C-reactive protein (CRP) in high altitude Bolivian peri-urban adolescents varies by adiposity, current illness, height, socioeconomic status, sex, and menarcheal status: The potential benefits and costs of adipose reserves in arduous environments.

OBJECTIVES: In non-industrialized and low-income populations, adipose stores can serve as a valuable buffer against harsh conditions such as seasonal food scarcity. However, these reserves may incur costs due to adipocytes' production of pro-inflammatory cytokines; inflammation is associated with increased risk for cardiometabolic diseases later in life. Life history theory posits that, especially in populations with high juvenile mortality, higher adiposity may nonetheless be advantageous if its benefits in early life outweigh its later costs. Relatively little is known about adolescents' C-reactive protein concentration (CRP; an inflammation biomarker) in such environments. We investigated CRP and its associations with several hypothesized predictors in adolescents in an economically diverse peri-urban Andean community. METHODS: We measured CRP in dried blood spots and collected data on anthropometrics, illnesses, socioeconomic status (SES), and menarcheal status in 59 female and 40 male adolescents ("Alteños", 11.0-14.9 years old) with normal vital signs in El Alto, Bolivia (~4150 m amsl). We used Cole's LMS method to standardize all anthropometrics for sex and age, and principal components analysis to construct a "fat-factor" variable loading on these standardized z-scores. We used multiple linear regression to assess the influence of fat-factor and other likely predictors on CRP rank. RESULTS: Compared to a national Bolivian growth reference, Alteños were, on average, shorter and leaner; only 6% were classified as overweight and none were obese. Pre-menarche females were on average leaner than post-menarche females. The best-fitting model explained 24% of the variance in CRP rank. Significant predictors were fat-factor, SES, current illness for males and pre-menarche females, and z-height for females. CONCLUSIONS: Our results are consistent with a tradeoff between investments in growth versus immune functioning, as might be expected in an environment with limited resources and high pathogen exposure (e.g., soil-transmitted helminths, poor sanitation). Thinner Alteños appear to maintain a minimum CRP concentration independent of fat-factor, while fatter (or less-thin) Alteños' CRP rises with fat-factor. Female Alteños appear to be trading off investment in immune response for investment in growth and maturation. Alteños' high rate of stunting and absence of obesity suggests chronic, presumably multifactorial, stress. Adipose stores likely buffer against some of these stressors and, in an environment such as this-in which many lack sufficient nutritious foods, potable water, adequate sewage, and health care-may confer a net lifetime benefit.

