Nevin Manimala

Nat Commun. 2022 Nov 12;13(1):6874. doi: 10.1038/s41467-022-34360-z.

ABSTRACT

Joint analyses of genomic datasets obtained in multiple different conditions are essential for understanding the biological mechanism that drives tissue-specificity and cell differentiation, but they still remain computationally challenging. To address this we introduce CLIMB (Composite LIkelihood eMpirical Bayes), a statistical methodology that learns patterns of condition-specificity present in genomic data. CLIMB provides a generic framework facilitating a host of analyses, such as clustering genomic features sharing similar condition-specific patterns and identifying which of these features are involved in cell fate commitment. We apply CLIMB to three sets of hematopoietic data, which examine CTCF ChIP-seq measured in 17 different cell populations, RNA-seq measured across constituent cell populations in three committed lineages, and DNase-seq in 38 cell populations. Our results show that CLIMB improves upon existing alternatives in statistical precision, while capturing interpretable and biologically relevant clusters in the data.

PMID:36371401 | DOI:10.1038/s41467-022-34360-z

Dig Liver Dis. 2022 Nov 9:S1590-8658(22)00749-6. doi: 10.1016/j.dld.2022.10.016. Online ahead of print.

ABSTRACT

BACKGROUND: Association between Hidradenitis Suppurativa (HS) and Inflammatory Bowel Disease (IBD) has been suggested.

AIMS: To assess characteristics of HS and IBD in patients with or without concomitant IBD.

METHODS: In a prospective, nested case-control study, each IBD patient with concomitant HS (Case) was retrospectively matched with 4 patients with HS and no IBD (Controls) for gender and age (±5 years).HS was classified according to the Hurley score and the International Hidradenitis Suppurativa Severity Score System (IHS4). Data were expressed as mean (Standard Deviation). Statistical analysis included Student-t Test or Mann-Whitney Test, χ2 test, univariate and multivariate logistic regression.

RESULTS: The study population included 125 patients with HS: 25 with IBD, 100 matched Controls with no IBD. IBD group included 19 (76%) Crohn’s disease and 6 (24%) Ulcerative Colitis patients. Obesity, familial HS and perianal HS were less frequent in Cases than in Controls (1[4%] vs 25(25%];p = 0.02; 1[4%] vs 21(21%];p = 0.04; 1[4%] vs 31(31%];p = 0.005, respectively).HS was less severe in Cases when assessed by the IHS4 (5.9 ± 4 vs 9 ± 6.7;p = 0.04).Complete drug-induced response for HS was more frequent in IBD (13[53%] vs28 (28%]; p = 0.04).

CONCLUSION: Clinical characteristics of HS and of patients differed between Cases and Controls. Present findings suggest the need to appropriately search and assess skin lesions compatible with HS in IBD.

PMID:36371384 | DOI:10.1016/j.dld.2022.10.016

Acad Radiol. 2022 Nov 9:S1076-6332(22)00572-4. doi: 10.1016/j.acra.2022.10.016. Online ahead of print.

ABSTRACT

RATIONALE AND OBJECTIVES: We investigated the diagnostic performance of dual-energy CT (DECT) virtual non-calcium (VNCa) and Rho/Z images for bone marrow infiltration of primary malignant bone tumors (PMBTs).

MATERIALS AND METHODS: We retrospectively analyzed 65 patients with PMBT who underwent DECT and MRI within 2 weeks. DECT was used to evaluate the presence and extent of marrow involvement surrounding PMBTs using the SCT, VNCa, and Rho/Z images. MRI was used as the reference standard for measurements. CT values of normal and involved bone marrow areas were measured on VNCa images, and Zeff values were measured on Rho/Z images. The statistical methods used were the 2*C chi-square test, ANOVA test, paired samples t test, and diagnostic performance of the different variables were evaluated using receiver operating characteristic curves.

