Genomic Characterization of a Dog-Mediated Rabies Outbreak in El Pedregal, Arequipa, Peru.

Background: Rabies, a re-emerging zoonosis with the highest known human case fatality rate, has been largely absent from Peru, except for endemic circulation in the Puno region on the Bolivian border and re-emergence in Arequipa City in 2015, where it has persisted. In 2021, an outbreak occurred in the rapidly expanding city of El Pedregal near Arequipa, followed by more cases in 2022 after nearly a year of epidemiological silence. While currently under control, questions persist regarding the origin of the El Pedregal outbreak and implications for maintaining rabies control in Peru. Methods: We sequenced 25 dog rabies virus (RABV) genomes from the El Pedregal outbreak (n=11) and Arequipa City (n=14) from 2021-2023 using Nanopore sequencing in Peru. Historical genomes from Puno (n=4, 2010-2012) and Arequipa (n=5, 2015-2019), were sequenced using an Illumina approach in the UK. In total, 34 RABV genomes were analyzed, including archived and newly obtained samples. The genomes were analyzed phylogenetically to understand the outbreak's context and origins. Results: Phylogenomic analysis identified two genetic clusters in El Pedregal: 2021 cases stemmed from a single introduction unrelated to Arequipa cases, while the 2022 sequence suggested a new introduction from Arequipa rather than persistence. In relation to canine RABV diversity in Latin America, all new sequences belonged to a new minor clade, Cosmopolitan Am5, sharing relatives from Bolivia, Argentina, and Brazil. Conclusion: Genomic insights into the El Pedregal outbreak revealed multiple introductions over a 2-year window. Eco-epidemiological conditions, including migratory worker patterns, suggest human-mediated movement drove introductions. Despite outbreak containment, El Pedregal remains at risk of dog-mediated rabies due to ongoing circulation in Arequipa, Puno, and Bolivia. Human-mediated movement of dogs presents a major risk for rabies re-emergence in Peru, jeopardizing regional dog-mediated rabies control. Additional sequence data is needed for comprehensive phylogenetic analyses.

Irrigation, migration and infestation: a case study of Chagas disease vectors and bed bugs in El Pedregal, Peru.

BACKGROUND: The city of El Pedregal grew out of a desert, following an agricultural irrigation project in southern Peru. OBJECTIVES: To describe infestation patterns by triatomines and bed bugs and their relationship to migration and urbanization. METHODS: We conducted door-to-door entomological surveys for triatomines and bed bugs. We assessed spatial clustering of infestations and compared the year of construction of infested to un-infested households. To gain a better understanding of the context surrounding triatomine infestations, we conducted in-depth interviews with residents to explore their migration histories, including previous experiences with infestation. FINDINGS: We inspected 5,164 households for Triatoma infestans (known locally as the Chirimacha); 21 (0.41%) were infested. These were extremely spatially clustered (Ripley's K p-value < 0.001 at various spatial scales). Infested houses were older than controls (Wilcoxon rank-sum: W = 33; p = 0.02). We conducted bed bug specific inspections in 34 households; 23 of these were infested. These were spatially dispersed across El Pedregal, and no difference was observed in construction age between bed bug infested houses and control houses (W = 6.5, p = 0.07). MAIN CONCLUSIONS: The establishment of agribusiness companies in a desert area demanded a permanent work force, leading to the emergence of a new city. Migrant farmers, seeking work opportunities or escaping from adverse climatic events, arrived with few resources, and constructed their houses with precarious materials. T. infestans, a Chagas disease vector, was introduced to the city and colonized houses, but its dispersal was constrained by presence of vacant houses. We discuss how changes in the socioeconomic and agricultural landscape can increase vulnerability to vector-borne illnesses.

Consensus Statement of the National Association of EMS Physicians International Association of Fire Chiefs and the International Association of Chiefs of Police: Best Practices for Collaboration Between Law Enforcement and Emergency Medical Services During Acute Behavioral Emergencies.

