Characterising illness stages and recovery trajectories of eating disorders in young people via remote measurement technology (STORY): a multi-centre prospective cohort study protocol.

BACKGROUND: Eating disorders (EDs) are serious, often chronic, conditions associated with pronounced morbidity, mortality, and dysfunction increasingly affecting young people worldwide. Illness progression, stages and recovery trajectories of EDs are still poorly characterised. The STORY study dynamically and longitudinally assesses young people with different EDs (restricting; bingeing/bulimic presentations) and illness durations (earlier; later stages) compared to healthy controls. Remote measurement technology (RMT) with active and passive sensing is used to advance understanding of the heterogeneity of earlier and more progressed clinical presentations and predictors of recovery or relapse. METHODS: STORY follows 720 young people aged 16-25 with EDs and 120 healthy controls for 12 months. Online self-report questionnaires regularly assess ED symptoms, psychiatric comorbidities, quality of life, and socioeconomic environment. Additional ongoing monitoring using multi-parametric RMT via smartphones and wearable smart rings ('Oura ring') unobtrusively measures individuals' daily behaviour and physiology (e.g., Bluetooth connections, sleep, autonomic arousal). A subgroup of participants completes additional in-person cognitive and neuroimaging assessments at study-baseline and after 12 months. DISCUSSION: By leveraging these large-scale longitudinal data from participants across ED diagnoses and illness durations, the STORY study seeks to elucidate potential biopsychosocial predictors of outcome, their interplay with developmental and socioemotional changes, and barriers and facilitators of recovery. STORY holds the promise of providing actionable findings that can be translated into clinical practice by informing the development of both early intervention and personalised treatment that is tailored to illness stage and individual circumstances, ultimately disrupting the long-term burden of EDs on individuals and their families.

Competencies for proficiency in basic point-of-care ultrasound in anesthesiology: national expert recommendations using Delphi methodology.

PURPOSE: Point-of-care ultrasound (POCUS) allows for rapid bedside assessment and guidance of patient care. Recently, POCUS was included as a mandatory component of Canadian anesthesiology training; however, there is no national consensus regarding the competencies to guide curriculum development. We therefore aimed to define national residency competencies for basic perioperative POCUS proficiency. METHODS: We adopted a Delphi process to delineate relevant POCUS competencies whereby we circulated an online survey to academic anesthesiologists identified as POCUS leads/experts (n = 25) at all 17 Canadian anesthesiology residency programs. After reviewing a list of competencies derived from the Royal College of Physicians and Surgeons of Canada's National Curriculum, we asked participants to accept, refine, delete, or add competencies. Three rounds were completed between 2022 and 2023. We discarded items with < 50% agreement, revised those with 50-79% agreement based upon feedback provided, and maintained unrevised those items with ≥ 80% agreement. RESULTS: We initially identified and circulated (Round 1) 74 competencies across 19 clinical domains (e.g., basics of ultrasound [equipment, nomenclature, clinical governance, physics]; cardiac [left ventricle, right ventricle, valve assessment, pericardial effusion, intravascular volume status] and lung ultrasound anatomy, image acquisition, and image interpretation; and clinical applications [monitoring and serial assessments, persistent hypotension, respiratory distress, cardiac arrest]). After three Delphi rounds (and 100% response rate maintained), panellists ultimately agreed upon 75 competencies. CONCLUSION: Through national expert consensus, this study identified POCUS competencies suitable for curriculum development and assessment in perioperative anesthesiology. Next steps include designing and piloting a POCUS curriculum and assessment tool(s) based upon these nationally defined competencies.