RESULTS: VNCa and Rho/Z images showed higher accuracy (91%, 92% vs. 67%) and sensitivity (90%, 92% vs. 69%) than SCT images for diagnosing bone marrow infiltration in patients with PMBT. The maximum longitudinal diameter of tumor involvement measurements was statistically different between VNCa and SCT, Rho/Z and SCT, MRI, and SCT (all p < 0.05, p = 0.047, p = 0.049, and p = 0.023, respectively). The maximum transverse diameter was statistically significant between SCT and MRI, VNCa and MRI, Rho/Z and MRI (all p < 0.05, and p = 0.015, and p = 0.044, and p = 0.047, respectively). The HU or Zeff values based on the area of interest of VNCa and Rho/Z images differed significantly between the normal and infiltrated bone marrow area (p < 0.001). Receiver operating characteristic curve analysis revealed area under the curves of 0.995 and 0.988, respectively, with cut-off values of -31.57 HU and 7.8, and the sensitivity of both was 96.9%.

CONCLUSION: DECT-VNCa and Rho/Z images have good diagnostic value when evaluating bone marrow infiltration in PMBTs.

PMID:36371375 | DOI:10.1016/j.acra.2022.10.016

Arab J Gastroenterol. 2022 Nov 9:S1687-1979(22)00081-8. doi: 10.1016/j.ajg.2022.10.003. Online ahead of print.

ABSTRACT

BACKGROUND AND STUDY AIMS: Choledochal cysts are rare congenital cystic dilatations of the bile ducts that occur in fewer than 1% of individuals. The disease is common in East Asia, and most of the literature concerns those populations, but some data about Western populations have been published recently. Long-term reports about the disease in Middle Eastern populations, however, are currently lacking. We report a single-center 20-year experience in diagnosing and managing choledochal anomalies.

PATIENTS AND METHODS: Participants were adult patients in whom choledochal cysts were diagnosed over a 20-year (2000-2019) period at a single tertiary academic care center. Clinical data, including radiologic imaging findings, were retrieved from the patients’ medical records. To describe the baseline characteristics of the population, we calculated descriptive statistics.

RESULTS: Choledochal anomalies were diagnosed in 19 adult patients, whose median age was 30 years (interquartile range [IQR], 23-67 years). Of the choledochal cysts 13 (68.4%) were classified as Todani type I, 4 (21.1%) as Todani type IV, and 3 (15.8%) as Todani type V (Caroli’s disease). No patient had underlying chronic liver disease, and liver synthetic function was preserved in all. Eighteen patients (94.7%) underwent surgery: cyst excision with Roux-en-Y hepaticojejunostomy in 17 and liver transplantation in 1. All 18 survived surgery, and the median postoperative hospital stay was 11 days (IQR, 5-34 days). All 18 were alive 90 days after surgery, and the median follow-up period was 40 months (IQR, 12-140 months). Seven patients (36.8%) developed postoperative surgical complications; 2 patients required rehospitalization, and 1 required reoperation.

CONCLUSION: This description of adults with choledochal cysts is the latest long-term report about this disease in the Middle East. In our 20-year experience, the disease characteristics in our patients were moderately consistent with those described previously.

PMID:36371373 | DOI:10.1016/j.ajg.2022.10.003

Vaccine. 2022 Nov 7:S0264-410X(22)01370-6. doi: 10.1016/j.vaccine.2022.10.088. Online ahead of print.

ABSTRACT

INTRODUCTION: The safety profiles of COVID-19 vaccines are incompletely evaluated in Japan.

OBJECTIVES: To examine the risk of serious adverse effects after COVID-19 mRNA vaccination (BNT162b2 and mRNA-1273) in cohort studies and self-controlled case series (SCCS).

METHODS: Using an administrative claims database linked with the COVID-19 vaccination registry in a city in Japan between September 2020 and September 2021, we identified health insurance enrolees aged ≥ 18 years. We evaluated the risk of acute myocardial infarction, appendicitis, Bell’s palsy, convulsions/seizures, disseminated intravascular coagulation, immune thrombocytopenia, pulmonary embolism, haemorrhagic or ischemic stroke, venous thromboembolism, and all-cause mortality, 21 days following any COVID-19 mRNA vaccination, compared with non-vaccination periods. For the cohort studies, we estimated incidence rate ratios (IRRs) by Poisson regression and rate differences (IRDs) by weighted least-squares regression, adjusting for sex, age, and Charlson comorbidity index. We applied a modified SCCS design to appropriately treat outcome-dependent exposures. For the modified SCCS, we estimated within-subject IRRs by weighted conditional Poisson regression. Subgroup analyses stratified by sex and age were also conducted.

