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Edsel B Ing,1 Gabriela Lahaie Luna,2 Andrew Toren,3 Royce Ing,4 John J Chen,5 Nitika Arora,6 Nurhan Torun,7 Otana A Jakpor,8 J Alexander Fraser,9 Felix J Tyndel,10 Arun NE Sundaram,10 Xinyang Liu,11 Cindy TY Lam,1 Vivek Patel,12 Ezekiel Weis,13 David Jordan,14 Steven Gilberg,14 Christian Pagnoux,15 Martin ten Hove21Department of Ophthalmology and Vision Sciences, University of Toronto Medical School, Toronto, 2Department of Ophthalmology, Queen’s University, Kingston, ON, 3Department of Ophthalmology, University of Laval, Quebec, QC, 4Toronto Eyelid, Strabismus and Orbit Surgery Clinic, Toronto, ON, Canada; 5Mayo Clinic, Department of Ophthalmology and Neurology, 6Mayo Clinic, Department of Ophthalmology, Rochester, MN, 7Department of Surgery, Division of Ophthalmology, Harvard Medical School, Boston, MA, 8Harvard Medical School, Boston, MA, USA; 9Department of Clinical Neurological Sciences and Ophthalmology, Western University, London, 10Department of Medicine, University of Toronto Medical School, Toronto, ON, Canada; 11Department of Medicine, Fudan University Shanghai Medical College, Shanghai, People’s Republic of China; 12Roski Eye Institute, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA; 13Departments of Ophthalmology, Universities of Alberta and Calgary, Edmonton and Calgary, AB, 14Department of Ophthalmology, University of Ottawa, Ottawa, ON, 15Vasculitis Clinic, Mount Sinai Hospital, Toronto, ON, CanadaPurpose: To develop and validate a diagnostic prediction model for patients with suspected giant cell arteritis (GCA).Methods: A retrospective review of records of consecutive adult patients undergoing temporal artery biopsy (TABx) for suspected GCA was conducted at seven university centers. The pathologic diagnosis was considered the final diagnosis. The predictor variables were age, gender, new onset headache, clinical temporal artery abnormality, jaw claudication, ischemic vision loss (VL), diplopia, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), and platelet level. Multiple imputation was performed for missing data. Logistic regression was used to compare our models with the non-histologic American College of Rheumatology (ACR) GCA classification criteria. Internal validation was performed with 10-fold cross validation and bootstrap techniques. External validation was performed by geographic site.Results: There were 530 complete TABx records: 397 were negative and 133 positive for GCA. Age, jaw claudication, VL, platelets, and log CRP were statistically significant predictors of positive TABx, whereas ESR, gender, headache, and temporal artery abnormality were not. The parsimonious model had a cross-validated bootstrap area under the receiver operating characteristic curve (AUROC) of 0.810 (95% CI =0.766–0.854), geographic external validation AUROC’s in the range of 0.75–0.85, calibration pH–L of 0.812, sensitivity of 43.6%, and specificity of 95.2%, which outperformed the ACR criteria.Conclusion: Our prediction rule with calculator and nomogram aids in the triage of patients with suspected GCA and may decrease the need for TABx in select low-score at-risk subjects. However, misclassification remains a concern.Keywords: temporal artery biopsy, diagnosis, prediction rule, nomogram, giant cell arteritis, validation

Cryptococcus gattii recently emerged as the causative agent of cryptococcosis in healthy individuals in western North America, despite previous characterization of the fungus as a pathogen in tropical or subtropical regions. As a foundation to study the genetics of virulence in this pathogen, we sequenced the genomes of a strain (WM276) representing the predominant global molecular type (VGI) and a clinical strain (R265) of the major genotype (VGIIa) causing disease in North America. We compared these C. gattii genomes with each other and with the genomes of representative strains of the two varieties of Cryptococcus neoformans that generally cause disease in immunocompromised people. Our comparisons included chromosome alignments, analysis of gene content and gene family evolution, and comparative genome hybridization (CGH). These studies revealed that the genomes of the two representative C. gattii strains (genotypes VGI and VGIIa) are colinear for the majority of chromosomes, with some minor rearrangements. However, multiortholog phylogenetic analysis and an evaluation of gene/sequence conservation support the existence of speciation within the C. gattii complex. More extensive chromosome rearrangements were observed upon comparison of the C. gattii and the C. neoformans genomes. Finally, CGH revealed considerable variation in clinical and environmental isolates as well as changes in chromosome copy numbers in C. gattii isolates displaying fluconazole heteroresistance.

Cryptococcus gattii recently emerged as the causative agent of cryptococcosis in healthy individuals in western North America, despite previous characterization of the fungus as a pathogen in tropical or subtropical regions. As a foundation to study the genetics of virulence in this pathogen, we sequenced the genomes of a strain (WM276) representing the predominant global molecular type (VGI) and a clinical strain (R265) of the major genotype (VGIIa) causing disease in North America. We compared these C. gattii genomes with each other and with the genomes of representative strains of the two varieties of Cryptococcus neoformans that generally cause disease in immunocompromised people. Our comparisons included chromosome alignments, analysis of gene content and gene family evolution, and comparative genome hybridization (CGH). These studies revealed that the genomes of the two representative C. gattii strains (genotypes VGI and VGIIa) are colinear for the majority of chromosomes, with some minor rearrangements. However, multiortholog phylogenetic analysis and an evaluation of gene/sequence conservation support the existence of speciation within the C. gattii complex. More extensive chromosome rearrangements were observed upon comparison of the C. gattii and the C. neoformans genomes. Finally, CGH revealed considerable variation in clinical and environmental isolates as well as changes in chromosome copy numbers in C. gattii isolates displaying fluconazole heteroresistance.