RéSUMé: OBJECTIF: L'échographie ciblée (POCUS) permet une évaluation rapide au chevet des patient·es et l'orientation des soins aux patient·es. Récemment, l'échographie ciblée a été incluse en tant que composante obligatoire de la formation en anesthésiologie au Canada; cependant, il n'y a pas de consensus national sur les compétences qui guideront l'élaboration des programmes d'études. Nous avons donc cherché à définir les compétences à inclure dans les programmes de résidence nationaux pour acquérir des compétences de base en échographie ciblée périopératoire. MéTHODE: Nous avons adopté un processus Delphi pour délimiter les compétences pertinentes en échographie ciblée, processus dans le cadre duquel nous avons fait circuler un sondage en ligne auprès d'anesthésiologistes universitaires identifié·es comme des responsables/expert·es en échographie ciblée (n = 25) dans les 17 programmes canadiens de résidence en anesthésiologie. Après avoir examiné une liste de compétences tirées du programme d'études national du Collège royal des médecins et chirurgiens du Canada, nous avons demandé aux participant·es d'accepter, de peaufiner, de supprimer ou d'ajouter des compétences. Trois rondes ont été complétées entre 2022 et 2023. Nous avons écarté les éléments ayant < 50 % d'accord, révisé ceux avec 50 à 79 % d'accord en fonction des commentaires fournis, et maintenu sans révision les éléments obtenant ≥ 80 % d'accord. RéSULTATS: Nous avons d'abord identifié et diffusé (ronde 1) 74 compétences dans 19 domaines cliniques (p. ex., les bases de l'échographie [équipement, nomenclature, gouvernance clinique, physique]; anatomie échographique cardiaque [ventricule gauche, ventricule droit, évaluation valvulaire, épanchement péricardique, état du volume intravasculaire] et pulmonaire [acquisition et interprétation d'images]; et applications cliniques [surveillance et évaluations en série, hypotension persistante, détresse respiratoire, arrêt cardiaque]). Après trois rondes Delphi (et un taux de réponse de 100 % maintenu), les panélistes se sont finalement mis·es d'accord sur 75 compétences. CONCLUSION: Grâce à un consensus d'expert·es au pays, cette étude a permis d'identifier les compétences en échographie ciblée adaptées à l'élaboration et à l'évaluation de programmes d'études en anesthésiologie périopératoire. Les prochaines étapes comprennent la conception et la mise à l'essai d'un programme d'études et d'outils d'évaluation en échographie ciblée basés sur ces compétences définies à l'échelle nationale.

Safety and Durability of Accelerated Infliximab Dosing Strategies in Pediatric IBD: A Single Center, Retrospective Study.

OBJECTIVES: Infliximab (IFX) is commonly used to treat children with inflammatory bowel disease (IBD). We previously reported that patients with extensive disease started on IFX at a dose of 10 mg/kg had greater treatment durability at year one. The aim of this follow-up study is to assess the long-term safety and durability of this dosing strategy in pediatric IBD. METHODS: We performed a retrospective single-center study of pediatric IBD patients started on IFX over a 10-year period. RESULTS: Two hundred ninety-one patients were included (mean age = 12.61, 38% female) with a follow-up range of 0.1-9.7 years from IFX induction. One hundred fifty-five (53%) were started at a dose of 10 mg/kg. Only 35 patients (12%) discontinued IFX. The median duration of treatment was 2.9 years. Patients with ulcerative colitis ( P ≤ 0.01) and patients with extensive disease ( P = 0.01) had lower durability, despite a higher starting dose of IFX ( P = 0.03). Adverse events (AEs) were observed to occur at a rate of 234 per 1000 patient-years. Patients with a higher serum IFX trough level (≥20 µg/mL) had a higher rate of AEs ( P = 0.01). Use of combination therapy had no impact on risk of AEs ( P = 0.78). CONCLUSIONS: We observed an excellent IFX treatment durability, with only 12% of patients discontinuing therapy over the observed timeframe. The overall rate of AEs was low, the majority being infusion reactions and dermatologic conditions. Higher IFX dose and serum trough level> 20 µg/mL were associated with higher risk of AEs, the majority being mild and not resulting in cessation of therapy.

A Case of Neonatal Lupus Presenting with Myocardial Dysfunction in the Absence of Congenital Heart Block (CHB): Clinical Management and Brief Literature Review of Neonatal Cardiac Lupus.

Neonatal lupus (NLE) is a rare acquired autoimmune disorder caused by transplacental passage of maternal autoantibodies to Sjogren's Syndrome A or B (SSA-SSB) autoantigens (Vanoni et al. in Clin Rev Allerg Immunol 53:469-476, 2017) which target fetal and neonatal tissues for immune destruction. The cardiac trademark of NLE is autoimmune heart block, which accounts for more than 80% of cases of complete atrioventricular heart block (AVB) in newborns with a structurally normal heart (Martin in Cardiol Young 24: 41-46, 2014). NLE presenting with cardiac alterations not involving rhythm disturbances are described in the literature, but they are rare. Here, we report a case of a neonate with high anti-SSA antibodies who developed severe ventricular dysfunction in the absence of rhythm abnormalities, endocardial fibroelastosis, and dilated cardiomyopathy (Trucco et al. in J Am Coll Cardiol 57:715-723, https://doi.org/10.1016/j.jacc.2010.09.044 , 2011), the most common cardiac presentations of NLE. The patient developed severe multiorgan dysfunction syndrome that required prolonged critical care support but fully recovered and was discharged home. We highlight the unusual clinical features of this NLE case and the importance of timely treatment of NLE allowing complete recovery of a critically ill neonate.

