Publications by authors named "P John Hart"

1,121 Publications

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Dietary Patterns of Insulinemia, Inflammation and Glycemia and Pancreatic Cancer Risk: Findings from the Women's Health Initiative.

Cancer Epidemiol Biomarkers Prev 2021 Apr 7. Epub 2021 Apr 7.

Division of Medical Oncology, The Ohio State University College of Medicine

Background: Pancreatic cancer risk is increasing in countries with high consumption of Western dietary patterns and rising obesity rates. We examined the hypothesis that specific dietary patterns reflecting hyperinsulinemia (empirical dietary index for hyperinsulinemia-EDIH), systemic inflammation (empirical dietary inflammatory pattern-EDIP), and postprandial glycemia (glycemic index-GI, glycemic load-GL) are associated with pancreatic cancer risk, including the potential modifying role of type 2 diabetes (T2D) and body mass index (BMI).

Methods: We calculated dietary scores from baseline (1993-1998) food frequency questionnaires among 129,241 women, 50-79 years-old in the Women's Health Initiative. We used multivariable-adjusted Cox regression to estimate hazard ratios (HR) and 95% confidence intervals (95%CI) for pancreatic cancer risk.

Results: During a median 19.9 years of follow-up, 850 pancreatic cancer cases were diagnosed. We observed no association between dietary scores and pancreatic cancer risk overall. However, risk was elevated among participants with longstanding T2D (present >3 years before pancreatic cancer diagnosis) for EDIH. For each 1 standard deviation increment in dietary score, the HRs (95%CIs) were: EDIH, 1.33(1.06-1.66); EDIP, 1.26(0.98-1.63); GI, 1.26(0.96-1.67); and GL, 1.23(0.96-1.57); though interactions were not significant (all Pinteraction >0.05). Separately, we observed inverse associations between GI, 0.86(0.76-0.96), Pinteraction=0.0068; and GL, 0.83 (0.73-0.93), Pinteraction=0.0075, with pancreatic cancer risk among normal-weight women.

Conclusion: We observed no overall association between the dietary patterns evaluated and pancreatic cancer risk, although women with T2D appeared to have greater cancer risk.

Impact: The elevated risk for hyperinsulinemic diets among women with longstanding T2D and the inverse association among normal-weight women warrant further examination.
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http://dx.doi.org/10.1158/1055-9965.EPI-20-1478DOI Listing
April 2021

ASSOCIATION OF HYPERGLYCAEMIA WITH HOSPITAL MORTALITY IN NONDIABETIC COVID-19 PATIENTS: A COHORT STUDY.

Diabetes Metab 2021 Mar 26:101254. Epub 2021 Mar 26.

M&H Research, LLC, San Antonio, Texas, USA. Electronic address:

Objective: Diabetes is a known risk factor for mortality in Coronavirus disease 2019 (COVID-19) patients. Our objective was to identify prevalence of hyperglycaemia in COVID-19 patients with and without prior diabetes and quantify its association with COVID-19 disease course.

Research Design And Methods: This observational cohort study included all consecutive COVID-19 patients admitted to John H Stroger Jr. Hospital, Chicago, IL from March 15, 2020 to May 3, 2020 and followed till May 15, 2020. The primary outcome was hospital mortality, and the studied predictor was hyperglycaemia [any blood glucose ≥ 7.78 mmol/L (140 mg/dL) during hospitalization].

Results: Of the 403 COVID-19 patients studied, 51 (12.7%) died; 335 (83.1%) were discharged while 17 (4%) were still in hospital. Hyperglycaemia occurred in 228 (56.6%) patients; 83 of these hyperglycaemic patients (36.4%) had no prior history of diabetes. Compared to the reference group no-diabetes / no-hyperglycaemia patients the no-diabetes / hyperglycaemia patients showed higher mortality [1.8% versus 20.5%, adjusted odds ratio 21.94 (95% confidence interval 4.04-119.0), P <  0.001]; improved prediction of death (P =  0.01) and faster progression to death (P <  0.01). Hyperglycaemia within the first 24 and 48 hours was also significantly associated with mortality (odds ratio 2.15 and 3.31, respectively).

Conclusions: Hyperglycaemia without prior diabetes was common (20.6% of hospitalized COVID-19 patients) and was associated with an increased risk of and faster progression to death. Development of hyperglycaemia in COVID-19 patients who do not have diabetes is an early indicator of progressive disease.
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http://dx.doi.org/10.1016/j.diabet.2021.101254DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7994287PMC
March 2021

Rotator Cuff Fatty Infiltration and Muscle Atrophy Do Not Impact Clinical Outcomes After Reverse Total Shoulder Arthroplasty for Glenohumeral Osteoarthritis with Intact Rotator Cuff.

J Shoulder Elbow Surg 2021 Mar 24. Epub 2021 Mar 24.