Emergency Medical Services (EMS) and law enforcement (LE) frequently work as a team in encounters with individuals experiencing acute behavioral emergencies manifesting with severe agitation and aggression. The optimal management is a rehearsed, coordinated effort by law enforcement and EMS providing the necessary interventions to address behaviors that endanger the patient, the responders, and the public. The purpose of this document is to provide guidance and direction in the shared responsibility of managing and caring for a person displaying behavioral instability with irrational, agitated, and/or violent behavior. This is a discussion of the roles of law enforcement, 911 call centers (hereafter referred to as the Emergency Call Centers or "ECCs"), Fire, and EMS. A coordinated and unified response enhances the safety and effective management of potentially serious situations posed by individuals experiencing such acute behavioral emergencies. This paper provides the framework for an approach endorsed by NAEMSP, IACP, and the IAFC.

Endoscopic Ultrasound for the Evaluation of Esophageal Injury After Catheter Ablation for Atrial Fibrillation.

BACKGROUND & AIM: Atrial fibrillation (AF) ablation is an increasingly utilized rhythm control strategy that can damage adjacent structures in the mediastinum including the esophagus. Atrioesophageal fistulas and esophagopericardial fistulas are life-threatening complications that are thought to progress from early esophageal mucosal injury (EI). Endoscopic ultrasound (EUS) has been proposed as a superior method than EGD to survey EI and damage to deeper structures. We aim to evaluate the safety of EUS in categorizing post-ablation EI and quantify EUS-detected lesions and their correlation with injury severity and clinical course. METHODS: 234 consecutive patients between 2006-2020 who underwent AF ablation followed by EUS for the purpose of EI screening were retrospectively reviewed. Kansas City Classification (KCC) was used to classify EI (Type 1, Type 2a/b, Type 3a/b). RESULTS: EUS identified pleural effusions (31.6%) of patients, mediastinal adventitia changes (22.2%), mediastinal lymphadenopathy (14.1%), pulmonary vein changes (10.6%), and esophageal wall changes (7.7%). EGD revealed 175 (75%) patients without and 59 (25%) with EI. Patients with Type 2a/b EI and no EI were compared with multivariate logistic regression, and the presence of esophageal wall abnormality on EUS with OR 72.85 (95% CI 13.9-380.7), female sex with OR 3.97 (95% CI 1.3-12.3), and number of energy deliveries with OR 1.01 (95% CI 1.003-1.03), were associated with the presence EI type 2a or 2b. Pre-ablation PPI use was not associated with decreased risk of EI. CONCLUSIONS: EUS safely assesses mediastinal damage after ablation for atrial fibrillation and may excel over EGD in evaluating mucosal lesions of uncertain significance, with reduced risk of gas embolization in the setting of a full thickness injury (entero-vascular fistula). We propose an EUS-first guided approach to post-AF ablation examination, followed by EGD if it is safe to do so.

Identification of a DNA methylation episignature for recurrent constellations of embryonic malformations.

The term "recurrent constellations of embryonic malformations" (RCEM) is used to describe a number of multiple malformation associations that affect three or more body structures. The causes of these disorders are currently unknown, and no diagnostic marker has been identified. Consequently, providing a definitive diagnosis in suspected individuals is challenging. In this study, genome-wide DNA methylation analysis was conducted on DNA samples obtained from the peripheral blood of 53 individuals with RCEM characterized by clinical features recognized as VACTERL and/or oculoauriculovertebral spectrum association. We identified a common DNA methylation episignature in 40 out of the 53 individuals. Subsequently, a sensitive and specific binary classifier was developed based on the DNA methylation episignature. This classifier can facilitate the use of RCEM episignature as a diagnostic biomarker in a clinical setting. The study also investigated the functional correlation of RCEM DNA methylation relative to other genetic disorders with known episignatures, highlighting the common genomic regulatory pathways involved in the pathophysiology of RCEM.

Discovery of DNA methylation signature in the peripheral blood of individuals with history of antenatal exposure to valproic acid.

PURPOSE: Valproic acid or valproate is an effective antiepileptic drug; however, embryonic exposure to valproate can result in a teratogenic disorder referred to as fetal valproate syndrome (OMIM #609442). Currently there are no diagnostic biomarkers for the condition. This study aims to define an episignature biomarker for teratogenic antenatal exposure to valproate. METHODS: DNA extracted from peripheral blood of individuals with teratogenic antenatal exposure to valproate was processed using DNA methylation microarrays. Subsequently, methylation profiling and construction of support vector machine classifiers were performed in R. RESULTS: Genomic DNA methylation analysis was applied, and a distinct DNA methylation profile was identified in the majority of affected individuals. This profile was used to develop a diagnostic episignature classifier. The valproate exposure episignature exhibited high sensitivity and specificity relative to a large reference data set of unaffected controls and individuals with a wide spectrum of syndromic disorders with episignatures. Gene set enrichment analysis demonstrated an enrichment for terms associated with cell adhesion, including significant overrepresentation of the cadherin superfamily. CONCLUSION: This study provides evidence of a robust peripheral blood-based diagnostic epigenetic biomarker for a prenatal teratogenic disorder.