Management of an Immunocompromised Pediatric Patient With Multiple Hospitalizations for Symptomatic COVID-19.

Relapse of infection due to SARS-CoV-2 has been rarely described and there is little guidance regarding the management of such cases in immunocompromised hosts. We present a case of an adolescent female with B-cell acute lymphoblastic leukemia hospitalized multiple times for symptomatic SARS-CoV-2 infection who was safely treated with 2 courses of remdesivir (RDV) and has had no additional readmissions to date. Though additional studies are needed to confirm the safety and efficacy of an additional course of RDV in the setting of relapsed or prolonged severe COVID-19, our observations suggest that a second course of RDV may be considered.

Pelvic pain: What are the symptoms and predictors for surgery, endometriosis and endometriosis severity.

BACKGROUND: Chronic pelvic pain (CPP) is a common condition which significantly impacts the quality of life and wellbeing of many women. Laparoscopy with histopathology is recommended for investigation of pelvic pain and identification of endometriosis with concurrent removal. Never-the-less, the association between endometriosis and pelvic pain is challenging, with endometriosis identified in only 30-50% of women with pain. AIMS: To explore the predictors for undergoing surgery, for identifying endometriosis and endometriosis severity in a cohort of women with CPP. MATERIALS AND METHODS: This study forms part of the Persistent Pelvic Pain project, a prospective observational cohort study (ANZCTR:ACTRN12616000150448). Women referred to a public gynaecology clinic with pain were randomised to one of two gynaecology units for routine care and followed for 36 months with 6-monthly surveys assessing demographics, medical history, quality of life, and pain symptoms measured on a Likert scale. Operative notes were reviewed and endometriosis staged. RESULTS: Of 471 women recruited, 102 women underwent laparoscopy or laparotomy, of whom 52 had endometriosis (n = 37 stage I-II; n = 15 Stage III-IV). Gynaecology unit, pelvic pain intensity and lower parity were all predictors of surgery (odds ratio (OR) 0.342; 95% CI 0.209-0.561; OR 1.303; 95% CI: 1.079-1.573; OR 0.767; 95% CI: 0.620-0.949, respectively). There were no predictors identified for endometriosis diagnosis and the only predictor of severity was increasing age (OR 1.155; 95% CI: 1.047-1.310). CONCLUSIONS: Gynaecology unit and pain intensity were key predictors of undergoing laparoscopy; however, pain severity did not predict endometriosis diagnosis or staging. These findings indicate the need to review current frameworks guiding practice toward surgery for pelvic pain.

TRPM4 channel inhibitors 9-phenanthrol and glibenclamide differentially decrease guinea pig detrusor smooth muscle whole-cell cation currents and phasic contractions.

Nonselective cation channels, consistent with transient receptor potential melastatin-4 (TRPM4), regulate detrusor smooth muscle (DSM) function. TRPM4 channels can exist as homomers or assemble with sulfonylurea receptors (SURs) as complexes. We evaluated contributions of TRPM4/SUR-TRPM4 channels to DSM excitability and contractility by examining the effects of TRPM4/SUR-TRPM4 channel modulators 9-phenanthrol, glibenclamide, and diazoxide on freshly-isolated guinea pig DSM cells (amphotericin-B perforated patch-clamp electrophysiology) and mucosa-free DSM strips (isometric tension recordings). In DSM cells, complete removal of extracellular Na+ decreased voltage-step-induced cation (non-K+ selective) currents. At high positive membrane potentials, 9-phenanthrol at 100 µM attenuated voltage step-induced currents more effectively than at 30 µM, revealing concentration-dependent, voltage-sensitive inhibition. In comparison to 9-phenanthrol, glibenclamide (100 µM) displayed lower inhibition of cation currents. In the presence of glibenclamide (100 µM), 9-phenanthrol (100 µM) further decreased the currents. The SUR-TRPM4 complex activator diazoxide (100-300 µM) weakly inhibited the currents. 9-Phenanthrol, but not glibenclamide or diazoxide, increased cell capacitance (a cell surface area indicator). In contractility studies, glibenclamide displayed lower potencies than 9-phenanthrol attenuating spontaneous and 20 mM KCl-induced DSM phasic contractions. While both compounds showed similar maximum inhibitions on DSM spontaneous phasic contractions, glibenclamide was generally less efficacious on 20 mM KCl-induced phasic contractions. In summary, the observed differential effects of 9-phenanthrol and glibenclamide on DSM excitability and contractility support unique mechanisms for the two compounds. The data suggest that SUR-TRPM4 complexes do not contribute to DSM function. This study advances our understanding of pharmacological effects of glibenclamide and 9-phenanthrol on DSM cell cation currents.

