Oral trazodone results in quantifiable sedation but does not result in a xylazine-sparing effect in healthy adult horses.

OBJECTIVE: To evaluate sedation and IV xylazine requirements to achieve 45% of baseline head height above ground measurements following oral (PO) administration of 2 trazodone dosages. METHODS: 8 healthy, adult mares of various weights and breeds belonging to a university teaching herd were utilized in a blinded, crossover study design. Horses were randomly assigned to 1 of 3 PO treatments: control (no trazodone), trazodone at 3 mg/kg (low dose [LD]), or trazodone at 6 mg/kg (high dose [HD]). Before treatment, cardiac auscultation, EquiSed sedation score, and head height above ground (HHAG; cm) measurements were performed (baseline) followed by feeding of the treatment mixture. After 120 minutes, sedation score and HHAG were recorded. Xylazine was administered IV (0.25 mg/kg bolus followed by 0.1 mg/kg/min) until HHAG reached 45% of baseline or a total dose of 1 mg/kg was reached. Individual data for xylazine dosage, sedation scores, and HHAG were analyzed using mixed linear models with repeated measures. RESULTS: Sedation scores were significantly improved (LD, P = .045; HD, P = .01) and HHAG was lowered (LD, P = .045; HD, P = .09) by trazodone administration. Xylazine dose requirements were increased by LD trazodone administration (increase of 0.26 ± 0.26 mg/kg; P = .03) and unchanged by HD (increase of 0.13 ± 0.25 mg/kg; P = .38). CONCLUSIONS: Oral trazodone administration increases quantifiable sedation in horses. Xylazine requirements are significantly increased by LD trazodone administration. CLINICAL RELEVANCE: Oral administration of LD trazodone may increase xylazine requirements. Further clinical studies are required to fully assess the clinical relevance of this finding on other parameters such as cardiovascular physiology.

Discovery and Optimization of N-Heteroaryl Indazole LRRK2 Inhibitors.

Inhibition of leucine-rich repeat kinase 2 is a genetically supported mechanism for the treatment of Parkinson's disease. We previously disclosed the discovery of an indazole series lead that demonstrated both safety and translational risks. The safety risks were hypothesized to be of unknown origin, so structural diversity in subsequent chemical matter was prioritized. The translational risks were identified due to a low brain Kpu,u in nonhuman primate studies, which raised concern over the use of an established peripheral biomarker as a surrogate for central target engagement. Given these challenges, the team sought to leverage structure- and property-based drug design and expanded efflux transporter profiling to identify structurally distinct leads with enhanced CNS drug-likeness. Herein, we describe the discovery of a "reinvented" indazole series with improved physicochemical properties and efflux transporter profiles while maintaining excellent potency and off-target kinase selectivity, which resulted in advanced lead, compound 23.

Lassa fever research priorities: towards effective medical countermeasures by the end of the decade.

In 2016, WHO designated Lassa fever a priority disease for epidemic preparedness as part of the WHO Blueprint for Action to Prevent Epidemics. One aspect of preparedness is to promote development of effective medical countermeasures (ie, diagnostics, therapeutics, and vaccines) against Lassa fever. Diagnostic testing for Lassa fever has important limitations and key advancements are needed to ensure rapid and accurate diagnosis. Additionally, the only treatment available for Lassa fever is ribavirin, but controversy exists regarding its effectiveness. Finally, no licensed vaccines are available for the prevention and control of Lassa fever. Ongoing epidemiological and behavioural studies are also crucial in providing actionable information for medical countermeasure development, use, and effectiveness in preventing and treating Lassa fever. This Personal View provides current research priorities for development of Lassa fever medical countermeasures based on literature published primarily in the last 5 years and consensus opinion of 20 subject matter experts with broad experience in public health or the development of diagnostics, therapeutics, and vaccines for Lassa fever. These priorities provide an important framework to ensure that Lassa fever medical countermeasures are developed and readily available for use in endemic and at-risk areas by the end of the decade.

Physiologic and behavioral effects of long-acting subcutaneous and transdermal buprenorphine in rats.