Department of Orthopaedic Surgery, New England Baptist Hospital, Boston, MA, USA; Boston Sports and Shoulder Center, Waltham, MA, USA. Electronic address:

Background: The clinical significance of rotator cuff muscle quality following reverse total shoulder arthroplasty (RTSA) remains uncertain. The purpose of this study was to evaluate the influence of rotator cuff fatty infiltration (FI) and muscle atrophy (MA) on clinical outcomes following RTSA for glenohumeral arthritis (GHOA).

Methods: One hundred and eight shoulders with primary glenohumeral arthritis that underwent RTSA with a lateralized glenosphere for GHOA with a minimum of 2-year follow-up were identified from a prospectively maintained registry. Each rotator cuff muscle was assessed on preoperative magnetic resonance imaging (MRI) for fatty infiltration (FI) and quantitative amount of muscle atrophy (MA). Pre- and Postoperative outcomes included American Shoulder and Elbow Surgeons score, Single Assessment Numerical Evaluation score, Visual Analog Scale pain score, and range-of-motion (ROM) measurements.

Results: Eighty-one patients with a mean age of 70.7 ± 5.4 years (range, 57 to 85) were included who underwent RTSA with a mean follow-up of 2.1 years (range: 2 to 3.9 years). There was a significant improvement in all outcome measures postoperatively (P < .01). Twenty-two patients (27.1%) had moderate to severe combined infraspinatus and teres minor FI. There was no significant difference in the postoperative external rotation or clinical outcomes when compared to those patients with only mild FI (P > .05). Forty-three patients (53.1%) had moderate to severe global rotator cuff fatty infiltration. There was no significant difference in postoperative outcomes when compared to those patients with only mild fatty infiltration (P < .01). Univariate analysis did not reveal any significant association between the degree of FI or muscle atrophy of any individual rotator cuff muscle and postoperative clinical outcomes or ROM. The size ratio of the posterior rotator cuff to the subscapularis muscle was positively correlated with preoperative SANE scores, but negatively correlated with absolute postoperative and change in preoperative to postoperative SANE scores; However, there were no significant correlations between this size ratio and the other outcome measures.

Conclusion: Rotator cuff muscle quality as assessed by MA and FI does not impact clinical outcomes following reverse total shoulder arthroplasty with a lateralized glenosphere in patients with glenohumeral arthritis and an intact rotator cuff.
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http://dx.doi.org/10.1016/j.jse.2021.03.135DOI Listing
March 2021

Predictors of Acromial and Scapular Stress Fracture after Reverse Shoulder Arthroplasty: An ASES Multicenter Study from the Complications of Reverse Arthroplasty Group.

J Shoulder Elbow Surg 2021 Mar 4. Epub 2021 Mar 4.

Department of Orthopaedic Surgery, New England Baptist Hospital, Boston, MA, USA; Boston Sports and Shoulder Center, Waltham, MA, USA. Electronic address:

Background: Acromial (ASF) and scapular spine (SSF) stress fractures are well-recognized complications of reverse shoulder arthroplasty (RSA), but much of the current data is derived from single-center or single implant studies with limited generalizability. This multicenter study from the American Shoulder and Elbow Surgeons (ASES) Complications of RSA Multicenter Research Group determined the incidence of ASF/SSF after RSA, and identified preoperative patient characteristics associated with their occurrence.

Methodology: Fifteen institutions including 21 ASES members across the United States participated in this study. Patients undergoing either primary or revision RSA between January 2013 and June 2019 with a minimum three-month follow-up were included. All definitions and inclusion criteria were determined using the Delphi method, an iterative survey process involving all primary investigators. Consensus was achieved when at least 75% of investigators agreed on each aspect of the study protocol. Only symptomatic ASF/SSF diagnosed by radiograph or computed tomography were considered. Multivariable logistic regression was performed to identify factors associated with ASF/SSF development.

Results: We identified 6,755 RSAs with an average follow-up of 19.8 months (range, 3-94). The total stress fracture incidence rate was 3.9% (n=264), of which 3.0% (n=200) were ASF and 0.9% (n=64) were SSF. Fractures occurred at an average 8.2 months (0-64) following RSA with 21.2% (n=56) following a trauma. Patient-related factors independently predictive of ASF were: chronic dislocation (OR, 3.67; p=0.04), massive rotator cuff tear without arthritis (OR, 2.51; p<0.01), rotator cuff arthropathy (OR, 2.14; p<0.01), self-reported osteoporosis (OR, 2.21; p<0.01), inflammatory arthritis (OR, 2.18; p<0.01), female sex (OR, 1.51; p=0.02), and older age (OR, 1.02 per 1-year increase; p=0.02). Factors independently associated with the development of SSF included: osteoporosis (OR, 2.63; p<0.01), female sex (OR, 2.34; p=0.01), rotator cuff arthropathy (OR, 2.12; p=0.03), and inflammatory arthritis (OR, 2.05; p=0.03).