RESULTS: We identified 184,491 enrolees [male: 87,218; mean (standard deviation) age: 64.2 (19.5) years] with 136,667 first and 127,322 s dose vaccinations. The risks of any outcomes did not increase in any analyses, except for the fact that the modified SCCS indicated an increased risk of pulmonary embolism after the first dose in women (within-subject IRR [95%CI]: 3.97 [1.18-13.32]).

CONCLUSION: The findings suggested that the COVID-19 mRNA vaccine was generally safe, whilst a signal of pulmonary embolism following the first dose of the COVID-19 mRNA vaccine was observed.

PMID:36371366 | DOI:10.1016/j.vaccine.2022.10.088

Surgery. 2022 Nov 9:S0039-6060(22)00799-1. doi: 10.1016/j.surg.2022.09.025. Online ahead of print.

ABSTRACT

BACKGROUND: Peritoneal lavage cytology for pancreatic ductal adenocarcinoma is conducted with both an intraoperative rapid diagnosis by Papanicolaou staining (cytology-rapid) and a final diagnosis by immunocytochemical staining at a later date (cytology-final) in our hospital. However, the clinical significance of cytology-final has not yet been elucidated.

METHODS: A total of 675 pancreatic ductal adenocarcinoma patients who underwent pancreatectomy and cytology between 2002 and 2018 were retrospectively reviewed. Diagnostic results of cytology-rapid and cytology-final and survival outcomes were analyzed.

RESULTS: A total of 43 patients (6.4%) were diagnosed as cytology-rapid (+), and all of them were ultimately diagnosed as cytology-final (+). Among the 632 patients with cytology-rapid (-), 19 (3.0%) were eventually diagnosed as cytology-final (+). The overall survival of patients with cytology-rapid (+) and that of patients with cytology-rapid (-) did not differ to a statistically significant extent (median survival time 26.4 vs 32.9 months; P = .106). In contrast, the overall survival of patients who were diagnosed as a false-negative result by cytology-rapid was significantly worse than that of patients diagnosed as a true negative (18.7 vs 34.8 months; P = .031). The overall survival of patients with cytology-final (+) was significantly worse than that of patients with cytology-final (-) (23.6 vs 34.8 months; P = .012). A multivariate analysis showed that cytology-final (+) was an independent prognostic factor for the OS (hazard ratio = 1.43; P = .049), whereas cytology-rapid (+) was not.

CONCLUSION: Immunocytochemical staining may be a useful complement to a diagnosis of cytology by conventional Papanicolaou staining in pancreatic ductal adenocarcinoma patients.

PMID:36371356 | DOI:10.1016/j.surg.2022.09.025

Adv Rheumatol. 2022 Nov 12;62(1):43. doi: 10.1186/s42358-022-00275-y.

ABSTRACT

BACKGROUND: Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by synovial inflammation, fibroblast-like synoviocytes (FLS) activation and joint destruction. Fasciola hepatica is a platyhelminth that releases excretory-secretory immunomodulatory products capable of suppressing the Th1 immune response. Despite the effectiveness of available treatments for inducing disease remission, current options are not successful in all patients and may cause side effects. Thus, we evaluated the therapeutic potential of F. hepatica extract on FLS from RA patients and arthritis models.

METHODS: FLS were isolated from synovial fluid of RA patients, cultured, and exposed to F. hepatica extract (60, 80, and 100 µg/ml) for different time points to assess cell viability, adherence, migration and invasion. For in vivo experiments, mice with antigen (AIA) and collagen (CIA) induced arthritis received a 200 µg/dose of F. hepatica extract daily. Statistical analysis was performed by ANOVA and Student’s t-test using GraphPad Prism 6.0.