OBJECTIVE: To investigate thermoregulation, thermal antinociception, food/kaolin intake, fecal output, and behavior following long-acting buprenorphine preparations in rats. ANIMALS: 8 adult male rats (Rattus norvegicus) were administered long-acting SC buprenorphine (SB; 0.65 mg/kg), transdermal buprenorphine (TB; 10 mg/kg), and controls in a randomized, cross-over design. METHODS: Body temperature, self-injury, sedation, food/kaolin intake, fecal output, and thermal withdrawal latencies were measured 1, 4, 8, 12, 24, 48, and 72 hours posttreatment. Data analysis was performed with mixed linear models. RESULTS: Self-injury was present between 1 and 12 hours and 4 and 12 hours following TB and SB, respectively; sedation was associated with TB at 12 to 24 hours. Withdrawal latencies were longer in both TB and SB groups than in the control group. Food intake decreased with time in all groups but was significantly lower 24 to 48 hours after TB and 24 to 72 hours after SB versus controls. Kaolin intake decreased from baseline 48 to 72 hours in the control group. Fecal output decreased from baseline 24 to 72 hours in all groups but was significantly lower than controls 24 hours following TB and 24 to 48 hours in SB. Body temperature increased from baseline at 1 hour, 1 to 12 hours, and 1 to 24 hours in the control, TB, and SB groups, respectively, and was significantly higher than the control group 1 to 72 hours following TB and 4 to 24 hours after SB. Transdermal buprenorphine and SB in normal rats produced antinociception, self-injurious behavior, hyperthermia, and decreased food/fecal output. CLINICAL RELEVANCE: Although these buprenorphine preparations may produce antinociception, untoward effects such as hyperthermia, self-injurious behavior, and reduced food intake/fecal output may be seen.

Substance use approaches among peer support specialists in community mental health early psychosis programs.

OBJECTIVE: Substance use (SU) is common among adolescents and young adults, including those experiencing early psychosis. Coordinated Specialty Care (CSC), a community-based multidisciplinary team-based service model, is increasingly used to support people experiencing first-episode psychosis. In addition to prescribers, clinicians, and vocational specialists, CSC includes peer support specialists who use their own living/lived experience with mental health and treatment to engage and support young people with their recovery goals. Peer support is also foundational in SU recovery. However, little is known about how peer support specialists navigate client SU in CSC. The purpose of this article is to detail CSC peer support SU practice. METHOD: Informed by community-based participatory research methods, a PhD-level qualitative researcher and a former peer support specialist conducted virtual interviews with 20 CSC peer support specialists. A multidisciplinary team including researchers with lived mental health experiences thematically coded interview transcripts. RESULTS: A spectrum of CSC peer support specialist SU responses emerged: (a) leverages lived SU experiences; (b) does not explore SU with clients; (c) shares client SU information with the CSC team; (d) educates, mentors, and advocates; (e) shares SU consequences and/or challenges substance use; (f) nonjudgmental, nondirective SU exploration; and (g) promotes harm reduction. CONCLUSIONS AND IMPLICATIONS FOR PRACTICE: CSC peer specialist SU practice is influenced by several contextual tensions that must be better understood and addressed in future research to improve peer SU practice. Study findings speak to practice nuances that are helpful for CSC peer support training and supervision. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Opportunities in Public Health Law: Supporting Current and Future Practitioners.

Law is a critical determinant of health that public health practitioners encounter in everyday practice. Yet most do not receive any formal public health law training. This article discusses tangible opportunities for strengthening the capacity of current and future practitioners to leverage law to advance health equity priorities.

A single center descriptive study of local anesthetic dose in knee arthroplasty: Was there evidence of local anesthetic systemic toxicity?