Conclusion: About 1 in 26 patients undergoing RSA will develop a symptomatic ASF or SSF, more frequently within the first year of surgery. Our results indicate that severe rotator cuff disease may play an important role in the occurrence of stress fractures following RSA. This information can be used to counsel patients about potential setbacks in recovery, especially among older women with suboptimal bone health. Strategies for prevention of ASF and SSF in these at-risk patients warrant further study. A follow-up study evaluating the impact of prosthetic factors on the incidence rates of ASF and SSF may prove highly valuable in the decision-making process.
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http://dx.doi.org/10.1016/j.jse.2021.02.008DOI Listing
March 2021

Associations of serum short-chain fatty acids with circulating immune cells and serum biomarkers in patients with multiple sclerosis.

Sci Rep 2021 Mar 4;11(1):5244. Epub 2021 Mar 4.

Telethon Kids Institute, University of Western Australia, PO Box 855, West Perth, WA, 6872, Australia.

Altered composition of gut bacteria and changes to the production of their bioactive metabolites, the short-chain fatty acids (SCFAs), have been implicated in the development of multiple sclerosis (MS). However, the immunomodulatory actions of SCFAs and intermediaries in their ability to influence MS pathogenesis are uncertain. In this study, levels of serum SCFAs were correlated with immune cell abundance and phenotype as well as with other relevant serum factors in blood samples taken at first presentation of Clinically Isolated Syndrome (CIS; an early form of MS) or MS and compared to healthy controls. There was a small but significant reduction in propionate levels in the serum of patients with CIS or MS compared with healthy controls. The frequencies of circulating T follicular regulatory cells and T follicular helper cells were significantly positively correlated with serum levels of propionate. Levels of butyrate associated positively with frequencies of IL-10-producing B-cells and negatively with frequencies of class-switched memory B-cells. TNF production by polyclonally-activated B-cells correlated negatively with acetate levels. Levels of serum SCFAs associated with changes in circulating immune cells and biomarkers implicated in the development of MS.
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http://dx.doi.org/10.1038/s41598-021-84881-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7933417PMC
March 2021

Biochemical Investigation of the Interaction of pICln, RioK1 and COPR5 with the PRMT5-MEP50 Complex.

Chembiochem 2021 Feb 24. Epub 2021 Feb 24.

Department of Chemical Biology, Max Planck Institute of Molecular Physiology, Otto-Hahn-Strasse 11, 44227, Dortmund, Germany.

The PRMT5-MEP50 methyltransferase complex plays a key role in various cancers and is regulated by different protein-protein interactions. Several proteins have been reported to act as adaptor proteins that recruit substrate proteins to the active site of PRMT5 for the methylation of arginine residues. To define the interaction between these adaptor proteins and PRMT5, we employed peptide truncation and mutation studies and prepared truncated protein constructs. We report the characterisation of the interface between the TIM barrel of PRMT5 and the adaptor proteins pICln, RioK1 and COPR5, and identify the consensus amino acid sequence GQF[D/E]DA[E/D] involved in binding. Protein crystallography revealed that the RioK1 derived peptide interacts with a novel PPI site.
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http://dx.doi.org/10.1002/cbic.202100079DOI Listing
February 2021

Dynamic changes in the pancreatitis activity scoring system during hospital course in a multicenter, prospective cohort.

J Gastroenterol Hepatol 2021 Feb 18. Epub 2021 Feb 18.

Division of Gastroenterology, Hepatology, and Nutrition, Ohio State University, Wexner Medical Center, Columbus, Ohio, USA.

Background And Aim: The primary aim was to validate the Pancreatitis Activity Scoring System (PASS) in a multicenter prospectively ascertained acute pancreatitis (AP) cohort. Second, we investigated the association of early PASS trajectories with disease severity and length of hospital stay (LOS).

Methods: Data were prospectively collected through the APPRENTICE consortium (2015-2018). AP severity was categorized based on revised Atlanta classification. Delta PASS (ΔPASS) was calculated by subtracting activity score from baseline value. PASS trajectories were compared between severity subsets. Subsequently, the cohort was subdivided into three LOS subgroups as short (S-LOS): 2-3 days; intermediate (I-LOS): 3-7 days; and long (L-LOS): ≥7 days. The generalized estimating equations model was implemented to compare PASS trajectories.