Health-related Quality of Life in Children With Sickle Cell Disease Undergoing Chronic Red Cell Transfusion Therapy.

Chronic red cell transfusion (CRCT) therapy is one of few disease-modifying treatments for sickle cell disease (SCD). This study evaluated health-related quality of life (HRQL) in children receiving CRCT relative to 2 comparison groups: children with similar, severe SCD and children with milder disease risk defined by SCD genotype. For this study, 67 children with SCD between the ages of 8 and 18 completed the self-report Pediatric Quality of Life Sickle Cell Disease module (PedsQL SCD) as part of a pilot clinical program during routine hematologic visits. A medical chart review was also performed. Linear regression suggested that children in the CRCT group had significantly higher self-reported HRQL ratings for domains related to pain, F2,64=4.07 (P=0.022) and pain-related functioning, F2,64=4.32 (P=0.017), compared with children with similar and milder disease risk. Exploratory analyses implied that children in the CRCT group also had fewer worries about SCD-related complications, F3,63=9.68 (P<0.001). These patient-perceived benefits of CRCT may have important implications for treatment decisions and for providing ancillary support for children with SCD and their families.

The effect of respiratory motion on electronic portal imaging device dosimetry.

There is an increasing need to develop methods for in vivo verification of the delivery of radiotherapy treatments. Electronic portal imaging devices (EPID's) have been demonstrated to be of use for this application. The basic principle is relatively straightforward, the EPID is used to measure a two-dimensional (2D) planar exit or portal dose map behind the patient during the treatment delivery that can provide information on any errors in linear accelerator output or changes in the patient anatomy. In this paper we focused on the effect of intra-fraction motion, particularly respiratory motion, on the measured 2D EPID dose-response. Measurements were made with a breast phantom undergoing one-dimensional (1D) sinusoidal motion with a range of amplitudes (0.5, 1.0, and 1.5 cm) and frequencies (12, 15, and 20  cycles/min). Further measurements were made with the phantom undergoing breathing sequences measured during patient planning computed tomography simulation. We made use of the quadratic calibration method that converts the EPID images to a surrogate for dose, equivalent thickness of Plastic Water® . Comparisons were made of the 2D thickness maps derived for the different motions compared to the static phantom case and the resulting dose difference analyzed over the "breast" region of interest. A 2D gamma analysis within the same region of interest was performed of the motion images compared to static reference image. Comparisons were made of 1D thickness profiles for the moving and static phantom. The 1D and 2D analyses show the method to be sensitive to the smallest motion amplitude of 0.5 cm tested in the phantom measurements. The results using the phantom demonstrate the method to be a potentially useful tool for monitoring intra-fraction motion during the delivery of patient radiotherapy treatments as well as more generally providing information on the effects of motion on EPID based in vivo dosimetric verification.

Clinician-rated and self-reported psychotic-like experiences in individuals accessing a specialist Youth Mental Health Service.