The Path to a Match for Interventional Cardiology Fellowship: A Major SCAI Initiative.

The field of interventional cardiology (IC) has evolved dramatically over the past 40 years. Training and certification in IC have kept pace, with the development of accredited IC fellowship training programs, training statements, and subspecialty board certification. The application process, however, remained fragmented with lack of a universal process or time frame. In recent years, growing competition among training programs for the strongest candidates resulted in time-limited offers and high-pressure situations that disadvantaged candidates. A grassroots effort was recently undertaken by a Society for Cardiovascular Angiography & Interventions task force, to create equity in the system by establishing a national Match for IC fellowship. This manuscript explores the rationale, process, and implications of this endeavor.

Utilization of an artificial intelligence-enhanced, web-based application to review bile duct brushing cytologic specimens: A pilot study.

BACKGROUND: The authors previously developed an artificial intelligence (AI) to assist cytologists in the evaluation of digital whole-slide images (WSIs) generated from bile duct brushing specimens. The aim of this trial was to assess the efficiency and accuracy of cytologists using a novel application with this AI tool. METHODS: Consecutive bile duct brushing WSIs from indeterminate strictures were obtained. A multidisciplinary panel reviewed all relevant information and provided a central interpretation for each WSI as being "positive," "negative," or "indeterminate." The WSIs were then uploaded to the AI application. The AI scored each WSI as positive or negative for malignancy (i.e., computer-aided diagnosis [CADx]). For each WSI, the AI prioritized cytologic tiles by the likelihood that malignant material was present in the tile. Via the AI, blinded cytologists reviewed all WSIs and provided interpretations (i.e., computer-aided detection [CADe]). The diagnostic accuracies of the WSI evaluation via CADx, CADe, and the original clinical cytologic interpretation (official cytologic interpretation [OCI]) were compared. RESULTS: Of the 84 WSIs, 15 were positive, 42 were negative, and 27 were indeterminate after central review. The WSIs generated on average 141,950 tiles each. Cytologists using the AI evaluated 10.5 tiles per WSI before making an interpretation. Additionally, cytologists required an average of 84.1 s of total WSI evaluation. WSI interpretation accuracies for CADx (0.754; 95% CI, 0.622-0.859), CADe (0.807; 95% CI, 0.750-0.856), and OCI (0.807; 95% CI, 0.671-0.900) were similar. CONCLUSIONS: This trial demonstrates that an AI application allows cytologists to perform a triaged review of WSIs while maintaining accuracy.

Increased Traumatic Brain Injury Severity and Mortality in Undocumented Immigrants.

BACKGROUND AND OBJECTIVES: Health disparities related to traumatic brain injury (TBI) have focused on socioeconomic status, race, and ethnicity. We sought to characterize TBI patterns and outcomes based on undocumented status. METHODS: Patients who presented to University of California, San Diego Health Trauma Center with a TBI between 2019 and 2022 were identified and stratified based on undocumented status. Undocumented immigrants were identified using validated methods of absent or invalid social security number and key terms through chart review. Demographic information, injury characteristics, and neurosurgical interventions were recorded. Univariable and multivariable analyses were performed to determine the impact of patient factors on outcomes. RESULTS: Of 1654 patients with TBI, 76 (4.6%) were undocumented. Undocumented immigrants were younger (50 vs 60 years; P < .001) and had higher Injury Severity Score (17 vs 13; P < .001). They presented from farther distances (12.8 vs 5.3 miles, P < .001) with greater midline shift (1.49 vs 0.91 mm; P = .003). A greater proportion had basal cistern compression/effacement (14% vs 4.6%; P = .001) and required neurosurgical intervention (18% vs 9.6%; P = .012). Undocumented immigrants had higher hospital charges ($208 403 vs $128 948; P < .001), length of stay (5 vs 4 days; P = .002), and were discharged to a health facility at a lower rate (18% vs 32%; P = .012). They had nearly double the mortality rate (14% vs 7.3%; P = .021), with undocumented status trending as a predictor on multivariable regression (odds ratio = 2.87; P = .052). CONCLUSION: Undocumented immigrants presented from farther distances with increased TBI severity, likely from both more severe trauma and delayed presentation, requiring more neurosurgical intervention. They also had greater length of stay, charges, and nearly double the mortality rate. Importantly, undocumented status was a strong predictor for mortality. Despite worse outcomes, they were discharged to a health care facility at a lower rate. Advocacy efforts should be directed at increasing health care coverage and migrant community engagement and education.