RESULTS: In vitro assays showed that extract decreased FLS cell viability at concentration of 100 µg/ml (83.8% ± 5.0 extract vs. 100.0% ± 0.0 control; p < 0.05), adherence in 20% (92.0 cells ± 5.8 extract vs. 116.3 cells ± 7.9 control; p < 0.05), migratory potential (69.5% ± 17.6 extract vs. 100.0% control; p < 0.05), and cell invasiveness potential through the matrigel (76.0% ± 8.4 extract vs. 100.0% control; p < 0.01). The extract reduced leukocyte migration by 56% (40 × 10⁴ leukocytes/knee ± 19.00) compared to control (90.90 × 10⁴ leukocytes/knee ± 12.90) (p < 0.01) and nociception (6.37 g ± 0.99 extract vs. 3.81 g ± 1.44 control; p < 0.001) in AIA and delayed clinical onset of CIA (11.75 ± 2.96 extract vs. 14.00 ± 2.56 control; p = 0.126).

CONCLUSION: Our results point out a potential immunomodulatory effect of F. hepatica extract in RA models. Therefore, the characterization of promising new immunomodulatory molecules should be pursued, as they can promote the development of new therapies. Trial registration Collection of synovial liquid and in vitro procedures were approved by the Ethics Committee with Certificate of Presentation of Ethical Appreciation in Plataforma Brasil (CAAE: 89044918.8.0000.5327; date of registration: 26/07/2018).

PMID:36371346 | DOI:10.1186/s42358-022-00275-y

J Otolaryngol Head Neck Surg. 2022 Nov 12;51(1):43. doi: 10.1186/s40463-022-00594-6.

ABSTRACT

BACKGROUND: The EIF1AX mutation has been identified in various benign and malignant thyroid lesions, with a higher prevalence in poorly differentiated thyroid carcinoma (PDTC) and anaplastic thyroid carcinoma, especially when combined with RAS or TP53 mutation. However, data and clinical significance of EIF1AX mutations in thyroid nodules is still limited. We investigated the prevalence of EIF1AX mutations and co-mutations in cytologically indeterminate thyroid nodules at our institution.

METHODS: A 5-year retrospective analysis was performed on surgically resected thyroid nodules with identified EIF1AX mutations on molecular testing with ThyroseqV3^®. Mutation type and presence of co-mutations were correlated with histopathologic diagnosis and clinical characteristics. Histopathology diagnoses were subsequently categorized as benign, borderline, malignant or aggressive malignant (≥ 10% PDTC component). Chi-square test was used to compare the malignancy associations of the: 1) A113_splice mutation compared to non-A113_splice mutations 2) singular A113_splice mutations compared to singular non-A113_splice mutations. Fisher’s Exact Test was used to determine the association of A113_splice mutation with aggressive malignancies compared to non-A113_splice mutations. A p value of 0.05 or less was considered statistically significant.

RESULTS: Out of 1583 patients who underwent FNA, 621 had further molecular testing. 31 cases (5%) harbored EIF1AX mutations. Of these cases, 12 (38.7%) were malignant, 2 (6.5%) were borderline, and 17 (55%) were benign. 4/31 cases (13%) were aggressive malignant (≥ 10% PDTC component). The most prevalent mutation was the A113_splice mutation at the junction of intron 5 and exon 6 (48%). All other mutations, except one, were located at the N-terminal in exon 2. 7/31 cases (22.6%) harbored ≥ 1 co-mutation(s), including 4 RAS, 3 TP53, 1 TERT and 1 PIK3CA, with 86% of them being malignant. All 4 nodules with RAS co-mutations were malignant including one PDTC.

