergency department providers are needed., (© 2024. The Author(s).)

Obsessive-compulsive disorder (OCD) affects ~1% of the population and exhibits a high SNP-heritability, yet previous genome-wide association studies (GWAS) have provided limited information on the genetic etiology and underlying biological mechanisms of the disorder. We conducted a GWAS meta-analysis combining 53,660 OCD cases and 2,044,417 controls from 28 European-ancestry cohorts revealing 30 independent genome-wide significant SNPs and a SNP-based heritability of 6.7%. Separate GWAS for clinical, biobank, comorbid, and self-report sub-groups found no evidence of sample ascertainment impacting our results. Functional and positional QTL gene-based approaches identified 249 significant candidate risk genes for OCD, of which 25 were identified as putatively causal, highlighting WDR6 , DALRD3 , CTNND1 and genes in the MHC region. Tissue and single-cell enrichment analyses highlighted hippocampal and cortical excitatory neurons, along with D1- and D2-type dopamine receptor-containing medium spiny neurons, as playing a role in OCD risk. OCD displayed significant genetic correlations with 65 out of 112 examined phenotypes. Notably, it showed positive genetic correlations with all included psychiatric phenotypes, in particular anxiety, depression, anorexia nervosa, and Tourette syndrome, and negative correlations with a subset of the included autoimmune disorders, educational attainment, and body mass index.. This study marks a significant step toward unraveling its genetic landscape and advances understanding of OCD genetics, providing a foundation for future interventions to address this debilitating disorder., Competing Interests: Chris German is employed by and hold stock or stock options in 23andMe, Inc. Erika L. Nurmi is on the Scientific Advisory Board for Myriad Genetics and Medical Advisory Board for Tourette Association of America and received Clinical trial funding from Emalex and Octapharma Pharmaceuticals. Jeremy Veenstra-VanderWeele has served on advisory boards or consulted with Roche, Novartis, and SynapDx; received research funding from Roche, Novartis, SynapDx, Seaside Therapeutics, Forest, Janssen, Acadia, Yamo, and MapLight; received stipends for editorial work from Wiley and Springer. Jens R. Wendland is a current employee and shareholder of Takeda Pharmaceuticals and a past employee and shareholder of F. Hoffmann-La Roche, Pfizer and Nestle Health Science. Cynthia M. Bulik reports: Pearson (author, royalty recipient).Peter Falkai reports no conflict of interest regarding this study and reports to have received financial support and Advisory Board: Richter, Recordati, Boehringer-Ingelheim, Otsuka, Janssen and Lundbeck. Hans J. Grabe has received travel grants and speakers honoraria from Fresenius Medical Care, Neuraxpharm, Servier and Janssen Cilag as well as research funding from Fresenius Medical Care. Ian B. Hickie is the Co-Director, Health and Policy at the Brain and Mind Centre (BMC) University of Sydney, Australia. The BMC operates an early-intervention youth services at Camperdown under contract to headspace. Professor Hickie has previously led community-based and pharmaceutical industry-supported (Wyeth, Eli Lily, Servier, Pfizer, AstraZeneca, Janssen Cilag) projects focused on the identification and better management of anxiety and depression. He is the Chief Scientific Advisor to, and a 3.2% equity shareholder in, InnoWell Pty Ltd which aims to transform mental health services through the use of innovative technologies. Benjamin M. Neale is a member of the scientific advisory board at Deep Genomics and Neumora. Christopher Pittenger consults and/or receives research support from Biohaven Pharmaceuticals, Freedom Biosciences, Ceruvia Lifesciences, Transcend Therapeutics, UCB BioPharma, and F-Prime Capital Partners. He owns equity in Alco Therapeutics. These relationships are not related to the current work. Dan J. Stein has received consultancy honoraria from Discovery Vitality, Johnson & Johnson, Kanna, L’Oreal, Lundbeck, Orion, Sanofi, Servier, Takeda and Vistagen. Eric A. Storch reports receiving research funding to his institution from the Ream Foundation, International OCD Foundation, and NIH. He was formerly a consultant for Brainsway and Biohaven Pharmaceuticals in the past 12 months. He owns stock less than $5000 in NView/Proem for distribution related to the YBOCS scales. He receives book royalties from Elsevier, Wiley, Oxford, American Psychological Association, Guildford, Springer, Routledge, and Jessica Kingsley. Ole A. Andreasson reports to be a consultant to Cortechs.ai, Precision Health AS, speakers honorarium from Otsuka, Lundbeck, Sunovion, Janssen. Anders D. Børglum has received speaker fee from Lundbeck. David Mataix-Cols receives royalties for contributing articles to UpToDate, Wolters Kluwer Health, and personal fees for editorial work from Elsevier, all unrelated to the current work. Murray B. Stein has in the past 3 years received consulting income from Acadia Pharmaceuticals, BigHealth, Biogen, Bionomics, Boehringer Ingelheim, Clexio, Eisai, EmpowerPharm, Engrail Therapeutics, Janssen, Jazz Pharmaceuticals, NeuroTrauma Sciences, Otsuka, PureTech Health, Sage Therapeutics, Sumitomo Pharma, and Roche/Genentech. Dr. Stein has stock options in Oxeia Biopharmaceuticals and EpiVario. He has been paid for his editorial work on Depression and Anxiety (Editor-in-Chief), Biological Psychiatry (Deputy Editor), and UpToDate (Co-Editor-in-Chief for Psychiatry). Joel Gelernter is paid for editorial work by the journal Complex Psychiatry. Pino Alonso has received funding from Biohaven, Boston Scientific, Medtronic. All other authors report no conflicts of interest.

Background: Background incidence rates (IRs) of health outcomes in Lyme disease endemic regions are useful to contextualize events reported during Lyme disease vaccine clinical trials or post-marketing. The objective of this study was to estimate and compare IRs of health outcomes in Lyme disease endemic versus non-endemic regions in the US during pre-COVID and COVID era timeframes., Methods: IQVIA PharMetrics® Plus commercial claims database was used to estimate IRs of 64 outcomes relevant to vaccine safety monitoring in the US during January 1, 2017-December 31, 2019 and January 1, 2020-December 31, 2021. Analyses included all individuals aged ≥ 2 years with ≥ 1 year of continuous enrollment. Outcomes were defined by International Classification of Diseases Clinical Modification, 10th Revision (ICD-10-CM) diagnosis codes. IRs and 95 % confidence intervals (CIs) were calculated for each outcome and compared between endemic vs. non-endemic regions, and pre-COVID vs. COVID era using IR ratios (IRR)., Results: The study population included 8.7 million (M) in endemic and 27.8 M in non-endemic regions. Mean age and sex were similar in endemic and non-endemic regions. In both study periods, the IRs were statistically higher in endemic regions for anaphylaxis, meningoencephalitis, myocarditis/pericarditis, and rash (including erythema migrans) as compared with non-endemic regions. Conversely, significantly lower IRs were observed in endemic regions for acute kidney injury, disseminated intravascular coagulation, heart failure, myelitis, myopathies, and systemic lupus erythematosus in both study periods. Most outcomes were statistically less frequent during the COVID-era., Conclusion: This study identified potential differences between Lyme endemic and non-endemic regions of the US in background IRs of health conditions during pre-COVID and COVID era timeframes to inform Lyme disease vaccine safety monitoring. These regional and temporal differences in background IRs should be considered when contextualizing possible safety signals in clinical trials and post-marketing of a vaccine targeted at Lyme disease prevention., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: JD, JHS, MZ, MSR, JDM, QJ, CI, and SB were employees and shareholders at Pfizer, Inc. at the time of this study. MDK, SM, CB, BC, RF, JNT and HK were consultants to Pfizer through their employment at IQVIA at the time of the study., (Copyright © 2024 Pfizer, Inc. Published by Elsevier Ltd.. All rights reserved.)

Background: Enterotoxigenic E. coli (ETEC) is a principal cause of diarrhea in travelers, deployed military personnel, and children living in low to middle-income countries. ETEC expresses a variety of virulence factors including colonization factors (CF) that facilitate adherence to the intestinal mucosa. We assessed the protective efficacy of a tip-localized subunit of CF antigen I (CFA/I), CfaE, delivered intradermally with the mutant E. coli heat-labile enterotoxin, LTR192G, in a controlled human infection model (CHIM)., Methods: Three cohorts of healthy adult subjects were enrolled and given three doses of 25 μg CfaE + 100 ng LTR192G vaccine intradermally at 3-week intervals. Approximately 28 days after the last vaccination, vaccinated and unvaccinated subjects were admitted as inpatients and challenged with approximately 2 × 10 7 cfu of CFA/I+ ETEC strain H10407 following an overnight fast. Subjects were assessed for moderate-to-severe diarrhea for 5 days post-challenge., Results: A total of 52 volunteers received all three vaccinations; 41 vaccinated and 43 unvaccinated subjects were challenged and assessed for moderate-to-severe diarrhea. Naïve attack rates varied from 45.5% to 64.7% across the cohorts yielding an overall efficacy estimate of 27.8% (95% confidence intervals: -7.5-51.6%). In addition to reducing moderate-severe diarrhea rates, the vaccine significantly reduced loose stool output and overall ETEC disease severity., Conclusions: This is the first study to demonstrate protection against ETEC challenge after intradermal vaccination with an ETEC adhesin. Further examination of the challenge methodology is necessary to address the variability in naïve attack rate observed among the three cohorts in the present study.