STUDY OBJECTIVE: Describe dosing of local anesthetic when both a periarticular injection (PAI) and peripheral nerve block (PNB) are utilized for knee arthroplasty analgesia, and compare the dosing of local to suggested maximum dosing, and look for evidence of local anesthetic systemic toxicity (LAST). DESIGN: A single center retrospective cohort study between May 2018 and November 2022. SETTING: A major academic hospital. PATIENTS: Patients who had both a PAI and PNB while undergoing primary, revision, total, partial, unilateral, or bilateral knee arthroplasty. INTERVENTIONS: None. MEASUREMENTS: Calculate the dose of local anesthetic given via PAI, PNB, and both routes combined as based on lean body weight and compare that to the suggested maximum dosing. Look for medications, clinical interventions, and critical event notes suggestive of a LAST event. MAIN RESULTS: There were 4527 knee arthroplasties where both a PAI and PNB were performed during the study period. When combining PAI and PNB doses, >75% of patients received more than the suggested maximum dose of 3 mg/kg lean body weight. The median local anesthetic dosing over the study period, 4.4 mg/kg (IQR 3.5,5.9), was 147% of the suggested maximum dose (IQR 117,197). There was no conclusive evidence of LAST among any of the patients in the study. CONCLUSIONS: Over the course of our study, we had 4527 knee arthroplasties with a median PAI and PNB local anesthetic dose that was 147% of the suggested maximum without any clear clinical evidence of a LAST event.

Effects of Exercise-Induced Laryngeal Obstruction in Adolescents: A Qualitative Study.

PURPOSE: The purpose of this study was to examine the influence of exercise-induced laryngeal obstruction (EILO) on adolescents. METHOD: Twenty patients (< 17 years) diagnosed with EILO participated in this study. Patients completed semistructured interviews examining their experience with the health care system, treatment, and the effects of EILO symptoms on quality of life. Interviews were analyzed using a combination of directed and conventional content analyses. Researchers identified seven overarching themes either prior to or during analysis, and 24 subthemes were inductively identified from patient interviews using open, axial, and selective coding. RESULTS: On average, patients went 1.9 years between symptom onset and EILO diagnosis. Patients described symptom onset as frightening and confusing. Even after initially reporting symptoms to a medical provider, patients went an average of 10.5 months before diagnosis. Patients perceived that delays in diagnosis prevented efficient management and allowed symptoms to escalate. Patients reported that EILO detrimentally influenced athletic performance, forcing them to pace themselves or cease participation altogether. Social and academic effects of EILO included missed classes, difficulty in physical education courses, and resentment from teammates if athletic performance declined. Both athletes and nonathletes indicated that EILO elicited feelings of fear, frustration, dread, guilt, and embarrassment. Patients reported that therapy with a speech-language pathologist (SLP) effectively addressed symptoms; however, employing rescue breathing techniques was often more difficult than anticipated. CONCLUSIONS: Physical and emotional sequelae associated with EILO may have widespread influence on patient quality of life. Therapy with an SLP reportedly ameliorated EILO symptoms; however, patients indicated that delayed diagnosis allowed negative effects to intensify prior to treatment.

Establishment of a novel cellular model for Alzheimer's disease in vitro studies.

Alzheimer's disease (AD) is a neurodegenerative disease characterized by memory loss, cognitive impairment, and behavioral and psychological symptoms of dementia. The limited efficacy of drugs for the treatment of neurodegenerative diseases reflects their complex etiology and pathogenesis. A novel in vitro model may help to bridge the gap between existing preclinical animal models and human clinical trials, thus identifying promising therapeutic targets that can be explored in upcoming clinical trials. By assisting in the identification of the mechanism of action and potential dangers, in vitro testing can also shorten the time and expense of translation. AIM: As a result of these factors, our objective is to develop a powerful and informative cellular model of AD within a short period of time. Through triggering the MAPK and NF-κß signaling pathways with the aid of small chemical compounds (PAF C-16 and BetA), respectively, in mouse microglial (SIM-A9) and neuroblast Neuro-2a (N2a) cell lines. RESULTS: PAF C-16, initiated an activation effect at a concentration of 3.12 nM to 25 nM in the SIM-A9 and N2a cell lines after 72 h. BetA, activated the NF-κß pathway with a concentration of 12.5 nM to 25 nM in the SIM-A9 and N2a cell lines after 72 h. The combination of the activator chemicals provided suitable activation for MEK1/2-ERK and NF-κß in more than three subcultures. Activators significantly initiate APP and MAPT gene expression, as well as the expression of proteins APP, ß. Amyloid, tau, and p-tau. The activation of the targeted pathways leads to significant morphological changes. CONCLUSION: We can infer that the MEK1/2-ERK and NF-κß pathways, respectively, are directly activated by the PAF C-16 and BetA chemicals. The activation of MEK1/2-ERK pathway results in the activation of the APP gene, which in turn activates the ß. Amyloid protein, which in turn results in plaque. Furthermore, NF-κß activation results in the activation of the MAPT gene, which leads to Tau and p-Tau protein activation, which ultimately results in tangles. This can be put into practice in just three days, with a high level of activity and stability that is passed down to the next three generations (subculture), with significant morphological changes. In microglial and neuroblast cell lines, we were successful in creating a novel AD-cell model.