Abstract: Background: Support and education for parents faced with managing a child with atopic dermatitis is crucial to the success of current treatments. Interventions aiming to improve parent management of this condition are promising. Unfortunately, evaluation is hampered by lack of precise research tools to measure change. Objectives: To develop a suite of valid and reliable research instruments to appraise parents’ self-efficacy for performing atopic dermatitis management tasks; outcome expectations of performing management tasks; and self-reported task performance in a community sample of parents of children with atopic dermatitis. Methods: The Parents’ Eczema Management Scale (PEMS) and the Parents’ Outcome Expectations of Eczema Management Scale (POEEMS) were developed from an existing self-efficacy scale, the Parental Self-Efficacy with Eczema Care Index (PASECI). Each scale was presented in a single self-administered questionnaire, to measure self-efficacy, outcome expectations, and self-reported task performance related to managing child atopic dermatitis. Each was tested with a community sample of parents of children with atopic dermatitis, and psychometric evaluation of the scales’ reliability and validity was conducted. Setting and participants: A community-based convenience sample of 120 parents of children with atopic dermatitis completed the self-administered questionnaire. Participants were recruited through schools across Australia. Results: Satisfactory internal consistency and test–retest reliability was demonstrated for all three scales. Construct validity was satisfactory, with positive relationships between self-efficacy for managing atopic dermatitis and general perceived self-efficacy; self-efficacy for managing atopic dermatitis and self-reported task performance; and self-efficacy for managing atopic dermatitis and outcome expectations. Factor analyses revealed two-factor structures for PEMS and PASECI alike, with both scales containing factors related to performing routine management tasks, and managing the child''s symptoms and behaviour. Factor analysis was also applied to POEEMS resulting in a three-factor structure. Factors relating to independent management of atopic dermatitis by the parent, involving healthcare professionals in management, and involving the child in the management of atopic dermatitis were found. Parents’ self-efficacy and outcome expectations had a significant influence on self-reported task performance. Conclusions: Findings suggest that PEMS and POEEMS are valid and reliable instruments worthy of further psychometric evaluation. Likewise, validity and reliability of PASECI was confirmed. [ABSTRACT FROM AUTHOR]

BACKGROUND: Reporting of known and suspected child abuse and neglect is a fundamental responsibility of health professionals in many countries including Australia. Nurses' duties to report child abuse and neglect are expressed in legislation, or in occupational policy documents. In this paper factors influencing nurses' compliance with mandated reporting are examined. OBJECTIVE: The purpose of this study was to examine the relationship between nurse characteristics, training, knowledge of legislative reporting duty and attitudinal factors on the reporting by nurses of different types of child abuse and neglect. METHODS: Logistic regression analyses were conducted to examine relationships between variables. DESIGN, SETTING AND PARTICIPANTS: A cross-sectional survey using the Child Abuse and Neglect Nurses' Questionnaire (CANNQ) was conducted. The respondents were 930 Registered Nurses (RNs) currently working across metropolitan, rural and remote locations throughout the state of Queensland, Australia. RESULTS: Nurses were confident and knowledgeable in their obligation to report physical [CPA] and sexual [CSA] abuse. They were less confident and knowledgeable about emotional abuse [CEA] and neglect [CN]. Recognition of the extent of harm to abused and neglected children was poor. Positive attitudes to mandatory reporting influenced better recognition of all forms of abuse and neglect and the likelihood of reporting CSA, CEA and CN; parenting experience influenced intention to report child sexual abuse, and CAN training predicted reporting of child neglect. CONCLUSIONS AND PRACTICE IMPLICATIONS: Results indicate that with training, nurses are a key choice for mandating child abuse and neglect reporting. Educational preparation and training for nurses should emphasise the serious impact of child abuse and neglect on children and families to improve recognition of the extent of harm and the likelihood of reporting. From a perspective of increasing compliance with the legislative duty, particular attention needs to be paid to recognition and reporting of CEA and CN. Further research is needed to determine whether factors influencing sound reporting can be successfully modified. [ABSTRACT FROM AUTHOR]

Abstract Background Long-range interactions between regulatory DNA elements such as enhancers, insulators and promoters play an important role in regulating transcription. As chromatin contacts have been found throughout the human genome and in different cell types, spatial transcriptional control is now viewed as a general mechanism of gene expression regulation. Chromosome Conformation Capture Carbon Copy (5C) and its variant Hi-C are techniques used to measure the interaction frequency (IF) between specific regions of the genome. Our goal is to use the IF data generated by these experiments to computationally model and analyze three-dimensional chromatin organization. Results We formulate a probabilistic model linking 5C/Hi-C data to physical distances and describe a Markov chain Monte Carlo (MCMC) approach called MCMC5C to generate a representative sample from the posterior distribution over structures from IF data. Structures produced from parallel MCMC runs on the same dataset demonstrate that our MCMC method mixes quickly and is able to sample from the posterior distribution of structures and find subclasses of structures. Structural properties (base looping, condensation, and local density) were defined and their distribution measured across the ensembles of structures generated. We applied these methods to a biological model of human myelomonocyte cellular differentiation and identified distinct chromatin conformation signatures (CCSs) corresponding to each of the cellular states. We also demonstrate the ability of our method to run on Hi-C data and produce a model of human chromosome 14 at 1Mb resolution that is consistent with previously observed structural properties as measured by 3D-FISH. Conclusions We believe that tools like MCMC5C are essential for the reliable analysis of data from the 3C-derived techniques such as 5C and Hi-C. By integrating complex, high-dimensional and noisy datasets into an easy to interpret ensemble of three-dimensional conformations, MCMC5C allows researchers to reliably interpret the result of their assay and contrast conformations under different conditions. Availability http://Dostielab.biochem.mcgill.ca