OBJETIVOS: En poblaciones no industrializadas y de bajos ingresos, las reservas adiposas pueden servir como un valioso amortiguador frente a condiciones duras como la escasez estacional de alimentos. Sin embargo, estas reservas pueden tener un coste debido a la producción de citoquinas proinflamatorias por parte de los adipocitos; la inflamación se asocia a un mayor riesgo de enfermedades cardiometabólicas en etapas posteriores de la vida. La teoría de la historia vital postula que, especialmente en poblaciones con una elevada mortalidad juvenil, una mayor adiposidad puede ser ventajosa si sus beneficios en los primeros años de vida compensan sus costes posteriores. Se sabe relativamente poco sobre la concentración de proteína C reactiva (PCR; un biomarcador de inflamación) de los adolescentes. Investigamos la PCR y sus asociaciones con varios predictores hipotéticos en adolescentes de una comunidad andina periurbana económicamente diversa. MÉTODOS: Se midió la PCR en muestras de sangre seca y se recogieron datos sobre antropometría, enfermedades, nivel socioeconómico (NSE) y menarquia en 59 mujeres y 40 varones adolescentes («alteños¼, 11,0­14,9 años de edad) con signos vitales normales en El Alto, Bolivia (~4150m amsl). Usamos el método LMS de Cole para estandarizar todos los parámetros antropométricos para sexo y edad, y análisis de componentes principales para construir una variable «factor de grasa¼ cargada en estos puntajes z­estandarizados. Se utilizó la regresión lineal múltiple para evaluar la influencia del factor grasa y otros posibles predictores en el rango de la PCR. RESULTADOS: En comparación con una referencia nacional boliviana de crecimiento, los alteños eran, en promedio, más bajos y más delgados; sólo el 6% estaban clasificados con sobrepeso y ninguno era obeso. Las chicas premenárquicos eran, en promedio, más delgados que las chicas postmenárquicos. El modelo de regresión que mejor se ajustaba explicaba el 24% de la varianza en el rango de PCR. Observamos una nueva asociación entre la adiposidad y la PCR. Cuando el factor adiposidad es >0, el rango de la PCR aumenta linealmente con el factor adiposidad. Cuando el factor adiposidad es <0, la PCR no varía con el factor adiposidad. Estos patrones sugieren que los Alteños más delgados mantienen una concentración mínima de PCR independiente del factor adiposidad, mientras que la PCR de los Alteños más gordos (menos delgados) aumenta con el factor adiposidad. Además, existe una mayor variación en el rango de la PCR en los adolescentes más delgados que en los más gordos. El autoinforme de una enfermedad actual en niños y niñas premenárquicas se asoció con una PCR significativamente más alta. La ausencia de una asociación significativa entre la enfermedad actual y la PCR en las chicas postmenárquicas puede reflejar confusión por cambios en la PCR durante el ciclo menstrual. Manteniendo constantes todos los demás factores predictivos, la PCR aumentó con el incremento del nivel socioeconómico. En las niñas, el aumento de la estatura se asoció a una disminución de la PCR, lo que sugiere que las niñas favorecen la inversión en crecimiento y maduración frente a la inversión en respuestas inmunitarias inflamatorias a corto plazo. En los chicos, no se observó una relación significativa entre la estatura y la PCR. La baja estatura y la delgadez de estos adolescentes sugieren que pueden estar invirtiendo en defensas humorales a más largo plazo (por ejemplo, anticuerpos contra helmintos), pero esta hipótesis requiere más estudios. CONCLUSIONES: La alta tasa de retraso en el crecimiento y la ausencia de obesidad de los alteños sugieren un estrés crónico, presumiblemente multifactorial. Muchas familias carecen de alimentos nutritivos suficientes, agua potable, alcantarillado adecuado y atención sanitaria. Es probable que las reservas adiposas amortigüen algunos de estos factores de estrés y confieran un beneficio neto a lo largo de la vida (la reducción de la mortalidad juvenil puede compensar cualquier aumento del riesgo de enfermedades cardiometabólicas en etapas posteriores de la vida). Sin embargo, estas compensaciones tienen un coste para los individuos y las sociedades. Reducir los riesgos de patógenos y mejorar la capacidad de los habitantes del altiplano para acceder sistemáticamente a agua limpia y a alimentos sanos suficientes y asequibles probablemente reportaría beneficios para la salud a lo largo de toda la vida.

Use of an artificial intelligence-generated vascular severity score improved plus disease diagnosis in retinopathy of prematurity.

OBJECTIVE: To evaluate whether providing clinicians with an artificial intelligence-based vascular severity score (AI-VSS) improves consistency in diagnosis of plus disease in retinopathy of prematurity (ROP). DESIGN: This is a multi-reader diagnostic accuracy imaging study. PARTICIPANTS: Eleven ROP experts (4 pediatric ophthalmologists, 7 retina specialists), 9 of which had been in practice for 10 or more years. METHODS: Retcam (Natus Medical Incorporated) fundus images were obtained from premature infants during routine ROP screening as part of the Imaging and Informatics in ROP study between January 2012 and July 2020. From all available exams, a subset of 150 eye exams from 110 infants were selected for grading. An AI-VSS was assigned to each set of images using the i-ROP DL system. The clinicians were asked to diagnose plus disease for each exam and assign an estimated VSS (range 1-9) at baseline, and then again one month later with AI-VSS assistance. A reference standard diagnosis (RSD) was assigned to each eye exam from the i-ROP study based on 3 masked expert labels and the ophthalmoscopic diagnosis. MAIN OUTCOME MEASURE: Mean linearly weighted kappa for plus disease diagnosis compared to the RSD. Area under the receiver operating characteristic and precision-recall curves (AUROC, AUPR) for 1-9 labels compared to RSD for plus disease. RESULTS: Expert agreement improved significantly from substantial (κ: 0.69 [0.59, 0.75]) to near perfect (κ: 0.81 [0.71, 0.86]) when AI-VSS was integrated. Additionally, there was a significant improvement in plus disease discrimination as measured by mean [95% confidence interval] AUROC (0.94 [0.92, 0.96] to 0.98 [0.96, 0.99], difference: 0.04 [0.01, 0.06]) and AUPR (0.86 [0.81, 0.90] to 0.95 [0.91, 0.97], difference: 0.09 [0.03, 0.14]). CONCLUSIONS: Providing ROP clinicians with an AI-based measurement of vascular severity in ROP was associated with both improved plus disease diagnosis and improved continuous severity labeling, as compared to a reference standard diagnosis for plus disease. If implemented in practice, AI-VSS could reduce inter-observer variability and standardize treatment for infants with ROP.

