Chromatic periodic activity down to 120 megahertz in a fast radio burst.

Fast radio bursts (FRBs) are extragalactic astrophysical transients1 whose brightness requires emitters that are highly energetic yet compact enough to produce the short, millisecond-duration bursts. FRBs have thus far been detected at frequencies from 8 gigahertz (ref. 2) down to 300 megahertz (ref. 3), but lower-frequency emission has remained elusive. Some FRBs repeat4-6, and one of the most frequently detected, FRB 20180916B7, has a periodicity cycle of 16.35 days (ref. 8). Using simultaneous radio data spanning a wide range of wavelengths (a factor of more than 10), here we show that FRB 20180916B emits down to 120 megahertz, and that its activity window is frequency dependent (that is, chromatic). The window is both narrower and earlier at higher frequencies. Binary wind interaction models predict a wider window at higher frequencies, the opposite of our observations. Our full-cycle coverage shows that the 16.3-day periodicity is not aliased. We establish that low-frequency FRB emission can escape the local medium. For bursts of the same fluence, FRB 20180916B is more active below 200 megahertz than at 1.4 gigahertz. Combining our results with previous upper limits on the all-sky FRB rate at 150 megahertz, we find there are 3-450 FRBs in the sky per day above 50 Jy ms. Our chromatic results strongly disfavour scenarios in which absorption from strong stellar winds causes FRB periodicity. We demonstrate that some FRBs are found in 'clean' environments that do not absorb or scatter low-frequency radiation.

Polypharmacy, over-the-counter medications, and aromatase inhibitor adherence in early-stage breast cancer.

PURPOSE: Polypharmacy is associated with negative health outcomes and decreased medication adherence. Polypharmacy is common in cancer populations, but few studies have evaluated the relationship between polypharmacy and aromatase inhibitor (AI) adherence. No studies have evaluated the relationship between over-the-counter (OTC) supplements and AI adherence. Our primary hypothesis was that polypharmacy would be associated with increased risk of premature AI discontinuation. METHODS: This exploratory analysis used data from the Exemestane and Letrozole Pharmacogenetics (ELPh) trial, a prospective, multicenter, randomized controlled trial that enrolled participants from 2005 to 2009. Included patients were female, postmenopausal, with stage 0-III breast cancer, who had completed indicated chemotherapy, surgery, and radiation. Participants were randomized to adjuvant exemestane or letrozole and completed serial clinical examinations and questionnaires for two years. Concomitant medication data were collected prospectively. Cox proportion models were used for statistical analysis of the relationship between polypharmacy, OTCs, medication class, and AI adherence. RESULTS: In the 490 analyzed participants, use of any prescription medications at baseline was associated with decreased risk of premature AI discontinuation (HR 0.56, p = 0.02). Use of selective serotonin reuptake inhibitors (SSRIs) or selective serotonin and norepinephrine reuptake inhibitors (SNRIs) at baseline was associated with decreased risk of premature AI discontinuation (HR 0.67, p = 0.04). Use of any OTCs was not associated with AI discontinuation. CONCLUSION: Baseline use of prescription medications but not OTCs was associated with increased AI persistence. Future research is needed to understand how this can be utilized to promote AI adherence.

Medial prefrontal cortex neurotransmitter abnormalities in posttraumatic stress disorder with and without comorbidity to major depression.

Posttraumatic stress disorder (PTSD) is a chronic psychiatric condition that follows exposure to a traumatic stressor. Though previous in vivo proton (1H) MRS) research conducted at 4 T or lower has identified alterations in glutamate metabolism associated with PTSD predisposition and/or progression, no prior investigations have been conducted at higher field strength. In addition, earlier studies have not extensively addressed the impact of psychiatric comorbidities such as major depressive disorder (MDD) on PTSD-associated 1H-MRS-visible brain metabolite abnormalities. Here we employ 7 T 1H MRS to examine concentrations of glutamate, glutamine, GABA, and glutathione in the medial prefrontal cortex (mPFC) of PTSD patients with MDD (PTSD+MDD+; N = 6) or without MDD (PTSD+MDD-; N = 5), as well as trauma-unmatched controls without PTSD but with MDD (PTSD-MDD+; N = 9) or without MDD (PTSD-MDD-; N = 18). Participants with PTSD demonstrated decreased ratios of GABA to glutamine relative to healthy PTSD-MDD- controls but no single-metabolite abnormalities. When comorbid MDD was considered, however, MDD but not PTSD diagnosis was significantly associated with increased mPFC glutamine concentration and decreased glutamate:glutamine ratio. In addition, all participants with PTSD and/or MDD collectively demonstrated decreased glutathione relative to healthy PTSD-MDD- controls. Despite limited findings in single metabolites, patterns of abnormality in prefrontal metabolite concentrations among individuals with PTSD and/or MDD enabled supervised classification to separate them from healthy controls with 80+% sensitivity and specificity, with glutathione, glutamine, and myoinositol consistently among the most informative metabolites for this classification. Our findings indicate that MDD can be an important factor in mPFC glutamate metabolism abnormalities observed using 1H MRS in cohorts with PTSD.

