Pancreas and islet morphology in cystic fibrosis: clues to the etiology of cystic fibrosis-related diabetes.

Cystic fibrosis (CF) is a multi-organ disease caused by loss-of-function mutations in CFTR (which encodes the CF transmembrane conductance regulator ion channel). Cystic fibrosis related diabetes (CFRD) occurs in 40-50% of adults with CF and is associated with significantly increased morbidity and mortality. CFRD arises from insufficient insulin release from ß cells in the pancreatic islet, but the mechanisms underlying the loss of ß cell function remain understudied. Widespread pathological changes in the CF pancreas provide clues to these mechanisms. The exocrine pancreas is the epicenter of pancreas pathology in CF, with ductal pathology being the initiating event. Loss of CFTR function results in ductal plugging and subsequent obliteration. This in turn leads to destruction of acinar cells, fibrosis and fatty replacement. Despite this adverse environment, islets remain relatively well preserved. However, islet composition and arrangement are abnormal, including a modest decrease in ß cells and an increase in α, δ and γ cell abundance. The small amount of available data suggest that substantial loss of pancreatic/islet microvasculature, autonomic nerve fibers and intra-islet macrophages occur. Conversely, T-cell infiltration is increased and, in CFRD, islet amyloid deposition is a frequent occurrence. Together, these pathological changes clearly demonstrate that CF is a disease of the pancreas/islet microenvironment. Any or all of these changes are likely to have a dramatic effect on the ß cell, which relies on positive signals from all of these neighboring cell types for its normal function and survival. A thorough characterization of the CF pancreas microenvironment is needed to develop better therapies to treat, and ultimately prevent CFRD.

Association of frailty with clinical outcomes in myelofibrosis: a retrospective cohort study.

There is limited understanding of the impact of frailty on clinical outcomes in patients with myelofibrosis (MF). In this retrospective cohort study on 439 chronic phase MF patients [mean age: 68·7 ± 12 years; median follow-up: 3·4 years (IQR 0·4-8·6)] from 2004 till 2018, we used a 35-variable frailty index (FI) to categorise patient's frailty status as fit (FI < 0·2, reference), prefrail (FI 0·2-0·29) or frail (FI ≥ 0·3). The association of frailty with overall survival (OS) and cumulative JAK inhibitor (JAKi) therapy failure was measured using hazard ratio (HR, 95% CI). In multivariable analysis, prefrail (HR 1·7, 1·1-2·5) and frail patients (HR 2·9, 1·6-5·5), those with higher DIPSS score (HR 2·5, 1·6-3·9) and transfusion dependency (HR 1·9, 1·3-2·9) had shorter OS. In a subset analysis of patients on JAKi treatment (n = 222), frail patients (HR 2·5, 1·1-5·7), patients with higher DIPSS score (HR 1·7, 1·0-3·1) and transfusion dependence (HR 1·7, 1·1-2·7) had higher cumulative incidence of JAKi failure. Age, comorbidities, ECOG performance status, and MPN driver mutations did not impact outcomes. Thus, higher frailty scores are associated with worse OS and increased JAKi failure in MF, and is a superior indicator of fitness in comparison to age, comorbidities, and performance status.

Association of Factors Influencing Selection of Upfront Hematopoietic Cell Transplantation versus Nontransplantation Therapies in Myelofibrosis.