Diagnostic utility of DNA methylation analysis in genetically unsolved pediatric epilepsies and CHD2 episignature refinement.

Sequence-based genetic testing identifies causative variants in ~ 50% of individuals with developmental and epileptic encephalopathies (DEEs). Aberrant changes in DNA methylation are implicated in various neurodevelopmental disorders but remain unstudied in DEEs. We interrogate the diagnostic utility of genome-wide DNA methylation array analysis on peripheral blood samples from 582 individuals with genetically unsolved DEEs. We identify rare differentially methylated regions (DMRs) and explanatory episignatures to uncover causative and candidate genetic etiologies in 12 individuals. Using long-read sequencing, we identify DNA variants underlying rare DMRs, including one balanced translocation, three CG-rich repeat expansions, and four copy number variants. We also identify pathogenic variants associated with episignatures. Finally, we refine the CHD2 episignature using an 850 K methylation array and bisulfite sequencing to investigate potential insights into CHD2 pathophysiology. Our study demonstrates the diagnostic yield of genome-wide DNA methylation analysis to identify causal and candidate variants as 2% (12/582) for unsolved DEE cases.

Nirsevimab and Hospitalization for RSV Bronchiolitis.

BACKGROUND: Respiratory syncytial virus (RSV) is the leading cause of bronchiolitis, resulting in 3 million hospitalizations each year worldwide. Nirsevimab is a monoclonal antibody against RSV that has an extended half-life. Its postlicensure real-world effectiveness against RSV-associated bronchiolitis is unclear. METHODS: We conducted a prospective, multicenter, matched case-control study to analyze the effectiveness of nirsevimab therapy against hospitalization for RSV-associated bronchiolitis in infants younger than 12 months of age. Case patients were infants younger than 12 months of age who were hospitalized for RSV-associated bronchiolitis between October 15 and December 10, 2023. Control patients were infants with clinical visits to the same hospitals for conditions unrelated to RSV infection. Case patients were matched to control patients in a 2:1 ratio on the basis of age, date of hospital visit, and study center. We calculated the effectiveness of nirsevimab therapy against hospitalization for RSV-associated bronchiolitis (primary outcome) by means of a multivariate conditional logistic-regression model with adjustment for confounders. Several sensitivity analyses were performed. RESULTS: The study included 1035 infants, of whom 690 were case patients (median age, 3.1 months; interquartile range, 1.8 to 5.3) and 345 were matched control patients (median age, 3.4 months; interquartile range, 1.6 to 5.6). Overall, 60 case patients (8.7%) and 97 control patients (28.1%) had received nirsevimab previously. The estimated adjusted effectiveness of nirsevimab therapy against hospitalization for RSV-associated bronchiolitis was 83.0% (95% confidence interval [CI], 73.4 to 89.2). Sensitivity analyses gave results similar to those of the primary analysis. The effectiveness of nirsevimab therapy against RSV-associated bronchiolitis resulting in critical care was 69.6% (95% CI, 42.9 to 83.8) (27 of 193 case patients [14.0%] vs. 47 of 146 matched control patients [32.2%]) and against RSV-associated bronchiolitis resulting in ventilatory support was 67.2% (95% CI, 38.6 to 82.5) (27 of 189 case patients [14.3%] vs. 46 of 151 matched control patients [30.5%]). CONCLUSIONS: In a real-world setting, nirsevimab therapy was effective in reducing the risk of hospitalized RSV-associated bronchiolitis. (Funded by the National Agency for AIDS Research-Emerging Infectious Disease and others; ENVIE ClinicalTrials.gov number, NCT06030505.).