Trauma-Informed Healthcare Leadership? Evidence and opportunities from interviews with leaders during COVID-19.

BACKGROUND: COVID-19 impacted the mental health of healthcare workers, who endured pressures as they provided care during a prolonged crisis. We aimed to explore whether and how a Trauma-Informed Care (TIC) approach was reflected in qualitative perspectives from healthcare leaders of their experience during COVID-19 (2020-2021). METHODS: Semi-structured interviews with healthcare leaders from four institutions were conducted. Data analysis consisted of four stages informed by interpretative phenomenological analysis: 1) deductive coding using TIC assumptions, 2) inductive thematic analysis of coded excerpts, 3) keyword-in-context coding of full transcripts for 6 TIC principles with integration into prior inductive themes, and 4) interpretation of themes through 6 TIC principles (safety; trustworthiness and transparency; peer support; collaboration and mutuality; empowerment, voice, and choice; and awareness of cultural, historical, and gender issues). RESULTS: The actions of leaders (n = 28) that were reported as successful and supportive responses to the COVID-19 pandemic or else missed opportunities reflected core principles of Trauma-Informed Care. To promote safety, leaders reported affirmative efforts to protect staff by providing appropriate physical protection, and enhanced psychological safety by providing channels for communication about emotional well-being. To promote trustworthiness and transparency, leaders listened to their staff, shared current COVID-19 information, and increased frequency of meetings to disseminate accurate information. To promote mutual support, strategies included wellness check-ins, sharing uplifting stories, affirming common goals, articulating fears, and leading by example. Examples of empowerment included: making time and adjusting modalities for flexible communication; naming challenges outside of the hospital; and functioning as a channel for complaints. Reported missed opportunities included needing more dedicated time and space for healthcare employees to process emotions, failures in leadership managing their own anxiety, and needing better support for middle managers. Awareness of the TIC principle of cultural, historical, and gender issues was largely absent. Results informed the nascent Trauma-Informed Healthcare Leadership (TIHL) framework. CONCLUSIONS: We propose the Trauma-Informed Healthcare Leadership framework as a useful schema for action and analysis. This approach yields recommendations for healthcare leaders including creating designated spaces for emotional processing, and establishing consistent check-ins that reference personal and professional well-being.

Subtypes of Alcohol Expectancies Are Differentially Associated With Alcohol Use for Bisexual and Heterosexual Women.

Background: Bisexual women, compared to heterosexual women, report greater amounts of alcohol use and heavy drinking. Alcohol expectancies (i.e., beliefs about alcohol outcomes) are a strong predictor of alcohol use, but few studies have examined the importance of alcohol expectancies in relation to alcohol use among bisexual women specifically or in comparison to heterosexual women. Objectives: The current study examined 262 heterosexual and 225 bisexual women using an online survey about alcohol use, sexual risk-taking, and alcohol expectancy subtypes (sexuality, tension reduction, and aggression). Results: Compared to heterosexual women, bisexual women reported greater sexuality and tension reduction expectancies after accounting for their level of drinking, but groups did not differ on aggression expectancies. Moreover, sexual identity status moderated the associations between sexuality and tension reduction expectancies and alcohol use, respectively. Specifically, our study findings suggested that sexuality and tension reduction alcohol expectancies were more strongly tied to alcohol use among bisexual women than heterosexual women. Conclusions: Taken together, in our study, bisexual women held stronger sexuality and tension reduction expectancies, as compared to heterosexual women. Interventions targeting alcohol expectancies may be considered when tailoring intervention content for this population.

Asian Cohort for Alzheimer's Disease (ACAD) pilot study on genetic and non-genetic risk factors for Alzheimer's disease among Asian Americans and Canadians.

