Plasma Matrix Metalloproteinase Concentrations and Risk of Interstitial Lung Disease in a Prospective Rheumatoid Arthritis Cohort.

OBJECTIVE: To evaluate the associations of plasma matrix metalloproteinases (MMPs) with prevalent and incident interstitial lung disease (ILD) in people with rheumatoid arthritis (RA). METHODS: Within a multicenter, prospective cohort of US veterans with RA, we performed a cross-sectional study of prevalent ILD and cohort study of incident ILD. ILD diagnoses were validated by medical record review of provider diagnoses and chest imaging and/or pathology reports. MMP-1, 3, 7, and 9 concentrations were measured in plasma samples, then standardized and categorized into quartiles. The associations of MMPs with prevalent and incident ILD were assessed with logistic (prevalent) and Cox (incident) regression models adjusted for RA-ILD risk factors. RESULTS: Among 2,312 participants (88.9% male; mean age 63.8 years), 96 had prevalent ILD. Incident ILD developed in 130 participants over 17,378 person-years of follow-up (crude incidence rate 7.5/1,000 person-years). Participants with the highest quartile of MMP-7 concentrations had a nearly four-fold increased odds of prevalent ILD (adjusted odds ratio 3.78 [95% confidence interval (95% CI) 1.86-7.65]) and over two-fold increased risk of incident ILD (adjusted hazard ratio 2.33 [95% CI 1.35-4.02]). Higher MMP-9 concentrations were also associated with prevalent and incident ILD, as well as negatively correlated with forced vital capacity among those with prevalent ILD (r = -0.30, P = 0.005). CONCLUSION: MMP-7 and MMP-9 were strongly associated with both prevalent and incident ILD in this large, multicenter RA cohort after adjustment for other RA-ILD risk factors. These population-level findings further support a potential pathogenic role for MMPs in RA-ILD and suggest that their measurement could facilitate RA-ILD risk stratification.

Development and Internal Validation of a Clinical and Genetic Risk Score for Rheumatoid Arthritis-Associated Interstitial Lung Disease.

OBJECTIVE: Although clinical and genetic risk factors have been identified for rheumatoid arthritis-associated interstitial lung disease (RA-ILD), there are no current tools allowing for risk stratification. We sought to develop and validate an ILD risk model in a large, multicentre, prospective RA cohort. METHODS: Participants in the Veterans Affairs RA (VARA) registry were genotyped for 12 single nucleotide polymorphisms (SNPs) associated with idiopathic pulmonary fibrosis. ILD was validated through systematic record review. A genetic risk score (GRS) was computed from minor alleles weighted by effect size with ILD, using backward selection. The GRS was combined with clinical risk factors within a logistic regression model. Internal validation was completed using bootstrapping, and model performance was assessed by the area under the receiver operating curve (AUC). RESULTS: Of 2,386 participants (89% male, mean age 69.5 years), 9.4% had ILD. Following backward selection, five SNPs contributed to the GRS. The GRS and clinical factors outperformed clinical factors alone in discriminating ILD (AUC 0.675 vs 0.635, p< 0.001). The shrinkage-corrected performance for combined and clinical-only models was 0.667 (95% CI 0.628, 0.712) and 0.623 (95% CI 0.584, 0.651), respectively. Twenty percent of the cohort had a combined risk score below a cut-point with >90% sensitivity. CONCLUSION: A clinical and genetic risk model discriminated ILD in a large, multicentre RA cohort better than a clinical-only model, excluding 20% of the cohort from low-yield testing. These results demonstrate the potential utility of a GRS in RA-ILD and support further investigation into individualized risk stratification and screening.

Risk of Prostate Cancer in US Veterans With Rheumatoid Arthritis.