Development and validation of a claims-based algorithm to identify patients with Neuromyelitis Optica Spectrum disorder.

INTRODUCTION: No validated algorithm exists to identify patients with neuromyelitis optica spectrum disorder (NMOSD) in healthcare claims data. We developed and tested the performance of a healthcare claims-based algorithm to identify patients with NMOSD. METHODS: Using medical record data of 101 adults with NMOSD, multiple sclerosis (MS), or myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD), we tested the sensitivity and specificity of claims-based algorithms developed through interviews with neurologists. We tested the best-performing algorithm's face validity using 2016-2019 data from IBM MarketScan Commercial and Medicare Supplemental databases. Demographics and clinical characteristics were reported. RESULTS: Algorithm inclusion criteria were age ≥ 18 years and (≥1 NMO diagnosis [or ≥ 1 transverse myelitis (TM) and ≥ 1 optic neuritis (ON) diagnosis] and ≥ 1 NMOSD drug) or (≥2 NMO diagnoses ≥90 days apart). Exclusion criteria were MS diagnosis or use of MS-specific drug after last NMO diagnosis or NMOSD drug; sarcoidosis diagnosis after last NMO diagnosis; or use of ≥1 immune checkpoint inhibitor. In medical record billing data of 50 patients with NMOSD, 30 with MS, and 21 with MOGAD, the algorithm had 82.0% sensitivity and 70.6% specificity. When applied to healthcare claims data, demographic and clinical features of the identified cohort were similar to known demographics of NMOSD. CONCLUSIONS: This clinically derived algorithm performed well in medical records. When tested in healthcare claims, demographics and clinical characteristics were consistent with previous clinical findings. This algorithm will enable a more accurate estimation of NMOSD disease burden using insurance claims datasets.

Sex ratio and age of onset in AQP4 antibody-associated NMOSD: a review and meta-analysis.

BACKGROUND: Aquaporin-4 (AQP4) antibody-associated neuromyelitis optica spectrum disorder (NMOSD) is an antibody-mediated inflammatory disease of the central nervous system. We have undertaken a systematic review and meta-analysis to ascertain the sex ratio and mean age of onset for AQP4 antibody associated NMOSD. We have also explored factors that impact on these demographic data. METHODS: A systematic search of databases was conducted according to the PRISMA guidelines. Articles reporting sex distribution and age of onset for AQP4 antibody-associated NMSOD were reviewed. An initially inclusive approach involving exploration with regression meta-analysis was followed by an analysis of just AQP4 antibody positive cases. RESULTS: A total of 528 articles were screened to yield 89 articles covering 19,415 individuals from 88 population samples. The female:male sex ratio was significantly influenced by the proportion of AQP4 antibody positive cases in the samples studied (p < 0.001). For AQP4 antibody-positive cases the overall estimate of the sex ratio was 8.89 (95% CI 7.78-10.15). For paediatric populations the estimate was 5.68 (95% CI 4.01-8.03) and for late-onset cases, it was 5.48 (95% CI 4.10-7.33). The mean age of onset was significantly associated with the mean life expectancy of the population sampled (p < 0.001). The mean age of onset for AQP4 antibody-positive cases in long-lived populations was 41.7 years versus 33.3 years in the remainder. CONCLUSIONS: The female:male sex ratio and the mean age of onset of AQP4 antibody-associated NMOSD are significantly higher than MS. The sex ratio increases with the proportion of cases that are positive for AQP4 antibodies and the mean age of onset increases with population life expectancy.

Spinal movement disorders in NMOSD, MOGAD, and idiopathic transverse myelitis: a prospective observational study.