INTRODUCTION: Clinical research in Alzheimer's disease (AD) lacks cohort diversity despite being a global health crisis. The Asian Cohort for Alzheimer's Disease (ACAD) was formed to address underrepresentation of Asians in research, and limited understanding of how genetics and non-genetic/lifestyle factors impact this multi-ethnic population. METHODS: The ACAD started fully recruiting in October 2021 with one central coordination site, eight recruitment sites, and two analysis sites. We developed a comprehensive study protocol for outreach and recruitment, an extensive data collection packet, and a centralized data management system, in English, Chinese, Korean, and Vietnamese. RESULTS: ACAD has recruited 606 participants with an additional 900 expressing interest in enrollment since program inception. DISCUSSION: ACAD's traction indicates the feasibility of recruiting Asians for clinical research to enhance understanding of AD risk factors. ACAD will recruit > 5000 participants to identify genetic and non-genetic/lifestyle AD risk factors, establish blood biomarker levels for AD diagnosis, and facilitate clinical trial readiness. HIGHLIGHTS: The Asian Cohort for Alzheimer's Disease (ACAD) promotes awareness of under-investment in clinical research for Asians. We are recruiting Asian Americans and Canadians for novel insights into Alzheimer's disease. We describe culturally appropriate recruitment strategies and data collection protocol. ACAD addresses challenges of recruitment from heterogeneous Asian subcommunities. We aim to implement a successful recruitment program that enrolls across three Asian subcommunities.

Preoperative management and postoperative complications in 9 dogs undergoing surgical treatment of thymic-associated myasthenia gravis.

Objective: Thymoma-associated paraneoplastic syndromes in dogs and cats include myasthenia gravis, hypercalcemia, exfoliative dermatitis, erythema multiforme, T-cell lymphocytosis, myocarditis, anemia, and polymyositis. Paraneoplastic myasthenia gravis (MG) is the most commonly reported paraneoplastic syndrome in dogs with thymic epithelial tumors. The objective of this study was to examine cases of canine thymic-associated MG treated surgically, with the specific objective of providing an updated clinical picture of the preoperative management, postoperative complications, and outcomes of these cases. Animals: Nine dogs with paraneoplastic MG underwent surgical removal of a thymic epithelial tumor. Procedure: Medical records of dogs with MG that received surgical treatment of a thymic epithelial tumor between January 1, 2012 and October 1, 2022 were obtained from 4 veterinary teaching hospitals. Descriptions of perioperative MG management, complications, and outcomes were reported. Results: Six of the 9 dogs received medical therapy for MG, with either a cholinesterase inhibitor (4 dogs) or a cholinesterase inhibitor and immunosuppressive agent (2 dogs), before surgery. The median duration of medical therapy for MG before surgery was 7.5 d (range: 2 to 60 d). Three of 9 dogs experienced immediate postoperative complications and were euthanized. Six of 9 dogs (66.6%) survived to discharge and 3 of 6 dogs that survived to discharge were alive at the time of writing. At the time of writing, 3 of 6 dogs had complete resolution of clinical signs attributable to MG and 2 of 6 had partial resolution. The median time from surgery to resolution of clinical signs of MG in these dogs was 63 d (range: 2 to 515 d). Conclusion: Dogs with thymic epithelial tumors and paraneoplastic MG are at a high risk for perioperative complications. Clinical relevance: The findings of this study corroborate previous literature stating that paraneoplastic MG is a poor prognostic indicator for dogs with thymic epithelial tumors, while also highlighting the variation in approaches to clinical management of thymic-associated MG in veterinary medicine and the lack of established protocols guiding perioperative management.