Importance: The travelers' gut microbiome is potentially assaulted by acute and chronic perturbations (e.g., diarrhea, antibiotic use, and different environments). Prior studies of the impact of travel and travelers' diarrhea (TD) on the microbiome have not directly compared antibiotic regimens, and studies of different antibiotic regimens have not considered travelers' microbiomes. This gap is important to be addressed as the use of antibiotics to treat or prevent TD-even in moderate to severe cases or in regions with high infectious disease burden-is controversial based on the concerns for unintended consequences to the gut microbiome and antimicrobial resistance (AMR) emergence. Our study addresses this by evaluating the impact of defined antibiotic regimens (single-dose treatment or daily prophylaxis) on the gut microbiome and resistomes of deployed servicemembers, using samples collected during clinical trials. Our findings indicate that the antibiotic treatment regimens that were studied generally do not lead to adverse effects on the gut microbiome and resistome and identify the relative risks associated with prophylaxis. These results can be used to inform therapeutic guidelines for the prevention and treatment of TD and make progress toward using microbiome information in personalized medical care., Competing Interests: The authors declare no conflict of interest.

The gram-negative bacterium Shigella is a leading cause of diarrheal morbidity and mortality in children in low- and middle-income countries. Several promising vaccine candidates are in late stages of clinical development against this increasingly antibiotic-resistant pathogen. However, considering the increasingly crowded and costly paediatric immunization schedule, and likely advent of other important new vaccines, it is unclear whether introduction of a Shigella vaccine would represent a high priority for international agencies or health ministries in low- and middle-income countries. To determine whether there is a compelling public health value proposition for a Shigella vaccine, we used the World Health Organization's Full Value of Vaccine Assessment analytic framework and formulated five broad scientific, policy, economic and commercial-related propositions regarding the development of a Shigella vaccine. We also explored the current regulatory, clinical, policy and commercial challenges to a Shigella -containing combination vaccine development and adoption. Through a series of literature reviews, expert consultations, social science field studies and model-based analyses, we addressed each of these propositions. As described in a series of separate publications that are synthesized here, we concluded that the economic and public health value of a Shigella vaccine may be greater than previously recognized, particularly if it is found to also be effective against less severe forms of diarrheal disease and childhood stunting. The decision by pharmaceutical companies to develop a standalone vaccine or a multipathogen combination will be a key factor in determining its relative prioritization by various stakeholders in low- and middle-income countries., ((c) 2024 The authors; licensee World Health Organization.)

Norovirus is attributed to nearly 1 out of every 5 episodes of diarrheal disease globally and is estimated to cause approximately 200,000 deaths annually worldwide, with 70,000 or more among children in developing countries. Noroviruses remain a leading cause of sporadic disease and outbreaks of acute gastroenteritis even in industrialized settings, highlighting that improved hygiene and sanitation alone may not be fully effective in controlling norovirus. Strengths in global progress towards a Norovirus vaccine include a diverse though not deep pipeline which includes multiple approaches, including some with proven technology platforms (e.g., VLP-based HPV vaccines). However, several gaps in knowledge persist, including a fulsome mechanistic understanding of how the virus attaches to human host cells, internalizes, and induces disease., Competing Interests: Declaration of Competing Interest BAL reports personal fees from Epidemiological Research and Methods, LLC. MO acknowledges financial support from ANID PIA/PUENTE AFB220003 and reports receiving grants and research support from Janssen Vaccines & Prevention B.V., Bharat Biotech International Limited, and HilleVax Inc. CFL declares that he receives research grant funding to his Institute from Takeda Vaccines Inc. and HilleVax Inc. for norovirus epidemiology and a norovirus vaccine phase II trial, respectively. All other authors declare no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Antibodies reactive with the SARS-CoV-2 receptor-binding domain (RBD) of the spike protein are associated with viral neutralization, however low antibody titers, specifically against SARS-CoV-2 variants, may result in reduced viral immunity post naturally acquired infection. A cohort study comprised of 121 convalescent individuals from northern Nevada was conducted looking at anti-RBD antibody levels by enzyme-linked immunosorbent assay. Serum was collected from volunteers by staff at the University of Nevada, Reno School of Medicine Clinical Research Center and assessed for antibodies reactive to various SARS-CoV-2 RBD domains relevant to the time of the study (2020-2021). A nonpaired group of vaccinated individuals were assessed in parallel. The goal of the study was to identify antibody levels against the RBD subunit in convalescent and vaccinated individuals from northern Nevada., Competing Interests: The authors have declared that no competing interests exist., (Copyright: This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.)

Introduction: Enterotoxigenic E. coli (ETEC) is a leading cause of diarrhea in travelers as well as for children living in low- to middle-income countries. ETEC adhere to intestinal epithelium via colonization factors (CFs). CFA/I, a common CF, is composed of a polymeric stalk and a tip-localized minor adhesive subunit, CfaE. Vaccine delivery by the transcutaneous immunization of dscCfaE was safe but was poorly immunogenic in a phase 1 trial when administered to volunteers with LTR(192G) and mLT. To potentially enhance the immunogenicity of CfaE while still delivering via a cutaneous route, we evaluated the safety and immunogenicity of two CfaE constructs administered intradermally (ID) with or without mLT., Methods: CfaE was evaluated as a donor strand-complemented construct (dscCfaE) and as a chimeric construct (Chimera) in which dscCfaE replaces the A1 domain of the cholera toxin A subunit and assembles non-covalently with the pentamer of heat-labile toxin B (LTB). Subjects received three ID vaccinations three weeks apart with either dscCfaE (1, 5, and 25 µg) or Chimera (2.6 and 12.9 µg) with and without 0.1 µg of mLT. Subjects were monitored for local and systemic adverse events. Immunogenicity was evaluated by serum and antibody-secreting cell (ASC) responses., Results: The vaccine was well-tolerated with predominantly mild and moderate local vaccine site reactions characterized by erythema, induration and post-inflammatory hyperpigmentation. High rates of serologic and ASC responses were seen across study groups with the most robust responses observed in subjects receiving 25 µg of dscCfaE with 0.1 mcg of LT(R192G)., Conclusion: Both ETEC adhesin vaccine prototypes were safe and immunogenic when co-administered with mLT by the ID route. The observed immune responses induced with the high dose of dscCfaE and mLT warrant further assessment in a controlled human infection model.

Shigellosis causes considerable public health burden, leading to excess deaths as well as acute and chronic consequences, particularly among children living in low-income and middle-income countries (LMICs). Several Shigella vaccine candidates are advancing in clinical trials and offer promise. Although multiple target populations might benefit from a Shigella vaccine, the primary strategic goal of WHO is to accelerate the development and accessibility of safe, effective, and affordable Shigella vaccines that reduce mortality and morbidity in children younger than 5 years living in LMICs. WHO consulted with regulators and policy makers at national, regional, and global levels to evaluate pathways that could accelerate regulatory approval in this priority population. Special consideration was given to surrogate efficacy biomarkers, the role of controlled human infection models, and the establishment of correlates of protection. A field efficacy study in children younger than 5 years in LMICs is needed to ensure introduction in this priority population., Competing Interests: Declaration of interests NB provides regulatory advice to the regulated industry. PBP receives funding from the Bill & Melinda Gates Foundation for Enterics for Global Health Shigella surveillance. DCK received funding from the Bill & Melinda Gates Foundation while at PATH, and chaired the WHO Product Development for Vaccines Advisory Committee until 2022. MSR consulted for Emergent Biosolutions and Limmatech Biologics while at the University of Nevada. All other authors declare no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Shigella species cause severe disease among travelers to, and children living in, endemic countries. Although significant efforts have been made to improve sanitation, increased antibiotic resistance and other factors suggest an effective vaccine is a critical need. Artificial Invaplex (Invaplex AR ) is a subunit vaccine approach complexing Shigella LPS with invasion plasmid antigens. In pre-clinical studies, the Invaplex AR vaccine demonstrated increased immunogenicity as compared to the first generation product and was subsequently manufactured under cGMP for clinical testing in a first-in-human Phase 1 study. The primary objective of this study was the safety of S. flexneri 2a Invaplex AR given by intranasal (IN) immunization (without adjuvant) in a single-center, open-label, dose-escalating Phase 1 trial and secondarily to assess immunogenicity to identify a dose of Invaplex AR for subsequent clinical evaluations. Subjects received three IN immunizations of Invaplex AR , two weeks apart, in increasing dose cohorts (10 µg, 50 µg, 250 µg, and 500 μg). Adverse events were monitored using symptom surveillance, memory aids, and targeted physical exams. Samples were collected throughout the study to investigate vaccine-induced systemic and mucosal immune responses. There were no adverse events that met vaccination-stopping criteria. The majority (96%) of vaccine-related adverse events were mild in severity (most commonly nasal congestion, rhinorrhea, and post-nasal drip). Vaccination with Invaplex AR induced anti-LPS serum IgG responses and anti-Invaplex IgA and IgG antibody secreting cell (ASC) responses at vaccine doses ≥250 µg. Additionally, mucosal immune responses and functional antibody responses were seen from the serum bactericidal assay measurements. Notably, the responder rates and the kinetics of ASCs and antibody lymphocyte secretion (ALS) were similar, suggesting that either assay may be employed to identify IgG and IgA secreting cells. Further studies with Invaplex AR will evaluate alternative immunization routes, vaccination schedules and formulations to further optimize immunogenicity. (Clinical Trial Registry Number NCT02445963)., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Published by Elsevier Ltd.)