Despite the curative potential of allogeneic hematopoietic cell transplantation (HCT) for myelofibrosis (MF), a significant number of patients with MF do not undergo HCT. Factors influencing treatment preferences in these patients have not been well studied. This study was conducted to identify patient-, disease-, and donor-related factors influencing the decision regarding HCT in patients with MF. A secondary objective was to compare survival between patients who elected upfront HCT and those who opted for nontransplantation therapy. We conducted a retrospective chart review amongst patients meeting criteria for transplant indication, evaluating clinical characteristics, treatment preferences, and outcomes. Of the 183 study eligible patients age <70 years, 129 (70%) developed an HCT indication. Age >60 years was significantly associated with higher rates of HLA-typing refusal (13 of 72 versus 1 of 44; P = .02). Caucasian ethnicity was significantly associated with an increased rate of identifying well-matched donors compared with non-Caucasian ethnicity (75% versus 48%; P = .02). Of the 69 patients with well-matched donors, 34 (49%) preferred to not pursue upfront HCT despite an indication for transplantation. Patient preference for nontransplantation therapies was the most common reason for declining HCT. We did not find any difference in survival between patients pursuing upfront HCT and those opting for nontransplantation therapies, although more patients in the HCT arm were in remission at the last follow-up. Patients of Caucasian ethnicity were significantly more likely than non-Caucasian patients to identify a well-matched donor. Despite availability of a well-matched donor, a significant proportion of MF patients with an indication for transplantation do not pursue HCT. Patient age, donor type, and patient preference play major roles in the selection of upfront HCT. Although a survival difference was not observed between upfront HCT versus non-transplant therapy, more patients in the HCT arm were in remission at the last follow-up.

Impact of preoperative antibiotics and other variables on integrated microbiome-host transcriptomic data generated from colorectal cancer resections.

BACKGROUND: Integrative multi-omic approaches have been increasingly applied to discovery and functional studies of complex human diseases. Short-term preoperative antibiotics have been adopted to reduce site infections in colorectal cancer (CRC) resections. We hypothesize that the antibiotics will impact analysis of multi-omic datasets generated from resection samples to investigate biological CRC risk factors. AIM: To assess the impact of preoperative antibiotics and other variables on integrated microbiome and human transcriptomic data generated from archived CRC resection samples. METHODS: Genomic DNA (gDNA) and RNA were extracted from prospectively collected 51 pairs of frozen sporadic CRC tumor and adjacent non-tumor mucosal samples from 50 CRC patients archived at a single medical center from 2010-2020. The 16S rRNA gene sequencing (V3V4 region, paired end, 300 bp) and confirmatory quantitative polymerase chain reaction (qPCR) assays were conducted on gDNA. RNA sequencing (IPE, 125 bp) was performed on parallel tumor and non-tumor RNA samples with RNA Integrity Numbers scores ≥ 6. RESULTS: PERMANOVA detected significant effects of tumor vs nontumor histology (P = 0.002) and antibiotics (P = 0.001) on microbial ß-diversity, but CRC tumor location (left vs right), diabetes mellitus vs not diabetic and Black/African Ancestry (AA) vs not Black/AA, did not reach significance. Linear mixed models detected significant tumor vs nontumor histology*antibiotics interaction terms for 14 genus level taxa. QPCR confirmed increased Fusobacterium abundance in tumor vs nontumor groups, and detected significantly reduced bacterial load in the (+)antibiotics group. Principal coordinate analysis of the transcriptomic data showed a clear separation between tumor and nontumor samples. Differentially expressed genes obtained from separate analyses of tumor and nontumor samples, are presented for the antibiotics, CRC location, diabetes and Black/AA race groups. CONCLUSION: Recent adoption of additional preoperative antibiotics as standard of care, has a measurable impact on -omics analysis of resected specimens. This study still confirmed increased Fusobacterium nucleatum in tumor.

Safety and adequacy of endoscopic ultrasound-guided random liver biopsy in comparison with transjugular and percutaneous approaches.

Background and study aims Endoscopic ultrasound-guided liver biopsy (EUS-LB) is an accepted technique for tissue acquisition. Traditionally, random LB has been performed with percutaneous (PC-LB) and transjugular (TJ-LB) approaches. The purpose of this study was to compare the safety profile and efficacy of EUS-LB, PC-LB, and TJ-LB. Patients and methods A retrospective analysis was performed at a tertiary academic medical center. Inclusion criteria for analysis were all adult patients who underwent EUS-LB since inception and TJ-LB/PC-LB over a 3-year span (June 2016 to June 2019). The primary outcome assessed was any adverse events. Secondary outcomes included technical success resulting in tissue acquisition and diagnostic adequacy of the sample for histologic analysis. Results A total of 513 patients were included for analysis. There were 135 EUS-LB, 287 PC-LB, and 91 TJ-LB. The most common indication for LB was abnormal liver function tests. For the primary outcome, the rate of adverse events was low with five reported (< 1 %). There were two in the EUS-LB group, two in the PC-LB group, and one in TJ-LB group, and this difference was not statistically significant ( P  = 0.585). The technical success rate was 100 % in each group. The rate of diagnostic adequacy was 100 % in TJ-LB group and 99 % in both EUS-LB and PC-LB groups. This difference was not statistically significant ( P  = 1.000). The most common histologic finding was non-specific changes (33.7 %) followed by non-alcoholic steatohepatitis (15.60 %). Conclusion In comparison with PC-LB and TJ-LB, EUS-LB has comparable safety profile, technical success rate, and diagnostic adequacy. EUS-LB should be considered as an option for random liver biopsy.