Results: There were 434 subjects analyzed including 322 (74%) mild, 86 (20%) moderately severe, and 26 (6%) severe AP. Severe AP subjects had the highest activity levels and the slowest rate of decline in activity (P = 0.039). Focusing on mild AP, L-LOS subjects (34%) had 28 points per day slower decline; whereas, S-LOS group (13%) showed 34 points per day sharper decrease compared with I-LOS (53%; P < 0.001). We noticed an outlier subset with a median admission-PASS of 466 compared with 140 in the rest. Morphine equivalent dose constituted 80% of the total PASS in the outliers (median morphine equivalent dose score = 392), compared with only 25% in normal-range subjects (score = 33, P value < 0.001).

Conclusions: This study highlighted that PASS can quantify AP activity. Significant differences in PASS trajectories were found both in revised Atlanta classification severity and LOS groups, which can be harnessed in AP monitoring/management (ClincialTrials.gov number, NCT03075618).
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http://dx.doi.org/10.1111/jgh.15430DOI Listing
February 2021

Biomarkers of Chronic Pancreatitis: A systematic literature review.

Pancreatology 2021 Mar 22;21(2):323-333. Epub 2021 Jan 22.

Department of Internal Medicine, Division of Gastroenterology, Hepatology, and Nutrition, The Ohio State University Wexner Medical Center, Columbus, OH, USA.

Background: Chronic pancreatitis (CP) does not have diagnostic or prognostic biomarkers. CP is the end stage of a progressive inflammatory syndrome that is diagnosed at late stages by morphologic features. To diagnose earlier stages of the disease, a new mechanistic definition was established based on identifying underlying pathogenic processes and biomarker evidence of disease activity and stage. Although multiple risk factors are known, the corresponding biomarkers needed to make a highly accurate diagnosis of earlier disease stages have not been established. The goal of this study is to systematically analyze the literature to identify the most likely candidates for development into biomarkers of CP.

Methods: We conducted a systematic review of candidate analytes from easily accessible biological fluids and identified 67 studies that compared CP to nonpancreatic-disease controls. We then ranked candidate biomarkers for sensitivity and specificity by area under the receiver operator curves (AUROCs).

Results: Five biomarkers had a large effect size (an AUROC > 0.96), whereas 30 biomarkers had a moderate effect size (an AUROC between 0.96 and 0.83) for distinguishing CP cases from controls or other diseases. However, the studies reviewed had marked variability in design, enrollment criteria, and biospecimen sample handling and collection.

Conclusions: Several biomarkers have the potential for evaluation in prospective cohort studies and should be correlated with risk factors, clinical features, imaging studies and outcomes. The Consortium for the Study of Chronic Pancreatitis, Diabetes and Pancreas Cancer provides recommendations for avoiding design biases and heterogeneity in sample collection and handling in future studies.
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http://dx.doi.org/10.1016/j.pan.2021.01.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7969447PMC
March 2021

FcγRIIb Expression Is Decreased on Naive and Marginal Zone-Like B Cells From Females With Multiple Sclerosis.

Front Immunol 2020 11;11:614492. Epub 2021 Jan 11.

Inflammation Laboratory, Telethon Kids Institute, University of Western Australia, Perth, WA, Australia.

B cells are critical to the development of multiple sclerosis (MS), but the mechanisms by which they contribute to the disease are poorly defined. We hypothesised that the expression of CD32b (FcγRIIb), a receptor for the Fc region of IgG with inhibitory activities in B cells, is lower on B cell subsets from people with clinically isolated syndrome (CIS) or MS. CD32b expression was highest on post-naive IgM B cell subsets in healthy controls. For females with MS or CIS, significantly lower CD32b expression was identified on IgM B cell subsets, including naive and IgM MZ-like B cells, when compared with control females. Lower CD32b expression on these B cell subsets was associated with detectable anti-Epstein Barr Virus viral capsid antigen IgM antibodies, and higher serum levels of B cell activating factor. To investigate the effects of lower CD32b expression, B cells were polyclonally activated in the presence of IgG immune complexes, with or without a CD32b blocking antibody, and the expression of TNF and IL-10 in B cell subsets was assessed. The reduction of TNF but not IL-10 expression in controls mediated by IgG immune complexes was reversed by CD32b blockade in naive and IgM MZ-like B cells only. However, no consequence of lower CD32b expression on these cells from females with CIS or MS was detected. Our findings highlight a potential role for naive and marginal zone-like B cells in the immunopathogenesis of MS in females, which requires further investigation.
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http://dx.doi.org/10.3389/fimmu.2020.614492DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7832177PMC
January 2021

Possible Role of Metformin as an Immune Modulator in the Tumor Microenvironment of Ovarian Cancer.

Int J Mol Sci 2021 Jan 16;22(2). Epub 2021 Jan 16.

College of Science, Health and Pharmacy, Roosevelt University, Schaumburg, IL 60173, USA.

