Citations

Abstract Background Much of our understanding about the natural history of pouch-related disorders has been generated from selected populations. We designed a geographically diverse, prospective registry to study the disease course among patients with 1 of 4 inflammatory conditions of the pouch. The primary objectives in this study were to demonstrate the feasibility of a prospective pouch registry and to evaluate the predominant treatment patterns for pouch-related disorders. Methods We used standardized diagnostic criteria to prospectively enroll patients with acute pouchitis, chronic antibiotic-dependent pouchitis (CADP), chronic antibiotic refractory pouchitis (CARP), or Crohn’s disease (CD) of the pouch. We obtained detailed clinical and demographic data at the time of enrollment, along with patient-reported outcome (PRO) measures. Results We enrolled 318 patients (10% acute pouchitis, 27% CADP, 12% CARP, and 51% CD of the pouch). Among all patients, 55% were on a biologic or small molecule therapy. Patients with CD of the pouch were more likely to use several classes of therapy (P < .001). Among patients with active disease at the time of enrollment, 23% with CARP and 40% with CD of the pouch were in clinical remission at 6 months after enrollment. Conclusions In a population where most patients had refractory inflammatory conditions of the pouch, we established a framework to evaluate PROs and clinical effectiveness. This infrastructure will be valuable for long-term studies of real-world effectiveness for pouch-related disorders.

SIGNIFICANCE When exploring relationships among clinical measures and patient‐reported outcome measures in adults with convergence insufficiency, worse symptoms (Convergence Insufficiency Symptom Survey [CISS] score) seemed to be correlated with worse reading function domain score (Adult Strabismus‐20 quality‐of‐life questionnaire). After treatment, improved symptoms were associated with improved reading function quality of life. PURPOSE This study aimed to explore relationships between clinical measures and patient‐reported outcome measures in adults undergoing treatment for symptomatic convergence insufficiency. METHODS In a prospective multicenter observational study, we evaluated adults with symptomatic convergence insufficiency (i.e., clinical measures of near exodeviation, receded near point of convergence, reduced near positive fusional vergence; CISS score ≥21). Fifty‐seven participants treated with vision therapy/exercises (n = 35) or base‐in prism (n = 22) were analyzed. Spearman correlation coefficients ( R ) were used to assess associations among the three clinical measures and patient‐reported outcome measures (CISS, Diplopia Questionnaire, four Adult Strabismus‐20 quality‐of‐life domains) before treatment (baseline) and after 10 weeks and 1 year. Associations were interpreted to be present when the lower limit of the 95% confidence interval (CI) was moderate to strong ( R ≥ 0.4). RESULTS Among multiple exploratory analyses, the only moderate to strong baseline correlation was between worse CISS and worse Adult Strabismus‐20 reading function scores ( R = 0.62; 95% CI, 0.43 to 0.76). Regarding change in measures with treatment, the only moderate to strong correlations were between improved CISS and improved Adult Strabismus‐20 reading function scores for prism at 10 weeks ( R = 0.78; 95% CI, 0.52 to 0.91) and 1 year ( R = 0.85; 95% CI, 0.65 to 0.94) and for vision therapy/exercises at 1 year ( R = 0.78; 95% CI, 0.57 to 0.89). CONCLUSIONS In exploratory analyses, we found positive correlations between CISS symptom scores and reading function quality‐of‐life scores. The absence of correlations between symptoms and individual clinical measures is consistent with clinical experience that, in convergence insufficiency, symptoms and clinical findings can be discordant.