Prise en charge préopératoire et complications postopératoires chez 9 chiens subissant un traitement chirurgical de la myasthénie grave associée au thymus. Objectif: Les syndromes paranéoplasiques associés au thymome chez le chien et le chat comprennent la myasthénie grave, l'hypercalcémie, la dermatite exfoliative, l'érythème polymorphe, la lymphocytose à cellules T, la myocardite, l'anémie et la polymyosite. La myasthénie paranéoplasique (MG) est le syndrome paranéoplasique le plus fréquemment rapporté chez les chiens atteints de tumeurs épithéliales thymiques. L'objectif de cette étude était d'examiner les cas de MG canine associée au thymus traités chirurgicalement, dans le but spécifique de fournir un tableau clinique actualisé de la prise en charge préopératoire, des complications postopératoires et des résultats de ces cas. Animaux: Neuf chiens atteints de MG paranéoplasique ont subi l'ablation chirurgicale d'une tumeur épithéliale thymique. Procédure: Les dossiers médicaux des chiens atteints de MG ayant reçu un traitement chirurgical d'une tumeur épithéliale thymique entre le 1er janvier 2012 et le 1er octobre 2022 ont été obtenues auprès de 4 hôpitaux universitaires vétérinaires. Des descriptions de la prise en charge péri-opératoire de la MG, des complications et des résultats ont été rapportées. Résultats: Six des 9 chiens ont reçu un traitement médical pour la MG, avec soit un inhibiteur de la cholinestérase (4 chiens), soit un inhibiteur de la cholinestérase et un agent immunosuppresseur (2 chiens), avant la chirurgie. La durée médiane du traitement médical de la MG avant la chirurgie était de 7,5 jours (plage : 2 à 60 jours). Trois des neuf chiens ont présenté des complications postopératoires immédiates et ont été euthanasiés. Six des 9 chiens (66,6 %) ont survécu jusqu'à leur sortie et 3 des 6 chiens qui ont survécu jusqu'à leur sortie étaient en vie au moment de la rédaction. Au moment de la rédaction de cet article, 3 chiens sur 6 présentaient une résolution complète des signes cliniques attribuables à la MG et 2 chiens sur 6 présentaient une résolution partielle. Le délai médian entre l'intervention chirurgicale et la résolution des signes cliniques de MG chez ces chiens était de 63 jours (plage : 2 à 515 jours). Conclusion: Les chiens atteints de tumeurs épithéliales thymiques et de MG paranéoplasique présentent un risque élevé de complications périopératoires. Pertinence clinique: Les résultats de cette étude corroborent la littérature antérieure indiquant que la MG paranéoplasique est un indicateur de mauvais pronostic pour les chiens atteints de tumeurs épithéliales thymiques, tout en soulignant également la variation des approches de prise en charge clinique de la MG associée au thymus en médecine vétérinaire et le manque de protocoles établis de gestion guidant les interventions périopératoires.(Traduit par Dr Serge Messier).

Joint modeling and multiple comparisons with the best of data from a SMART with survival outcomes.

A dynamic treatment regimen (DTR) is a sequence of decision rules that can alter treatments or doses based on outcomes from prior treatment. In the case of two lines of treatment, a DTR specifies first-line treatment, and second-line treatment for responders and treatment for non-responders to the first-line treatment. A sequential, multiple assignment, randomized trial (SMART) is one such type of trial that has been designed to assess DTRs. The primary goal of our project is to identify the treatments, covariates, and their interactions result in the best overall survival rate. Many previously proposed methods to analyze data with survival outcomes from a SMART use inverse probability weighting and provide non-parametric estimation of survival rates, but no other information. Other methods have been proposed to identify and estimate the optimal DTR, but inference issues were seldom addressed. We apply a joint modeling approach to provide unbiased survival estimates as a mechanism to quantify baseline and time-varying covariate effects, treatment effects, and their interactions within regimens. The issue of multiple comparisons at specific time points is addressed using multiple comparisons with the best method.

Association between nociplastic pain and premature endocrine therapy discontinuation in breast cancer patients.

PURPOSE: At least 5 years of adjuvant endocrine therapy (ET) is recommended for patients with hormone receptor-positive invasive breast cancer to reduce cancer recurrence risk. Up to half of patients prematurely discontinue ET, often due to musculoskeletal pain. Nociplastic pain is abnormal central nervous system pain processing without evidence of tissue or neuronal damage. This study aimed to evaluate the relationship between baseline nociplastic pain and ET discontinuation. METHODS: This was a retrospective, single center, cohort study. Included patients were female, had stage 0-III invasive breast cancer, did not receive neoadjuvant therapy, and completed quality of life questionnaires prior to breast surgery, including Fibromyalgia Survey for nociplastic pain. Clinical data including duration of ET were abstracted from the medical record. Patient characteristics were analyzed with t-tests and Chi-squared tests, as appropriate. Univariate and multivariable regressions were performed with Cox proportional hazard models. RESULTS: Six hundred eighty-one patients diagnosed between 2012 and 2019 met inclusion criteria; 480 initiated ET and were included in the analysis. Of these 480 patients, 203 (42.3%) prematurely discontinued initial ET therapy. On univariate analysis, tamoxifen use (hazard ratio [HR] 0.70, p = 0.021) and premenopausal status (HR 0.73, p = 0.04) were inversely associated with ET discontinuation, while Fibromyalgia Score was positively associated (HR 1.04, p = 0.043). On multivariable analysis, baseline Fibromyalgia Score remained associated with ET discontinuation. CONCLUSION: Nociplastic pain present prior to surgery was associated with premature ET discontinuation. Fibromyalgia Score screening may be useful for evaluating ET discontinuation risk. Treatments targeting nociplastic pain may be more effective for treating ET-emergent pain.

Dynamic enrichment of Bayesian small-sample, sequential, multiple assignment randomized trial design using natural history data: a case study from Duchenne muscular dystrophy.