Growing evidence suggests that the immune component of the tumor microenvironment (TME) may be highly involved in the progression of high-grade serous ovarian cancer (HGSOC), as an immunosuppressive TME is associated with worse patient outcomes. Due to the poor prognosis of HGSOC, new therapeutic strategies targeting the TME may provide a potential path forward for preventing disease progression to improve patient survival. One such postulated approach is the repurposing of the type 2 diabetes medication, metformin, which has shown promise in reducing HGSOC tumor progression in retrospective epidemiological analyses and through numerous preclinical studies. Despite its potential utility in treating HGSOC, and that the immune TME is considered as a key factor in the disease's progression, little data has definitively shown the ability of metformin to target this component of the TME. In this brief review, we provide a summary of the current understanding of the effects of metformin on leukocyte function in ovarian cancer and, coupled with data from other related disease states, posit the potential mechanisms by which the drug may enhance the anti-tumorigenic effects of immune cells to improve HGSOC patient survival.
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http://dx.doi.org/10.3390/ijms22020867DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7830067PMC
January 2021

High performance in risk stratification of intraductal papillary mucinous neoplasms by confocal laser endomicroscopy image analysis with convolutional neural networks (with video).

Gastrointest Endosc 2021 Jan 16. Epub 2021 Jan 16.

Division of Gastroenterology, Hepatology, and Nutrition, Division of Internal Medicine, The Ohio State University Wexner Medical Center, Columbus, Ohio. Electronic address:

Background And Aims: EUS-guided needle-based confocal laser endomicroscopy (EUS-nCLE) can differentiate high-grade dysplasia/adenocarcinoma (HGD-Ca) in intraductal papillary mucinous neoplasms (IPMNs) but requires manual interpretation. We sought to derive predictive computer-aided diagnosis (CAD) and artificial intelligence (AI) algorithms to facilitate accurate diagnosis and risk stratification of IPMNs.

Methods: A post-hoc analysis of a single-center prospective study evaluating EUS-nCLE (2015-2019; INDEX study) was conducted using 15,027 video frames from 35 consecutive subjects with histopathologically proven IPMNs (18 with HGD-Ca). We designed 2 CAD-convolutional neural network (CNN) algorithms: (1) guided segmentation-based model (SBM), where the CNN-AI system was trained to detect and measure papillary epithelial thickness and darkness (indicative of cellular and nuclear stratification), and (2) a reasonably agnostic holistic-based model (HBM) where the CNN-AI system automatically extracted nCLE features for risk stratification. For the detection of HGD-Ca in IPMNs, the diagnostic performance of the CNN-CAD algorithms was compared with that of the American Gastroenterological Association (AGA) and revised Fukuoka guidelines.

Results: Compared with guidelines, both n-CLE-guided CNN-CAD algorithms yielded higher sensitivity (HBM: 83.3%, SBM: 83.3%, AGA: 55.6%, Fukuoka: 55.6%) and accuracy (SBM: 82.9%, HBM: 85.7%, AGA: 68.6%, Fukuoka: 74.3%) for diagnosing HGD-Ca, with comparable specificity (SBM: 82.4%, HBM: 88.2%, AGA: 82.4%, Fukuoka: 94.1%). Both CNN-CAD algorithms, the guided (SBM) and agnostic (HBM) models were comparable in risk stratifying IPMNs.

Conclusion: EUS-nCLE based CNN-CAD algorithms can accurately risk stratify IPMNs. Future multicenter validation studies and AI model improvements could enhance the accuracy and fully automatize the process for real-time interpretation.
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http://dx.doi.org/10.1016/j.gie.2020.12.054DOI Listing
January 2021

Immediate Postoperative Insulin Requirements May Predict Metabolic Outcome after Total Pancreatectomy and Islet Autotransplantation.

J Diabetes Res 2020 21;2020:9282310. Epub 2020 Dec 21.

The Ohio State University Wexner Medical Center, Columbus, OH, USA 43210.

Chronic pancreatitis (CP) is a progressive disease that leads to eventual loss of endocrine and exocrine function. Total pancreatectomy and islet autotransplantation (TPIAT) is a treatment option for patients with CP; however, predicting postoperative metabolic outcomes remains elusive. In this single-center retrospective study, we report pre-TPIAT characteristics, beta cell function indices, islet yield, and post-TPIAT glucose management data to further understand their relationship. Islet yield, glucose level, and insulin requirement for 72 hours postoperatively were collected for a total of 13 TPIAT recipients between 9-2013 and 9-2018. In addition, their glucose control and basal insulin requirements at 3, 6, and 12 months post-TPIAT were analyzed. All 13 subjects had normal baseline fasting glucose levels. Median islet yield was 4882 IEq/kg (interquartile range 3412 to 8987). Median postoperative total insulin requirement on day 3 was 0.43 units/kg. Pre-TPIAT baseline glucose, insulin, or c-peptide level did not have a significant correlation with the islet yield. Similarly, there was no correlation between islet yield and insulin requirement at 72-hour postoperatively. However, there was an inverse correlation between the absolute islet yield (IEq) and insulin requirement at 6 months and 12 months following post-TPIAT. Further analysis of the relationship between 72-hour post-op insulin requirement and insulin requirement at discharge, 3, 6, and 12 months showed a positive correlation. Despite the finding of inverse correlation of islet yield with long-term basal insulin requirement, this study was not able to detect a correlation between the preoperative parameters to postoperative short-term or long-term outcome as noted in other studies. The 72-hour postoperative insulin requirement is a helpful postoperative predictor of patients needing long-term insulin management following TPIAT. This observation may identify a high-risk group of patients in need of more intensive diabetes education and insulin treatment prior to hospital discharge.
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http://dx.doi.org/10.1155/2020/9282310DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7772034PMC
December 2020