Avian Influenza A(H5N1) Virus among Dairy Cattle, Texas, USA.

During March and April 2024, we studied dairy cattle specimens from a single farm in Texas, USA, using multiple molecular, cell culture, and next-generation sequencing pathogen detection techniques. Here, we report evidence that highly pathogenic avian influenza A(H5N1) virus strains of clade 2.3.4.4b were the sole cause of this epizootic.

Operative Epidemiology of the First Five Years in a New African Neurosurgery Training Center: The Experience in Rural Kenya at Tenwek Hospital 2016 to 2021.

BACKGROUND: One strategy to increase the availability of neurosurgical services in underserved regions within Sub-Saharan African countries is to create new residency training programs outside of cosmopolitan cities where programs may already exist. In 2016 Tenwek Hospital in rural western Kenya began offering full-time neurosurgical services and in 2020 inaugurated a residency training program. This review highlights the operative epidemiology of the first 5 years of the hospital's neurosurgical department. METHODS: A retrospective review of all cases performed by a neurosurgeon at Tenwek Hospital between September 2016 and February 2022 was performed. Patient demographics, surgical indications, length of stay, and in-hospital mortality rates were collected. RESULTS: A total of 1756 cases were retrievable. Of these, 1006 (57.3%) were male and mean age was 30 years (range 1 day to 97 years). Mean length of stay was 11 ± 2 days and in-hospital mortality rate was 4.4% (77 patients). The most common pathologies in children comprised hydrocephalus and spina bifida (42.5% and 21.1%, respectively); in adults, cranial trauma (28.2%), oncology (25.2%), and degenerative spine (18.5%) were most common. Trauma was the leading cause of death. CONCLUSIONS: The neurosurgical caseload of a rural hospital in an underserved area can provide not only an adequate neurosurgical volume, but a robust and varied exposure that is necessary for training safe and competent surgeons who are willing to remain in their countries of origin.

Sacral neuromodulation device biofilm differs in the absence and presence of infection, harbors antibiotic resistance genes, and is reproducible in vitro.

INTRODUCTION/PURPOSE: Sacral neuromodulation (SNM) is effective therapy for overactive bladder refractory to oral therapies, and non-obstructive urinary retention. A subset of SNM devices is associated with infection requiring surgical removal. We sought to compare microbial compositions of explanted devices in the presence and absence of infection, by testing phase, and other clinical factors, and to investigate antibiotic resistance genes present in the biofilms. We analyzed resistance genes to antibiotics used in commercially-available anti-infective device coating/pouch formulations. We further sought to assess biofilm reconstitution by material type and microbial strain in vitro using a continuous-flow stir tank bioreactor, which mimics human tissue with an indwelling device. We hypothesized that SNM device biofilms would differ in composition by infection status, and genes encoding resistance to rifampin and minocycline would be frequently detected. MATERIALS/METHODS: Patients scheduled to undergo removal or revision of SNM devices were consented per IRB-approved protocol (IRB 20-415). Devices were swabbed intraoperatively upon exposure, with controls and precautions to reduce contamination of the surrounding field. Samples and controls were analyzed with next-generation sequencing and RT-PCR, metabolomics, and culture-based approaches. Associations between microbial diversity or microbial abundance, and clinical variables were then analyzed using t-tests and ANOVA. Reconstituted biofilm deposition in vitro using the bioreactor was compared by microbial strain and material type using plate-based assays and scanning electron microscopy. RESULTS: Thirty seven devices were analyzed, all of which harbored detectable microbiota. Proteobacteria, Firmicutes and Actinobacteriota were the most common phyla present overall. Beta-diversity differed in the presence versus absence of infection (p = 0.014). Total abundance, based on normalized microbial counts, differed by testing phase (p < 0.001), indication for placement (p = 0.02), diabetes mellitus (p < 0.001), cardiac disease (p = 0.008) and history of UTI (p = 0.008). Significant microbe-metabolite interaction networks were identified overall and in the absence of infection. 24% of biofilms harbored the tetA tetracycline/minocycline resistance gene and 53% harbored the rpoB rifampin resistance gene. Biofilm was reconstituted across tested strains and material types. Ceramic and titanium did not differ in biofilm deposition for any tested strain. CONCLUSIONS: All analyzed SNM devices harbored microbiota. Device biofilm composition differed in the presence and absence of infection and by testing phase. Antibiotic resistance genes including to rifampin and tetracycline/minocycline, which are used in commercially-available anti-infective pouches, were frequently detected. Isolated organisms from SNM devices demonstrated the ability to reconstitute biofilm formation in vitro. Biofilm deposition was similar between ceramic and titanium, materials used in commercially-available SNM device casings. The findings and techniques used in this study together provide the basis for the investigation of the next generation of device materials and coatings, which may employ novel alternatives to traditional antibiotics. Such alternatives might include bacterial competition, quorum-sensing modulation, or antiseptic application, which could reduce infection risk without significantly selecting for antibiotic resistance.