The Effect of Socioeconomic Status and Race/Ethnicity on the Risk of Presenting With Advanced Stage at Diagnosis in Embryonal Tumors.

We evaluated whether socioeconomic status (SES), race/ethnicity, and their interaction were associated with the presentation of advanced stage at diagnosis in embryonal tumors. Children 0 to 19 years of age diagnosed with embryonal tumors between 2006 and 2018 were identified from the US Surveillance, Epidemiology, and End Results program database specialized with Census Tract SES/Rurality. SES quintile was derived from a composite index for census tracts. We performed logistic regression to estimate odds ratios (ORs) and 95% confidence intervals by SES and race/ethnicity, adjusting for sex, age, and diagnosis year. Overall, no significant associations were found between either SES or race/ethnicity and the risk of presenting with advanced stage at diagnosis, although patterns of risk reductions were observed in atypical teratoid/rhabdoid tumors and embryonal rhabdomyosarcoma with increasing SES. In the stratified analysis, decreased odds of presenting with advanced-stage embryonal rhabdomyosarcoma were observed for Hispanics with higher SES (OR: 0.24, 95% Confidence Interval: 0.08-0.75) compared with Hispanics with lower SES. Future studies incorporating individual-level SES, cancer-specific staging information, and potential demographic, clinical, epidemiological, and genetic risk factors are warranted to confirm our findings.

A randomized controlled trial evaluating the effects of nurse-led triage of 911 calls.

To better connect non-emergent 911 callers to appropriate care, Washington, DC, routed low-acuity callers to nurses. Nurses could provide non-emergent transportation to a health centre, recommend self-care or return callers to the traditional 911 system. Over about one year, 6,053 callers were randomized (1:1) to receive a business-as-usual response (ncontrol = 3,023) or further triage (ntreatment = 3,030). We report on seven of nine outcomes, which were pre-registered ( https://osf.io/xderw ). The proportion of calls resulting in an ambulance dispatch dropped from 97% to 56% (ß = -1.216 (-1.324, -1.108), P < 0.001), and those resulting in an ambulance transport dropped from 73% to 45% (ß = -3.376 (-3.615, -3.137), P < 0.001). Among those callers who were Medicaid beneficiaries, within 24 hours, the proportion of calls resulting in an emergency department visit for issues classified as non-emergent or primary care physician (PCP) treatable dropped from 29.5% to 25.1% (ß = -0.230 (-0.391, -0.069), P < 0.001), and the proportion resulting in the caller visiting a PCP rose from 2.5% to 8.2% (ß = 1.252 (0.889, 1.615), P < 0.001). Over the longer time span of six months, we failed to detect evidence of impacts on emergency department visits, PCP visits or Medicaid expenditures. From a safety perspective, 13 callers randomized to treatment were eventually diagnosed with a time-sensitive illness, all of whom were quickly triaged to an ambulance response. These short-term effects suggest that nurse-led triage of non-emergent calls can safely connect callers to more appropriate, timely care.

Young people in iNaturalist: a blended learning framework for biodiversity monitoring.