Insulinemic and Inflammatory Dietary Patterns Show Enhanced Predictive Potential for Type 2 Diabetes Risk in Postmenopausal Women.

Diabetes Care 2021 Mar 8;44(3):707-714. Epub 2021 Jan 8.

Interdisciplinary PhD Program in Nutrition, The Ohio State University, Columbus, OH

Objective: The empirical dietary index for hyperinsulinemia (EDIH) and empirical dietary inflammatory pattern (EDIP) scores assess the insulinemic and inflammatory potentials of habitual dietary patterns, irrespective of the macronutrient content, and are based on plasma insulin response or inflammatory biomarkers, respectively. The glycemic index (GI) and glycemic load (GL) assess postprandial glycemic potential based on dietary carbohydrate content. We tested the hypothesis that dietary patterns promoting hyperinsulinemia, chronic inflammation, or hyperglycemia may influence type 2 diabetes risk.

Research Design And Methods: We calculated dietary scores from baseline (1993-1998) food frequency questionnaires among 73,495 postmenopausal women in the Women's Health Initiative, followed through March 2019. We used multivariable-adjusted Cox regression to estimate hazard ratios (HRs) and 95% CIs for type 2 diabetes risk. We also estimated multivariable-adjusted absolute risk of type 2 diabetes.

Results: During a median 13.3 years of follow-up, 11,009 incident cases of type 2 diabetes were diagnosed. Participants consuming the most hyperinsulinemic or proinflammatory dietary patterns experienced greater risk of type 2 diabetes; HRs (95% CI) comparing highest to lowest dietary index quintiles were EDIH 1.49 (1.32-1.68; < 0.0001) and EDIP 1.45 (1.29-1.63; < 0.0001). The absolute excess incidence for the same comparison was 220 (EDIH) and 271 (EDIP) cases per 100,000 person-years. GI and GL were not associated with type 2 diabetes risk: GI 0.99 (0.88-1.12; = 0.46) and GL 1.01 (0.89-1.16; = 0.30).

Conclusions: Our findings in this diverse cohort of postmenopausal women suggest that lowering the insulinemic and inflammatory potentials of the diet may be more effective in preventing type 2 diabetes than focusing on glycemic foods.
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http://dx.doi.org/10.2337/dc20-2216DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7896263PMC
March 2021

Diagnostic yield of endoscopic ultrasound-guided tissue acquisition in autoimmune pancreatitis: a systematic review and meta-analysis.

Endosc Int Open 2021 Jan 1;9(1):E66-E75. Epub 2021 Jan 1.

University of Colorado Anschutz Medical Campus, Aurora, Colorado, United States.

 There is limited evidence on the diagnostic performance of endoscopic ultrasound (EUS)-guided tissue acquisition in autoimmune pancreatitis (AIP). The aim of this meta-analysis was to provide a pooled estimate of the diagnostic performance of EUS-guided fine-needle aspiration (FNA) and fine-needle biopsy (FNB) in patients with AIP.  Computerized bibliographic search was performed through January 2020. Pooled effects were calculated using a random-effects model by means of DerSimonian and Laird test. Primary endpoint was diagnostic accuracy compared to clinical diagnostic criteria. Additional outcomes were definitive histopathology, pooled rates of adequate material for histological diagnosis, sample adequacy, mean number of needle passes. Diagnostic sensitivity and safety data were also analyzed.  Fifteen studies with 631 patients were included, of which four were prospective series and one randomized trial. Overall diagnostic accuracy of EUS tissue acquisition was 54.7 % (95 % confidence interval, 40.9 %-68.4 %), with a clear superiority of FNB over FNA (63 %, 52.7 % to 73.4 % versus 45.7 %, 26.5 %-65 %; p < 0.001). FNB provided level 1 of histological diagnosis in 44.2 % of cases (30.8 %-57.5 %) as compared to 21.9 % (10 %-33.7 %) with FNA (  < 0.001). The rate of definitive histopathology of EUS tissue sampling was 20.7 % (12.9 %-28.5 %) and it was significantly higher with FNB (24.3 %, 11.8 %-36.8 %) as compared to FNA (14.7 %, 5.4 %-23.9 %;  < 0.001). Less than 1 % of subjects experienced post-procedural acute pancreatitis.  The results of this meta-analysis demonstrate that the diagnostic performance of EUS-guided tissue acquisition is modest in patients with AIP, with an improved performance of FNB compared to FNA.
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http://dx.doi.org/10.1055/a-1293-7279DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7775812PMC
January 2021