Doses of medial rectus muscle recessions for divergence insufficiency-type esotropia.

We evaluated whether doses of bilateral medial rectus recessions greater than Parks's tables yielded superior outcomes for adult-onset divergence insufficiency. Forty-two patients underwent bilateral medial rectus recessions. Dose was analyzed as the average total per muscle (surgery + suture adjustment if performed) and compared with the standard dose tables (based on preoperative distance esodeviation), as difference between dose performed and dose indicated by Parks's tables. Each participant was classified as having received either Parks's dose (within 0.5 mm) or a dose greater than Parks's dose. Success was defined as "rarely" or "never" diplopia in distance straight-ahead gaze and reading. For patients classified as success, the mean difference between actual surgical dose performed and Parks's dose was calculated. Success was 91% (29/32) in those receiving greater than Parks's dose versus 67% (6/9) with Parks's dose (difference = 24%; 95% CI, -5% to 60%). The mean surgical dose was 1.0 mm greater than Parks's tables for the 35 successes (at 10 weeks) versus 0.7 mm greater for the 6 failures (difference = 0.4 mm; 95% CI, -0.2 to 0.9). For medial rectus recessions in adult-onset divergence insufficiency-type esotropia, a surgical dose 1 mm greater than Parks's tables, for each muscle, is a reasonable strategy.

Helicobacter pylori exposure among the Awajún of the Peruvian Amazon: Prevalence and environmental, social, and biological associations.

OBJECTIVES: Helicobacter pylori (H. pylori)-a gastric bacteria affecting almost 50% of the global population and leading to ulcers and cancer in severe cases-is a growing health concern among Indigenous populations who report a high burden of reported poor general health and gastrointestinal distress. We test hypothesized associations between H. pylori exposure patterns and environmental, social, and biological conditions among a sample of 212 Indigenous Awajún adults (112 males, 100 females, ages 18-65 years) living in the northern Peruvian Amazon. MATERIALS AND METHODS: Dried blood spots were analyzed for H. pylori-specific IgG using a recently developed enzyme-linked immunosorbent assay. Resulting seropositivity rates and antibody concentrations, proxying past exposures to H. pylori were analyzed in relation to relevant environmental (toilet type, floor material, reported water quality), social (household size and education level), and biological (age, sex, BMI, blood pressure, immune and metabolic biomarkers) factors using multivariable regression analyses. RESULTS: We found near ubiquitous seropositivity for H. pylori exposure in our sample (99.1% seropositive). In the regression analyses, elevations in H. pylori antibody concentrations were significantly higher among males compared to females (ß = 0.36, p = 0.01). No associations were found with any other factors. DISCUSSION: Anthropological research in the study communities suggests that the male bias in elevations of H. pylori antibody concentrations is related to cultural and biological factors. Future research is needed to further unravel these biocultural dynamics and determine whether elevations in H. pylori antibody concentrations have clinical relevance for gastrointestinal health outcomes in this population.

An exploratory study investigating the impact of the bladder tumor microbiome on Bacillus Calmette Guerin (BCG) response in non-muscle invasive bladder cancer.