AIM: The prevalence of psychotic-like experiences (PLEs) was explored in a sample of 14- to 25-year-olds with non-psychotic mental health difficulties. Associations between PLEs, psychopathology, functioning, trauma history, and pathways to care were examined. METHODS: Data were collected for 202 young people. Clinicians rated PLEs using the Primary Care Checklist (PCC) and functioning using Global Assessment Scales. Eighty-three young people completed self-report assessments of PLEs using the Prodromal Questionnaire (PQ-16) and measures of social anxiety, depression, trauma history, and pathways to care. RESULTS: There was a high prevalence of PLEs in the sample. The prevalence of PLEs was higher when young people self-rated their experiences. Endorsement frequencies for PLEs ranged from 3.5 to 24% on the PCC and 22 to 70% on the PQ-16. Higher scores on the PQ-16 were associated with more pathways into care and greater exposure to traumatic life events. CONCLUSIONS: PLEs are common in young people with non-psychotic mental health difficulties and may reflect increased severity and complexity of mental health difficulties. Routine screening and further assessment of PLEs are important in understanding and responding to such experiences. Screening should include self-rating of PLEs as well as clinician-rated scales. PRACTITIONER POINTS: Clinical Implications Psychotic-like experiences are common in young people with severe non-psychotic mental health problems and should be routinely screened in mental health services. Psychotic-like experiences were found to be more prevalent when using a self-report screening tool compared to a clinician-rated measure. The presence of psychotic-like experiences may reflect more severe and complex mental health problems and may also cause delays in young people accessing the right kind of support. ;Limitations This study only assessed the presence or absence of psychotic-like experiences. Further studies should use more detailed assessments to understand more about the nature of such experiences and how they are appraised and responded to. This study is cross-sectional, and therefore, the direction of the relationships between psychotic-like experiences and depression, anxiety, functioning, and trauma cannot be specified. Longitudinal studies are needed to examine the impact of psychotic-like experiences on long-term outcomes.

Structural and Functional Characterization of the JH2 Pseudokinase Domain of JAK Family Tyrosine Kinase 2 (TYK2).

JAK (Janus family of cytoplasmic tyrosine kinases) family tyrosine kinase 2 (TYK2) participates in signaling through cytokine receptors involved in immune responses and inflammation. JAKs are characterized by dual kinase domain: a tyrosine kinase domain (JH1) that is preceded by a pseudokinase domain (JH2). The majority of disease-associated mutations in JAKs map to JH2, demonstrating its central regulatory function. JH2s were considered catalytically inactive, but JAK2 JH2 was found to have low autoregulatory catalytic activity. Whether the other JAK JH2s share ATP binding and enzymatic activity has been unclear. Here we report the crystal structure of TYK2 JH2 in complex with adenosine 5'-O-(thiotriphosphate) (ATP-γS) and characterize its nucleotide binding by biochemical and biophysical methods. TYK2 JH2 did not show phosphotransfer activity, but it binds ATP and the nucleotide binding stabilizes the protein without inducing major conformational changes. Mutation of the JH2 ATP-binding pocket increased basal TYK2 phosphorylation and downstream signaling. The overall structural characteristics of TYK2 JH2 resemble JAK2 JH2, but distinct stabilizing molecular interactions around helix αAL in the activation loop provide a structural basis for differences in substrate access and catalytic activities among JAK family JH2s. The structural and biochemical data suggest that ATP binding is functionally important for both TYK2 and JAK2 JH2s, whereas the regulatory phosphorylation appears to be a unique property of JAK2. Finally, the co-crystal structure of TYK2 JH2 complexed with a small molecule inhibitor demonstrates that JH2 is accessible to ATP-competitive compounds, which offers novel approaches for targeting cytokine signaling as well as potential therapeutic applications.

Associations between prenatal traffic-related air pollution exposure and birth weight: Modification by sex and maternal pre-pregnancy body mass index.

BACKGROUND: Prenatal traffic-related air pollution exposure is linked to adverse birth outcomes. However, modifying effects of maternal body mass index (BMI) and infant sex remain virtually unexplored. OBJECTIVES: We examined whether associations between prenatal air pollution and birth weight differed by sex and maternal BMI in 670 urban ethnically mixed mother-child pairs. METHODS: Black carbon (BC) levels were estimated using a validated spatio-temporal land-use regression (LUR) model; fine particulate matter (PM2.5) was estimated using a hybrid LUR model incorporating satellite-derived Aerosol Optical Depth measures. Using stratified multivariable-adjusted regression analyses, we examined whether associations between prenatal air pollution and calculated birth weight for gestational age (BWGA) z-scores varied by sex and maternal pre-pregnancy BMI. RESULTS: Median birth weight was 3.3±0.6kg; 33% of mothers were obese (BMI ≥30kg/m(3)). In stratified analyses, the association between higher PM2.5 and lower birth weight was significant in males of obese mothers (-0.42 unit of BWGA z-score change per IQR increase in PM2.5, 95%CI: -0.79 to -0.06) ( PM2.5×sex×obesity Pinteraction=0.02). Results were similar for BC models (Pinteraction=0.002). CONCLUSIONS: Associations of prenatal exposure to traffic-related air pollution and reduced birth weight were most evident in males born to obese mothers.