OBJECTIVE: Patients with rheumatoid arthritis (RA) have an increased risk of select cancers, including lymphoma and lung cancer. Whether RA influences prostate cancer risk is uncertain. We aimed to determine the risk of prostate cancer in patients with RA compared to patients without RA in the Veterans Health Administration (VA). METHODS: We performed a matched (up to 1:5) cohort study of male patients with and without RA in the VA from 2000 to 2018. RA status, as well as covariates, were obtained from national VA databases. Prostate cancer was identified through linked VA cancer databases and the National Death Index. Multivariable Cox models compared prostate cancer risk between patients with RA and patients without RA, including models that accounted for retention in the VA system. RESULTS: We included 56,514 veterans with RA and 227,284 veterans without RA. During 2,337,104 patient-years of follow-up, 6,550 prostate cancers occurred. Prostate cancer incidence (per 1,000 patient-years) was 3.50 (95% confidence interval [95% CI] 3.32-3.69) in patients with RA and 2.66 (95% CI 2.58-2.73) in patients without RA. After accounting for confounders and censoring for attrition of VA health care, RA was modestly associated with a higher prostate cancer risk (adjusted HR [HRadj ] 1.12 [95% CI 1.04-1.20]). There was no association between RA and prostate cancer mortality (HRadj 0.92 [95% CI 0.73-1.16]). CONCLUSION: RA was associated with a modestly increased risk of prostate cancer, but not prostate cancer mortality, after accounting for relevant confounders and several potential sources of bias. However, even minimal unmeasured confounding could explain these findings.

Genetic, social, and environmental risk factors in rheumatoid arthritis-associated interstitial lung disease.

OBJECTIVE: MUC5B and TOLLIP single nucleotide polymorphisms (SNPs) and cigarette smoking were associated with rheumatoid arthritis-interstitial lung disease (RA-ILD) in a predominantly Northern European population. We evaluated whether RA-ILD is associated with these genetic variants and HLA-DRB1 shared epitope (SE) alleles in a large RA cohort stratified by race and smoking history. METHODS: HLA-DRB1 SE alleles and MUC5B rs35705950 and TOLLIP rs5743890 SNPs were genotyped in U.S. veterans with RA. ILD was validated through medical record review. Genetic associations with ILD were assessed in logistic regression models overall and in subgroups defined by race and smoking status, with additive interactions assessed by the relative excess risk of interaction (RERI). RESULTS: Of 2,556 participants (88% male, 77% White), 238 (9.3%) had ILD. The MUC5B variant was associated with ILD (OR 2.25 [95% CI 1.69, 3.02]), whereas TOLLIP and HLA-DRB1 SE were not. The MUC5B variant was less frequent among Black/African American participants (5.8% vs. 22.6%), though its association with RA-ILD was numerically stronger (OR 4.23 [1.65, 10.86]) compared to all other participants (OR 2.32 [1.70, 3.16]). Those with the MUC5B variant and a smoking history had numerically higher odds of ILD (OR 4.18 [2.53, 6.93]) than non-smokers (OR 2.41 [1.16, 5.04]). Additive interactions between MUC5B-race and MUC5B-smoking were not statistically significant. CONCLUSION: In this large RA cohort, the MUC5B promoter variant was associated with >2-fold higher odds of RA-ILD. While this variant is less common among Black/African American patients, its presence in this population carried >4-fold higher odds of RA-ILD.

Cystic meningioangiomatosis and cerebellar ependymoma in a child with neurofibromatosis type 2.

We report a case of multifocal cystic meningioangiomatosis (MA), an exceptionally uncommon diagnosis even in patients with type 2 neurofibromatosis (NF2). A 2-year-old male with personal as well as family history of genetically-confirmed NF2 presented with incidental findings of MA after imaging for closed-head injury. Computed tomography and magnetic resonance imaging revealed multifocal subcortical and basal ganglia cysts, enhancing tumor-like vascular encasement, and a cerebellar ependymoma with atypical features. Given the paucity of available literature describing this pathology, imaging findings are discussed to further characterize this elusive disease. Radiologists must keep in mind that children with NF2 may not only present with MA, but also a constellation of MA with classic NF tumors, including ependymoma as in this case.

Descriptive Epidemiology of Pediatric Drowning Patients Presenting to a Large Southern US Children's Hospital.

