Miracle-dz/UniFAR-FTUs huggingface dataset:
Diffusion-weighted image improves detectability of magnetic resonance cholangiopancreatography for pancreatic ductal adenocarcinoma concomitant with intraductal papillary mucinous neoplasm

Abstract The present study is aimed to clarify the utility of magnetic resonance cholangiopancreatography (MRCP) and the additional value of diffusion-weighted imaging (DWI) in diagnosing pancreatic ductal adenocarcinoma (PDAC) concomitant with intraductal papillary mucinous neoplasm (IPMN). This retrospective study involved 38 patients with PDAC concomitant with IPMN and 114 patients (control) who were randomly selected from 320 patients with IPMN without PDAC and were matched with cases for magnetic resonance imaging (MRI) strength (1.5 T/3.0 T). Two radiologists reviewed the 2 MR image sets with relevant clinical information blinded, first MRCP alone and then combined MRI set including DWI. Diagnostic capability and interobserver agreement were assessed by using receiver operating characteristics curve (Az) analysis and weighted κ statistics. Az values for the 2 observers were 0.834 and 0.821 for MRCP alone and 0.964 and 0.926 for the combined MRI (P < .001 and P < .001), respectively. The sensitivity of MRCP alone was 61% (23/38), with both observers failing to diagnose PDACs located at the end of tail or away from the pancreatic duct. Meanwhile, with combined MRI, sensitivity was significantly increased for both observers (61% to 92%, P = .002; 61% to 87%, P = .004). Moreover, the interobserver agreement was higher with combined MRI (κ = 0.85) than MRCP alone (κ = 0.59). MRCP and DWI might be a superior option with a higher diagnostic capability of PDAC concomitant with IPMN than MRCP alone, especially for tumors away from the pancreatic duct.
Automated Knee Osteoarthritis Assessment Increases Physicians’ Agreement Rate and Accuracy: Data from the Osteoarthritis Initiative

Objective. To assess the impact of a computerized system on physicians’ accuracy and agreement rate, as compared with unaided diagnosis. Methods. A set of 124 unilateral knee radiographs from the Osteoarthritis Initiative (OAI) study were analyzed by a computerized method with regard to Kellgren-Lawrence (KL) grade, as well as joint space narrowing, osteophytes, and sclerosis Osteoarthritis Research Society International (OARSI) grades. Physicians scored all images, with regard to osteophytes, sclerosis, joint space narrowing OARSI grades and KL grade, in 2 modalities: through a plain radiograph (unaided) and a radiograph presented together with the report from the computer assisted detection system (aided). Intraclass correlation between the physicians was calculated for both modalities. Furthermore, physicians’ performance was compared with the grading of the OAI study, and accuracy, sensitivity, and specificity were calculated in both modalities for each of the scored features. Results. Agreement rates for KL grade, sclerosis, and osteophyte OARSI grades, were statistically increased in the aided versus the unaided modality. Readings for joint space narrowing OARSI grade did not show a statistically difference between the 2 modalities. Readers’ accuracy and specificity for KL grade >0, KL >1, sclerosis OARSI grade >0, and osteophyte OARSI grade >0 was significantly increased in the aided modality. Reader sensitivity was high in both modalities. Conclusions. These results show that the use of an automated knee OA software increases consistency between physicians when grading radiographic features of OA. The use of the software also increased accuracy measures as compared with the OAI study, mostly through increases in specificity.
Genomic and Molecular Abnormalities in Gynecologic Clear Cell Carcinoma

Gynecologic clear cell carcinoma is a rare histology, accounting for ~5% of all ovarian and endometrial cancers in the United States. Compared to other types of gynecologic cancer, they are generally less responsive to standard therapy and have an overall worse prognosis. In addition, mounting evidence suggests that the landscape of genetic and molecular abnormalities observed in these tumors is distinct from other cancers that arise from the same sites of origin. On a molecular level, these tumors characteristically display upregulation of the PI3K-AKT-mTOR and RAS-RAF-MAPK signaling axes, frequent loss of ARID1a, and overexpression of MDM2. Evidence also suggests that these tumors are more likely to express programmed death ligand 1 or demonstrate microsatellite instability than other gynecologic cancers. Despite these important differences, there has been relatively little investigation into histology-specific treatment of clear cell gynecologic cancers, representing an opportunity for new drug development. In this article, we review the unique genetic and molecular features of gynecologic clear cell cancers with an emphasis on potential therapeutic targets. The results of completed studies of treatment for clear cell carcinoma are also presented. We conclude with a discussion of ongoing clinical trials and potential avenues for future study.
Alanyl-glutamine heals indomethacin induced gastric ulceration in rats via anti-secretory and anti-apoptotic mechanisms.