Background: At diagnosis, up to one-third of patients with Crohn's disease (CD) have a complicated phenotype with stricturing (B2) or penetrating (B3) behavior or require early surgery. We evaluated protein biomarkers and antimicrobial antibodies in serum archived years before CD diagnosis to assess whether complicated diagnoses were associated with a specific serological signature., Methods: Prediagnosis serum was obtained from 201 patients with CD and 201 healthy controls. Samples were evaluated with a comprehensive panel of 1129 proteomic markers (SomaLogic) and antimicrobial antibodies. CD diagnosis and complications were defined by the International Classification of Diseases-Ninth Revision and Current Procedural Terminology codes. Cox regression models were utilized to assess the association between markers and the subsequent risk of being diagnosed with complicated CD. In addition, biological pathway and network analyses were performed., Results: Forty-seven CD subjects (24%) had a B2 (n = 36) or B3 (n = 9) phenotype or CD-related surgery (n = 2) at diagnosis. Subjects presenting with complicated CD at diagnosis had higher levels of antimicrobial antibodies six years before diagnosis as compared with those diagnosed with noncomplicated CD. Twenty-two protein biomarkers (reflecting inflammatory, fibrosis, and tissue protection markers) were found to be associated with complicated CD. Pathway analysis of the altered protein biomarkers identified higher activation of the innate immune system and complement or coagulation cascades up to six years before diagnosis in complicated CD., Conclusions: Proteins and antimicrobial antibodies associated with dysregulated innate immunity, excessive adaptive response to microbial antigens, and fibrosis precede and predict a complicated phenotype at the time of diagnosis in CD patients., (Copyright © 2023 AGA Institute. All rights reserved.)

Background: Medication nonadherence is a problem that impacts both the patient and the health system., Objective: The objective of this study was to evaluate the impact of a novel smartphone app with patient-response-directed clinical intervention on medication adherence and blood glucose control in noninsulin-dependent patients with type 2 diabetes mellitus (T2DM)., Methods: We enrolled 50 participants with T2DM not on insulin with smartphones from a rural health care center in Northern Nevada for participation in this case-crossover study. Participants underwent a standard of care arm and an intervention arm. Each study arm was 3 months long, for a total of 6 months of follow-up. Participants had a hemoglobin A 1c (HbA 1c ) lab draw at enrollment, 3 months, and 6 months. Participants had monthly "medication adherence scores" (MAS) and "Self-Efficacy for Appropriate Medication Use Scale" (SEAMS) questionnaires completed at baseline and monthly for the duration of the study. Our primary outcomes of interest were the changes in HbA 1c between study arms. Secondary outcomes included the evaluation of the difference in the proportion of participants achieving a clinically meaningful reduction in HbA 1c and the difference in the number of participants requiring diabetes therapy escalation between study arms. Exploratory outcomes included the analysis of the variation in medication possession ratio (MPR), MAS, and SEAMS during each study arm., Results: A total of 30 participants completed both study arms and were included in the analysis. Dropouts were higher in participants enrolled in the standard of care arm first (9/25, 36% vs 4/25, 16%). Participants had a median HbA 1c of 9.1%, had been living with T2DM for 6 years, had a median age of 66 years, and had a median of 8.5 medications. HbA 1c reduction was 0.69% in the intervention arm versus 0.35% in the standard of care arm (P=.30). A total of 70% (21/30) of participants achieved a clinically meaningful reduction in HbA 1c of 0.5% in the app intervention arm versus 40% (12/30) in the standard of care arm (odds ratio 2.29, 95% CI 0.94-5.6; P=.09). Participants had higher odds of a therapy escalation while in the standard of care arm (18/30, 60% vs 5/30, 16.7%, odds ratio 4.3, 95% CI 1.2-15.2; P=.02). The median MPR prior to enrollment was 109%, 112% during the study's intervention arm, and 102% during the standard of care arm. The median real-time MAS was 93.2%. The change in MAS (1 vs -0.1; P=.02) and SEAMS (1.9 vs -0.2; P<.001) from baseline to month 3 was higher in the intervention arm compared to standard of care., Conclusions: A novel smartphone app with patient-response-directed provider intervention holds promise in the ability to improve blood glucose control in complex non-insulin-dependent T2DM and is worthy of additional study., (©Amneet Rai, Mark Riddle, Rajendra Mishra, Nhien Nguyen, Kelly Valine, Megan Fenney. Originally published in JMIR Diabetes (https://diabetes.jmir.org), 10.08.2023.)

Objective: Maryland's Behavioral Health Integration in Pediatric Primary Care (BHIPP) is a child psychiatry access program offering child-adolescent psychiatry consultation, resource and referral networking, and direct-to-patient mental health intervention. This study investigated characteristics of patients for whom primary care providers sought BHIPP services., Methods: Data from 6,939 unique patient contacts between October 2012 and March 2020 were collected on service type, demographic characteristics, presenting concerns, clinical severity, clinicians' diagnostic impressions, current treatments, and BHIPP recommendations. Descriptive statistics and latent class analysis were used., Results: Of the 6,939 patient contacts, 38.6% were for direct-to-patient mental health intervention, 27.3% for child-adolescent psychiatry consultation, and 34.2% for resource and referral networking. In total, 50.3% of patients were female, 58.7% were White, and 32.7% were already receiving mental health services. Latent class analysis identified four classes of presenting concerns: anxiety only (44.2%); behavior problems only (30.7%); mood and anxiety (17.1%); and attention, behavior, and learning problems (8.0%). Compared with patients in the anxiety-only class, those in the attention, behavior, and learning problems class were more likely to receive direct-to-patient mental health intervention (OR=3.59), and BHIPP clinicians were more likely to recommend in-office behavioral interventions for those in the mood and anxiety class (OR=1.62) and behavior problems-only class (OR=1.55)., Conclusions: Patients supported through BHIPP varied in presenting concerns, condition severity and complexity, current receipt of services, and BHIPP utilization. Latent class analysis yielded more clinically useful information about the nature and complexity of patients' concerns than did consideration of individual presenting concerns., Competing Interests: The authors report no financial relationships with commercial interests.