PURPOSE: Intravesical Bacillus Calmette-Guerin (BCG) is standard of care for intermediate- and high-risk non-muscle invasive bladder cancer (NMIBC). The effect of the bladder microbiome on response to BCG is unclear. We sought to characterize the microbiome of bladder tumors in BCG-responders and non-responders and identify potential mechanisms that drive treatment response. MATERIALS AND METHODS: Patients with archival pre-treatment biopsy samples (2012-2018) were identified retrospectively. Prospectively, urine and fresh tumor samples were collected from individuals with high-risk NMIBC (2020-2023). BCG response was defined as tumor-free 2 years from induction therapy. Extracted DNA was sequenced for 16S rRNA and shotgun metagenomics. Primary outcomes were species richness (α-diversity) and microbial composition (ß-diversity). Paired t-tests were performed for α-diversity (Observed species/Margalef). Statistical analysis for ß-diversity (weighted and unweighted UniFrac distances, weighted Bray-Curtis dissimilarity) were conducted through Permanova, with 999 permutations. RESULTS: Microbial species richness (P < 0.001) and composition (P = 0.001) differed between BCG responders and non-responders. Lactobacillus spp. were significantly enriched in BCG-responders. Shotgun metagenomics identified possible mechanistic pathways such as assimilatory sulfate reduction. CONCLUSION: A compositional difference exists in the tumor microbiome of BCG responders and non-responders with Lactobacillus having increased abundance in BCG responders.

The altered TBI fecal microbiome is stable and functionally distinct.

Introduction: Patients who suffer a traumatic brain injury (TBI) often experience chronic and sometimes debilitating sequelae. Recent reports have illustrated both acute and long-term dysbiosis of the gastrointestinal microbiome with significant alterations in composition and predicted functional consequences. Methods: Working with participants from past research, metagenomic stability of the TBI- associated fecal microbiome (FMB) was evaluated by custom qPCR array comparing a fecal sample from 2015 to one collected in 2020. Metatranscriptomics identified differently expressed bacterial genes and biochemical pathways in the TBI FMB. Microbiota that contributed the largest RNA amounts identified a set of core bacteria most responsible for functional consequences of the TBI FMB. Results: A remarkably stable FMB metagenome with significant similarity (two-tail Spearman nonparametric correlation p < 0.001) was observed between 2015 and 2020 fecal samples from subjects with TBI. Comparing the 2020 TBI FMB metagenome to FMBs from healthy controls confirmed and extended the dysbiotic genera and species. Abundance differences between average TBI and healthy FMBs revealed Bacteroides caccae, B. uniformis, Blautia spp., Collinsella spp., Dialister spp., and Ordoribacter spp. were significantly different. Functionally, the Parabacteroides genus contributed the highest percentage of RNA sequences in control FMBs followed by the Bacteroides genus as the second highest contributor. In the TBI FMB, the Corynebacterium genus contributed the most RNA followed by the Alistipes genus. Corynebacterium and Pseudomonas were distinct in the top 10 contributing genera in the TBI FMB while Parabacteroides and Ruminococcus were unique to the top 10 in controls. Comparing RNA profiles, TBI samples had ∼1.5 fold more expressed genes with almost 700 differently expressed genes (DEGs) mapped to over 100 bacterial species. Bioinformatic analysis associated DEGs with pathways led identifying 311 functions in the average TBI FMB profile and 264 in the controls. By average profile comparison, 30 pathways had significantly different abundance (p < 0.05, t-test) or were detected in >80% of the samples in only one of the cohorts (binary distinction). Discussion: Functional differences between TBI and healthy control FMBs included amino acid metabolism, energy and carbon source usage, fatty acid metabolism, bacterial cell wall component production and nucleic acid synthesis and processing pathways. Together these data shed light on the functional consequences of the dysbiotic TBI FMB decades after injury.

Implementation of a minimally invasive cell culture system to measure the regulation of inflammation in a school-based sample of adolescents.

Dysregulated inflammation underlies many human diseases, and measures of responsiveness to activation, and sensitivity to inhibition, provide important information beyond baseline assessments of chronic inflammation. This study implements a simplified cell culture protocol in a school-based setting, using finger stick capillary blood collected from 333 adolescents (age 11.4-15.6 years) incubated with lipopolysaccharide (LPS). Median cytokine responses for IL6, IL1ß, and TNFα were 61.9, 26.2, and 11.2 pg/mL, respectively. Samples were also incubated with LPS and glucocorticoid (GC) to measure GC sensitivity. Median responses were reduced in the presence of GC inhibition for IL6 (20.3 pg/mL), IL1ß (10.5 pg/mL), and TNFα (3.3 pg/mL). Minimally invasive cell culture protocols provide novel opportunities for measuring inflammatory phenotypes in a wide range of non-clinical settings.