CONCLUSION: Our study reports the largest cohort of EIF1AX mutations in Bethesda III/IV FNA samples with surgical follow-up to our knowledge. The presence of the EIF1AX mutation confers a 45.2% risk of malignancy (ROM) or borderline after surgery. However, the coexistence of EIF1AX mutations with other driver mutations such as RAS, TERT or TP53 conferred an 86% ROM. While 55% of thyroid nodules were benign at the time of surgery, the possible malignant transformation of these nodules, had they not been resected, is unknown. Finally, 13% of the nodules with EIF1AX mutations were aggressive with a significant PDTC component. These findings can further aid in clinical decisions for patients with thyroid nodules.

PMID:36371345 | DOI:10.1186/s40463-022-00594-6

Injury. 2022 Nov 4:S0020-1383(22)00807-5. doi: 10.1016/j.injury.2022.11.005. Online ahead of print.

ABSTRACT

BACKGROUND: To compare pain and function in patients with unstable posterior pelvic fractures stabilized with posterior fixation who undergo iliosacral screw removal versus those who retain their iliosacral screws.

METHODS: A prospective observational cohort study identified 59 patients who reported pain at least 4 months after iliosacral screw fixation of an unstable posterior pelvic ring fracture from 2015-2019. The primary intervention was iliosacral screw removal versus a matched iliosacral screw retention control group. Patient-reported pain was measured with the 10-point Brief Pain Inventory, and patient-reported function was measured with the Majeed Pelvic Outcome Score. Both measured within 6 months of the intervention.

RESULTS: Before iliosacral screw removal, the mean pain was 4.7 (SD, 3.0) compared with 4.7 (SD, 3.0) in the matched control group. Following iliosacral screw removal, the average pain in the screw removal group was 3.7 (SD, 2.7) and 3.3 (SD, 2.5) in the matched control group. We found no evidence that iliosacral screw removal reduced pain in this population (mean difference, 0.2 points; 95% CI, -1.0 to 1.5; p = 0.71). In addition, the improvement in function after iliosacral screw removal was not statistically indistinguishable from zero (mean difference, 3.1 points; 95% CI, -4.6 to 10.9; p = 0.42).

CONCLUSIONS: The results suggest that iliosacral screw removal offers no significant pelvic pain or function benefit when compared with a matched control group. Surgeons should consider these data when managing patients with pelvic pain who are candidates for iliosacral screw removal.

PMID:36371316 | DOI:10.1016/j.injury.2022.11.005

J Cyst Fibros. 2022 Nov 9:S1569-1993(22)01390-X. doi: 10.1016/j.jcf.2022.10.008. Online ahead of print.

ABSTRACT

BACKGROUND: The availability of new diagnostic algorithms for cystic fibrosis (CF), changing population demographics and programs that impact family planning decisions can influence incidence rates. Thus, previously reported incidence rates in Canada and the United States (US) may be outdated. The objectives of this study were to estimate contemporary CF incidence rates in Canada and the US and to determine if the incidence rate has changed over time.

METHOD: This population-based cohort study utilized data between 1995-2019 from the Canadian CF Registry (CCFR), Statistics Canada, US CF Foundation Patient Registry (CFFPR) data, and US Center for Disease Control (CDC) National Vital Statistics System. Incidence was estimated using the number of live CF births by year, sex, and geographic region using Poisson regression, with the number of live births used as the denominator. To account for delayed diagnoses, we imputed the proportion of diagnoses expected given historical trends, and varying rates of newborn screening (NBS) implementation by region.

RESULTS: After accounting for implementation of NBS and delayed diagnoses, the estimated incidence rate for CF in 2019 was 1:3848 (95% CI: 1:3574, 1:4143) live births in Canada compared to 1:5130 (95% CI:1:4996, 1:5267) in the US. There was substantial regional variation in incidence rates within both Canada and the US. Since 1995, incidence rates have decreased at a rate of 1.6% per year in both countries (p<0.001).

CONCLUSION: Contemporary CF incidence rates suggest CF incidence is lower than previously reported and varies widely within North America. This information is important for resource planning and for tracking how programs (e.g., genetic counselling, modulator availability etc.) may impact the incidence of CF moving forward.

PMID:36371312 | DOI:10.1016/j.jcf.2022.10.008