In Duchenne muscular dystrophy (DMD) and other rare diseases, recruiting patients into clinical trials is challenging. Additionally, assigning patients to long-term, multi-year placebo arms raises ethical and trial retention concerns. This poses a significant challenge to the traditional sequential drug development paradigm. In this paper, we propose a small-sample, sequential, multiple assignment, randomized trial (snSMART) design that combines dose selection and confirmatory assessment into a single trial. This multi-stage design evaluates the effects of multiple doses of a promising drug and re-randomizes patients to appropriate dose levels based on their Stage 1 dose and response. Our proposed approach increases the efficiency of treatment effect estimates by (i) enriching the placebo arm with external control data, and (ii) using data from all stages. Data from external control and different stages are combined using a robust meta-analytic combined (MAC) approach to consider the various sources of heterogeneity and potential selection bias. We reanalyze data from a DMD trial using the proposed method and external control data from the Duchenne Natural History Study (DNHS). Our method's estimators show improved efficiency compared to the original trial. Also, the robust MAC-snSMART method most often provides more accurate estimators than the traditional analytic method. Overall, the proposed methodology provides a promising candidate for efficient drug development in DMD and other rare diseases.

An Interventional Response Phenotyping Study in Chronic Low Back Pain: Protocol for a Mechanistic Randomized Controlled Trial.

Evidence-based treatments for chronic low back pain (cLBP) typically work well in only a fraction of patients, and at present there is little guidance regarding what treatment should be used in which patients. Our central hypothesis is that an interventional response phenotyping study can identify individuals with different underlying mechanisms for their pain who thus respond differentially to evidence-based treatments for cLBP. Thus, we will conduct a randomized controlled Sequential, Multiple Assessment, Randomized Trial (SMART) design study in cLBP with the following three aims. Aim 1: Perform an interventional response phenotyping study in a cohort of cLBP patients (n = 400), who will receive a sequence of interventions known to be effective in cLBP. For 4 weeks, all cLBP participants will receive a web-based pain self-management program as part of a run-in period, then individuals who report no or minimal improvement will be randomized to: a) mindfulness-based stress reduction, b) physical therapy and exercise, c) acupressure self-management, and d) duloxetine. After 8 weeks, individuals who remain symptomatic will be re-randomized to a different treatment for an additional 8 weeks. Using those data, we will identify the subsets of participants that respond to each treatment. In Aim 2, we will show that currently available, clinically derived measures, can predict differential responsiveness to the treatments. In Aim 3, a subset of participants will receive deeper phenotyping (n = 160), to identify new experimental measures that predict differential responsiveness to the treatments, as well as to infer mechanisms of action. Deep phenotyping will include functional neuroimaging, quantitative sensory testing, measures of inflammation, and measures of autonomic tone.

Early Antibiotic Exposure in Low-Risk Late Preterm and Term Infants.

OBJECTIVE: This study aimed to examine the epidemiology of antibiotic exposure and early onset sepsis (EOS) in late preterm and term infants born via cesarean section with rupture of membranes less than 10 minutes. STUDY DESIGN: Retrospective review of 1,187 late preterm and term infants born at Brooke Army Medical Center between January 1, 2012 and August 29, 2019. Subjects were assessed for factors related to antibiotic treatment. Statistical analysis was performed to compare infants treated with antibiotics versus observation. RESULT: An early blood culture was obtained from 234 (19.7%) infants; 170 (14.3%) were treated with antibiotics. Infants treated with antibiotics were significantly younger (p < 0.0001), smaller (p < 0.0001), more often diagnosed with respiratory distress (p < 0.0001), and were more frequently admitted to the neonatal intensive care unit (p < 0.0001). There were no cases of culture proven EOS. CONCLUSION: Although this population lacks risk factors for the development of EOS, a significant percentage was treated with antibiotics. This population may benefit from future antibiotic stewardship efforts. KEY POINTS: · This population is at risk for respiratory morbidity.. · There were no cases of culture proven early onset sepsis.. · This is a group of interest for antibiotic stewardship..

Utility of the Neonatal Early-Onset Sepsis Calculator in a Low-Risk Population.