Thyrotropin Causes Dose-dependent Biphasic Regulation of cAMP Production Mediated by Gs and Gi/o Proteins.

The thyrotropin (TSH) receptor (TSHR) signals via G proteins of all four classes and ß-arrestin 1. Stimulation of TSHR leads to increasing cAMP production that has been reported as a monotonic dose-response curve that plateaus at high TSH doses. In HEK 293 cells overexpressing TSHRs (HEK-TSHR cells), we found that TSHR activation exhibits an "inverted U-shaped dose-response curve" with increasing cAMP production at low doses of TSH and decreased cAMP production at high doses (>1 mU/ml). Since protein kinase A inhibition by H-89 and knockdown of ß-arrestin 1 or ß-arrestin 2 did not affect the decreased cAMP production at high TSH doses, we studied the roles of TSHR downregulation and of Gi/Go proteins. A high TSH dose (100 mU/ml) caused a 33% decrease in cell-surface TSHR. However, because inhibiting TSHR downregulation with combined expression of a dominant negative dynamin 1 and ß-arrestin 2 knockdown had no effect, we concluded that downregulation is not involved in the biphasic cAMP response. Pertussis toxin, which inhibits activation of Gi/Go, abolished the biphasic response with no statistically significant difference in cAMP levels at 1 and 100 mU/ml TSH. Concordantly, co-knockdown of Gi/Go proteins increased cAMP levels stimulated by 100 mU/ml TSH from 55% to 73% of the peak level. These data show that biphasic regulation of cAMP production is mediated by Gs and Gi/Go at low and high TSH doses, respectively, which may represent a mechanism to prevent overstimulation in TSHR-expressing cells. SIGNIFICANCE STATEMENT: We demonstrate biphasic regulation of TSH-mediated cAMP production involving coupling of the TSH receptor (TSHR) to Gs at low TSH doses and to Gi/o at high TSH doses. We suggest that this biphasic cAMP response allows the TSHR to mediate responses at lower levels of TSH and that decreased cAMP production at high doses may represent a mechanism to prevent overstimulation of TSHR-expressing cells. This mechanism could prevent chronic stimulation of thyroid gland function.

Halogen-Free Flame-Retardant Compounds. Thermal Decomposition and Flammability Behavior for Alternative Polyethylene Grades.

The effect of six halogen-free flame retardant (FR) formulations was investigated on the thermal stability of two low-density polyethylenes (LDPE) and one linear low-density polyethylene (LLDPE), by means of thermogravimetric analysis (TGA) under nitrogen and air atmosphere. The relative data were combined with flammability properties and the overall performance of the FRs was correlated with the type of branching in the polyethylene grades and to their processing behavior. The thermal degradation kinetics was further determined based on the Kissinger and Coats-Redfern methods. In terms of flammability, the addition of a triazine derivative and ammonium polyphosphate at a loading of 35 wt. %. was found to be the most efficient, leading to UL 94 V0 ranking in the case of the LDPE grade produced in an autoclave reactor.

Core Measures for Congestive Heart Failure in a Tertiary Care Setting in Pakistan.