OBJECTIVES Alanyl-glutamine (AG) is a dipeptide that fuels enterocytes and has a co-adjuvant role during gut healing. The current study aimed to investigate the potential ulcer-healing effect of AG in indomethacin-induced gastropathy. METHODS Animals (n = 10 rats/group) were randomly allocated into 5 groups. Gastric ulcerated rats were administered AG, AG + dexamethasone (DEXA), or pantoprazole post indomethacin exposure. RESULTS Comparable to pantoprazole, AG inhibited H-KATPase pump and elevated the pH of gastric juice. Moreover, the dipeptide increased the serum/mucosal contents of GLP-1, pS473-Akt, and cyclin-D1. On the other hand, AG abated serum TNF-α and gastric mucosal content of pS45-β catenin, pS9-GSK3β, pS133-CREB, pS536-NF-κB, H2O2, claudin-1, and caspase-3. The administration of DEXA prior to AG hampered its effect on almost all the measured parameters. CONCLUSIONS AG confers its anti-ulcerogenic/anti-secretory potentials by repressing the proton pump to increase the gastric juice pH via boosting p-CREB, p-Akt, p-GSK-3β, and GLP-1. Also, it inhibits apoptosis through suppressing NF-κB/TNF-α/H2O2/claudin-1 cue. This trajectory contributes to loosen the tight junction priming AG-mediated GLP-1/β-catenin/cyclin-D1 that results in pronounced increase in gastric mucosa proliferation. Therefore, the crosstalk between multiple pathways orchestrates the action of AG against gastric ulceration.
Treatment for latent tuberculosis infection in low- and middle-income countries: progress and challenges with implementation and scale-up

ABSTRACT Introduction: Treatment of latent tuberculosis infection (LTBI) is a crucial but neglected component of global tuberculosis control. The 2018 United Nations High-Level Meeting committed world leaders to provide LTBI treatment to at least 30 million people, including 4 million children<5 years, 20 million other household contacts and 6 million HIV-infected people by 2022. Areas covered: This review searched MEDLINE between 1990 and 2019 and discussed: i) high-risk groups to be prioritized for diagnosis and treatment of LTBI; ii) challenges with diagnosing LTBI in programmatic settings; iii) LTBI treatment options including isoniazid monotherapy, shorter regimens (rifampicin-monotherapy, rifampicin-isoniazid and rifapentine-isoniazid) and treatments for contacts of drug-resistant patients; iv) issues with programmatic scale-up of treatment including policy considerations, ruling out active TB, time to start treatment, safety, uninterrupted drug supplies and treatment adherence; and v) recording and reporting. Expert opinion: In 2017, <1.5 million persons were reported to be treated for LTBI. This must rapidly increase to 6 million persons annually. If HIV programs focus on HIV-infected people already accessing or about to start antiretroviral therapy and TB programs focus on household contacts, these targets could be achieved. Isoniazid remains the current treatment of choice although shorter courses of rifapentine-isoniazid are possible alternatives.
Comorbid personality disorders in manic bipolar I disorder patients is associated with increased use of long-acting injectable antipsychotic treatment and higher rates of rehospitalization