Abstract Background Transmissible spongiform encephalopathy describes a family of diseases affecting both man and animals. Current tests for the diagnosis of these diseases are based on the detection of an abnormal misfolded form of the host protein PrP which is found within the central nervous and lymphoreticular systems of affected animals. Recently, concern that this marker may not be as reliable as previously thought, coupled with an urgentneed for a pre-clinical live animal test, has led to the search for alternative assays for the detection of TSE disease. Methods This "proof of concept" study, examines the use of differential protein expression profiling using surface enhanced laser desorption and ionisationtime of flight mass spectrometry (SELDI-TOF) for the diagnosis of TSE disease. Spectral output from all proteins selectively captured from individual murine brain homogenate samples, are compared as "profiles" in groups of infected and non-infected animals. Differential protein expression between groups is thus highlighted and statistically significant protein "peaks" used to construct a panel of disease specific markers. Studies at both terminal stages of disease and throughout the time course of disease have shown a disease specific protein profile or "disease fingerprint" which could be used to distinguish between groups of TSE infected and uninfected animals at an early time point of disease. Results Our results show many differentially expressed proteins in diseased and control animals, some at early stages of disease. Three proteins identified by SELDI-TOF analysis were verified by immunohistochemistry in brain tissue sections. We demonstrate that by combining the most statistically significant changes in expression, a panel of markers can be constructed that can distinguish between TSE diseased and normal animals. Conclusion Differential protein expression profiling has the potential to be used for the detection of disease in TSE infected animals. Having established that a "training set" of potential markers can be constructed, more work would be required to further test the specificity and sensitivity of the assay in a "testing set". Based on these promising results, further studies are being performed using blood samples from infected sheep to assess the potential use of SELDI-TOF as a pre-mortem blood based diagnostic.

Abstract Background The transmissible spongiform encephalopathies (TSEs) are a group of neurodegenerative diseases affecting both human and animals. The neuroanatomical changes which occur in the central nervous system (CNS) of TSE infected animals include vacuolation, gliosis, neuronal loss and the deposition of a disease specific protein, PrPSc. Experimental murine models of scrapie, a TSE of sheep, have revealed that pathology may be confined to specific brain areas with targeting of particular neuronal subsets depending on route of injection and scrapie isolate. To assess the biochemical changes which are taking place in these targeted areas it was necessary to develop a reliable sampling procedure (microdissection) which could be used for a variety of tests such as western blotting and magnetic resonance spectroscopy. Methods The method described is for the microdissection of murine brains. To assess the usefulness of this dissection technique for producing similar sample types for analysis by various down-stream biochemical techniques, the areas dissected were analysed for PrPSc by western blotting and compared to immunocytochemical (ICC) techniques. Results Results show that the method generates samples yielding a consistent protein content which can be analysed for PrPSc. The areas in which PrPSc is found by western blotting compares well with localisation visualised by immunocytochemistry. Conclusion The microdisssection method described can be used to generate samples suitable for a range of biochemical techniques. Using these samples a range of assays can be carried out which will help to elucidate the molecular and cellular mechanisms underlying TSE pathogenesis. The method would also be useful for any study requiring the investigation of discrete areas within the murine brain.

Activating autophagy may be therapeutically beneficial, and we have previously shown that azathioprine (AZA), an immunomodulatory drug, induces autophagy. Here, we evaluated the induction of autophagy by the thiopurines AZA, mercaptopurine (6-MP) and thioguanine (6-TG) in THP-1 macrophages and investigated the mechanism of action in the context of this cellular process. The cytotoxicity of thiopurines was evaluated using an LDH assay. Induction of endogenous LC3 by thiopurines was evaluated using immunostaining. To confirm autophagy activation by thiopurines, a GFP-RFP-LC3 reporter plasmid was used to monitor the maturation of autophagosomes to autolysosomes. Induction of apoptosis by thiopurines was evaluated using Annexin V/PI staining, and ER stress was assessed via RT‒PCR analysis of XBP1 splicing. To gain insight into the mechanism of action of thiopurines, mTORC1 activity and eIF2α-S51 phosphorylation were evaluated by immunoblotting. Thiopurines were not cytotoxic to cells and induced strong time- and concentration-dependent autophagy. Thiopurines activate autophagy with complete progression through the pathway. Induction of autophagy by thiopurines occurred independently of apoptosis and ER stress. Immunoblotting revealed that AZA inhibited mTORC1 activity, and AZA and 6-TG increased eIF2α-S51 phosphorylation. In contrast, 6-MP had a minor effect on either signalling pathway. Thiopurines are strong inducers of autophagy, and autophagy induction should be considered among the mechanisms responsible for patient response to thiopurines., (© 2024. The Author(s).)

The Clinical and Laboratory Standards Institute (CLSI) M27 guidelines are the recommended and most commonly used protocols for broth microdilution antifungal susceptibility testing of yeasts. However, these guidelines are limited to the use of 96-well assay plates, limiting assay capacity. With the increased risk of fungal resistance emerging in the community, it is important to have alternative protocols available, that offer higher throughput and can screen more than eight to ten potential antifungal compounds per plate. This study presents an optimised broth microdilution minimum inhibitory concentration (MIC) method for testing the susceptibility of yeasts in an efficient high throughput screening setup, with minimal growth variability and maximum reproducibility. We extend the M27 guidelines and optimise the conditions for 384-well plates. Validation of the assay was performed with ten clinically used antifungals (fluconazole, amphotericin B, 5-fluorocytosine, posaconazole, voriconazole, ketoconazole, itraconazole, caspofungin diacetate, anidulafungin and micafungin) against Candida albicans and Cryptococcus neoformans., (© 2024. Crown.)

The plethora of genome sequences produced in the postgenomic age has not resolved many of our most pressing biological questions. Correlating gene expression with an interrogatable and easily observable characteristic such as the surrogate phenotype conferred by a reporter gene is a valuable approach to gaining insight into gene function. Many reporters including lacZ , amdS, and the fluorescent proteins mRuby3 and mNeonGreen have been used across all manners of organisms. Described here is an investigation into the creation of a robust, synthetic, fusion reporter system for Cryptococcus neoformans that combines some of the most useful fluorophores available in this system with the versatility of the counter-selectable nature of amdS . The reporters generated include multiple composition and orientation variants, all of which were investigated for differences in expression. Evaluation of known promoters from the TEF1 and GAL7 genes was undertaken, elucidating novel expression tendencies of these biologically relevant C. neoformans regulators of transcription. Smaller than lacZ but providing multiple useful surrogate phenotypes for interrogation, the fusion ORF serves as a superior whole-cell assay compared to traditional systems. Ultimately, the work described here bolsters the array of relevant genetic tools that may be employed in furthering manipulation and understanding of the WHO fungal priority group pathogen C. neoformans .