Background: Little is known about specific obsessive-compulsive clinical features associated with lifetime history of suicide attempt in individuals with obsessive-compulsive disorder (OCD) and major depression., Methods: The study sample included 515 adults with OCD and a history of major depression. In exploratory analyses, we compared the distributions of demographic characteristics and clinical features in those with and without a history of attempted suicide and used logistic regression to evaluate the association between specific obsessive-compulsive clinical features and lifetime suicide attempt., Results: Sixty-four (12%) of the participants reported a lifetime history of suicide attempt. Those who had attempted suicide were more likely to report having experienced violent or horrific images (52% vs. 30%; p < 0.001). The odds of lifetime suicide attempt were more than twice as great in participants with versus without violent or horrific images (O.R. = 2.46, 95%, CI = 1.45-4.19; p < 0.001), even after adjustment for other risk correlates of attempted suicide, including alcohol dependence, post-traumatic stress disorder, parental conflict, excessive physical discipline, and number of episodes of depression. The association between violent or horrific images and attempted suicide was especially strong in men, 18-29 year olds, those with post-traumatic stress disorder, and those with particular childhood adversities., Conclusions: Violent or horrific images are strongly associated with lifetime suicide attempts in OCD-affected individuals with a history of major depression. Prospective clinical and epidemiological studies are needed to elucidate the basis of this relationship., Competing Interests: Declaration of competing interest The authors have no conflict of interest to declare., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Objectives: Vasopressors are a cornerstone in the management of sepsis, marked by distributive shock often unresponsive to fluid resuscitation. Prior research and clinician surveys have suggested that earlier usage of vasopressors corresponds to improved outcomes., Methods: A retrospective cohort was constructed using patient data contained within the Medical Information Mart for Intensive Care-IV database. Analytic cohort included a total of 2079 patients meeting sepsis-3 criteria with a ≥2-point rise in Sequential Organ Failure Assessment score and administered norepinephrine (NE) as first-line vasopressor within 24 hours of admission to the intensive care unit (ICU). Patients receiving other vasopressors or missing documented fluid resuscitation information were excluded. Primary end points included mortality, use of invasive mechanical ventilation and length of stay which were analyzed in a multivariate logistic regression model for the primary effect of time from ICU admission to NE administration using covariates., Results: Time to NE use was defined as either early, using <6 hours from time of ICU admission or late using >6 hours to ≤24 hours. Patients who received early NE had significantly lower adjusted odds of mortality (0.75, 95% CI 0.57 to 0.97, p=0.026), higher adjusted odds of invasive mechanical ventilation (1.48, 95% CI 1.01 to 2.16, p=0.045), no significant difference in hospital length of stay (difference in days 0.6 (95% CI -3.24 to 2.04)) and lower ICU length of stay (difference in days -0.9 (95% CI -1.74 to -0.01)), as compared with the late NE group., Conclusion: Among patients admitted to the ICU for sepsis, early use of NE was associated with significantly lower odds of mortality but higher odds of mechanical ventilation, and no significant difference in length of hospital stay but less time in the ICU. Furthermore, the volume of fluids received prior to NE use may have a significant impact on optimal NE timing., Level of Evidence: Level IV-therapeutic care/management., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background & Aims: Better biomarkers for prediction of ulcerative colitis (UC) development and prognostication are needed. Anti-integrin αvβ6 (anti-αvβ6) autoantibodies have been described in patients with UC. We tested for the presence of anti-αvβ6 antibodies in the preclinical phase of UC and studied their association with disease-related outcomes after diagnosis., Methods: Anti-αvβ6 autoantibodies were measured in 4 longitudinal serum samples collected from 82 subjects who later developed UC and 82 matched controls from a Department of Defense preclinical cohort (PREDICTS [Proteomic Evaluation and Discovery in an IBD Cohort of Tri-service Subjects]). In a distinct, external validation cohort (Crohn's and Colitis Canada Genetic Environmental Microbial project cohort), we tested 12 pre-UC subjects and 49 matched controls. Furthermore, anti-αvβ6 autoantibodies were measured in 2 incident UC cohorts (COMPASS [Comprehensive Care for the Recently Diagnosed IBD Patients], n = 55 and OSCCAR [Ocean State Crohn's and Colitis Area Registry], n = 104) and associations between anti-αvβ6 autoantibodies and UC-related outcomes were defined using Cox proportional hazards model., Results: Anti-αvβ6 autoantibodies were significantly higher among individuals who developed UC compared with controls up to 10 years before diagnosis in PREDICTS. The anti-αvβ6 autoantibody seropositivity was 12.2% 10 years before diagnosis and increased to 52.4% at the time of diagnosis in subjects who developed UC compared with 2.7% in controls across the 4 time points. Anti-αvβ6 autoantibodies predicted UC development with an area under the curve of at least 0.8 up to 10 years before diagnosis. The presence of anti-αvβ6 autoantibodies in preclinical UC samples was validated in the GEM cohort. Finally, high anti-αvβ6 autoantibodies was associated with a composite of adverse UC outcomes, including hospitalization, disease extension, colectomy, systemic steroid use, and/or escalation to biologic therapy in recently diagnosed UC., Conclusions: Anti-integrin αvβ6 autoantibodies precede the clinical diagnosis of UC by up to 10 years and are associated with adverse UC-related outcomes., (Copyright © 2023 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Objective: To identify a panel of serum biomarkers that could specifically identify imminent cases of rheumatoid arthritis (RA) before diagnosis., Methods: Serum samples were collected at 4 time points from active component US military personnel, including 157 anti-citrullinated protein antibody (ACPA)-seropositive and 50 ACPA-seronegative RA subjects, 100 reactive arthritis (ReA) subjects, and 76 healthy controls. The cohorts were split into 2 phases, with samples tested on independent proteomic platforms for each phase. Classification models of RA diagnosis based on samples obtained within 6 months prior to diagnosis were developed both in univariate analyses and by multivariate random forest modeling of training sample sets and testing sample sets from each phase., Results: Increases in serum analytes, including C-reactive protein levels, serum amyloid A, and soluble programmed cell death 1 (PD-1), were observed in seropositive RA subjects at the time point closest to diagnosis, up to several years before diagnosis. Only a small fraction of RA subjects had levels above the 95th percentile of healthy control levels until the time period within 6 months of diagnosis. For classification of RA diagnosis using samples obtained within 6 months prior to diagnosis, soluble PD-1 provided superior specificity compared to ReA cases (>89%), with a sensitivity of 48% for RA classification. An 8-analyte model provided superior sensitivity (69%), with comparable specificity relative to ReA (>82%)., Conclusion: Our findings demonstrate that imminent RA diagnosis could be classified with high specificity, relative to healthy controls and ReA cases, using a panel of cytokines measured in serum samples collected within 6 months before actual diagnosis., (© 2022 American College of Rheumatology. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.)

Background & Aims: Anti-granulocyte macrophage-colony stimulating factor autoantibodies (aGMAbs) are detected in patients with ileal Crohn's disease (CD). Their induction and mode of action during or before disease are not well understood. We aimed to investigate the underlying mechanisms associated with aGMAb induction, from functional orientation to recognized epitopes, for their impact on intestinal immune homeostasis and use as a predictive biomarker for complicated CD., Methods: We characterized using enzyme-linked immunosorbent assay naturally occurring aGMAbs in longitudinal serum samples from patients archived before the diagnosis of CD (n = 220) as well as from 400 healthy individuals (matched controls) as part of the US Defense Medical Surveillance System. We used biochemical, cellular, and transcriptional analysis to uncover a mechanism that governs the impaired immune balance in CD mucosa after diagnosis., Results: Neutralizing aGMAbs were found to be specific for post-translational glycosylation on granulocyte macrophage-colony stimulating factor (GM-CSF), detectable years before diagnosis, and associated with complicated CD at presentation. Glycosylation of GM-CSF was altered in patients with CD, and aGMAb affected myeloid homeostasis and promoted group 1 innate lymphoid cells. Perturbations in immune homeostasis preceded the diagnosis in the serum of patients with CD presenting with aGMAb and were detectable in the noninflamed CD mucosa., Conclusions: Anti-GMAbs predict the diagnosis of complicated CD long before the diagnosis of disease, recognize uniquely glycosylated epitopes, and impair myeloid cell and innate lymphoid cell balance associated with altered intestinal immune homeostasis., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Irritable bowel syndrome (IBS) is a disorder of gut-brain interaction characterized by abdominal pain, bowel habits alterations, constipation, and/or diarrhea. Adverse childhood experiences (ACEs) are events such as abuse and mental illness causing childhood trauma. Studies report higher prevalence of ACEs in patients with IBS with varied effect consistency and association strength. A systematic review and meta-analysis were conducted to evaluate current literature, assess heterogeneity and research gaps in this relationship. A search across PubMed, Embase, PsycINFO, and Google Scholar with keywords ('childhood adversity' OR 'childhood trauma' OR 'adverse childhood events') AND ('irritable colon' OR 'irritable bowel syndrome') yielded 106 studies. A restricted maximum likelihood model of 15 chosen studies with 272,686 participants found the association between ACEs and IBS to be uncertain given the considerable heterogeneity (I 2 =93.58%, p<0.001). Objective reporting methods for ACE and IBS, study size, and study quality explained some heterogeneity. Twelve studies showed publication bias (Egger's test, p<0.001), which further weakened interpretation. Gender-stratified subanalysis of three studies found ACEs associated with IBS in females (pOR=2.20, 95% CI (1.13 to 4.29), I 2 =66.90%) with substantial heterogeneity, but no association in males (pOR=1.30, 95% CI (0.62 to 2.78)). This meta-analysis explores the current literature to understand the biopsychosocial perspective of IBS and ACEs' role as risk factors. However, the risk of publication and design/study quality biases substantiates the need for further research. If an association is confirmed, further mechanistic research and development of targeted psychological therapies may be warranted., Competing Interests: Competing interests: None declared., (© American Federation for Medical Research 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

In this study, we aimed to examine the association between gastrointestinal (GI) symptom presence during severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and the prevalence of GI symptoms and the development of post-infectious irritable bowel syndrome (PI-IBS). We used data from a prospective cohort and logistic regression to examine the association between GI symptom status during confirmed SARS-CoV-2 infection and prevalence of persistent GI symptoms at ≥45 days. We also report the incidence of PI-IBS following SARS-CoV-2 infection. Of the 1475 participants in this study, 33.8% ( n = 499) had GI symptoms during acute infection. Cases with acute GI symptoms had an odds of persisting GI symptoms 4 times higher than cases without acute GI symptoms (odds ratio (OR) 4.29, 95% confidence interval (CI) 2.45-7.53); symptoms lasted on average 8 months following infection. Of those with persisting GI symptoms, 67% sought care for their symptoms and incident PI-IBS occurred in 3.0% ( n = 15) of participants. Those with acute GI symptoms after SARS-CoV-2 infection are likely to have similar persistent symptoms 45 days and greater. These data indicate that attention to a potential increase in related healthcare needs is warranted.