OBJECTIVE: To compare early-onset sepsis (EOS) risk estimation and recommendations for infectious evaluation and/or empiric antibiotics using a categorical risk assessment versus the Neonatal Early-Onset Sepsis Calculator in a low-risk population. STUDY DESIGN: Retrospective chart review of late preterm (≥350/7-366/7 weeks' gestational age) and term infants born at the Brooke Army Medical Center between January 1, 2012 and August 29, 2019. We evaluated those born via cesarean section with rupture of membranes (ROM) < 10 minutes. Statistical analysis was performed to compare recommendations from a categorical risk assessment versus the calculator. RESULTS: We identified 1,187 infants who met inclusion criteria. A blood culture was obtained within 72 hours after birth from 234 (19.7%) infants and 170 (14.3%) received antibiotics per routine clinical practice, using categorical risk assessment. Respiratory distress was the most common indication for evaluation, occurring in 173 (14.6%) of patients. After applying the Neonatal Early-Onset Sepsis Calculator to this population, the recommendation was to obtain a blood culture on 166 (14%), to start or strongly consider starting empiric antibiotics on 164 (13.8%), and no culture or antibiotics on 1,021 (86%). Utilizing calculator recommendations would have led to a reduction in frequency of blood culture (19.7 vs. 14%, p < 0.0001) but no reduction in empiric antibiotics (14.3 vs. 13.8%, p = 0.53). There were no cases of culture-proven EOS. CONCLUSION: This population is low risk for development of EOS; however, 19.7% received an evaluation for infection and 14.3% received antibiotics. Utilization of the Neonatal Early-Onset Sepsis Risk Calculator would have led to a significant reduction in the evaluation for EOS but no reduction in antibiotic exposure. Consideration of delivery mode and indication for delivery may be beneficial to include in risk assessments for EOS. KEY POINTS: · Cesarean section with rupture of membranes at delivery confers low risk for EOS.. · Respiratory distress often triggers an EOS evaluation.. · Delivery mode should be considered in EOS risk..

The effect of oral guaifenesin on pediatric chronic rhinitis: A pilot study.

OBJECTIVES: To investigate the effectiveness of guaifenesin in the relief of nasal symptoms in children with chronic rhinitis (CR). We hypothesized that guaifenesin use over a 14-day study period would improve subjective nasal complaints in pediatric patients with chronic rhinitis, as measured by the SinoNasal-5 (SN-5) survey. We also hypothesized improvement in nasal volume and cross-sectional area with guaifenesin. STUDY DESIGN: Randomized, placebo-controlled, parallel group, masked clinical trial. METHODS: The study consisted of a 14-day, randomized, placebo-controlled, parallel group, masked clinical trial of oral guaifenesin for CR in children aged 7-18 years. A 2:1 ratio of subjects on active medication to placebo was used. The study was approved by the Western Institutional Review Board. On initial enrollment and at the conclusion of therapy, the SN-5 was completed by parents, acoustic rhinometry measurements performed, and mucus sampling for rheology was obtained. RESULTS: 30 subjects were enrolled in the study, with 20 receiving guaifenesin and 10 placebo. Treatment with guaifenesin for 14 days produced a significant mean change towards clinical improvement in SN-5 scores compared with placebo (p = 0.013). There was no significant difference in quality of life assessment scores between the two groups or in any of the acoustic rhinometry parameters. Many of the study subjects had difficulty producing a mucus sample sufficient for analysis. CONCLUSIONS: Based upon our pilot data, it appears that guaifenesin treatment may produce objective improvements in pediatric patients with CR. Further research with larger samples sizes, inclusion of children younger than 6, and biophysical mucus analyses is warranted. LEVEL OF EVIDENCE: Level 2b.

Cerebrospinal fluid biomarkers in the Longitudinal Early-onset Alzheimer's Disease Study.

INTRODUCTION: One goal of the Longitudinal Early Onset Alzheimer's Disease Study (LEADS) is to define the fluid biomarker characteristics of early-onset Alzheimer's disease (EOAD). METHODS: Cerebrospinal fluid (CSF) concentrations of Aß1-40, Aß1-42, total tau (tTau), pTau181, VILIP-1, SNAP-25, neurogranin (Ng), neurofilament light chain (NfL), and YKL-40 were measured by immunoassay in 165 LEADS participants. The associations of biomarker concentrations with diagnostic group and standard cognitive tests were evaluated. RESULTS: Biomarkers were correlated with one another. Levels of CSF Aß42/40, pTau181, tTau, SNAP-25, and Ng in EOAD differed significantly from cognitively normal and early-onset non-AD dementia; NfL, YKL-40, and VILIP-1 did not. Across groups, all biomarkers except SNAP-25 were correlated with cognition. Within the EOAD group, Aß42/40, NfL, Ng, and SNAP-25 were correlated with at least one cognitive measure. DISCUSSION: This study provides a comprehensive analysis of CSF biomarkers in sporadic EOAD that can inform EOAD clinical trial design.

Pathogenic variants in the Longitudinal Early-onset Alzheimer's Disease Study cohort.