The Increase in Household Transmission of Pertussis Associated With Diagnostic Delays.

BACKGROUND: Pertussis is a highly contagious respiratory illness that can be especially dangerous to young children. Transmission of pertussis often occurs in household settings and is impacted by the timing of treatment and postexposure chemoprophylaxis. This study analyzes the risk for secondary household transmission and if delays in diagnosing pertussis increased the risk for household transmission. METHODS: We conducted 2 population-based studies using a large nationally representative administrative claims database. The first study utilized a stratified monthly incidence model to compare the incidence of pertussis among enrollees exposed to a family member with pertussis versus those not exposed. The second study was conducted at a household level following the index case of pertussis in each household. We identified diagnostic delays in the initial household case and used a logistic regression model to evaluate if such delays were associated with a greater risk for transmission. RESULTS: The incidence rate ratio of pertussis was 938.99 [95% confidence interval (CI): 880.19-1001.73] among enrollees exposed to a family member with pertussis relative to those not exposed. The odds of secondary household transmission in households where the index case experienced a diagnostic delay was 5.10 (CI: 4.44-5.85) times the odds of transmission when the index case was not delayed. We found that longer delays were associated with a greater risk for secondary household transmission (P < 0.0001). CONCLUSIONS: There is a high rate of secondary transmission of pertussis in household settings. Diagnostic delays increase the likelihood that pertussis will transmit in the household.

Comparing multiple infection control measures in a nursing home setting: a simulation study.

OBJECTIVE: Compare the effectiveness of multiple mitigation measures designed to protect nursing home residents from infectious disease outbreaks. DESIGN: Agent-based simulation study. SETTING: Simulation environment of a small nursing home. METHODS: We collected temporally detailed and spatially fine-grained location information from nursing home healthcare workers (HCWs) using sensor motes. We used these data to power an agent-based simulation of a COVID-19 outbreak using realistic time-varying estimates of infectivity and diagnostic sensitivity. Under varying community prevalence and transmissibility, we compared the mitigating effects of (i) regular screening and isolation, (ii) inter-resident contact restrictions, (iii) reduced HCW presenteeism, and (iv) modified HCW scheduling. RESULTS: Across all configurations tested, screening every other day and isolating positive cases decreased the attack rate by an average of 27% to 0.501 on average, while contact restrictions decreased the attack rate by an average of 35%, resulting in an attack rate of only 0.240, approximately half that of screening/isolation. Combining both interventions impressively produced an attack rate of only 0.029. Halving the observed presenteeism rate led to an 18% decrease in the attack rate, but if combined with screening every 6 days, the effect of reducing presenteeism was negligible. Altering work schedules had negligible effects on the attack rate. CONCLUSIONS: Universal contact restrictions are highly effective for protecting vulnerable nursing home residents, yet adversely affect physical and mental health. In high transmission and/or high community prevalence situations, restricting inter-resident contact to groups of 4 was effective and made highly effective when paired with weekly testing.

Infantile traumatic pericallosal aneurysm: illustrative case.

BACKGROUND: Traumatic aneurysms are a rare sequela of nonaccidental head trauma in infants. The rate of nonaccidental trauma (NAT) in the pediatric population is increasing; therefore, traumatic aneurysms are an important consideration in the evaluation of pediatric patients with abusive head trauma. OBSERVATIONS: A 24-day-old infant with no significant past medical or birth history presented with twitching and poor oral intake for 1 day. The patient was found to have bilateral subdural hematomas, multifocal contusions, and traumatic subarachnoid hemorrhage. NAT work-up was remarkable for a period of repeated and prolonged abuse. Magnetic resonance angiography revealed a right pericallosal traumatic aneurysm that was treated by means of coil and Onyx embolization. LESSONS: Traumatic intracranial aneurysms are a rare but serious sequela of pediatric abusive trauma. Traumatic intracranial aneurysms should be considered in the setting of intracranial pathology associated with high-energy trauma. Despite new methods for the management of traumatic aneurysms, this pathology remains challenging to identify and treat, and the prognosis remains poor because of the diffuse injury often involved in these patients.