Introduction: In recent U.S. Military conflicts, hemorrhage remains the leading cause of preventable death with 30%-40% mortality rates. Management consists of effective bleeding control and rapid resuscitation with blood products. Rapid and accurate circulatory access is crucial in battlefield trauma management. This study evaluates the insertion success rate and time to successfully insert the NIO automatic intraosseous (IO) device and the Tactical Advanced Lifesaving IO Needle (TALON) manual IO device. The primary outcome is successful first attempt insertion. Secondary outcomes are the time taken for the successful insertion, user-reported "ease of use" for both devices, and user-reported device preference., Materials and Methods: This is a prospective randomized crossover study comparing the NIO and TALON devices. As they are often the frontline health care providers, combat medics (68W) were recruited to participate in this study. They were randomized into two cohorts based on the IO device and location they would start first. Each medic performed a total of four IO cannulations on the proximal tibia and the humeral head of cadaveric human models., Results: Sixty medics participated in the study, performing a total of 240 IO insertions, 120 with NIO (60 at the proximal tibia and 60 at the humeral head) and 120 with TALON (60 at the proximal tibia and 60 at the humeral head). The first attempt success rate was 89.2% for the NIO and 83.3% for the TALON, P = .19. The time to successful first attempt insertion for the NIO [M = 24.71 seconds, SD = 4.72] and the TALON, [M = 24.70 seconds, SD = 4.74] were similar, P = .98. The differences between the success of device insertion and time to successful insertion did not achieve statistical significance. The "ease of use" score (5-point Likert Scale) for the NIO [M = 4.73] and the TALON, [M = 4.11], demonstrated a significant difference, P < .001. Ninety percent [n = 54] of the combat medics preferred the NIO versus only 10% [n = 6] preferred TALON., Conclusions: Our findings indicate that the overall insertion success rate and time to successful insertion were similar between NIO automatic IO device and the TALON manual IO device. In our study, Army combat medics learned how to use both devices rapidly but felt the NIO automatic IO device easier to use and overwhelmingly preferred this device., (© The Association of Military Surgeons of the United States 2021. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: It is unclear if state laws supporting breastfeeding are associated with exclusive breastfeeding (EBF) practice among low-income mothers participating in the Special Supplemental Nutrition Program for Women, Infants, and Children (WIC). The main objectives of our study were to assess the relationship between such laws and EBF among WIC-participating mothers and to assess whether this association varied by employment status. We also assessed how mother's exposure to WIC breastfeeding consultation was associated with EBF., Methods: A cross-sectional study was conducted across seven WIC program locations (i.e., Georgia, Massachusetts, Nevada, Pennsylvania, Wisconsin, Wyoming, Chickasaw Nation) between July-August 2020. Data were collected using convenient sampling from each program location and surveys were administered electronically or on paper to WIC-participating mothers. We restricted our analysis to data from 1161 WIC-participating mothers with infants aged zero to five months old. Multivariable mixed models were used to estimate the relationship between our exposures of interest (i.e., number of laws supporting breastfeeding, employment-related breastfeeding laws, WIC breastfeeding consultation) and EBF, while controlling for potential confounders and accounting for clustering by program location. Effect modification by employment status was assessed on the additive and multiplicative scales., Results: Among WIC-participating mothers living in program locations with no employment-related breastfeeding laws, EBF was 26% less prevalent for employed mothers compared to unemployed mothers (adjusted prevalence ratios [aPR]: 0.74, 95% CI: 0.67,0.83). Among all mothers, a one-unit increase in laws supporting breastfeeding was not associated with EBF (aPR: 0.88, 95% CI: 0.71,1.10). However, among employed mothers, living in areas with more employment-related laws was associated with a higher prevalence of EBF (aPR: 1.43, 95% CI: 0.83, 2.44). Infants whose mothers received a WIC breastfeeding consultation had 33% higher prevalence of being exclusively breastfed compared to infants whose mothers did not receive a WIC breastfeeding consultation (aPR: 1.33, 95% CI: 1.05,1.70)., Conclusions: Infants whose WIC-participating mothers were employed, were less likely to be exclusively breastfed, but our effect modification analyses showed that laws supporting breastfeeding at the workplace may promote EBF among employed women. EBF was more prevalent among mothers who received a WIC breastfeeding consultation compared to those who did not receive such a consultation., (© 2022. The Author(s).)

We are at an exciting moment in time with the advancement of many vaccines, including a shigella vaccine for the world. It is instructive to look at the long road that some vaccines have traveled to recognize the remarkable accomplishments of those who were pioneers, appreciate the evolution of scientific and applied technology, and inform the future history of a vaccine that would have great potential for global health. To achieve this valuable retrospective, a narrative historical literature review was undertaken utilizing PubMed and Embase databases with relevant search terms. Retrieved articles were reviewed and information was organized into historical themes, landmark discoveries, and important vaccine development parallels. The literature reviewed was synthesized into major eras of shigella vaccine development from pathogen discovery and first attempts to empirical approaches of killed whole-cell and live-attenuated approaches, and a modern era that applied recombinant DNA engineering and structural vaccinology. The history of shigella vaccine development has largely followed the evolutionary path of vaccine development over the last 120 years, but with important lessons learned that should be considered as we embark on the future chapters of bringing to the world a safe and effective vaccine for global health.

The Deployment and Travel Medicine Knowledge, Attitude, Practice and Outcomes Study investigates the various clinician and traveler contributions to medical outcomes within the U.S. Military Health System. Travelers' diarrhea is among the most common travel-related illnesses, making travelers' diarrhea self-treatment (TDST) important for traveler health. A cohort of 80,214 adult travelers receiving malaria chemoprophylaxis for less than 6 weeks of travel were identified within the U.S. Department of Defense Military Health System Data Repository. Associated prescriptions for TDST medications within 2 weeks of chemoprophylaxis prescriptions were identified. Prescription patterns were compared by service member versus beneficiary status and site of care, military facility versus civilian facility. At military facilities, medical provider demographics were analyzed by clinical specialty and categorized as travel medicine specialists versus nonspecialists. Overall, there was low prescribing of TDST, particularly among civilian providers and military nonspecialists, despite guidelines recommending self-treatment of moderate to severe travelers' diarrhea. This practice gap was largest among service member travelers, but also existed for beneficiaries. Compared with nonspecialists, military travel medicine specialists were more likely to prescribe a combination of an antibiotic and antimotility agent to beneficiaries, more likely to provide any form of TDST to service members, and more likely to prescribe azithromycin than quinolones when using antibiotics. Our study suggests that enhancing provider knowledge and use of travelers' diarrhea treatment recommendations combined with improved access to formal travel medicine services may be important to increase the quality of care.

Objectives: proving causality between an exposure and outcome can be difficult in humans. Here, we utilize the Bradford Hill (BH) criteria to summarize the causal relationship between Campylobacter infection and the development of Irritable Bowel Syndrome (IBS)., Methods: we utilized the BH criteria to assess the strength, consistency, specificity, temporality, biological gradient, plausibility, coherence, experiment, and analogy of the current evidence linking Campylobacter to IBS. Through a consensus amongst all authors, the confidence of each criterion was graded as high, moderate, low, or very low., Results: a total of four criteria (strength, temporality, plausibility, and analogy) were graded as high; four criteria (consistency, biological gradient, coherence, and experiment) were graded as moderate; and one criterion (specificity) was graded as low. Large-scale epidemiological studies report a risk ratio of 2.7-5.6 for developing IBS after campylobacter. In rodent models, Campylobacter jejuni 81-176 can cause loose stool months after the infection is cleared and share common pathophysiology as IBS patients such as elevated intestinal TLR-4 and IL-8, antibodies to CdtB and vinculin, increased intraepithelial lymphocytes, and small intestinal bacterial overgrowth., Conclusions: Campylobacter infection appear to cause IBS in a subset of patients. This may hold implication in risk factor identification, public health policy, and possibly treatment., (© The Author(s) 2022. Published by Oxford University Press on behalf of FEMS.)