Supplemental Digital Content is available in the text. Personality disorder comorbidity is considered a poor prognostic factor among bipolar disorder patients. However, an evidence-based pharmacological treatment for this sub-population is lacking, and only few studies investigated the impact of personality disorder on bipolar disorder-I course. Here, we studied the effect of comorbid personality disorder on the administrated psychopharmacotherapy and rehospitalization risk among manic bipolar disorder-I patients. A sample of 340 patients with bipolar disorder-I, who were hospitalized with acute manic episode between 2005 and 2013, were retrospectively followed for a mean duration of 1129 days. Drug treatment at discharge and rehospitalization rates during follow-up time were compared between bipolar disorder-I patients with (n = 55) or without (n = 285) personality disorder comorbidity. Multivariate survival analyses adjusted for covariates were conducted. During the study period, 39.4% of bipolar disorder-I patients were rehospitalized due to a mood episode. Comorbid personality disorder was significantly associated with higher rates of long-acting injectable antipsychotics administration at discharge from hospitalization (adjusted odds ratio 2.66, 95% confidence interval: 1.19–5.94, P = 0.017). Comorbid personality disorder significantly increased the adjusted risk of rehospitalization due to a mood episode (hazard ratio = 2.04, 95% confidence interval: 1.29–3.23, P = 0.002). In conclusion, comorbid personality disorder in manic bipolar disorder-I patients is associated with increased use of long-acting injectable antipsychotics and higher rates of rehospitalization.
No effect of cognitive behavioral patient education for patients with pain catastrophizing before total knee arthroplasty: a randomized controlled trial

Background and purpose — Pain catastrophizing contributes to acute and long-term pain after total knee arthroplasty (TKA) but currently there are only limited treatment options. This study investigates the effectiveness of patient education in pain coping among patients with moderate to high pain catastrophizing score before TKA. Secondary outcomes were physical function, quality of life, self-efficacy, and pain catastrophizing. Patients and methods — The study was a parallel-group randomized controlled trial including patients with moderate to high levels of pain catastrophizing. 60 patients were recruited from December 2015 to June 2018. The mean age of the patients was 66 (47–82) years and 40 were women. The patients were randomized to either cognitive-behavioral therapy (CBT) based pain education or usual care. The primary outcome measure was pain under activity measured with the Visual Analog Scale (VAS). All outcomes were measured preoperatively, at 3 months, and at 1 year after surgery. Results — We found no difference in the primary outcome measure, VAS during activity, between the 2 groups but both groups had large reductions over time. The CBT-based pain education group reduced their VAS score by 37 mm (95% CI 27–46) and the control group by 40 mm (CI 31–49). We found no statistically significantly differences between the 2 groups in any of the secondary outcomes. Interpretation — Future research is warranted to identify predictors of persistent pain and interventions for the approximately 20% of patients with persisting pain after a TKA.
Drug–nutrient interactions: discovering prescription drug inhibitors of the thiamine transporter ThTR-2 (SLC19A3)

ABSTRACT Background Transporter-mediated drug–nutrient interactions have the potential to cause serious adverse events. However, unlike drug–drug interactions, these drug–nutrient interactions receive little attention during drug development. The clinical importance of drug–nutrient interactions was highlighted when a phase III clinical trial was terminated due to severe adverse events resulting from potent inhibition of thiamine transporter 2 (ThTR-2; SLC19A3). Objective In this study, we tested the hypothesis that therapeutic drugs inhibit the intestinal thiamine transporter ThTR-2, which may lead to thiamine deficiency. Methods For this exploration, we took a multifaceted approach, starting with a high-throughput in vitro primary screen to identify inhibitors, building in silico models to characterize inhibitors, and leveraging real-world data from electronic health records to begin to understand the clinical relevance of these inhibitors. Results Our high-throughput screen of 1360 compounds, including many clinically used drugs, identified 146 potential inhibitors at 200 μM. Inhibition kinetics were determined for 28 drugs with half-maximal inhibitory concentration (IC50) values ranging from 1.03 μM to >1 mM. Several oral drugs, including metformin, were predicted to have intestinal concentrations that may result in ThTR-2–mediated drug–nutrient interactions. Complementary analysis using electronic health records suggested that thiamine laboratory values are reduced in individuals receiving prescription drugs found to significantly inhibit ThTR-2, particularly in vulnerable populations (e.g., individuals with alcoholism). Conclusions Our comprehensive analysis of prescription drugs suggests that several marketed drugs inhibit ThTR-2, which may contribute to thiamine deficiency, especially in at-risk populations.
Assessment of serum lipid profile in early pregnancy and its relation with pre eclampsia: a prospective study