Dental implant failures in Utah and US veteran cohorts.

INTRODUCTION: Approximately, 5.5 million dental implants are estimated to be surgically placed in the United States yearly, with an anticipated long-term failure rate ranging from 3% to 10%. At the Salt Lake City Dental Clinic within the Department of Veterans Affairs (VHA), specific protocols have been established to mandate that clinicians present every dental implant case for review by a committee. To understand the effectiveness of this approach, a comparative data analysis was undertaken to compare local dental implant failure data against national VHA data. METHODS: Leveraging electronic health records of veterans spanning from 2000 to 2021, we gathered procedural records related to dental implant placement or failure, demographic information, and medical history for individuals who received dental care at various dental clinics within the nationwide VHA network. Subsequently, statistical analyses were conducted using mixed-effects Poisson regression models with cluster-robust standard errors. Incident rate ratios (IRRs) for Utah-specific and nationwide cohorts were ascertained. RESULTS: The Utah VHA dental clinical data showed that there was a slightly lower prevalence of implant failure at 6.7% compared to the national cohort, which had a rate of 6.9%. The implant level failure rates were also low, with 4.20 (confidence interval [CI]: 3.68, 4.81) per 1000 implant placements per year for Utah cohorts. The adjusted IRR indicated a relative 16% reduction in risk among Utah Veterans (IRR 0.84, 95% CI [0.76-0.92]; p < 0.001). CONCLUSIONS: The stringent protocols in place at Salt Lake City, which integrate evidence-based practices and expert opinion for evaluating patient suitability for dental implant placement and subsequent care, contributed to the reduced risk among Utah Dental Clinic veterans pool compared to veterans of other states.

Cystic Fibrosis Carrier States Are Associated With More Severe Cases of Bronchiectasis.

Background: People with cystic fibrosis (CF) are at increased risk for bronchiectasis, and several reports suggest that CF carriers may also be at higher risk for developing bronchiectasis. The purpose of this study was to determine if CF carriers are at risk for more severe courses or complications of bronchiectasis. Methods: Using MarketScan data (2001-2021), we built a cohort consisting of 105 CF carriers with bronchiectasis and 300 083 controls with bronchiectasis but without a CF carrier diagnosis. We evaluated if CF carriers were more likely to be hospitalized for bronchiectasis. In addition, we examined if CF carriers were more likely to be infected with Pseudomonas aeruginosa or nontuberculous mycobacteria (NTM) or to have filled more antibiotic prescriptions. We considered regression models for incident and rate outcomes that controlled for age, sex, smoking status, and comorbidities. Results: The odds of hospitalization were almost 2.4 times higher (95% CI, 1.116-5.255) for CF carriers with bronchiectasis when compared with non-CF carriers with bronchiectasis. The estimated odds of being diagnosed with a Pseudomonas infection for CF carriers vs noncarriers was about 4.2 times higher (95% CI, 2.417-7.551) and 5.4 times higher (95% CI, 3.398-8.804) for being diagnosed with NTM. The rate of distinct antibiotic fill dates was estimated to be 2 times higher for carriers as compared with controls (95% CI, 1.735-2.333), and the rate ratio for the total number of days of antibiotics supplied was estimated as 2.8 (95% CI, 2.290-3.442). Conclusions: CF carriers with bronchiectasis required more hospitalizations and more frequent administration of antibiotics as compared with noncarriers. Given that CF carriers were also more likely to be diagnosed with Pseudomonas and NTM infections, CF carriers with bronchiectasis may have a phenotype more resembling CF-related bronchiectasis than non-CF bronchiectasis.

Metastatic gastric cancer target lesion complete response with Claudin18.2-CAR T cells.