Objective: To summarize the current state of the research literature on nonverbal learning disability (NVLD), including criteria used to define NVLD in research contexts and the quality of the extant research; and to determine what research can tell us about ways in which NVLD is distinct from DSM neurodevelopmental disorders and typical development., Method: A systematic search of 7 databases was conducted to identify research on NVLD published through February 2019. Criteria used to define NVLD were extracted from identified studies and sorted by category. Each study was assessed for risk of bias and rated "good," "fair," or "poor;" findings from studies rated good or fair were summarized., Results: A total of 61 articles (63 studies) met inclusion criteria. There was great heterogeneity in the criteria used to define NVLD. Deficits in visuospatial ability/intelligence was the most common criterion used, followed by discrepancy between verbal and nonverbal intelligence (VIQ>PIQ split of 10 or greater). All studies were cross-sectional and most included small, poorly described samples. Most studies focused on children and young adolescents. Eight studies were rated as good, 42 as fair, and 13 as poor. Review of results from the 50 good or fair studies suggest that there is sufficient evidence that youths with NVLD (as defined by significant deficits in visuospatial abilities) can be clearly differentiated from their typically developing peers, those with verbal learning disorders, and from other clinical groups (eg, individuals with high functioning autism)., Conclusion: A standard set of criteria for determining an NVLD diagnosis would greatly improve research studies and the possibility of inclusion in the DSM and the International Classification of Diseases., (Copyright © 2021 American Academy of Child and Adolescent Psychiatry. Published by Elsevier Inc. All rights reserved.)

Background: Travellers' diarrhoea (TD) is the most common travel-related illness with an estimated 10 million people afflicted annually. Outcome measures to assess the efficacy of primary and secondary TD interventions were historically based on diarrhoea frequency with ≥1 associated gastrointestinal symptom. Furthermore, efficacy determination is often made on the presence or absence of TD, rather than on TD illness severity. Current severity classifications are based on subjective consideration of impact of illness on activity. We sought to develop a standardized scoring system to characterize TD severity to potentially apply as a secondary outcome in future field studies., Methods: Data on multiple signs and symptoms were obtained from a previously published multisite TD treatment trial conducted by the US Department of Defense (TrEAT TD). Correlation, regression and multiple correspondence analyses were performed to assess impact on activity and a TD severity score was established., Results: Numerous signs and symptoms were associated with impaired function, with malaise and nausea most strongly associated [odds ratio (OR) 5.9-44.3, P < 0.0001 and OR 2.8-37.1, P < 0.0001, respectively). Based on co-varying symptomatology, a TD severity score accounting for diarrhoea frequency in addition to several signs and symptoms was a better predictor of negative impact on function than any single sign/symptom (X2 = 127.16, P < 0.001). Additionally, there was a significant difference (P < 0.0001) in the mean TD severity score between those with acute watery diarrhoea (3.9 ± 1.9) and those with dysentery or acute febrile illness (6.2 ± 2.0)., Conclusions: The newly developed disease severity score better predicted a negative impact on activity due to TD than did any single sign or symptom. Incorporating multiple parameters into the TD severity score better captures illness severity and moves the field towards current recommendations for TD management by considering symptoms with high functional impact. Further validation of this score is needed in non-military travellers and other settings., (© The Author(s) 2021. Published by Oxford University Press on behalf of International Society of Travel Medicine. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Travellers' diarrhoea (TD) is the most common clinical syndrome affecting travellers. This narrative review summarizes key discoveries reported in the last two years related to TD and suggests areas for future research., Methods: A PubMed literature search was conducted for novel data in TD research published between 12 January 2018 and 12 January 2020. Inclusion was based on contribution to epidemiology, aetiology, diagnostics, management and long-term consequences and relevance to public health, discovery and clinical practice., Results: The initial literature search yielded 118 articles. We retrieved 72 and reviewed 31 articles for inclusion. The findings support our understanding that TD incidence varies by traveller group and environment with students and military-travel remaining moderately high risk, and control of food and water in mass gathering events remain an important goal. The growth of culture-independent testing has led to a continued detection of previously known pathogens, but also an increased detection frequency of norovirus. Another consequence is the increase in multi-pathogen infections, which require consideration of clinical, epidemiological and diagnostic data. Fluoroquinolone resistant rates continue to rise. New data on non-absorbable antibiotics continue to emerge, offering a potential alternative to current recommendations (azithromycin and fluoroquinolones), but are not recommended for febrile diarrhoea or dysentery or regions/itineraries where invasive pathogens are likely to cause illness. Recent studies investigated the interaction of the microbiome in TD prevention and consequences, and while discriminating features were identified, much uncertainty remains. The prevalence of extended-spectrum beta-lactamase-producing Enterobacteriaceae (ESBL-PE) acquisition and carriage is increasing. Finally, continued research documents the post-infectious consequences, whereas mechanisms of reactive arthritis and post-infectious IBS necessitate further investigation., Conclusions: Globally, TD remains an important travel health issue and advances in our understanding continue. More research is needed to mitigate risk factors where possible and develop risk-based management strategies to reduce antibiotic usage and its attendant consequences., (© The Author(s) 2021. Published by Oxford University Press on behalf of International Society of Travel Medicine. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: We assessed the compliance with self-collection of stool smears on Whatman® FTA® Elute Card (FTA Card) and detection of travellers' diarrhoea (TD)-associated pathogens by using a quantitative Polymerase Chain Reaction (PCR) assay [customized TaqMan® array card (TAC)] in a prospective, observational cohort of travellers., Methods: Enrolled travellers documented symptoms on a travel diary and collected an FTA Card during a diarrhoeal episode, or at the end of travel if they remained asymptomatic. TAC testing was performed on FTA Cards from TD cases and 1:1 matched asymptomatic controls and 1:1 matched loose stool cases that did not meet TD criteria. Odds ratios were used to determine the association between detected pathogens and TD., Results: Of 2456 travellers, 484 (19.7%) completed an illness diary and met TD criteria, and 257 (53.1%) collected an FTA Card during the TD episode. FTA Cards were stored for a median of 2 years at room temperature (IQR: 1-4 years) before extraction and testing. The overall TAC detection rate in TD cases was 58.8% (95% CI: 52.5-64.8). Enterotoxigenic Escherichia coli was the most common pathogen in TD cases (26.8%), and 3.5% of samples were positive for norovirus. The odds of detecting TD-associated pathogens in 231 matched cases and asymptomatic controls were 5.4 (95% CI: 3.6-8.1) and 2.0 (95% CI: 1.1-3.7) in 121 matched TD and loose stool cases (P < 0.05). Enteroaggregative E. coli was the most common pathogen detected in asymptomatic controls and loose stool cases. Detection of diarrhoeagenic E. coli, Shigella/enteroinvasive E. coli and Campylobacter spp. was significantly associated with TD., Conclusion: FTA Cards are a useful adjunct to traditional stool collection methods for evaluating the pathogen-specific epidemiology of TD in austere environments. Qualitative detection of pathogens was associated with TD. Measures to improve compliance and quality of FTA Card collection with decreased storage duration may further optimize detection., (© The Author(s) 2021. Published by Oxford University Press on behalf of International Society of Travel Medicine. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Cholera is a well known cause of significant disease, particularly in resource-poor nations, but it is very rare in developed countries. The morbidity and mortality of cholera is resultant from large-volume diarrhea, hypovolemia, and electrolyte derangement. In the following case, a 60-year-old man with no recent travel history presented to the emergency department with muscle cramping, abdominal pain, and gastrointestinal distress. It was later confirmed that he was suffering from cholera. On presentation, he was hyperkalemic with ECG changes and soon went into a hypovolemic shock. After a complicated hospital course, he fortunately made a complete recovery. This case demonstrates that common complaints may result in uncommon diagnoses. It is important to pay attention to the clinical situation and intervene accordingly., (© The Association of Military Surgeons of the United States 2021. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

This study sought to estimate the net benefits and return on investment (ROI, %) of the Coping and Promoting Strength (CAPS) program to families and insurers, respectively, using data from a multi-year follow up of 136 US families who had participated in a randomized efficacy trial of CAPS. CAPS is a brief parent-focused psychosocial intervention that was compared to information monitoring in the trial. Of the 136 original participants, 113 (83%) completed follow-up interviews 7.1 years, on average, after the CAPS study baseline (mean follow-up age: 15.8 years; range: 13.1 to 20.8 years). Parent-reported willingness-to-pay values and estimates of behavioral healthcare cost savings from delayed onset of anxiety were used to simulate the average net benefits of CAPS to families and insurance plans, respectively, assuming patients pay 20% coinsurance. Psychologists in private offices were expected to charge an average of approximately $195 per CAPS session or $1417 in total in 2020 dollars. The estimated family share of the total CAPS session cost was $283 per youth, while the insurer share was $1134 per youth. Given these costs, the CAPS intervention was estimated to result in average overall net benefits of $1033 per youth (95% CI: -$546 to $2611). Families gained $344 (95% CI: $232 to $455 per family) for an ROI of 121%. Insurance plans on average gained a net savings of $689 per youth (95% CI: -$778 to $2156 per youth) for an average ROI of 61%. In this multiyear follow-up of offspring of anxious parents, exposure to the CAPS pediatric anxiety prevention program was found to be more economically efficient than was waiting for an anxiety disorder to be diagnosed. ClinicalTrials.gov Identifier: NCT00847561., (© 2021. Society for Prevention Research.)