Targeted Tick-Borne Disease Recognition: Assessing Risk for Improved Public Health.

Tick-borne diseases (TBDs) pose a rapidly growing threat to public health. The incidence of TBDs is on the rise, necessitating a comprehensive understanding of the risk factors beyond demographic considerations. This brief report combines a preliminary review of the literature with geographical case mapping to identify the various factors influencing TBD risk. The report highlights the vulnerability of outdoor workers, the importance of outdoor activities, and the role of education in adopting preventive behaviors. Pet ownership and interactions with animals are also associated with an increased risk. The state of Illinois is used as a case study for this report, revealing regional variations in TBD incidence, and linking them to agricultural practices, forested areas, and park accessibility. These findings inform recommendations for targeted prevention strategies, emphasizing the need for detailed geographical data to enhance public health efforts in curbing TBD incidence and risk.

Food insecurity is a risk factor for metabolic dysfunction-associated steatotic liver disease in Latinx children.

INTRODUCTION: Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most common chronic liver disease among US children. Studies have associated food insecurity with MASLD in adults, but there are few studies of pediatric MASLD, particularly in high-risk populations. We assessed the impact of household food insecurity at 4 years of age on MASLD in Latinx children. METHODS: Using a prospective cohort design, Latina mothers were recruited during pregnancy and followed with their children until early to mid-childhood. Our primary exposure was household food insecurity at 4 years of age measured using the validated US Household Food Security Food Module. Our primary outcome, MASLD, was defined as alanine transaminase (ALT) ≥95th% for age/gender plus body mass index (BMI) ≥85% at time of ALT measurement (assessed between ages 5-12). We used multivariable logistic regression models to test for independent associations between household food insecurity and pediatric MASLD. RESULTS: Among 136 children, 28.7% reported household food insecurity at 4 years of age and 27.2% had MASLD in early to middle childhood. Approximately 49% of children with MASLD and 21% of children without MASLD were food insecure (p < 0.01). Exposure to household food insecurity at age 4 was independently associated with a 3.7-fold higher odds of MASLD later in childhood (95% CI: 1.5-9.0, p < 0.01). CONCLUSIONS: Exposure to household food insecurity at 4 years of age was associated with increased risk for MASLD later in childhood. Further studies are needed to explore mechanism(s) and impact of reducing food insecurity on risk for MASLD.

Association of social support with quality of life in patients with polyneuropathy.

The aim of this study was to examine the impact of social support on quality of life (QoL) in patients with polyneuropathy. One hundred and fifty-four patients with polyneuropathy were enrolled from a neuromuscular clinic. The QoL Instrument and the Medical Outcome Study-Social Support Survey (MOS-SSS) were used to assess QoL and social support, respectively. Disease severity and clinical factors were also assessed. Neuropathy patients had a lower QoL compared to a previously published normative sample (p < 0.0001) and an MOS-SSS comparable to other patients with chronic disease. Social support correlated weakly with the self esteem and emotional well being mental health dimensions (rs :0.20-0.38) but not the physical health QoL (PH-QoL) domains. Physical and mental QoL also correlated significantly with presence of pain (rs : -0.39 and -0.42, respectively) and number of autonomic symptoms (rs : -0.39 and -0.30, respectively). Social support independently predicts MH-QoL when controlling for age, gender, pain, and the Toronto Clinical Neuropathy Score (TCNS; p < 0.0001). TCNS and gender are independently related to PH-QoL (p < 0.05). This study demonstrates that improved social support serves as an independent predictor of MH-QoL when controlling for age, gender, pain, and severity of neuropathy. Future studies examining the effects of improving social support on QoL in patients with polyneuropathy are recommended.

Use of light-weight foaming polylactic acid as a lung-equivalent material in 3D printed phantoms.