Treatment of hematologic malignancies with patient-derived anti-CD19 chimeric antigen receptor (CAR) T-cells has demonstrated long-term remissions for patients with otherwise treatment-refractory advanced leukemia and lymphoma. Conversely, CAR T-cell treatment of solid tumors, including advanced gastric cancer (GC), has proven more challenging due to on-target off-tumor toxicities, poor tumor T-cell infiltration, inefficient CAR T-cell expansion, immunosuppressive tumor microenvironments, and demanding preconditioning regimens. We report the exceptional results of autologous Claudin18.2-targeted CAR T cells (CT041) in a patient with metastatic GC, who had progressed on four lines of combined systemic chemotherapy and immunotherapy. After two CT041 infusions, the patient had target lesion complete response and sustained an 8-month overall partial response with only minimal ascites. Moreover, tumor-informed circulating tumor DNA (ctDNA) reductions coincided with rapid CAR T-cell expansion and radiologic response. No severe toxicities occurred, and the patient's quality of life significantly improved. This experience supports targeting Claudin18.2-positive GC with CAR T-cell therapy and helps to validate ctDNA as a biomarker in CAR T-cell therapy. Clinical Insight: Claudin18.2-targeted CAR T cells can safely provide complete objective and ctDNA response in salvage metastatic GC.

Deficient butyrate metabolism in the intestinal microbiome is a potential risk factor for recurrent kidney stone disease.

Intestinal microbiome dysbiosis is a known risk factor for recurrent kidney stone disease (KSD) with prior data suggesting a role for dysfunctional metabolic pathways other than those directly utilizing oxalate. To identify alternative mechanisms, the current study analyzed differences in the metabolic potential of intestinal microbiomes of patients (n = 17) and live-in controls (n = 17) and determined their relevance to increased risk for KSD using shotgun metagenomic sequencing. We found no differences in the abundance of genes associated with known oxalate degradation pathways, supporting the notion that dysfunction in other metabolic pathways plays a role in KSD. Further analysis showed decreased abundance of key enzymes involved in butyrate biosynthesis in patient intestinal microbiomes. Furthermore, de novo construction of microbial genomes showed that the majority of genes significantly enriched in non-stone formers are affiliated with Faecalibacterium prausnitzii, a major butyrate producer. Specifically pertaining to butyrate metabolism, the majority of abundant genes mapped back to F. prausnitzii, Alistipes spp., and Akkermansia muciniphila. No differences were observed in ascorbate or glyoxylate metabolic pathways. Collectively, these data suggest that impaired bacterial-associated butyrate metabolism may be an oxalate-independent mechanism that contributes to an increased risk for recurrent KSD. This indicates that the role of the intestinal microbiome in recurrent KSD is multi-factorial, which is representative of the highly intertwined metabolic nature of this complex environment. Future bacteria-based treatments must not be restricted to targeting only oxalate metabolism.

Dissemination in time as a requirement for diagnosis of multiple sclerosis: Time for a change?

The requirement to demonstrate dissemination in time (DIT) in order to diagnose multiple sclerosis (MS) has been enshrined in the literature since earliest efforts to establish diagnostic critera. However, various diagnostic criteria over the years, including the 2017 McDonald criteria, have inconsistently utilized this concept. This Viewpoint contends that current criteria for DIT are inadequate and sometimes inappropriate. It recommends continuing to consider DIT in the diagnosis of MS, but advocates utilizing all available information with high specificity for the disease, including the presence of large numbers of typical lesions, to make the diagnosis. This approach enables early initiation of disease-modifying treatment in situations with a favorable risk-benefit ratio.

A functional identification platform reveals frequent, spontaneous neoantigen-specific T cell responses in patients with cancer.

The clinical impact of tumor-specific neoantigens as both immunotherapeutic targets and biomarkers has been impeded by the lack of efficient methods for their identification and validation from routine samples. We have developed a platform that combines bioinformatic analysis of tumor exomes and transcriptional data with functional testing of autologous peripheral blood mononuclear cells (PBMCs) to simultaneously identify and validate neoantigens recognized by naturally primed CD4+ and CD8+ T cell responses across a range of tumor types and mutational burdens. The method features a human leukocyte antigen (HLA)-agnostic bioinformatic algorithm that prioritizes mutations recognized by patient PBMCs at a greater than 40% positive predictive value followed by a short-term in vitro functional assay, which allows interrogation of 50 to 75 expressed mutations from a single 50-ml blood sample. Neoantigens validated by this method include both driver and passenger mutations, and this method identified neoantigens that would not have been otherwise detected using an in silico prediction approach. These findings reveal an efficient approach to systematically validate clinically actionable neoantigens and the T cell receptors that recognize them and demonstrate that patients across a variety of human cancers have a diverse repertoire of neoantigen-specific T cells.