INTRODUCTION: One goal of the Longitudinal Early-onset Alzheimer's Disease Study (LEADS) is to investigate the genetic etiology of early onset (40-64 years) cognitive impairment. Toward this goal, LEADS participants are screened for known pathogenic variants. METHODS: LEADS amyloid-positive early-onset Alzheimer's disease (EOAD) or negative early-onset non-AD (EOnonAD) cases were whole exome sequenced (N = 299). Pathogenic variant frequency in APP, PSEN1, PSEN2, GRN, MAPT, and C9ORF72 was assessed for EOAD and EOnonAD. Gene burden testing was performed in cases compared to similar-age cognitively normal controls in the Parkinson's Progression Markers Initiative (PPMI) study. RESULTS: Previously reported pathogenic variants in the six genes were identified in 1.35% of EOAD (3/223) and 6.58% of EOnonAD (5/76). No genes showed enrichment for carriers of rare functional variants in LEADS cases. DISCUSSION: Results suggest that LEADS is enriched for novel genetic causative variants, as previously reported variants are not observed in most cases. HIGHLIGHTS: Sequencing identified eight cognitively impaired pathogenic variant carriers. Pathogenic variants were identified in PSEN1, GRN, MAPT, and C9ORF72. Rare variants were not enriched in APP, PSEN1/2, GRN, and MAPT. The Longitudinal Early-onset Alzheimer's Disease Study (LEADS) is a key resource for early-onset Alzheimer's genetic research.

Influence of closed glove exchange on bacterial contamination of the hands of the surgical team.

OBJECTIVE: To determine if closed glove exchange (CGE) increases hand contamination. STUDY DESIGN: Prospective experimental study. SAMPLE POPULATION: Surgical teams participating in 65 individual surgical procedures were included, resulting in 200 individual enrollments. METHODS: At the completion of surgery, gloves were removed and hands were swabbed. The inside of the gown cuff was swabbed. Each participant regloved, using a closed gloving technique. The new gloves were removed, and hands were swabbed for culture a second time. Swabs underwent standard bacterial culture. RESULTS: Before glove exchange, or baseline, contamination was found on 17/200 dominant hands and 13/200 nondominant hands. After performing CGE, contamination was found on 14/200 and 15/200 dominant and nondominant hands, respectively. No difference was detected between the number of CFUs cultured from a surgeon's hands before CGE and the number of CFUs cultured from a surgeon's hands post-CGE (one sided sign test, p = .61). Twelve (12) different bacterial species were identified, the most common were Staphylococcus spp. (97/154; 63%). CONCLUSION: Closed glove exchange did not increase bacterial hand contamination over baseline levels. CLINICAL SIGNIFICANCE: We found no evidence to support discontinuing CGE.

In vitro elution of amikacin from four hydrogel preparations: A pilot study.

OBJECTIVE: To determine in vitro elution of amikacin from poloxamer 407 NF, 1% carboxymethylcellulose (CMC), 3% CMC, 5% CMC, and control (sterile water). STUDY DESIGN: Descriptive in vitro. SAMPLE POPULATION: Triplicate samples from each experimental group. METHODS: Amikacin solution was prepared in poloxamer 407 NF, 1% CMC, 3% CMC, 5% CMC, or sterile water. Then, 1 ml of phosphate-buffered saline (PBS) was added to each of three aliquots per base and the samples were incubated at 37°C. PBS was removed and replaced at 1, 4, 8, 12, 24, 48, 72, 96, 120, 144, 168, 192, 216, and 240 hours and amikacin concentration was measured. RESULTS: The highest median concentration of amikacin in the eluent of poloxamer 407 NF, 3% CMC, and 5% CMC was observed at 48 hours: 3300, 3030, and 2190 µg/ml, respectively. The highest median concentration of amikacin in the eluent of 1% CMC and sterile water were observed at 1 hour: 13300 and 15600 µg/ml, respectively. Median eluent concentration of amikacin exceeded 2000 µg/ml (the reported minimum inhibitory concentration [MIC] of certain biofilm-producing methicillin-resistant Staphylococcus pseudintermedius) from 24 to 96 hours for poloxamer 407 NF, 24-72 hours for 3% CMC, 48-72 hours for 5% CMC, 1-4 hours for 1% CMC, and 1-4 hours for sterile water. CONCLUSION: Amikacin elution from tested substances reached or exceeded target MIC during the 240 hours tested. CLINICAL SIGNIFICANCE: Hydrogel-amikacin solutions may be useful topical treatment options for some infected wounds. In vivo safety and efficacy should be evaluated.

Pelvic limb anesthesia and analgesia in dogs undergoing tibial plateau leveling osteotomy (TPLO): A survey of board-certified anesthesiologists.