Abstract The INSPIRE trial was a Phase 3, open‐label, multicenter trial (LTI‐301) that enrolled patients with pulmonary arterial hypertension (PAH) ≥ 18 years of age who transitioned to Yutrepia from nebulized treprostinil (Transition) or added Yutrepia to prostacyclin naïve patients on ≤2 nonprostacyclin oral therapies. The objectives of the trial were to evaluate the safety and tolerability of Yutrepia (dry‐powder formulation of treprostinil) in patients with PAH. The primary safety measures were the incidence of adverse events (AEs) and serious AEs. Exploratory efficacy measures were also assessed during the trial. Transition patients initiated Yutrepia at a dose comparable to their nebulized treprostinil dose while prostacyclin naïve patients received 26.5‐mcg QID; up‐titration in 26.5‐mcg increments was permitted for both groups. A total of 121 patients were enrolled, of which 29 patients discontinued from the trial, with the most common reason being AEs. Eighty percent of the Transition group and 96% of the prostacyclin naïve group titrated to a dose ≥79.5 mcg QID at Day 360, respectively, with one patient achieving a dose of 212‐mcg QID. The most common AEs were cough, headache, upper respiratory tract infection, dyspnea, dizziness, throat irritation, diarrhea, chest discomfort, fatigue, and nasopharyngitis. Most of these events were considered treatment‐related though mild to moderate in severity and expected for prostacyclin therapy administered by inhalation. In an evaluation of exploratory efficacy measures, patients remained stable or improved over the 1 year of treatment. Yutrepia was found to be a convenient, safe, and well‐tolerated inhaled prostacyclin treatment option for PAH patients.

Lay SummaryWe demonstrate low rates of breakthrough coronavirus disease 2019 (COVID-19) infection and mild course of illness following severe acute respiratory syndrome coronavirus 2 vaccination in a large cohort of inflammatory bowel disease patients. Residence in southern United States and lower median anti-receptor binding antibody level were associated with development of COVID-19.

AbstractBackgroundThere is insufficient evidence regarding postoperative systemic antibiotic prophylaxis use for more than 24 h following cardiovascular implantable electronic devices (CIED) implantation and its impact on infection prevention. However, this strategy remains a common practice in many institutions.MethodsWe conducted a systematic review and meta‐analysis including studies that compared the outcomes of patients: (1) who received preoperative plus 24 h or more of postoperative antibiotic prophylaxis (intervention group); and (2) who received either preoperative only or preoperative plus less than 24 h of antibiotic prophylaxis (control group). Risk of bias was assessed with ROBINS‐I and ROB‐2 tools. Risk ratio (RR) was pooled using random‐effect meta‐analyses with inverse variance method.ResultsEight studies that included two randomized controlled trials (RCTs) and six cohort studies with a total of 26,187 patients were included in the analysis. Overall, there were no differences in outcomes between the two groups, which included rates of CIED infection (RR 0.77, 95% CI 0.42, 1.42), mortality (RR 1.19, 95% CI 0.69, 2.06), pocket hematoma (RR 1.15, 95% CI 0.44, 3.00) or reintervention (RR 0.87, 95% CI 0.22, 3.46). Of note, the results were primarily impacted by the larger RCT.ConclusionsThere was no benefit of postoperative antibiotic prophylaxis for more than 24 h following CIED implantation in the current systematic review and meta‐analysis. This supports the practice advocated by current guidelines which foster antibiotic stewardship and may result in reductions of adverse drug events, selection for antibiotic resistance, and financial costs of prolonged postoperative antibiotic prophylaxis.

Study Design. Retrospective analysis on prospectively collected data. Objective. To determine the effectiveness of elective spine surgery in patients with Parkinson disease (PD). Background Context. PD has become increasingly prevalent in an aging population. While surgical treatment for degenerative spine pathology is often required in this population, previous literature has provided mixed results regarding its effectiveness. Methods. Data from the Quality Outcomes Database (QOD) was queried between April 2013 and January 2019. Three surgical groups were identified: (1) elective lumbar surgery, (2) elective cervical surgery for myelopathy, (3) elective cervical surgery for radiculopathy. Patients without PD were propensity matched against patients with PD in a 5:1 ratio without replacement based on American Society of Anesthesiology grade, arthrodesis, surgical approach, number of operated levels, age, and baseline Oswestry Disability Index, Numerical Rating Scale (NRS) extremity pain, NRS back pain, and EuroQol 5-Dimensions (EQ-5D). The mean difference was calculated for continuous outcomes (Oswestry Disability Index, NRS leg pain, NRS back pain, and EQ-5D at 3 and 12 mo after surgery) and the risk difference was calculated for binary outcomes (patient satisfaction, complications, readmission, reoperation, and mortality). Results. For the lumbar analysis, PD patients had a higher rate of reoperation at 12 months (risk difference=0.057, P=0.015) and lower mean EQ-5D score at 12 months (mean difference=−0.053, P=0.005) when compared with patients without PD. For the cervical myelopathy cohort, PD patients had lower NRS neck pain scores at 3 months (mean difference=−0.829, P=0.005) and lower patient satisfaction at 3 months (risk difference=−0.262, P=0.041) compared with patients without PD. For the cervical radiculopathy cohort, PD patients demonstrated a lower readmission rate at 3 months (risk difference=−0.045, P=0.014) compared with patients without PD. Conclusion. For the matched analysis, in general, patients with and without PD had similar patient-reported outcomes and complication, readmission, and reoperation rates. These results demonstrate that a diagnosis of PD alone should not represent a major contraindication to elective spine surgery.