Participation in authentic research in the field and online through Community and Citizen Science (CCS) has shown to bring learning benefits to volunteers. In online CCS, available platforms present distinct features, ranging from scaffolding the process of data collection, to supporting data analysis and enabling volunteers to initiate their own studies. What is yet not well understood is how best to design CCS programmes that are educational, inclusive, and accessible by diverse volunteers, including young people and those with limited prior science experiences who are rather few in CCS. In this study, we interviewed 31 young people, aged 7-20 years old, who used iNaturalist, an online biodiversity monitoring platform, and identified how different forms of participation online and in the field facilitated (or inhibited) certain forms of learning, as defined by the Environmental Science Agency framework. Findings revealed that iNaturalist enabled participation of young people including those with limited science experiences and facilitated science learning such as the development of science competence and understanding. A blended learning framework for biodiversity monitoring in CCS is presented as a means to support the development of hybrid, educational, and inclusive CCS programmes for young people.

The complexity of treatment-resistant depression: A data-driven approach.

BACKGROUND: Recent systematic reviews highlight great variability in defining and assessing treatment-resistant depression (TRD). A key problem is that definitions are consensus rather than data-led. This study seeks to offer a comprehensive socio-demographic and clinical description of a relevant sample. METHODS: As part of a pragmatic randomized controlled trial, patients (N = 129) were managed in primary care for persistent depression and diagnosed with TRD. Data included previous treatment attempts, characteristics of the depressive illness, functioning, quality of life, co-occurring problems including suicidality, psychiatric and personality disorders, physical health conditions, and adverse events. RESULTS: Findings show a severe and chronic course of depression with a duration of illness of 25+ years. Overall, 82.9 % had at least one other psychiatric diagnosis and 82.2 % at least one personality disorder; 69.8 % had significant musculoskeletal, gastrointestinal, genitourinary, or cardiovascular and respiratory physical health problems. All but 14 had severe difficulties in social and occupational functioning and reported severely impaired quality of life. Suicidal ideation was high: 44.9 % had made at least one serious suicide attempt and several reported multiple attempts with 17.8 % reporting a suicide attempt during childhood or adolescence. Of the patients, 79.8 % reported at least one adverse childhood experience. LIMITATIONS: Potential for recall bias, not examining possible interactions, and absence of a control group. CONCLUSIONS: Our findings reveal a complex and multifaceted condition and call for an urgent reconceptualization of TRD, which encompasses many interdependent variables and experiences. Individuals with TRD may be at a serious disadvantage in terms of receiving adequate treatment.

Re-evaluation of the methodology for estimating the US specialty physician workforce.

Increasing pursuit of subspecialized training has quietly revolutionized physician training, but the potential impact on physician workforce estimates has not previously been recognized. The Physicians Specialty Data Reports of the Association of American Medical Colleges, derived from specialty designations in the American Medical Association (AMA) Physician Professional Data (PPD), are the reference source for US physician workforce estimates; by 2020, the report for pathologists was an undercount of 39% when compared with the PPD. Most of the difference was due to the omission of pathology subspecialty designations. The rest resulted from reliance on only the first of the AMA PPD's 2 specialty data fields. Placement of specialty designation in these 2 fields is sensitive to sequence of training and is thus affected by multiple or intercalated (between years of residency training) fellowships. Both these phenomena have become progressively more common and are not unique to pathology. Our findings demonstrate the need to update definitions and methodology underlying estimates of the US physician workforce for pathology and suggest a like need in other specialties affected by similar trends.

Investigating the dose-dependency of the midgut escape barrier using a mechanistic model of within-mosquito dengue virus population dynamics.

Arboviruses can emerge rapidly and cause explosive epidemics of severe disease. Some of the most epidemiologically important arboviruses, including dengue virus (DENV), Zika virus (ZIKV), Chikungunya (CHIKV) and yellow fever virus (YFV), are transmitted by Aedes mosquitoes, most notably Aedes aegypti and Aedes albopictus. After a mosquito blood feeds on an infected host, virus enters the midgut and infects the midgut epithelium. The virus must then overcome a series of barriers before reaching the mosquito saliva and being transmitted to a new host. The virus must escape from the midgut (known as the midgut escape barrier; MEB), which is thought to be mediated by transient changes in the permeability of the midgut-surrounding basal lamina layer (BL) following blood feeding. Here, we present a mathematical model of the within-mosquito population dynamics of DENV (as a model system for mosquito-borne viruses more generally) that includes the interaction of the midgut and BL which can account for the MEB. Our results indicate a dose-dependency of midgut establishment of infection as well as rate of escape from the midgut: collectively, these suggest that the extrinsic incubation period (EIP)-the time taken for DENV virus to be transmissible after infection-is shortened when mosquitoes imbibe more virus. Additionally, our experimental data indicate that multiple blood feeding events, which more closely mimic mosquito-feeding behavior in the wild, can hasten the course of infections, and our model predicts that this effect is sensitive to the amount of virus imbibed. Our model indicates that mutations to the virus which impact its replication rate in the midgut could lead to even shorter EIPs when double-feeding occurs. Mechanistic models of within-vector viral infection dynamics provide a quantitative understanding of infection dynamics and could be used to evaluate novel interventions that target the mosquito stages of the infection.