OBJECTIVES: Drowning is the leading cause of death for children ages 1 to 4, and it is among the leading causes of death for children of all ages. National data show disparities in drowning risk for certain racial groups. This study aimed to describe characteristics of patients presenting after a drowning event to guide focused drowning prevention outreach efforts. METHODS: This was a retrospective chart review study designed to analyze the epidemiologic and demographic characteristics of drowning-related injuries and deaths that presented to a large, urban, southern US pediatric hospital from 2016 to 2019. All patients aged 0 to 19 years were identified using International Classification of Diseases, Ninth Revision and Tenth Revision codes for drowning or submersion injuries. RESULTS: One hundred sixty-two patients met the inclusion criteria for the study. Submersion injuries were most common in the 1- to 5-year-old age group. Fifty-eight percent of patients were male. The analysis of race showed that 65% of patients were White and 33% of patients were Black. Pools were the setting for 78% of drowning events. Fifty-four percent of patients received cardiopulmonary resuscitation. Sixty-four percent of patients required hospitalization after the injury. CONCLUSIONS: Characteristics of drowning victims may vary significantly from national data, depending on the area involved. This finding highlights the need for assessing local data to better inform local outreach. Further research is necessary to understand why such variance exists. Drowning prevention education, tailored toward pool safety and preschool-age children, should be a focus of injury prevention efforts.

Telemedicine in pediatric surgery.

IMPORTANCE: Telemedicine is an emerging strategy for healthcare delivery that has the potential to expand access, optimize efficiency, minimize cost, and enhance patient satisfaction. OBJECTIVE: To review the current spectrum, potential strategies, and implementation process of telemedicine in pediatric surgery. DESIGN: Review and opinion design. SETTING: n/a. PARTICIPANTS: n/a. MAIN OUTCOMES AND MEASURES: n/a. RESULTS: n/a. CONCLUSIONS AND RELEVANCE: Telemedicine is an emerging approach with the potential to facilitate efficient, cost-effective delivery of pediatric surgical services. BRIEF ABSTRACT: Telemedicine is an emerging strategy for healthcare delivery that has the potential to expand access, optimize efficiency, minimize cost, and enhance patient satisfaction. The objectives of this review are to explore common terms in telemedicine, provide an overview of current legislative and billing guidelines, review the current state of telemedicine in surgery and pediatric surgery, and provide basic themes for successful implementation of a pediatric surgical telemedicine program. TYPE OF STUDY: Review. LEVEL OF EVIDENCE: Level V.

Surgical Management of Gastroesophageal Reflux Disease in Patients with Severe Esophageal Dysmotility.

BACKGROUND: Gastroesophageal reflux disease (GERD) and esophageal dysmotility are often disqualifying criteria for fundoplication due to dysphagia complications. A tailored partial fundoplication may improve GERD in patients with severe esophageal motility disorders. We evaluate this approach on GERD improvement in non-achalasia esophageal dysmotility patients. METHODS: A single-institution prospective database was reviewed (2007-2016), with inclusion criteria of GERD, previous diagnosis of non-achalasia esophageal motility disorder, and laparoscopic partial fundoplication. Diagnosis of previous achalasia diagnosis or diffused esophageal spasm was excluded. Motility studies, pre- and post-upper gastrointestinal imaging (UGI), esophageal symptom scores, antacid, and PPI use were collected pre-op, 6 months, 12 months, and long-term (LT). Statistical analysis was made using SPSS v.23.0.0, α = 0.05. RESULTS: Fifty-two patients met the inclusion criteria. A total of 17.3% had esophageal body amotility, 79.6% had severe esophageal dysmotility. A total of 65.9% women (mean age 64 ± 15.7), mean peristalsis 45.3 ± 32.6%, and failed peristalsis 36.0 ± 32.2%. Mean LES residual pressure was 15.0 ± 18.0 mmHg, and 40.7% had hypotensive LES. Mean follow-up time was 25 months [1-7 years], with significant improvement in symptoms and reduction in PPI and antacid use at all time-points compared to pre-op. A total of 74% had UGI studies at 12 months; all showed persistent dysmotility. Six patients had radiographic hiatal hernia recurrence, with only one being clinically symptomatic postoperatively. Three required dilation for persistent dysphagia. CONCLUSIONS: A tailored partial fundoplication may be effective in symptom relief for non-achalasia patients with esophageal motility disorders and GERD. Significant symptom improvement, low HHR, and PPI use clearly indicate this approach to be effective for this population.