Background: Optic disc drusen (ODD) represent an important differential diagnosis of papilledema caused by intracranial hypertension, but their distinction may be difficult in clinical practice. The aim of this study was to train, validate, and test a dedicated deep learning system (DLS) for binary classification of ODD vs papilledema (including various subgroups within each category), on conventional mydriatic digital ocular fundus photographs collected in a large international multiethnic population., Methods: This retrospective study included 4,508 color fundus images in 2,180 patients from 30 neuro-ophthalmology centers (19 countries) participating in the Brain and Optic Nerve Study with Artificial Intelligence (BONSAI) Group. For training and internal validation, we used 857 ODD images and 3,230 papilledema images, in 1,959 patients. External testing was performed on an independent data set (221 patients), including 207 images with ODD (96 visible and 111 buried), provided by 3 centers of the Optic Disc Drusen Studies Consortium, and 214 images of papilledema (92 mild-to-moderate and 122 severe) from a previously validated study., Results: The DLS could accurately distinguish between all ODD and papilledema (all severities included): area under the receiver operating characteristic curve (AUC) 0.97 (95% confidence interval [CI], 0.96-0.98), accuracy 90.5% (95% CI, 88.0%-92.9%), sensitivity 86.0% (95% CI, 82.1%-90.1%), and specificity 94.9% (95% CI, 92.3%-97.6%). The performance of the DLS remained high for discrimination of buried ODD from mild-to-moderate papilledema: AUC 0.93 (95% CI, 0.90-0.96), accuracy 84.2% (95% CI, 80.2%-88.6%), sensitivity 78.4% (95% CI, 72.2%-84.7%), and specificity 91.3% (95% CI, 87.0%-96.4%)., Conclusions: A dedicated DLS can accurately distinguish between ODD and papilledema caused by intracranial hypertension, even when considering buried ODD vs mild-to-moderate papilledema., Competing Interests: The authors report no conflicts of interest., (Copyright © 2024 by North American Neuro-Ophthalmology Society.)

Background:  Pectus excavatum deformities are usually repaired with a minimally invasive approach in which a metal bar is used to correct the chest wall abnormality. We aimed to evaluate long-term outcomes and patient satisfaction after surgical correction., Methods:  Patients who underwent pectus excavatum repair and subsequent bar removal at a single tertiary care center from January 2000 to December 2020 were identified. A retrospective chart review was performed, and a telephone survey was conducted to evaluate perceived inward chest movement, need for surgeon reevaluation, surgical reintervention, and overall satisfaction. Data are presented as medians with interquartile ranges (IQRs) and frequencies with percentages., Results:  A total of 583 patients were included. The survey response rate was 26.2% ( n  = 153). The respondents were predominantly male (80.4%, n  = 123) with a median age at surgical correction of 14.9 years (IQR 12.9, 16.1) and a median Haller index (HI) of 3.8 (IQR 3.4, 4.5). Median time to bar removal was 2.9 years (IQR 2.5, 3.0) with a median age at removal of 17.7 years (IQR 15.5, 19.0). Median time from surgery to survey follow-up was 9.6 years (IRQ 5.0, 11.4) with respondents having a median age at follow-up of 25 years (IQR 22.0, 28.4). The satisfaction rate was 96.7% ( n  = 148) with a reintervention rate of 2.0% ( n  = 3). The perceived inward chest movement was 30.7% ( n  = 47) with 12.8% ( n  = 6) of those requesting surgical reevaluation., Conclusion:  There is a high level of satisfaction many years after correction of pectus excavatum and bar removal. With the advent of cryoablative therapy since 2017, patient satisfaction improved by experience of less postoperative pain. Reintervention rate is low despite some patients reporting a perceived chest wall inward movement., Competing Interests: None declared., (Thieme. All rights reserved.)

Introduction: The American Urological Association guidelines recommend against the performance of ultrasound and other imaging modalities in the evaluation of patients with cryptorchidism before expert consultation. We aimed to examine our institutional experience with cryptorchidism and measure adherence to currently available guidelines., Methods: An institutional review board-approved retrospective review of ultrasound utilization in the evaluation of patients with cryptorchidism was performed from June 1, 2016, to June 30, 2019, at a single tertiary level pediatric hospital., Results: We identified 1796 patients evaluated in surgical clinics for cryptorchidism. Surgical intervention was performed in 75.2% (n = 1351) of the entire cohort. Ultrasound was performed in 42% (n = 754), most of which were ordered by referring physicians (91% n = 686). Of those who received an ultrasound, surgical intervention was performed in 78% (n = 588). Those 166 patients (22%) who did not undergo surgical intervention were referred with ultrasounds suggesting inguinal testes; however, all had normal physical examinations or mildly retractile testes at the time of consultation and were discharged from the outpatient clinic. There were 597 patients referred without an ultrasound, 81% (n = 483) were confirmed to have cryptorchidism at the time of specialist physical examination and underwent definitive surgical intervention, the remainder (19%, n = 114) were discharged from the outpatient clinics., Conclusions: Ultrasound evaluation of cryptorchidism continues despite high-quality evidence-based guidelines that recommend otherwise, as they should have little to no bearing on the surgeon's decision to operate or the type of operation. Instead, physical examination findings should guide surgical planning., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Introduction: Pectus bar stabilizers are routinely used for bar fixation in the repair of pectus excavatum. We aimed to determine the optimum technique for bar fixation by reviewing our institutional experience with the use of bilateral, unilateral, and no stabilizer placement. Methods: Retrospective single pediatric center review of patients who underwent minimally invasive bar placement for pectus excavatum and subsequent bar removal between December 2001 and July 2019 was performed. Demographic data, details about the surgery, the number of bars and stabilizers used, and follow-up information were collected. Stabilizer-related complications included pain requiring stabilizer removal, surgical site infections (SSIs), and bar displacement. Data are presented as medians with interquartile ranges (IQRs) and frequencies with percentages. Results: A total of 561 patients were included. The cohort was predominantly male (83.1%, n  = 466) with a median age at the time of bar placement of 15 years (IQR 12.4, 16.3) and a median Haller index of 3.8 (IQR 3.4, 4.5). Pain attributed to the stabilizer site that required removal was observed only in the bilateral stabilizer group (2.5%, n  = 13). SSI related to the stabilizer site occurred in 1.8% ( n  = 9) of the bilateral stabilizer cases and 2.1% ( n  = 1) of the unilateral stabilizer cases. Bar displacement was observed in 0.6% ( n  = 3) of the bilateral stabilizer cases and 2 of those patients also had an SSI. There were no complications in the no stabilizer group. Conclusion: As the trend moves toward unilateral and no stabilizer use, we observe fewer cases of pain requiring stabilizer removal with no increase in bar displacements.