Objective: Child psychiatry access programs (CPAPs) help increase access to mental health services. This study aimed to provide information on the types of pediatric primary care clinicians (PPCCs) who call Maryland's CPAP., Methods: Descriptive statistics and multinomial logistic regressions were conducted with data from 676 PPCCs who called Maryland's CPAP at least once between October 2012 and June 2019., Results: On average, PPCCs contacted Maryland's CPAP 6.8 times. Providers who called seven or more times were more likely to have an allopathic or osteopathic medicine degree and to specialize in pediatrics. Providers calling from rural regions were less likely to call only for referrals., Conclusions: Most PPCCs contacted the CPAP for consultation or referrals but not both. PPCCs in rural areas were more likely to call for consultation, suggesting that they may be more likely to manage the care of patients with mental health conditions themselves, because of a lack of resources in their locations.

Introduction: Enterotoxigenic Escherichia coli (ETEC) is a common cause of infectious diarrhoea and a leading cause of morbidity and mortality in children living in resource-limited settings. It is also the leading cause of travellers' diarrhoea among civilian and military travellers. Its dual importance in global public health and travel medicine highlights the need for an effective vaccine. ETEC express colonization factors (CFs) that mediate adherence to the small intestine. An epidemiologically prevalent CF is coli surface antigen 6 (CS6). We assessed the safety and immunogenicity of a CS6-targeted candidate vaccine, CssBA, co-administered intramuscularly with the double-mutant heat-labile enterotoxin, dmLT [LT(R192G/L211A)]., Methods: This was an open-label trial. Fifty subjects received three intramuscular injections (Days 1, 22 and 43) of CssBA alone (5 µg), dmLT alone (0.1 µg) or CssBA (5, 15, 45 µg) + dmLT (0.1 and 0.5 µg). Subjects were actively monitored for adverse events for 28 days following the third vaccination. Antibody responses (IgG and IgA) were characterized in the serum and from lymphocyte supernatants (ALS) to CS6 and the native ETEC heat labile enterotoxin, LT., Results: Across all dose cohorts, the vaccine was safe and well-tolerated with no vaccine-related severe or serious adverse events. Among vaccine-related adverse events, a majority (98%) were mild with 79% being short-lived vaccine site reactions. Robust antibody responses were induced in a dose-dependent manner with a clear dmLT adjuvant effect. Response rates in subjects receiving 45 µg CssBA and 0.5 µg dmLT ranged from 50 to 100% across assays., Conclusion: This is the first study to demonstrate the safety and immunogenicity of CssBA and/or dmLT administered intramuscularly. Co-administration of the two components induced robust immune responses to CS6 and LT, paving the way for future studies to evaluate the efficacy of this vaccine target and development of a multivalent, subunit ETEC vaccine., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Published by Elsevier Ltd.)

Background: Travelers' diarrhea (TD) is one of the most common illnesses affecting modern-day travelers, including military personnel. Previous work has shown that afflicted travelers may alter their itineraries and be confined to bed rest due to symptoms, and military personnel may become incapable of completing operational requirements. Examination of signs, symptoms, and severity of diarrheagenic pathogens can inform clinical diagnosis and prioritization of future surveillance and research activities., Methods: Utilizing a global laboratory network, culture and molecular testing were performed in parallel at each site on a group of core pathogens, and definitions for acute diarrhea (AD), severe AD, acute gastroenteritis (AGE), and severe AGE were determined using data elements in the modified Vesikari scale. We included 210 cases of TD reporting all variables of interest in our severity assessment analysis., Results: Out of all cases, 156/210 (74%) met criteria for severe AD and 35/210 (17%) for severe AGE. Examination of severity by pathogen revealed that, at non-military sites, 17/19 (89%) of enteropathogenic Escherichia coli (E. coli) (EPEC) infections, 28/32 (88%) of enterotoxigenic E. coli (ETEC) infections, and 13/15 (87%) of Shigella/enteroinvasive E. coli (EIEC) infections resulted in severe AD cases. At the military site, all infections of ETEC (6/6), Shigella-EIEC (4/4), and enteroaggregative E. coli (EAEC) resulted in AD. Norovirus infections at non-military and military sites resulted in 27% (14/51) and 33% (3/9) severe AGE cases, respectively., Conclusions: This study found a high percentage of participants enrolled at both military and non-military sites experienced severe AD with concerning numbers of severe cases at non-military sites reporting hospitalization and reductions in performance. Since travelers with mild TD symptoms are less likely to present to health care workers than those with more severe TD, there is a potential selection bias in this study that may have overestimated the proportion of more severe outcomes among all individuals who could have participated in the GTD study. Future research should examine other covariates among pathogen and host, such as treatment and comorbid conditions, that may contribute to the presence of signs and symptoms and their severity., (Copyright © 2021. Published by Elsevier Ltd.)

The objective of this systematic review and meta-analysis was to estimate the proportion of postinfectious reactive arthritis (ReA) after bacterial enteric infection from one of four selected pathogens. We collected studies from PubMed, Web of Science, and Embase, which assessed the proportion of postinfectious ReA published from January 1, 2000 to April 1, 2018. Papers were screened independently by title, abstract, and full text; papers in English, Spanish, and Portuguese utilizing a case-control (CC) or cohort study design, with a laboratory confirmed or probable acute bacterial enteric infection and subsequent ReA, were included. The proportion of ReA cases was pooled between and across pathogens. Factors that can induce study heterogeneity were explored using univariate meta-regression, including region, sample size, study design, and ReA case ascertainment. Twenty-four articles were included in the final review. The estimated percentage of cases across studies describing Campylobacter -associated ReA ( n  = 11) was 1.71 (95% confidence interval [CI] 0.49-5.84%); Salmonella ( n  = 17) was 3.9 (95% CI 1.6-9.1%); Shigella ( n  = 6) was 1.0 (95% CI 0.2-4.9%); and Yersinia ( n  = 7) was 3.4 (95% CI 0.8-13.7%). Combining all four pathogens, the estimated percentage of cases that developed ReA was 2.6 (95% CI 1.5-4.7%). Due to high heterogeneity reflected by high I 2 values, results should be interpreted with caution. However, the pooled proportion developing ReA from studies with sample sizes ( N ) <1000 were higher compared with N  > 1000 (6% vs. 0.3%), retrospective cohort studies were lower (1.1%) compared with CC or prospective cohorts (6.8% and 5.9%, respectively), and those where ReA cases are identified through medical record review were lower (0.3%) than those identified by a specialist (3.9%) or self-report (12%). The estimated percentage of people who developed ReA after infection with Campylobacter , Salmonella , Shigella , or Yersinia is relatively low (2.6). In the United States, this estimate would result in 84,480 new cases of ReA annually.

Background: Persistent motor or vocal tic disorder (PMVT) has been hypothesized to be a forme fruste of Tourette syndrome (TS). Although the primary diagnostic criterion for PMVT (presence of motor or vocal tics, but not both) is clear, less is known about its clinical presentation., Objective: The goals of this study were to compare the prevalence and number of comorbid psychiatric disorders, tic severity, age at tic onset, and family history for TS and PMVT., Methods: We analyzed data from two independent cohorts using generalized linear equations and confirmed our findings using meta-analyses, incorporating data from previously published literature., Results: Rates of obsessive-compulsive disorder (OCD) and attention deficit hyperactivity disorder (ADHD) were lower in PMVT than in TS in all analyses. Other psychiatric comorbidities occurred with similar frequencies in PMVT and TS in both cohorts, although meta-analyses suggested lower rates of most psychiatric disorders in PMVT compared with TS. ADHD and OCD increased the odds of comorbid mood, anxiety, substance use, and disruptive behaviors, and accounted for observed differences between PMVT and TS. Age of tic onset was approximately 2 years later, and tic severity was lower in PMVT than in TS. First-degree relatives had elevated rates of TS, PMVT, OCD, and ADHD compared with population prevalences, with rates of TS equal to or greater than PMVT rates., Conclusions: Our findings support the hypothesis that PMVT and TS occur along a clinical spectrum in which TS is a more severe and PMVT a less severe manifestation of a continuous neurodevelopmental tic spectrum disorder. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society., (© 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.)