Purpose To summarise the clinical, molecular and biochemical phenotype of mannosyl-oligosaccharide glucosidase-related congenital disorders of glycosylation (MOGS-CDG), which presents with variable clinical manifestations, and to analyse which clinical biochemical assay consistently supports diagnosis in individuals with bi-allelic variants in MOGS. Methods Phenotypic characterisation was performed through an international and multicentre collaboration. Genetic testing was done by exome sequencing and targeted arrays. Biochemical assays on serum and urine were performed to delineate the biochemical signature of MOGS-CDG. Results Clinical phenotyping revealed heterogeneity in MOGS-CDG, including neurological, immunological and skeletal phenotypes. Bi-allelic variants in MOGS were identified in 12 individuals from 11 families. The severity in each organ system was variable, without definite genotype correlation. Urine oligosaccharide analysis was consistently abnormal for all affected probands, whereas other biochemical analyses such as serum transferrin analysis was not consistently abnormal. Conclusion The clinical phenotype of MOGS-CDG includes multisystemic involvement with variable severity. Molecular analysis, combined with biochemical testing, is important for diagnosis. In MOGS-CDG, urine oligosaccharide analysis via matrix-assisted laser desorption/ionisation time-of-flight mass spectrometry can be used as a reliable biochemical test for screening and confirmation of disease.

AbstractCongenital disorders of glycosylation are a continuously expanding group of monogenic disorders of glycoprotein and glycolipid glycan biosynthesis. These disorders mostly manifest with multisystem involvement. Individuals with ALG8‐CDG commonly present with hypotonia, protein‐losing enteropathy, and hepatic involvement. Here, we describe seven unreported individuals diagnosed with ALG8‐CDG based on biochemical and molecular testing and we identify nine novel variants in ALG8, bringing the total to 26 individuals with ALG8‐CDG in the medical literature. In addition to the typical multisystem involvement documented in ALG8‐CDG, our cohort includes the two oldest patients reported and further expands the phenotype of ALG8‐CDG to include stable intellectual disability, autism spectrum disorder and other neuropsychiatric symptoms. We further expand the clinical features in a variety of organ systems including ocular, musculoskeletal, dermatologic, endocrine, and cardiac abnormalities and suggest a comprehensive evaluation and monitoring strategy to improve clinical management.