PURPOSE:  Heart failure presents a huge burden for individual patients and the healthcare system as a whole. This study aims to assess the adherence to these core measures as identified by the Joint Commission on Accreditation of Healthcare Organizations (JCAHO)/ American Heart Association (AHA) by physicians of Pakistan. MATERIALS AND METHODOLOGY:  We conducted a cross-sectional study in Shifa International Hospital, Islamabad, Pakistan from the period of April 2013 to April 2016. Patients with a primary diagnosis of heart failure were drawn from a coding section of hospital's record department. Data was evaluated to assess how strictly doctors were following core measures identified by JCAHO/AHA for the given diagnosis. Inclusion criteria for this study were patients ≥ 17 years of age and patients with a primary diagnosis of heart failure according to New York Heart Association (NYHA) classification. Patients with congenital anomalies and structural heart wall problems, like sarcoidosis, hemochromatosis, and amyloidosis, were excluded from the study. RESULTS:  Mean ejection fraction (EF) was found to be 27.23 ± 11.72 percent. Symptoms assessment of heart failure was done in 16/421 (3.8%) patients according to NYHA classification and in 405/421 (96.2%) patients according to outpatient-based heart failure assessment based on physician's experience other than NYHA classification. Left ventricle ejection fraction (LVEF) was assessed in 411/421 (97%) patients. Out of these, 336/411 (81.7%) patients had EF < 40%. Mean EF was found to be significantly higher in females as compared to males (p < 0.001). Three hundred and thirty-six out of 411 (81.7%) patients with EF < 40% needed angiotensin converting enzyme inhibitors (ACEi) and beta-blocker (BB) prescriptions. ACEi were prescribed only to 230/336 (68.7%) patients and 248/336 (73.8%) patients were given BB with documented contraindication to ACEi and BB in 7.36% and 17% patients, respectively. There was no significant association between gender and mean duration of hospitalization (p = 0.411). No significant association was found between EF ≤ 40% and mean duration of hospitalization (p = 0.426). CONCLUSION:  We found that symptom assessment of congestive heart failure (CHF) patients, according to NYHA guidelines, are strikingly low. Also, a significant percentage of patients who need ACEi and BB are not prescribed the required medications despite echocardiography showing low left ventricular function.

Recognition and management of hyperinsulinemic hypoglycemia after bariatric surgery.

Hyperinsulinemic hypoglycemia with neuroglycopenia is an increasingly recognized complication of Roux-en-Y gastric bypass (RYGB) due to the changes in gut hormonal milieu. Physicians should be aware of this complication to ensure timely and effective treatment of post-RYGB patients, who present to them with hypoglycemic symptoms. Possible causes of hypoglycemia in these patients include late dumping syndrome, nesidioblastosis and rarely insulinoma. Systematic evaluation including history, biochemical analysis, and diagnostic testing might help in distinguishing among these diagnoses. Continuous glucose monitoring is also a valuable tool, revealing the episodes in the natural environment and can also be used to monitor treatment success. Treatment should begin with strict low carbohydrate diet, followed by medication therapy. Therapy with diazoxide, acarbose, calcium channel blockers and octreotide have been proven to be beneficial, but the response apparently is highly variable. When other treatment options fail, surgical options can be considered.

Psychopathology in bariatric surgery candidates: a review of studies using structured diagnostic interviews.

Psychiatric disorders are not uncommon among severely obese patients who present for bariatric surgery. This paper (1) reviews the results of the published studies using the structured interviews to assess psychopathology in bariatric surgery candidates; (2) compares the prevalence rates of psychiatric disorders across these studies with the data from other population samples; and (3) assesses whether sociodemographic variables appear to affect these prevalence rates. We searched online resources, PubMed, PsychINFO and reference lists of all the relevant articles to provide an overview of evidence so far and highlight some details in the assessment and comparisons of different samples in different countries. The prevalence estimates in the non-treatment obese group did not appear to differ substantially from the general population group in the US or the Italian population samples, although they were relatively higher for the German population. However, the rates of psychopathology in the bariatric surgery candidates were considerably higher than the other two population groups in all the samples. Overall, the most common category of lifetime Axis I disorders in all the studies was affective disorders, with anxiety disorders being the most common category of current Axis I disorders. Certain demographic characteristics are also associated with higher rates of psychopathology, such as, female gender, low socioeconomic status, higher BMI. Overall, methodological and sociodemographic differences make these studies difficult to compare and these differences should be taken into account when interpreting the results.