Competing Interests: M. W. D. Thorne has received honoraria from Biogen, Novartis, EMS Serono, and Roche to participate in Ad boards and attend medical conferences. S. M. Mirsattari has received honoraria for speaking engagements for UCB Canada Inc, Eisai Co. Ltd (Canada), and Sunovion Pharmaceuticals Canada Inc. He has been a member of the Epilepsy National Advisory Board for UCB Canada Inc, Eisai Co Ltd (Canada), Sunovion Pharmaceuticals Canada Inc, Jazz Pharmaceuticals Inc, and Paladin Labs Inc. The other authors report no conflicts of interest.

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

With the emergence of the human pathogen Candida auris as a threat to human health, there is a strong demand to identify effective medicines to prevent the harm caused by such drug-tolerant human fungi. Herein, a series of 33 new derivatives of bensulfuron methyl (BSM) were synthesized and characterized by 1 H NMR, 13 C NMR, and HRMS. Among the target compounds, 8a possessed the best K i value of 1.015 μM against C. auris acetohydroxyacid synthase (CauAHAS) and an MIC value of 6.25 μM against CBS10913, a clinically isolated strain of C. auris. Taken together the structures of BSM and the synthesized compounds, it was found that methoxy groups at both meta-position of pyrimidine ring are likely to provide desirable antifungal activities. Quantum calculations and molecular dockings were performed to understand the structure-activity relationships. The present study has hence provided some interesting clues for the discovery of novel antibiotics with this distinct mode of action., (© 2023 John Wiley & Sons Ltd.)

The Spt-Ada-Gcn Acetyltransferase (SAGA) complex is a highly conserved co-activator found across eukaryotes. It is composed of a number of modules which can vary between species, but all contain the core module. Hfi1 (known as TADA1 in Homo sapiens ) is one of the proteins that forms the core module, and has been shown to play an important role in maintaining complex structural integrity in both brewer's yeast and humans. In this study we successfully identified the gene encoding this protein in the important fungal pathogen, Cryptococcus neoformans , and named it HFI1 . The hfi1 Δ mutant is highly pleiotropic in vitro, influencing phenotypes, ranging from temperature sensitivity and melanin production to caffeine resistance and titan cell morphogenesis. In the absence of Hfi1, the transcription of several other SAGA genes is impacted, as is the acetylation and deubiquination of several histone residues. Importantly, loss of the gene significantly impacts virulence in a murine inhalation model of cryptococcosis. In summary, we have established that Hfi1 modulates multiple pathways that directly affect virulence and survival in C. neoformans , and provided deeper insight into the importance of the non-enzymatic components of the SAGA complex.

Background: Initial treatment of hypertrophic pyloric stenosis (HPS) is correction of electrolyte disturbances with fluid resuscitation. In 2015, our institution implemented a fluid resuscitation protocol based on previous data that focused on minimizing blood draws and allowing immediate ad libitum feeds postoperatively. Our aim was to describe the protocol and subsequent outcomes., Methods: We conducted a single-center retrospective review of patients diagnosed with HPS from 2016 to 2023. All patients were given ad libitum feeds postoperatively and discharged home after tolerating three consecutive feeds. The primary outcome was the postoperative hospital length of stay (LOS). Secondary outcomes included the number of preoperative labs drawn, time from arrival to surgery, time from surgery to initiation of feeds, time from surgery to full feeds, and re-admission rate., Results: The study included 333 patients. A total of 142 patients (42.6%) had electrolytic disturbances that required fluid boluses in addition to 1.5x maintenance fluids. The median number of lab draws was 1 (IQR 1,2), with a median time from arrival to surgery of 19.5 hours (IQR 15.3,24.9). The median time from surgery to first and full feed was 1.9 hours (IQR 1.2,2.7) and 11.2 hours (IQR 6.4,18.3), respectively. Patients had a median postoperative LOS of 21.8 hours (IQR 9.7,28.9). Re-admission rate within the first 30 postoperative days was 3.6% ( n = 12) with 2.7% of re-admissions occurring within 72 hours of discharge. One patient required re-operation due to an incomplete pyloromyotomy., Discussion: This protocol is a valuable tool for perioperative and postoperative management of patients with HPS while minimizing uncomfortable intervention., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: To determine whether acromegaly is associated with increased extraocular muscle (EOM) size at time of presentation., Methods: Patients with a new diagnosis of acromegaly in a single tertiary care clinic with a CT scan that adequately delineated the EOMs were included. Control subjects were age- and sex-matched patients with a new diagnosis of nonfunctioning pituitary adenoma. Retrospective chart review was performed to extract baseline clinical and laboratory parameters including growth hormone, insulin-like growth factor 1, thyroid stimulating hormone, free T3, and free T4. A single neuroradiologist analyzed all CT scans and measured the maximum diameter and cross-sectional area of the superior rectus, inferior rectus, medial rectus, and lateral rectus in both eyes of all patients., Results: We evaluated 17 patients with acromegaly and 18 control subjects. Mean maximum diameter of the superior, inferior, medial, and lateral recti were 4.80 mm (SD = 0.81), 4.67 mm (SD = 0.54), 4.86 mm (SD = 0.77), and 4.53 mm (SD = 0.70) respectively, in the acromegaly group. In the control group, they were 3.62 mm (SD = 0.58),3.71 mm (SD = 0.46), 3.66 mm (SD = 0.32), and 3.21 mm (SD = 0.44), respectively. The maximum diameter and cross-sectional area of all 4 EOMs measured in the acromegaly group were significantly larger ( P < 0.001) compared with the control group., Conclusions: Patients with acromegaly present with significantly enlarged EOMs compared with control subjects with nonfunctioning pituitary adenomas., Competing Interests: The authors report no conflicts of interest., (Copyright © 2023 by North American Neuro-Ophthalmology Society.)