The 3D printing of lung-equivalent phantoms using conventional polylactic acid (PLA) filaments requires the use of low in-fill printing densities, which can produce substantial density heterogeneities from the air gaps within the resulting prints. Light-weight foaming PLA filaments produce microscopic air bubbles when heated to 3D printing temperatures. In this study, the expansion of foaming PLA filament was characterised for two 3D printers with different nozzle diameters, in order to optimise the printing flow rates required to achieve a low density print when printed at 100% in-fill printing density, without noticeable internal air gaps. Effective densities as low as 0.28 g cm- 3 were shown to be achievable with only microscopic air gaps. Light-weight foaming PLA filaments are a cost-effective method for achieving homogeneous lung-equivalency in 3D printed phantoms for use in radiotherapy imaging and dosimetry, featuring smaller air gaps than required to achieve low densities with conventional PLA filaments.

Improving Surveillance of Human Tick-Borne Disease Risks: Spatial Analysis Using Multimodal Databases.

BACKGROUND: The extent of tick-borne disease (TBD) risk in the United States is generally unknown. Active surveillance using entomological measures, such as presence and density of infected nymphal Ixodes scapularis ticks, have served as indicators for assessing human risk, but results have been inconsistent and passive surveillance via public health systems suggests TBDs are underreported. OBJECTIVE: Research using various data sources and collection methods (eg, Google Trends, apps, and tick bite encounters [TBEs] reports) has shown promise for assessing human TBD risk. In that vein, and engaging a One Health perspective, this study used multimodal databases, geographically overlaying patient survey data on TBEs and concomitant reports of TBDs with data drawn from other sources, such as canine serological reports, to glean insights and to determine and assess the use of various indicators as proxies for human TBD risk. METHODS: This study used a mixed methods research strategy, relying on triangulation techniques and drawing on multiple data sources to provide insights into various aspects of human disease risk from TBEs and TBDs in the United States. A web-based survey was conducted over a 15-month period beginning in December 2020 to collect data on TBEs. To maximize the value of the covariate data, related analyses included TBE reports that occurred in the United States between January 1, 2000, and March 31, 2021. TBEs among patients diagnosed with Lyme disease were analyzed at the county level and compared to I scapularis and I pacificus tick presence, human cases identified by the Centers for Disease Control and Prevention (CDC), and canine serological data. Spatial analyses employed multilayer thematic mapping and other techniques. RESULTS: After cleaning, survey results showed a total of 249 (75.7%) TBEs spread across 148 respondents (61.9% of all respondents, 81.7% of TBE-positive respondents); 144 (4.7%) counties in 30 states (60%) remained eligible for analysis, with an average of 1.68 (SD 1.00) and median of 1 (IQR 1) TBEs per respondent. Analysis revealed significant spatial matching at the county level among patient survey reports of TBEs and disease risk indicators from the CDC and other official sources. Thematic mapping results included one-for-one county-level matching of reported TBEs with at least 1 designated source of human disease risk (ie, positive canine serological tests, CDC-reported Lyme disease, or known tick presence). CONCLUSIONS: Use of triangulation methods to integrate patient data on TBE recall with established canine serological reports, tick presence, and official human TBD information offers more granular, county-level information regarding TBD risk to inform clinicians and public health officials. Such data may supplement public health sources to offer improved surveillance and provide bases for developing robust proxies for TBD risk among humans.

Understanding Habitats and Environmental Conditions of White-Tailed Deer Population Density and Public Health Data to Aid in Assessing Human Tick-Borne Disease Risk.

The extent of tick-borne diseases (TBDs) in the United States is largely unknown and underreported. Equitable diagnostic and treatment options may vary by geographic location. Triangulating multi-modal data sources informed by a One Health approach provides robust proxies for human TBD risk. Using data from the Indiana Department of Natural Resources collected from hunters during the white-tailed deer (Odocoileus virginianus) hunting season and other sources, we employ a mixed-methods approach based on thematic mapping and mixed effects modelling to determine if deer population density aligns with official disease data at the county level from (1) positive canine serological reports for, anaplasmosis, and Lyme Disease (LD); (2) positive human cases of ehrlichiosis, anaplasmosis, LD, and Spotted Fever rickettsioses; and (3) tick infectivity. We propose the need for multimodal data analysis using a variety of potential proxies to better estimate disease risk and inform public health policy and practice. We find similar spatial distributions between deer population density and human and canine TBDs in northeastern and southern Indiana, which are rural and mixed geographic areas. Overall, LD is more prevalent in the northwest, central-western, and southeastern counties, while ehrlichiosis is more common in the southern counties. These findings hold true across humans, canines, and deer.