Obsessive-compulsive disorder (OCD) affects 1-2% of the population, and, as with other complex neuropsychiatric disorders, it is thought that rare variation contributes to its genetic risk. In this study, we performed exome sequencing in the largest OCD cohort to date (1,313 total cases, consisting of 587 trios, 41 quartets and 644 singletons of affected individuals) and describe contributions to disease risk from rare damaging coding variants. In case-control analyses (n = 1,263/11,580), the most significant single-gene result was observed in SLITRK5 (odds ratio (OR) = 8.8, 95% confidence interval 3.4-22.5, P = 2.3 × 10 -6 ). Across the exome, there was an excess of loss of function (LoF) variation specifically within genes that are LoF-intolerant (OR = 1.33, P = 0.01). In an analysis of trios, we observed an excess of de novo missense predicted damaging variants relative to controls (OR = 1.22, P = 0.02), alongside an excess of de novo LoF mutations in LoF-intolerant genes (OR = 2.55, P = 7.33 × 10 -3 ). These data support a contribution of rare coding variants to OCD genetic risk., (© 2021. The Author(s), under exclusive licence to Springer Nature America, Inc.)

This study examined the effects of a family-based intervention Coping and Promoting Strength (CAPS) relative to a control condition, information-monitoring (IM), to prevent the onset of anxiety disorders in offspring of anxious parents six years after their initial assessment. One hundred thirty six families participated in the original randomized trial; 113 (83%) completed the one time follow-up assessment. Presence of anxiety disorders and severity of symptoms in offspring were assessed by masked evaluators using the Anxiety Disorders Interview Schedule; parents and offspring also completed questionnaires assessing offspring anxiety. Using the intention to treat sample from the original trial, Cox regression models showed significant intervention main effects in the rate of onset of anxiety disorders from baseline to follow-up (anxiety disorder: hazard ratio (HR) = 2.55, 95% CI: 1.54, 4.21) but growth curves suggest effects occurred within the first year after program completion. No group differences were found in the cumulative incidence of anxiety disorders at the six-year follow-up. Additional intervention appears needed to maintain the initial positive effects long-term to reduce the risk for downstream disability.Clinical Trials Registration: NCT00847561.

Background: Multiple factors contribute to variation in disease burden, including the type and quality of data, and inherent properties of the models used. Understanding how these factors affect mortality estimates is crucial, especially in the context of public health decision making. We examine how the quality of the studies selected to provide mortality data, influence estimates of burden and provide recommendations about the inclusion of studies and datasets to calculate mortality estimates., Methods: To determine how mortality estimates are affected by the data used to generate model outputs, we compared the studies used by The Institute of Health Metrics and Evaluation (IHME) and Maternal and Child Epidemiology Estimation (MCEE) modelling groups to generate enterotoxigenic Escherichia coli (ETEC) and Shigella-associated mortality estimates for 2016. Guided by an expert WHO Working Group, we applied a modified Newcastle-Ottawa Scale (NOS) to evaluate the quality of studies used by both modelling groups., Results: IHME and MCEE used different sets of ETEC and Shigella studies in their models and the majority of studies were high quality. The distribution of the NOS scores was similar between the two modelling groups. We observed an overrepresentation of studies from some countries in SEAR, AFR and WPR compared to other WHO regions., Conclusion: We identified key differences in study inclusion and exclusion criteria used by IHME and MCEE and discuss their impact on datasets used to generate diarrhoea-associated mortality estimates. Based on these observations, we provide a set of recommendations for future estimates of mortality associated with enteric diseases., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Youth treated with antipsychotic medications are high risk for weight gain, increased lipids/glucose, and development of metabolic syndrome. Little is known about the dietary intake/nutritional adequacy in this vulnerable population, and effect on weight gain. This secondary data analysis describes the baseline intake and changes in diet after receiving healthy lifestyle education/counseling over 6 months, in a sample of youth with antipsychotic-induced weight gain. Methods: The U.S. Department of Agriculture (USDA) Automated Multiple-Pass Method 24-hour dietary recall was administered to 117 youth at baseline, 3 months, and 6 months. Parent/child received personalized healthy lifestyle education sessions over 6 months. Baseline intake was compared with the USDA Recommended Daily Allowance using independent samples t -tests. Individual dietary covariates were examined for change over 6 months using longitudinal linear mixed modeling. Influence of each on body mass index (BMI) z -score change was tested in a pooled group analysis and then compared by treatment group. Results: Pooled analysis revealed baseline consumption high in carbohydrates, fat, protein, sugar, and refined grains, while low in fruit/vegetables, whole grains, fiber, and water. Change over 6 months demonstrated a statistically significant decrease in daily calories ( p  = 0.002), carbohydrates ( p  = 0.003), fat ( p  = 0.012), protein ( p  = 0.025), sugar ( p  = 0.008), refined grains ( p  = 0.008), total dairy ( p  = 0.049), and cheese ( p  = 0.027). Small increases in fruits/vegetables were not statistically significant, although the Healthy Eating Index subscores for total vegetables ( p  = 0.013) and dark green/orange vegetables ( p  = 0.034) were. No dietary covariates were predictors of change in BMI z -score. Nondietary predictors were parent weight/BMI and treatment group, with the metformin and switch groups experiencing significant decreases in BMI z -score. Conclusions: Further pediatric studies are necessary to assess the effects of antipsychotic medications on dietary intake, and test efficacy of healthy lifestyle interventions on change in nutrition. The relationship of nutrition to cardiometabolic health in this population must be further investigated. Clinical Trial Registration number: NCT02877823.

Background: Travelers' diarrhea (TD) is common among military personnel deployed to tropical and subtropical regions. It remains unclear how TD and subsequent antibiotic treatment impact the resident microflora within the gut, especially given increased prevalence of antibiotic resistance among enteric pathogens and acquisition of multidrug-resistant organisms. We examined functional properties of the fecal microflora in response to TD, along with subsequent antibiotic treatment., Methods: Fecal samples from US and UK military service members deployed to Djibouti, Kenya, and Honduras who presented with acute watery diarrhea were collected. A sample was collected at acute presentation to the clinic (day 0, before antibiotics), as well as 7 and/or 21 days following a single dose of antibiotics (azithromycin [500 mg], levofloxacin [500 mg], or rifaximin [1650 mg], all with loperamide). Each stool sample underwent culture and TaqMan reverse transcription polymerase chain reaction analyses for pathogen and antibiotic resistance gene detection. Purified DNA from each sample was analyzed using the HumiChip3.1 functional gene array., Results: In total, 108 day 1 samples, 50 day 7 samples, and 94 day 21 samples were available for analysis from 119 subjects. Geographic location and disease severity were associated with distinct functional compositions of fecal samples. There were no overt functional differences between pre- and postantibiotic treatment samples, nor was there increased acquisition of antibiotic resistance determinants for any of the antibiotic regimens., Conclusions: These results indicate that single-dose antibiotic regimens may not drastically alter the functional or antibiotic resistance composition of fecal microflora, which should inform clinical practice guidelines and antimicrobial stewardship., Clinical Trials Registration Number: NCT01618591., (Published by Oxford University Press on behalf of Infectious Diseases Society of America 2021.)

SARS-COV-2 (COVID-19) is a novel virus that has caused over 28 million cases worldwide and over 900,000 deaths since early 2020, rightfully being classified as a pandemic. COVID-19 is diagnosed via polymerase chain reaction testing which looks at cycle threshold (CT) values of two genes, N2 and E. This study examined CT values of COVID-positive patients at the VA hospital in Reno as well as other lab values and comorbidities to determine if any could aid clinicians in predicting the need for hospitalization and higher levels of care. Multiple variables, including N2 CT value, absolute lymphocyte count (ALC), D-dimer, erythrocyte sedimentation rate, C-reactive protein, fibrinogen, and ferritin were evaluated for potential associations with N2 CT value as well as required level of care (based on World Health Organization [WHO] ordinal score). The results suggest that patients with a N2 CT value less than 34 are four times more likely to have WHO ordinal scores of 4-8 (p = .0021) while controlling for age and comorbidities (DM, cardiac, kidney, and lung disease). Patients of age 55 or greater were 15.18 times more likely to have WHO ordinal scores of 4-8 (p = .012) controlling for N2 CT value and comorbidities. Furthermore, patients with ALC less than 1 were 5.88 times more likely to have WHO ordinal score of 4-8 (p = .00024). N2 CT values also appear to be associated with many commonly obtained markers such as ALC, white blood cell count, C-reactive protein, and D-dimer. Patients with N2 CT values less than 34 were 3.49 times more likely to have ALC values less than 1, controlling for age and comorbidities (p = .0072) while patients 55 or older were 6.66 times more likely to have ALC less than 1 (p = .027). Finally, this study confirms previous conclusions that patients with advanced age had more severe infections and thus will likely require higher levels of care., (© 2021 Wiley Periodicals LLC.)