Delayed Processing of Secretin-Induced Pancreas Fluid Influences the Quality and Integrity of Proteins and Nucleic Acids.

Pancreas 2021 Jan;50(1):17-28

From the Division of Gastroenterology, Hepatology, and Nutrition, Department of Internal Medicine.

Objectives: Endoscopic pancreatic function tests are used to diagnose pancreatic diseases and are a viable source for the discovery of biomarkers to better characterize pancreatic disorders. However, pancreatic fluid (PF) contains active enzymes that degrade biomolecules. Therefore, we tested how preservation methods and time to storage influence the integrity and quality of proteins and nucleic acids.

Methods: We obtained PF from 9 subjects who underwent an endoscopic pancreatic function test. Samples were snap frozen at the time of collection; after 1, 2, and 4 hours on ice; or after storage overnight at 4°C with or without RNase or protease inhibitors (PIs). Electrophoresis and mass spectrometry analysis determined protein abundance and quality, whereas nucleic acid integrity values determined DNA and RNA degradation.

Results: Protein degradation increased after 4 hours on ice and DNA degradation after 2 hours on ice. Adding PIs delayed degradation. RNA was significantly degraded under all conditions compared with the snap frozen samples. Isolated RNA from PF-derived exosomes exhibited similar poor quality as RNA isolated from matched PF samples.

Conclusions: Adding PIs immediately after collecting PF and processing the fluid within 4 hours of collection maintains the protein and nucleic acid integrity for use in downstream molecular analyses.
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http://dx.doi.org/10.1097/MPA.0000000000001717DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7883383PMC
January 2021

Predictors of hospital transfer and associated risks of mortality in acute pancreatitis.

Pancreatology 2021 Jan 14;21(1):25-30. Epub 2020 Dec 14.

Division of Gastroenterology, Hepatology, and Nutrition, The Ohio State University Wexner Medical Center, Columbus, OH, USA. Electronic address:

Background: There is limited research in prognosticators of hospital transfer in acute pancreatitis (AP). Hence, we sought to determine the predictors of hospital transfer from small/medium-sized hospitals and outcomes following transfer to large acute-care hospitals.

Methods: Using the 2010-2013 Nationwide Inpatient Sample (NIS), patients ≥18 years of age with a primary diagnosis of AP were identified. Hospital size was classified using standard NIS Definitions. Multivariable analyses were performed for predictors of "transfer-out" from small/medium-sized hospitals and mortality in large acute-care hospitals.

Results: Among 381,818 patients admitted with AP to small/medium-sized hospitals, 13,947 (4%) were transferred out to another acute-care hospital. Multivariable analysis revealed that older patients (OR = 1.04; 95%CI 1.03-1.06), men (OR = 1.15; 95%CI 1.06-1.24), lower income quartiles (OR = 1.54; 95%CI 1.35-1.76), admission to a non-teaching hospital (OR = 3.38; 95%CI 3.00-3.80), gallstone pancreatitis (OR = 3.32; 95%CI 2.90-3.79), pancreatic surgery (OR = 3.14; 95%CI 1.76-5.58), and severe AP (OR = 3.07; 95%CI 2.78-3.38) were predictors of "transfer-out". ERCP (OR = 0.53; 95%CI 0.43-0.66) and cholecystectomy (OR = 0.14; 95%CI 0.12-0.18) were associated with decreased odds of "transfer-out". Among 507,619 patients admitted with AP to large hospitals, 31,058 (6.1%) were "transferred-in" from other hospitals. The mortality rate for patients "transferred-in" was higher than those directly admitted (2.54% vs. 0.91%, p < 0.001). Multivariable analysis revealed that being "transferred-in" from other hospitals was an independent predictor of mortality (OR = 1.47; 95% CI 1.22-1.77).

Conclusions: Patients with AP transferred into large acute-care hospitals had a higher mortality than those directly admitted likely secondary to more severe disease. Early implementation of published clinical guidelines, triage, and prompt transfer of high-risk patients may potentially offset these negative outcomes.
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http://dx.doi.org/10.1016/j.pan.2020.12.001DOI Listing
January 2021

Associations between tobacco use patterns and demographic characteristics of sexual minority and heterosexual youth: Results from a nationwide online survey.