Abstract Background: Biopsy diagnoses of benign breast disease (BBD) confer a 1.5- to 4-fold increased risk of developing breast cancer (BC) compared with women without BBD. Previously, we reported that decreased numbers of specific immune cell types in lobules of BBD biopsies predicted increased BC risk, suggesting the promise of future tissue biomarker studies to define BC risk markers among BBD patients. Thus, we applied protein-based GeoMx® Digital Spatial Profiling (DSP) to BBD biopsies preceding BC (cases) and to BBD biopsies from cancer-free patients (controls) to identify possible BC risk markers, which we then evaluated in subsequent BC tissues and in surrounding normal lobules of cases. Methods: Archived pathology slides of BBD biopsies were reviewed and used to guide preparation of TMAs containing 1.0-mm diameter FFPE cores of lobules from an age- and cohort-period-matched set of 91 cases and 88 controls from the Mayo Clinic BBD Cohort. For patients who later developed BC, we prepared TMAs of BC tissue and surrounding mapped normal lobules. We applied GeoMx® DSP (immune and canonical signaling proteins) to both sets of TMAs. Following QC and data normalization, associations of case status with log-transformed biomarker expression in lobules of BBD biopsies were carried out using linear mixed modeling approaches, accounting for multiple ROIs per individual. Biomarkers significantly associated with case status (p<0.05) were further examined in BCs and adjacent normal lobules, using similar approaches. Results: The mean age at BBD biopsy was 52 years, and at BC diagnosis of cases, 61.4 years (mean time from BBD to BC was 10.2 years). A family history of BC was more frequent among cases (70% versus 43%; chi-square p=0.002). Of 72 biomarkers tested, 46 (64.4%) were evaluable after QC and normalization and 5 were associated with BC risk after adjustment for family history of BC: BCL2 (p=0.005), STING (p=0.006), CD44 (p=0.02), S100 protein (p=0.03) and pan-AKT (p=0.05); each showed higher levels in lobules of BBD biopsies of controls than cases. Three unique patterns appeared when examining these biomarkers across tissue type within cases: for BCL2 (p=5 x 10-9) and STING (p=2 x 10-19), levels were high in both BC and lobules surrounding BC but low in preceding BBD; for GAPDH (p=4 x 10-53) and pan-AKT (p=2 x 10-33), levels were high in BC, low in preceding BBD, and moderate in lobules surrounding BC; and for CD44 (p=2 x 10-6) and S100B (p=2 x 10-49), levels were low in BC, high in lobules surrounding BC and moderate in preceding BBD. Conclusions: Using a novel TMA of lobules in combination with DSP, we preliminarily identified immune-based and PI3 kinase-related protein biomarkers in BBD biopsies associated with BC risk. In case-only analyses, these markers demonstrated complex differences between lobules in BBD biopsies, subsequent BCs and adjacent normal lobules. Citation Format: Robert Alan Vierkant, Jodi M. Carter, Stacey J. Winham, Chen Wang, Jennifer M. Kachergus, Ji Shi, Raymond M. Moore, Bryan M. McCauley, Laura M. Pacheco-Spann, E A. Thompson, Derek C. Radisky, Amy C. Degnim, Mark E. Sherman. Towards prediction of breast cancer risk in benign biopsies with high-plex GeoMx spatial protein profiling [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2203.

Abstract Purpose: Many studies have highlighted the aberrant expression and prognostic significance of individual proteins in either the Rb (particularly cyclin D1, p16INK4A, and pRb) or the p53 (p53 and p21Waf1) pathways in non–small cell lung cancer. We hypothesize that cumulative abnormalities within each and between these pathways would have significant prognostic potential regarding survival. Experimental Design: Our study population consisted of 106 consecutive surgically resected cases of predominantly early-stage non–small cell lung cancer from the National Cancer Institute-Mayo Clinic series, and assessment of proteins involved both immunohistochemical (cyclin D1, p21Waf1, pRb, p16INK4A, and p53) and mutational analysis (p53) in relationship to staging and survival. Results: Cyclin D1 overexpression was noted in 48% of the tumors, p16INK4A negative in 53%, pRb negative in 17%, p53 immunopositive in 50%, p53 mutation frequency in 48%, and p21Waf1 overexpression in 47%, none with prognostic significance. Cyclin D1 overexpression in pRb-negative tumors revealed a significantly worse prognosis with a mean survival of 2.3 years (P = 0.004). A simultaneous p53 mutation dramatically reduced the mean survival time to 0.9 years (P = 0.007). Cyclin D1 overexpression with either a p53 mutation or a p53 overexpression was also associated with a significantly poorer prognosis (P = 0.0033 and 0.0063, respectively). Conclusions: Some cumulative abnormalities in the Rb and p53 pathways (e.g., cyclin D1 overexpression and p53 mutations) significantly cooperate to predict a poor prognosis; however, the complexity of the cell cycle protein interaction in any given tumor warrants caution in interpreting survival results when specific protein abnormalities are taken in isolation.