Introduction: Clinical remission has been achieved with infliximab in patients with refractory ulcerative colitis (UC). However, there is conflicting data regarding its effectiveness as rescue therapy in adult acute severe colitis. Furthermore, pediatric inflammatory bowel disease (IBD) is associated with more severe disease that may be less amenable to attempted rescue. We reviewed our experience and outcomes with pediatric severe colitis after attempted inpatient rescue with infliximab., Methods: A single-institution, retrospective review was conducted of pediatric patients with UC or indeterminate colitis who received inpatient rescue infliximab therapy from 1/2000 to 1/2019. Rescue infliximab therapy was considered if a child failed non-biologic therapy or progressed to fulminant or toxic colitis. Primary outcome was failed therapy resulting in colectomy. A p-value of <0.05 determined significance., Results: Thirty patients met inclusion criteria. The median age at administration of rescue infliximab treatment was 14 years [IQR 13,17]. Rescue therapy with infliximab was successful in 33% (n = 10), while 67% (n = 20) underwent colectomy. Children on maintenance steroids were less likely to be successfully rescued with infliximab and require colectomy (p = 0.03). Children requiring colectomy had a longer hospital stay (p = 0.03), more abdominal radiographs (p = 0.01), and were on a longer duration of antibiotics (p = <0.01) compared to children who were successfully rescued with infliximab. There was no difference in baseline vital signs or laboratory abnormalities between the two groups., Conclusion: In severe acute ulcerative or indeterminate colitis cases where infliximab has not been previously used, rescue infliximab can be used to avoid colectomy but has a high failure rate., Level of Evidence: IV., Type of Study: Retrospective study., (Copyright © 2023 Elsevier Inc. All rights reserved.)

The optimal approach to COVID-19 surveillance in congregate populations remains unclear. Our study at the US Naval Academy in Annapolis, Maryland, USA, assessed the concordance of antibody prevalence in longitudinally collected dried blood spots and saliva in a setting of frequent PCR-based testing. Our findings highlight the utility of salivary-based surveillance.