Differential effects of TRPM4 channel inhibitors on Guinea pig urinary bladder smooth muscle excitability and contractility: Novel 4-chloro-2-[2-(2-chloro-phenoxy)-acetylamino]-benzoic acid (CBA) versus classical 9-phenanthrol.

Non-selective cation channels in urinary bladder smooth muscle (UBSM) are thought to mediate increases in cellular excitability and contractility. For transient receptor potential melastatin type-4 (TRPM4) channels, the evidence primarily relies on the inhibitor 9-phenanthrol, which exhibits pharmacological limitations. Recently, 4-chloro-2-[2-(2-chloro-phenoxy)-acetylamino]-benzoic acid (CBA) has been discovered as a novel TRPM4 channel blocker. We examined how, in comparison to 9-phenanthrol, CBA affects the excitability of freshly isolated guinea pig UBSM cells and the contractility of UBSM strips. Additionally, non-selective TRPM4 channel inhibitor flufenamic acid (FFA) and potentiator BTP2 (also known as YM-58483) were studied in UBSM cells. Unlike robust inhibition for 9-phenanthrol already known, CBA (up to 100 µM) displayed either no or a very weak reduction (<20%) in spontaneous phasic, 20 mM KCl-induced, and electrical field stimulated contractions. For 300 µM CBA, reductions were higher except for an increase in the frequency of KCl-induced contractions. In UBSM cells, examined under amphotericin B-perforated patch-clamp, CBA (30 µM) did not affect the membrane potential (I = 0) or voltage step-induced whole-cell cation currents, sensitive to 9-phenanthrol. The currents were not inhibited by FFA (100 µM), increased by BTP2 (10 µM), nor enhanced under a strongly depolarizing holding voltage of -16 or + 6 mV (vs. -74 mV). None of the three compounds affected the cell capacitance, unlike 9-phenanthrol. In summary, the novel inhibitor CBA and nonselective FFA did not mimic the inhibitory properties of 9-phenanthrol on UBSM function. These results suggest that TRPM4 channels, although expressed in UBSM, play a distinct role rather than direct regulation of excitability and contractility.

Assessing Tick-Borne Disease Risk and Surveillance: Toward a Multi-Modal Approach to Diagnostic Positioning and Prediction.

The true extent of tick-borne disease (TBD) incidence and risk among humans is largely unknown, posing significant public health challenges. This study offers an exploratory analysis of a multimodal dataset and is part of a larger ongoing project to determine if entomological data, canine serological reports, self-reported human tick bite encounters (TBEs), and/or associated TBD diagnoses can serve as proxies for human disease risk. Focusing on the United States (U.S.), it characterizes self-reported TBD diagnoses (specifically, anaplasmosis, ehrlichiosis, and Lyme disease), co-infections, and their frequency and distribution across U.S. counties in relation to the presence of other factors related to TBD risk. Survey data was used to construct a list of TBEs localizable to individual U.S. counties. National data regarding these counties­namely the presence of official Lyme Disease (LD) case reports from the Centers for Disease Control and Prevention, as well as the tick vectors I. scapularis and I. pacificus within a given county­were then linked with survey-reported TBEs, tabulated by diagnosis (including co-infections), to determine the distribution of county-level endpoints across diagnostic categories. In addition, data on the presence of positive serological diagnostic tests conducted in canines were considered due to their potential utility as a proxy for TBD and TBE risk. The final dataset contained 249 TBEs localized to a total of 144 counties across 30 states. Diagnostic categories included respondents with LD (n = 70) and those with anaplasmosis and ehrlichiosis diagnoses and co-infections (n < 20 per diagnostic category). TBEs also were indicated by respondents who did not report TBD diagnoses, with some indicating uncertainty. The distribution of respondent-reported TBEs varied between canine TBDs, with LD-positive respondents reporting noticeably larger proportions of TBEs in counties with canine LD and smaller proportions in counties with canine anaplasmosis, compared to respondents without an LD diagnosis; a notional logistic regression suggests these differences may be significant (canine LD: Odds Ratio [OR] = 6.04, p = 0.026) (canine anaplasmosis: OR = 0.50, p = 0.095). These results suggest that certain widely available diagnostic TBD data in animals (in this case, domesticated dogs) may be sensitive to differences in human TBD risk factors and thus may have utility as proxies in future research. In the absence of an available standardized, unified, and national TBD database, such proxies, along with relevant surveys and reports, may provide a much-needed working solution for scientists and clinicians studying TBDs.