Background: Pathophysiology of pre eclampsia and atherosclerosis seems to be similar as a hyperlipidemic state, due to hormonal changes in pregnancy. We tried to assess the relationship between maternal plasma lipid concentration and risk of developing pre eclampsia. Methods: This is a prospective cohort study, for a period of one year from August 2009 to August 2010. Total no of subjects (N=270) were divided into two groups: Control group: who remained normotensive during study and Study group: who developed pre-eclampsia. Results: The mean level of cholesterol in study group was (226.74±39.77 mg/dl) significantly higher as compared to control group (164±22.48 mg/dl). That was statistically significant (p=0.001). Mean levels of cholesterol in mild PET group was 216±28.90mg/dl and in severe PET group was 252.3±50.63 mg/dl respectively, that was also significantly higher as compared to control group (p=0.001). In our study mean levels of Triglyceride was 153.95±23.52 mg/dl in control group and 205.25±42.48 mg/dl in study group. There were statistically significant difference between the groups (p=0.001). In mild PET mean value of Triglyceride was 198.99±36.12 mg/dl and in severe PET it was 220.35± 53.13mg/dl. It was seen that both the study group had significantly higher mean value as compared to control group (p=0.001). Conclusions: In present study we have observed that maternal dyslipidemia in early second trimester is associated with increased risk of developing pre eclampsia. So dyslipidemia in early second trimester is a very good predictor of pre eclampsia.
Reply to Adjuvant chemotherapy and prognosis in patients with breast cancer.

We thank Dr Kilickap et al. for their comments on our article in which prior adjuvant therapy was found to be associated with a poorer outcome in multivariate analysis from the time of metastatic occurrence [1]. We do not share their statement that this result is a consequence of an insufficient initial treatment of breast cancer patients followed in our cancer center since we cannot judge of treatment modalities in the past with current guidelines. Our treatment decisions were established during a multidisciplinary tumor broad according to international standards of care of the corresponding periods. T1 status and lymph node negative patients represent 48.3% and 37% of the cohort, respectively, which explains in part why only 40% (312 of 794) of all hormonal receptor positive patients received hormonotherapy. In previous studies, similar proportions were reported [2, 3]. Besides, as stated in our article, the frequency of hormonotherapy increased along the different periods of treatment (Figure 1), consistent with the arrival of tamoxifen in early breast cancer treatment in the 1980s and the gradual extension of adjuvant hormonotherapy indications. The fact that women with metastatic breast cancer who received adjuvant chemotherapy seem to have a poorer survival rate than chemotherapy-naive patients has already been enlightened in other studies [4, 5]. In a retrospective Spanish study of 1436 stages I–IIIa breast cancer patients, metastatic recurrence occurred in 297 patients and the use of anthracyclines previously as adjuvant therapy worsened the prognosis with a median survival of 20 months without anthracyclines versus 17 months with anthracyclines (P = 0.0008) [6]. Recently, the analysis of the subset of colorectal patients who experienced tumor recurrence after initial therapy for stage II or III colon cancers (FU-based adjuvant chemotherapy versus surgery only) clearly indicated that patients initially treated with adjuvant chemotherapy had a shorter survival following recurrence (median 14.2 versus 11.5 months, P = 0.0005) [7]. Such results are not surprising since patients who received adjuvant chemotherapy represent a population with more aggressive tumors than those to whom adjuvant chemotherapy was not proposed. Furthermore, the poorer outcome after recurrence in this subset of patients may be due to the emergence of cell clones initially resistant to drugs with less chemosensitivity at the onset of a metastatic stage [7, 8]. Another explanation could be found in a lower dose intensity of the following chemotherapy regimens in patients who previously received adjuvant chemotherapy secondary to a poorer performance status, a higher depression rate or
PLK4 deubiquitination by Spata2‐CYLD suppresses NEK7‐mediated NLRP3 inflammasome activation at the centrosome

