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.

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.

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.

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.

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.

Assessment of international MOGAD diagnostic criteria in patients with overlapping MOG-associated disease and multiple sclerosis phenotypes.

BACKGROUND: The clinical spectrum and diagnosis of myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) has evolved in the setting of an optimized anti-MOG-IgG cell-based assay and expert consensus. The McDonald criteria for MS have been revised multiple times to improve the accuracy and specificity of diagnosis on a framework based on clinical presentation, MRI findings, and CSF results. While the uses of MS and MOGAD diagnostic criteria are helpful for typical cases, such utility for patients with overlapping clinical, laboratorial, and imaging features is unknown, posing diagnostic and management uncertainties. OBJECTIVES: To report a multicenter cohort of patients with overlapping phenotypic features of MOGAD and MS and evaluate the application of new MOGAD diagnostic criteria. METHODS: A collaborative retrospective cohort study was performed to identify patients with both positive serum anti-MOG-IgG and fulfillment of the MS revised 2017 McDonald criteria. Clinical and radiographic features of patients fulfilling inclusion criteria were reviewed longitudinally, including relapses, repeated MRI, and MOG-IgG testing in detail to allow the panel of expert opinion to assign to each case. The International MOGAD Panel proposed criteria were applied at onset and last follow-up to each case and compared to the expert author diagnosis assignment based on presentation, clinical and imaging features, and response to treatment. RESULTS: Ten of 225 (4%) MOG-IgG seropositive cases met study inclusion criteria [seven of 10 were female; age at initial event: eight adults (mean age 26.8 years), two adolescents (mean age 14.5 years)]. AQP4-IgG was negative for all. Apart from serum titers of MOG-IgG, distinguishing clinical and radiographic features [i.e., clinical severity of the initial demyelinating event, radiographic features (optic nerve/spine/brain), and presence/absence of lesion normalization on serial scans] led to consensus of three separate classifications differing by degrees of shared features of MOGAD and MS. Patients were classified by expert panel into (1) Classic MOGAD even with MS-like, well-defined brain lesions, when severe events and most T2 lesions normalized (n = 5; MOG-IgG titers 1:100, 1:20, 1:160, 1:40, 1:200); (2) Classic RRMS included cases thought to have likely false positive or clinically irrelevant MOG-IgG, due to mild clinical events and no radiographic normalization of well-defined MS-like lesions (n = 3; MOG titers 1:20, 1:100, 1:40); (3) MOGAD and MS overlapping phenotype was defined by those with a combination of mild and severe clinical events, partial T2 lesion normalization, both well- and ill-defined lesions (n = 2; MOG titers 1:20, 1:100). The application of the International MOGAD Panel criteria categorized five patients (50%) in agreement with expert assignment. One additional patient was classified in agreement to assignment when MOGAD criteria were applied after serial MOG-IgG titers testing. DISCUSSION: While the International MOGAD Panel diagnostic criteria have helped with accuracy for the diagnosis of this condition, in a group of patients seropositive for MOG-IgG with overlapping clinical and imaging features of RRMS criteria review may lead to increased accuracy. Serial serologies, repeated imaging, close attention to clinical course, and response to therapy are possible variables to consider for further refinement of MOGAD diagnostic criteria.

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.

Comprehensive EHMT1 variants analysis broadens genotype-phenotype associations and molecular mechanisms in Kleefstra syndrome.

The shift to a genotype-first approach in genetic diagnostics has revolutionized our understanding of neurodevelopmental disorders, expanding both their molecular and phenotypic spectra. Kleefstra syndrome (KLEFS1) is caused by EHMT1 haploinsufficiency and exhibits broad clinical manifestations. EHMT1 encodes euchromatic histone methyltransferase-1-a pivotal component of the epigenetic machinery. We have recruited 209 individuals with a rare EHMT1 variant and performed comprehensive molecular in silico and in vitro testing alongside DNA methylation (DNAm) signature analysis for the identified variants. We (re)classified the variants as likely pathogenic/pathogenic (molecularly confirming Kleefstra syndrome) in 191 individuals. We provide an updated and broader clinical and molecular spectrum of Kleefstra syndrome, including individuals with normal intelligence and familial occurrence. Analysis of the EHMT1 variants reveals a broad range of molecular effects and their associated phenotypes, including distinct genotype-phenotype associations. Notably, we showed that disruption of the "reader" function of the ankyrin repeat domain by a protein altering variant (PAV) results in a KLEFS1-specific DNAm signature and milder phenotype, while disruption of only "writer" methyltransferase activity of the SET domain does not result in KLEFS1 DNAm signature or typical KLEFS1 phenotype. Similarly, N-terminal truncating variants result in a mild phenotype without the DNAm signature. We demonstrate how comprehensive variant analysis can provide insights into pathogenesis of the disorder and DNAm signature. In summary, this study presents a comprehensive overview of KLEFS1 and EHMT1, revealing its broader spectrum and deepening our understanding of its molecular mechanisms, thereby informing accurate variant interpretation, counseling, and clinical management.

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.

Protocol of a prospective multicenter study on comorbidity impact on multiple sclerosis and antibody-mediated diseases of the central nervous system (COMMIT).

Comorbidities in patients with multiple sclerosis (MS) and antibody-mediated diseases of the central nervous system (CNS) including neuromyelitis optica spectrum disorder (NMOSD), and myelin oligodendrocyte glycoprotein (MOG)-antibody-associated disease (MOGAD) are common and may influence the course of their neurological disease. Comorbidity may contribute to neuronal injury and therefore limit recovery from attacks, accelerate disease progression, and increase disability. This study aims to explore the impact of comorbidity, particularly vascular comorbidity, and related risk factors on clinical and paraclinical parameters of MS, NMOSD and MOGAD. We propose COMMIT, a prospective multicenter study with longitudinal follow-up of patients with MS, NMOSD, and MOGAD, with or without comorbidities, as well as healthy subjects as controls. Subjects will be stratified by age, sex and ethnicity. In consecutive samples we will analyze levels of inflammation and neurodegeneration markers in both fluid and cellular compartments of the peripheral blood and cerebrospinal fluid (CSF) using multiple state-of-the-art technologies, including untargeted proteomics and targeted ultrasensitive ELISA assays and quantitative reverse transcription polymerase chain reaction (RT-qPCR) as well as high-dimensional single-cell technologies i.e., mass cytometry and single-cell RNA sequencing. Algorithm-based data analyses will be used to unravel the relationship between these markers, optical coherence tomography (OCT) and magnetic resonance imaging (MRI), and clinical outcomes including frequency and severity of relapses, long-term disability, and quality of life. The goal is to evaluate the impact of comorbidities on MS, NMOSD, and MOGAD which may lead to development of treatment approaches to improve outcomes of inflammatory demyelinating diseases of the CNS.