BACKGROUND: Retrospective studies suggest that spinal movement disorders, especially tonic spasms, are prevalent in NMOSD. However, there have been no prospective studies evaluating spinal movement disorders in NMOSD, MOGAD, and idiopathic transverse myelitis (ITM). METHODS: Patients referred to a tertiary neuroimmunology clinic for spinal cord demyelination (excluding MS) were evaluated. All patients answered a movement disorders survey and underwent a movement disorder-focused exam. Movement disorders were compared among patients with NMOSD with and without AQP4-IgG, MOGAD, and ITM. Patients with and without involuntary movements were also compared to identify predictors of spinal movement disorders. RESULTS: Sixty-three patients were evaluated from 2017 to 2021 (71% females, median age 49 years, range 18-72 years, median disease duration 12 months, range 1-408). Of the total, 49% had ITM, 21% had NMOSD without AQP4-IgG, 19% had NMOSD with AQP4-IgG, and 11% had MOGAD. Movement disorders were present in 73% of the total patients and were most frequent in NMOSD with AQP4-IgG (92%) and least frequent in MOGAD (57%). The most frequent spinal movement disorders were tonic spasms (57%), focal dystonia (25%), spinal tremor (16%), spontaneous clonus (9.5%), secondary restless limb syndrome (9.5%), and spinal myoclonus (8%). Multivariate analysis showed that longitudinally extensive myelitis and AQP4-IgG are independent risk factors for the development of spinal movement disorders, while MOG-IgG and African American race were associated with a lower risk of developing these movement disorders. CONCLUSIONS: Spinal movement disorders are highly prevalent in non-MS demyelinating disorders of the spinal cord. Prevalence rates exceed those reported in MS and retrospective NMOSD studies.

Coaxial plastic stent placement within lumen-apposing metal stents for the management of pancreatic fluid collections: a systemic review and meta-analysis.

Background/Aims: Coaxial placement of double pigtail plastic stents (DPPS) through lumen-apposing metal stents (LAMSs) is commonly performed to reduce the risk of LAMS obstruction, bleeding, and stent migration when used for the drainage of pancreatic fluid collections (PFCs). A systematic review and meta-analysis were performed to compare the outcomes of LAMS alone and LAMS with coaxial DPPS placement in the management of PFCs. Methods: A systematic review was conducted to identify studies comparing LAMS and LAMS/DPPS for PFC drainage. Primary outcomes included the rate of clinical success, overall adverse events (AEs), bleeding, infection, occlusion, and stent migration. The pooled effect size was summarized using a random-effects model and compared between LAMS and LAMS/DPPS by calculating odds ratios (ORs). Results: Nine studies involving 709 patients were identified (338 on LAMS and 371 on LAMS/DPPS). LAMS/DPPS was associated with a reduced risk of stent obstruction (OR, 0.59; p=0.004) and infection (OR, 0.55; p=0.001). No significant differences were observed in clinical success (OR, 0.96; p=0.440), overall AEs (OR, 0.57; p=0.060), bleeding (OR, 0.61; p=0.120), or stent migration (OR, 1.03; p=0.480). Conclusions: Coaxial DPPS for LAMS drainage of PFCs is associated with a reduced risk of stent occlusion and infection; however, no difference was observed in the overall AE rates or bleeding.

Enhancing Mass Vaccination Programs with Queueing Theory and Spatial Optimization.

Background: Mass vaccination is a cornerstone of public health emergency preparedness and response. However, injudicious placement of vaccination sites can lead to the formation of long waiting lines or queues, which discourages individuals from waiting to be vaccinated and may thus jeopardize the achievement of public health targets. Queueing theory offers a framework for modeling queue formation at vaccination sites and its effect on vaccine uptake. Methods: We developed an algorithm that integrates queueing theory within a spatial optimization framework to optimize the placement of mass vaccination sites. The algorithm was built and tested using data from a mass canine rabies vaccination campaign in Arequipa, Peru. We compared expected vaccination coverage and losses from queueing (i.e., attrition) for sites optimized with our queue-conscious algorithm to those obtained from a queue-naive version of the same algorithm. Results: Sites placed by the queue-conscious algorithm resulted in 9-19% less attrition and 1-2% higher vaccination coverage compared to sites placed by the queue-naïve algorithm. Compared to the queue-naïve algorithm, the queue-conscious algorithm favored placing more sites in densely populated areas to offset high arrival volumes, thereby reducing losses due to excessive queueing. These results were not sensitive to misspecification of queueing parameters or relaxation of the constant arrival rate assumption. Conclusion: One should consider losses from queueing to optimally place mass vaccination sites, even when empirically derived queueing parameters are not available. Due to the negative impacts of excessive wait times on participant satisfaction, reducing queueing attrition is also expected to yield downstream benefits and improve vaccination coverage in subsequent mass vaccination campaigns.