The innate immune sensor NLRP3 assembles an inflammasome complex with NEK7 and ASC to activate caspase‐1 and drive the maturation of proinflammatory cytokines IL‐1β and IL‐18. NLRP3 inflammasome activity must be tightly controlled, as its over‐activation is involved in the pathogenesis of inflammatory diseases. Here, we show that NLRP3 inflammasome activation is suppressed by a centrosomal protein Spata2. Spata2 deficiency enhances NLRP3 inflammasome activity both in the macrophages and in an animal model of peritonitis. Mechanistically, Spata2 recruits the deubiquitinase CYLD to the centrosome for deubiquitination of polo‐like kinase 4 (PLK4), the master regulator of centrosome duplication. Deubiquitination of PLK4 facilitates its binding to and phosphorylation of NEK7 at Ser204. NEK7 phosphorylation in turn attenuates NEK7 and NLRP3 interaction, which is required for NLRP3 inflammasome activation. Pharmacological or shRNA‐mediated inhibition of PLK4, or mutation of the NEK7 Ser204 phosphorylation site, augments NEK7 interaction with NLRP3 and causes increased NLRP3 inflammasome activation. Our study unravels a novel centrosomal regulatory pathway of inflammasome activation and may provide new therapeutic targets for the treatment of NLRP3‐associated inflammatory diseases.
Association analysis between ARG1 gene polymorphisms and idiopathic dilated cardiomyopathy

Abstract The current study aimed at investigate the potential association of ARG1 polymorphisms in subjects affected by idiopathic dilated cardiomyopathy (IDCM). We have investigated 352 subjects affected by IDCM and 352 population-matched healthy controls by exploiting case-control study. The serum lipids were quantified using spectrophotometric assay, serum arginase activity was done by enzyme colorimetric assay and 2 polymorphisms (rs2781666 and rs2781667) in ARG1 were typed by polymerase chain reaction (PCR) followed by restriction fragment length polymorphism (RFLP) to find out disease associate allele/haplotype segregating in subjects affected by IDCM. Significantly high arginase activity was found to be associated with IDCM subjects when compared with population-matched healthy controls (P < .0001). The higher arginase level in IDCM subjects is negatively correlated with nitrite and nitrate (r = –0.4687, and r = –0.6435, respectively) in our study. There was a significant difference in the distribution of rs2781666 and rs2781667 genotypes of ARG1 polymorphism in patients and controls (P < .0001). Similarly, variant allele T at both loci showed a significant association with the disease phenotypes (P < .0001). Haplotype TT at rs2781666G/T and rs2781667C/T also showed a significantly association (P < .0001). To our knowledge, this is the first report to show a significant involvement of ARG1 polymorphisms to produce IDCM symptoms in subjects originating in Pakistan.
EN-FACE OPTICAL COHERENCE TOMOGRAPHY IN PATIENTS WITH EPIRETINAL MEMBRANE: Intuitive Method for Predicting Functional Outcomes.

PURPOSE To evaluate the correlation between en-face optical coherence tomography (OCT) parameters and functional outcomes before and after idiopathic epiretinal membrane (ERM) surgery. METHODS This retrospective cohort study involved 80 eyes from 80 patients who underwent surgery for idiopathic ERM. Best-corrected visual acuity, metamorphopsia assessment (M-score), and OCT were assessed before surgery and six months after. The adhesive zone (A-zone) and retinal fold, a novel en-face OCT parameter reflecting inner retinal layer changes, were evaluated. Correlations between the area of A-zone and the number of retinal folds on en-face OCT images and other B-scan OCT parameters were evaluated regarding visual outcomes before and after ERM surgery. RESULTS The defect size of the ellipsoid zone, interdigitation zone, and external limiting membrane were significantly correlated with preoperative and postoperative 6-month best-corrected visual acuity (all P < 0.05). The central foveal thickness, A-zone area, number of marginal retinal folds, and fovea involvement in the A-zone were correlated with the preoperative and postoperative 6-month M-score (all P < 0.05). The A-zone area was significantly associated with the preoperative and postoperative 6-month M-score in a multiple linear regression model (P < 0.001, P = 0.008, respectively), and the number of marginal retinal folds was significantly associated with the preoperative M-score (P < 0.001) and marginally significantly with the postoperative 6-month M-score (P = 0.106). CONCLUSION The A-zone area and the number of marginal retinal folds were significantly associated with the M-score before and after ERM surgery. These novel en-face OCT parameters can serve as a novel surrogate tool for predicting the functional outcomes in idiopathic ERM.