Mosquito immune cells enhance dengue and Zika virus dissemination in Aedes aegypti.

Mosquito-borne viruses cause more than 400 million annual infections and place over half of the world's population at risk. Despite this importance, the mechanisms by which arboviruses infect the mosquito host and disseminate to tissues required for transmission are not well understood. Here, we provide evidence that mosquito immune cells, known as hemocytes, play an integral role in the dissemination of dengue virus (DENV) and Zika virus (ZIKV) in the mosquito Aedes aegypti. We establish that phagocytic hemocytes are a focal point for virus infection and demonstrate that these immune cell populations facilitate virus dissemination to the ovaries and salivary glands. Additional transfer experiments confirm that virus-infected hemocytes confer a virus infection to non-infected mosquitoes more efficiently than free virus in acellular hemolymph, revealing that hemocytes are an important tropism to enhance virus dissemination in the mosquito host. These data support a "trojan horse" model of virus dissemination where infected hemocytes transport virus through the hemolymph to deliver virus to mosquito tissues required for transmission and parallels vertebrate systems where immune cell populations promote virus dissemination to secondary sites of infection. In summary, this study significantly advances our understanding of virus infection dynamics in mosquitoes and highlights conserved roles of immune cells in virus dissemination across vertebrate and invertebrate systems.

Processing difficulty while reading words with neighbors is not due to increased foveal load: Evidence from eye movements.

Words with high orthographic relatedness are termed "word neighbors" (angle/angel; birch/birth). Activation-based models of word recognition assume that lateral inhibition occurs between words and their activated neighbors. However, studies of eye movements during reading have not found inhibitory effects in early measures assumed to reflect lexical access (e.g., gaze duration). Instead, inhibition in eye-movement studies has been found in later measures of processing (e.g., total time, regressions in). We conducted an eye-movement boundary change study (Rayner, Cognitive Psychology, 7(1), 65-81, 1975) that manipulated the parafoveal preview of the word following the neighbor word (word N+1). In this way, we explored whether the late inhibitory effects seen with transposed letter words and words with higher-frequency neighbors result from reduced parafoveal preview due to increased foveal load and/or interference during late stages of lexical processing (the L2 stage within the E-Z Reader framework). For word N+1, while there were clear preview effects, there was not an effect of the neighborhood status of word N, nor a significant interaction. This suggests that the late inhibitory effects of earlier eye-movement studies are driven by misidentification of neighbor words rather than being due to increased foveal load.

Rapid, high-capacity adsorption of iodine from aqueous environments with amide functionalized covalent organic frameworks.

The uses and production of radionuclides in nuclear energy production and medical therapy are becoming more significant in today's world. While these applications have many benefits, they can produce harmful pollutants, such as radioactive iodine, that need to be sequestered. Effective capture and storage of radioactive iodine waste remains a major challenge for nuclear energy generation and nuclear medicine. Here we report the highly efficient capture of iodine in a series of mesoporous, two-dimensional (2D) covalent organic frameworks, called COFamides, which contain amide sidechains in their pores. COFamides are capable of rapidly removing iodine from aqueous solution at concentrations as low as 50 ppm, with total capacities greater than 650 wt%. In order to explain the high affinity of the COFamide series for iodine and iodide species in water, we performed a computational analysis of the interactions between the COFamide framework and iodine guests. These studies suggest that the origin of the large iodine capacity in these materials can be explained by the presence of multiple, cooperative, non-covalent interactions between the framework and both iodine, and iodide species.