Background: The Arizona-Texas-Oklahoma-Memphis-Arkansas Consortium practice management guideline was created to standardize management of blunt liver or spleen injury across pediatric trauma centers. We describe our outcomes since guideline adoption at our institution and hypothesize that blunt liver or spleen injury may be managed more expeditiously than currently reported without compromising safety., Methods: A retrospective cohort study was conducted on patients younger than 18 years presenting with blunt liver and/or splenic injuries from March 2016 to March 2021 at one participating center., Results: A total of 199 patients were included. There were no clinically relevant differences for age, body mass index, or sex among the cohort. Isolated splenic injuries (n = 91 [46%]) and motor vehicle collisions (n = 82 [41%]) were the most common injury and mechanism, respectively. The overall median length of stay (LOS) was 1.2 days (interquartile range, 0.45-3.3 days). Intensive care unit utilization was 23% (n = 46). There was no statistically significant difference in median LOS among patients with isolated solid organ injuries, regardless of injury grade. There were no readmissions associated with non-operative management., Conclusion: The Arizona-Texas-Oklahoma-Memphis-Arkansas Consortium guideline fosters high rates of nonoperative management with low intensive care unit utilization and LOS while demonstrating safety in implementation, irrespective of injury grade., Level of Evidence: Therapeutic/Care Management; Level IV., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Revisional bariatric surgeries are increasing for weight recurrence and return of co-morbidities. Herein, we compare weight loss and clinical outcomes following primary Roux-en-Y Gastric Bypass (P-RYGB), adjustable gastric banding to RYGB (B-RYGB), and sleeve gastrectomy to RYGB (S-RYGB) to determine if primary versus secondary RYGB offer comparable benefits., Methods: Participating institutions' EMRs and MBSAQIP databases were used to identify adult patients who underwent P-/B-/S-RYGB from 2013 to 2019 with a minimum one-year follow-up. Weight loss and clinical outcomes were assessed at 30 days, 1 year, and 5 years. Our multivariable model controlled for year, institution, patient and procedure characteristics, and excess body weight (EBW)., Results: 768 patients underwent RYGB: P-RYGB n = 581 [75.7%]; B-RYGB n = 106 [13.7%]; S-RYGB n = 81 [10.5%]. The number of secondary RYGB procedures increased in recent years. The most common indications for B-RYGB and S-RYGB were weight recurrence/nonresponse (59.8%) and GERD (65.4%), respectively. Mean time from index operation to B-RYGB or S-RYGB was 8.9 and 3.9 years, respectively. After adjusting for EBW, 1 year %TWL (total weight loss) and %EWL (excess weight loss) were greater after P-RYGB (30.4%, 56.7%) versus B-RYGB (26.2%, 49.4%) or S-RYGB (15.6%, 37%). Overall comorbidity resolution was comparable. Secondary RYGB patients had a longer adjusted mean length of stay (OR 1.17, p = 0.071) and a higher risk of pre-discharge complications or 30-day reoperation., Conclusion: Primary RYGB offers superior short-term weight loss outcomes compared to secondary RYGB, with decreased risk of 30-day reoperation., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: The Midwest Pediatric Surgery Consortium (MWPSC) suggested a simple aspiration of primary spontaneous pneumothorax (PSP) protocol, failing which, Video-Assisted Thoracoscopic Surgery (VATS) should be considered. We describe our outcomes using this suggested protocol., Methods: A single institution retrospective analysis was conducted on patients between 12 and 18 years who were diagnosed with PSP from 2016 to 2021. Initial management involved aspiration alone with a ≤12 F percutaneous thoracostomy tube followed by clamping of the tube and chest radiograph at 6 h. Success was defined as ≤2 cm distance between chest wall and lung at the apex and no air leak when the clamp was released. VATS followed if aspiration failed., Results: Fifty-nine patients were included. Median age was 16.8 years (IQR 15.9, 17.3). Aspiration was successful in 33% (20), while 66% (39) required VATS. The median LOS with successful aspiration was 20.4 h (IQR 16.8, 34.8), while median LOS after VATS was 3.1 days (IQR 2.6, 4). In comparison, in the MWPSC study, the mean LOS for those managed with a chest tube after failed aspiration was 6.0 days (±5.5). Recurrence after successful aspiration was 45% (n = 9), while recurrence after VATS was 25% (n = 10). Median time to recurrence after successful aspiration was sooner than that of the VATS group [16.6 days (IQR 5.4, 19.2) vs. 389.5 days (IQR 94.1, 907.0) p = 0.01]., Conclusion: Simple aspiration is safe and effective initial management for children with PSP, although most will require VATS. However, early VATS reduces length of stay and morbidity., Level of Evidence: IV. Retrospective study., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Introduction: Same-day discharge (SDD) after laparoscopic appendectomy for acute nonperforated appendicitis is safe, without an increased rate of postoperative complications, emergency department visits, or readmissions. We aimed to evaluate caregiver satisfaction with this protocol., Methods: Patients discharged on the day of laparoscopic appendectomy for nonperforated acute appendicitis were identified between January 2022 and August 2022. Surveys to evaluate satisfaction with the protocol were distributed to the caregivers via email or text message 96 h after discharge. Telephone surveys were conducted if there were no responses to the initial online survey. The surveys assessed comfort with SDD, postoperative pain control adequacy, postoperative provider contact, and overall satisfaction. The protocol focused on avoidance of narcotics in the postoperative period and immediate return to a regular diet., Results: A total of 255 cases of nonperforated acute appendicitis underwent SDD. The survey response rate was 50.6% (n = 129). Most respondents were Caucasian (69.0%, n = 89) and male (51.9%, n = 67) with a median age of 12.0 y (IQR 8.9,14.7). The median postoperative length of hospital stay was 3.8 h (interquartile range [IQR] 3.2,4.8). The overall satisfaction rate was 91.5%, with 118 caregivers feeling satisfied with SDD. Most caregivers felt comfortable with the SDD protocol (89.9%, n = 116), with 22.5% (n = 29) calling a medical provider postoperatively. Approximately nine out of 10 caregivers reported that pain was adequately controlled (91.5%, n = 118). In contrast, those that were dissatisfied reported issues with pain control and anxiety with SDD after a surgical procedure., Conclusions: Caregiver satisfaction and comfort with same-day discharge following laparoscopic appendectomy is high with appropriate anticipatory guidance and preoperative education., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Family support is offered to Australian parents of young children using a mix of targeted and universal child and family health services including nurse-home-visiting programmes. These rely on the voluntary engagement of families. In this study, the capacity to engage and retain families, including those at risk of becoming involved with child protection services, was examined. The broad objective was to identify nursing practices used at the interface of health and child protection services and to articulate those practices. Child and Family Health Nurses (CFHN) ( n = 129) participated in a pragmatic, multilevel mixed-methods study. A questionnaire was used to identify nursing practices in the first phase of this study followed by focus groups in the second phase to describe these practices in more detail. Three practice themes were identified and described: enrolment, retention and conclusion of the nurse-family relationship. Universal child and family health services feature flexible, advanced, and multidimensional family support services including child protection practices. This paper focuses on practices employed by nurses to engage and retain families where child protection concerns are identified.

Objective: To assess the clinical implications of cryoanalgesia for pain management in children undergoing minimally invasive repair of pectus excavatum (MIRPE)., Background: MIRPE entails significant pain management challenges, often requiring high postoperative opioid use. Cryoanalgesia, which blocks pain signals by temporarily ablating intercostal nerves, has been recently utilized as an analgesic adjunct. We hypothesized that the use of cryoanalgesia during MIRPE would decrease postoperative opioid use and length of stay (LOS)., Materials and Methods: A multicenter retrospective cohort study of 20 US children's hospitals was conducted of children (age below 18 years) undergoing MIRPE from January 1, 2014, to August 1, 2019. Differences in total postoperative, inpatient, oral morphine equivalents per kilogram, and 30-day LOS between patients who received cryoanalgesia versus those who did not were assessed using bivariate and multivariable analysis. P value <0.05 is considered significant., Results: Of 898 patients, 136 (15%) received cryoanalgesia. Groups were similar by age, sex, body mass index, comorbidities, and Haller index. Receipt of cryoanalgesia was associated with lower oral morphine equivalents per kilogram (risk ratio=0.43, 95% confidence interval: 0.33-0.57) and a shorter LOS (risk ratio=0.66, 95% confidence interval: 0.50-0.87). Complications were similar between groups (29.8% vs 22.1, P =0.07), including a similar rate of emergency department visit, readmission, and/or reoperation., Conclusions: Use of cryoanalgesia during MIRPE appears to be effective in lowering postoperative opioid requirements and LOS without increasing complication rates. With the exception of preoperative gabapentin, other adjuncts appear to increase and/or be ineffective at reducing opioid utilization. Cryoanalgesia should be considered for patients undergoing this surgery., Competing Interests: The authors report no conflicts of interest., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Study Objective: There is little guidance for managing pubertally identified Mullerian anomalies in patients with anorectal malformations (ARMs). We sought to assess these unique issues., Design: Retrospective review SETTING: Single-institution study PARTICIPANTS: Natal female patients aged 10-25, with an ARM, cloaca, or exstrophy, who presented from 2009 to 2019 with a gynecologic concern were included., Intervention: Data collection was performed and included the presenting problem, psychological evaluation, fertility and sexuality concerns, and management strategies for these problems., Main Outcome Measures: The main outcome was unique needs that had to be addressed in the young adult population and the type of colorectal and gynecological procedures needed on representation., Results: Twelve patients were identified; all had gynecologic concerns. Ten had ARMs, including cloaca (n = 3) and cloacal exstrophy (n = 5). Median age at representation was 14.6 years (IQR = 12.7, 15.3). Colorectal revisions included posterior sagittal anorectoplasty (n = 1), resection of bowel attached to urogenital sinus (n = 1), and appendicostomy revision (n = 1). Gynecologic issues included dysmenorrhea (n = 8), obstructed Mullerian anomaly (n = 6), and introital stenosis (n = 5). Behavioral health concerns (n = 9) and fertility/sexuality concerns (n = 4) were identified. Median time from first visit to reconstruction was 1.5 years (IQR = 0.5, 1.5), providing multiple visits to achieve consensus among patients and providers before intervention, including vaginal or introital repair (n = 5) and hysterectomy of obstructed uterine horns (n = 3)., Conclusions: Goal-directed follow-up is required before surgical management to identify psychological and reproductive issues in patients with ARMs who have gynecologic concerns. Patient input and psychologic consultation are helpful for patients requiring staged reconstruction., Competing Interests: Conflict of Interest Statement No authors have any conflicts of interest to declare., (Copyright © 2022. Published by Elsevier Inc.)