OBJECTIVE: To report the locoregional anesthesia and analgesia preferences of veterinary anesthesiologists for use in dogs undergoing a TPLO and determine any association with specialty college, time from board-certification, or employment sector. STUDY DESIGN: Cross sectional study. SAMPLE POPULATION: Diplomates of the American (ACVAA) and European (ECVAA) Colleges of Veterinary Anesthesia and Analgesia. METHODS: An electronic survey was distributed to diplomates and responses were used to determine associations between preferred methods. RESULTS: The survey response rate was 28% (141/500) with 69% (97/141) of ACVAA diplomates and 31% of diplomates with ECVAA (44/141) certification. Peripheral nerve block (PNB) was preferred by 79% (111/141) of all diplomates, lumbosacral epidural (LE) by 21% (29/141), and peri-incisional infiltration (PI) by <1% (1/141). There was no association (p = .283) with specialty college. There was an association (p < .001) with time from board-certification with increased preference for LE when >10-years from certification and PI preferred by only those board-certified >20-years ago. There was an association with employment sector (p = .003) with more academic diplomates preferring LE. Anesthesiologists reported that treatment decisions were affected by various factors including time pressure and surgeon influence. CONCLUSION: Diplomates of ACVAA and ECVAA prefer PNB as the locoregional method of pelvic limb anesthesia in dogs undergoing TPLO. A greater percentage of newer and private practice diplomates prefer PNB while a larger percentage of senior and academic diplomates prefer LE. Decision making is multifactorial and includes perceived time pressure and surgeon influence. CLINICAL SIGNIFICANCE: Veterinary anesthesiologists prefer and frequently use PNB in dogs undergoing TPLO and surgeon influence may affect their chosen treatment.

Treatment and outcome following substantial ketamine overdose in a dog.

A 9-year-old, 3.7 kg (8.14 lb) neutered male Yorkshire terrier mix was treated following a ketamine overdose after subcutaneous ureteral bypass surgery. Due to an error in communication and misinterpretation of an electronic treatment sheet, the dog was inadvertently placed on a continuous rate infusion (CRI) of ketamine at 67.6 mg/kg per hour, rather than the intended 0.2 mg/kg per hour rate. Four hours after initiation of the ketamine CRI, the dog developed signs indicative of a ketamine overdose including tachycardia, hyperthermia, anisocoria, and hypoglycemia. It was determined the dog had received an iatrogenic overdose of ketamine; the infusion had been running at 67.6 mg/kg per hour, resulting in 270 mg/kg of ketamine over 4 h. Aggressive supportive measures were undertaken, and the dog gradually recovered over an 18-hour period, without lasting consequences of the overdose. To the authors' knowledge, there are no current published reports of a ketamine overdose of this magnitude in a dog. This case report documents an iatrogenic 338 times intravenous ketamine overdose in a dog, which was successfully managed with supportive care. In addition, it highlights the importance of doctor-technician communication and the potential errors in using electronic treatment sheets.

Traitement et résultat à la suite d'une surdose importante de kétamine chez un chien. Un Yorkshire terrier mélangé mâle de 9 ans et pesant 3,7 kg (8,14 lb) a été traité à la suite d'une surdose de kétamine après un pontage urétéral sous-cutané. En raison d'une erreur de communication et d'une mauvaise interprétation d'une feuille de traitement électronique, le chien a été placé par inadvertance sous une perfusion à débit continu (IRC) de kétamine à 67,6 mg/kg par heure, au lieu du débit prévu de 0,2 mg/kg par heure. Quatre heures après le début de l'IRC de kétamine, le chien a développé des signes indiquant une surdose de kétamine, notamment de la tachycardie, de l'hyperthermie, de l'anisocorie et de l'hypoglycémie. Il a été déterminé que le chien avait reçu une surdose iatrogène de kétamine; la perfusion fonctionnait à 67,6 mg/kg par heure, entraînant 270 mg/kg de kétamine en 4 h. Des mesures de soutien agressives ont été mises en place et le chien s'est progressivement rétabli sur une période de 18 heures, sans conséquences durables du surdosage.À la connaissance des auteurs, il n'existe actuellement aucun rapport publié sur une surdose de kétamine de cette ampleur chez un chien. Ce rapport de cas documente une surdose iatrogène de kétamine de 338 fois par voie intraveineuse chez un chien, qui a été gérée avec succès avec des soins de soutien. De plus, il met en évidence l'importance de la communication médecin-technicien et les erreurs potentielles dans l'utilisation des fiches de traitement électroniques.(Traduit par Dr Serge Messier).