Arboviral infections, including dengue (DNV), chikungunya (CHIKV), and Zika (ZIKV), impact both travelers and native populations of endemic regions. We sought to assess the disease burden of arboviral infections in the Military Health System, the validity of arboviral diagnostic codes, and the role of pretravel counseling on insect avoidance precautions. We searched for diagnostic codes consistent with arboviral infection and grouped them into DNV, CHIKV, ZIKV, Japanese encephalitis virus (JEV), and Other. Demographic data were evaluated. A subset of charts in each category were reviewed for diagnostic validity and travel characteristics. In all, 10,547 unique subjects carried 17,135 arboviral diagnostic codes, including 1,606 subjects (15.2%) coded for DNV, 230 (2.2%) for ZIKV, 65 (0.6%) for CHIKV, and 4,317 (40.9%) for JEV. A chart review was performed on 807 outpatient charts, yielding outpatient diagnostic code positive predictive values of 60.5% (DNV), 15.3% (ZIKV), and 64.5% (CHIKV); there were no valid cases of JEV. Dengue represented the greatest burden of arboviral infections with 2.2 cases per 100,000 military healthcare enrollees over the 2012-2019 fiscal years. More than 80% of subjects with arboviral infection did not have documented pretravel counseling. Arboviral infections represent a significant disease burden in young travelers to endemic regions. After adjustment for diagnostic validity, DNV represented the greatest burden. Diagnostic codes for ZIKV and JEV overestimate the burden of these diseases. Low rates of pretravel visits represent an opportunity for increased emphasis on insect exposure precautions.

Purpose: To identify the most accurate diagnostic imaging modality to detect optic disc drusen (ODD) between B-scan ultrasonography (US), fundus photography, fundus autofluorescence (FAF), and enhanced depth imaging optical coherence tomography (EDI-OCT)., Design: Comparative diagnostic analysis., Methods: Two hundred five eyes of 105 patients referred to 2 tertiary care neuro-ophthalmology clinics for suspected ODD were recruited: 108 eyes had ODD and 97 did not have ODD. All eyes received a full in-person ophthalmic exam with 3D view of the optic nerve and all 4 imaging modalities. Images were independently reviewed by 3 masked neuro-ophthalmologists to determine the presence or absence of ODD. Final interpretation was made through consensus. The reference standard was defined as the attending ophthalmologist's clinical judgement based on open chart review, with access to all image modalities and clinical information, including disease course. Main outcome measures were sensitivity, specificity, accuracy, and precision for each imaging modality. Examiner confidence was quantified as the proportion of eyes in which the reviewers were certain of their decision., Results: The EDI-OCT had the highest sensitivity and accuracy (95%, 97%) to detect ODD, compared with FAF (84%, 92%), US (74%, 86%), and fundus photography (38%, 66%), respectively. All image modalities had high specificity (> 97%) and precision (> 93%). The EDI-OCT also had highest examiner confidence (96%) compared with all others (88%)., Conclusions: Among all modalities, EDI-OCT was the imaging modality with the highest diagnostic utility for the detection of ODD and should be considered as the preferred initial diagnostic modality., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Verb and action knowledge deficits are reported in persons with Parkinson's disease (PD), even in the absence of dementia or mild cognitive impairment. However, the impact of these deficits on combinatorial semantic processing is less well understood. Following on previous verb and action knowledge findings, we tested the hypothesis that PD impairs the ability to integrate event-based thematic fit information during online sentence processing. Specifically, we anticipated persons with PD with age-typical cognitive abilities would perform more poorly than healthy controls during a visual world paradigm task requiring participants to predict a target object constrained by the thematic fit of the agent-verb combination. Twenty-four PD and 24 healthy age-matched participants completed comprehensive neuropsychological assessments. We recorded participants' eye movements as they heard predictive sentences (The fisherman rocks the boat) alongside target, agent-related, verb-related, and unrelated images. We tested effects of group (PD/control) on gaze using growth curve models. There were no significant differences between PD and control participants, suggesting that PD participants successfully and rapidly use combinatory thematic fit information to predict upcoming language. Baseline sentences with no predictive information (e.g., Look at the drum) confirmed that groups showed equivalent sentence processing and eye movement patterns. Additionally, we conducted an exploratory analysis contrasting PD and controls' performance on low-motion-content versus high-motion-content verbs. This analysis revealed fewer predictive fixations in high-motion sentences only for healthy older adults. PD participants may adapt to their disease by relying on spared, non-action-simulation-based language processing mechanisms, although this conclusion is speculative, as the analyses of high- vs. low-motion items was highly limited by the study design. These findings provide novel evidence that individuals with PD match healthy adults in their ability to use verb meaning to predict upcoming nouns despite previous findings of verb semantic impairment in PD across a variety of tasks., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Aveni et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)