Tob Prev Cessat 2020 15;6:69. Epub 2020 Dec 15.

Tobacco Center for Regulatory Science, American Heart Association, Dallas, United States.

Introduction: Youth are at risk for tobacco use, and previous research has pointed to increased vulnerabilities associated with sexual minority identity. For example, LGB youth have increased odds for using tobacco than their heterosexual peers, and bisexual youth have higher odds of smoking than other sexual identity groups. As new tobacco products proliferate and health risks from dual/poly use grow, increased understanding of tobacco use patterns by sexual minority youth is needed.

Methods: For 3117 youth, aged 13-18 years, who completed an online questionnaire in 2017 and identified their sexual orientation [minority (e.g. lesbian/gay, bisexual, or pansexual) vs majority (heterosexual)] and gender, we classified current tobacco use into four categories: e-cigarette only, other product only (such as cigarette, cigar, or smokeless tobacco; not an e-cigarette), dual/poly use, and no use. Analyses were conducted separately for male and female participants. Multinomial logistic regression was employed.

Results: Female sexual minority youth had nearly twofold odds of dual/ poly tobacco use (OR=1.95; 95% CI: 1.12-3.40), compared to their heterosexual counterparts. For male youth, sexual minority identification was not significantly associated with dual/poly use. No significant differences were found in sexual minority and heterosexual youth e-cigarette only or other tobacco only use groups. Tobacco use patterns also significantly differed by age, race, place of residence, and parental education level.

Conclusions: Study findings reveal greater odds of dual/poly tobacco use for female sexual minority youth. Tailored tobacco prevention and cessation programs or interventions are needed for sexual minority youth most at risk of tobacco use, especially multiple product use.
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http://dx.doi.org/10.18332/tpc/130348DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7737560PMC
December 2020

C-Reactive Protein and Cancer-Diagnostic and Therapeutic Insights.

Front Immunol 2020 19;11:595835. Epub 2020 Nov 19.

Roosevelt University, College of Science, Health and Pharmacy, Schaumburg, IL, United States.

Cancer disease describes any pathology involving uncontrolled cell growth. As cells duplicate, they can remain localized in defined tissues, forming tumor masses and altering their microenvironmental niche, or they can disseminate throughout the body in a metastatic process affecting multiple tissues and organs. As tumors grow and metastasize, they affect normal tissue integrity and homeostasis which signals the body to trigger the acute phase inflammatory response. C-reactive protein (CRP) is a predominant protein of the acute phase response; its blood levels have long been used as a minimally invasive index of any ongoing inflammatory response, including that occurring in cancer. Its diagnostic significance in assessing disease progression or remission, however, remains undefined. By considering the recent understanding that CRP exists in multiple isoforms with distinct biological activities, a unified model is advanced that describes the relevance of CRP as a mediator of host defense responses in cancer. CRP in its monomeric, modified isoform (mCRP) modulates inflammatory responses by inserting into activated cell membranes and stimulating platelet and leukocyte responses associated with acute phase responses to tumor growth. It also binds components of the extracellular matrix in involved tissues. Conversely, CRP in its pentameric isoform (pCRP), which is the form quantified in diagnostic measurements of CRP, is notably less bioactive with weak anti-inflammatory bioactivity. Its accumulation in blood is associated with a continuous, low-level inflammatory response and is indicative of unresolved and advancing disease, as occurs in cancer. Herein, a novel interpretation of the diagnostic utility of CRP is presented accounting for the unique properties of the CRP isoforms in the context of the developing pro-metastatic tumor microenvironment.
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http://dx.doi.org/10.3389/fimmu.2020.595835DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7727277PMC
November 2020

Soy-tomato enriched diet reduces inflammation and disease severity in a pre-clinical model of chronic pancreatitis.

Sci Rep 2020 12 11;10(1):21824. Epub 2020 Dec 11.

James Comprehensive Cancer Center, The Ohio State University, Columbus, USA.

Chronic pancreatitis (CP) is a fibro-inflammatory syndrome in individuals who develop persistent pathological responses to parenchymal injury or stress. Novel therapeutic or dietary interventions that could lessen inflammation in this disease could significantly improve quality of life in patients with CP. Complex dietary foods like soy and tomatoes are composed of active metabolites with anti-inflammatory effects. Data from our group reports that bioactive agents in soy and tomatoes can reduce pro-inflammatory cytokines and suppressive immune populations. Additionally, our team has developed a novel soy-tomato juice currently being studied in healthy individuals with no toxicities, and good compliance and bioavailability. Thus, we hypothesize that administration of a soy-tomato enriched diet can reduce inflammation and severity of CP. C57BL/6 mice were injected intraperitoneally with 50 μg/kg caeurlein (7 hourly injections, twice weekly) for 6 weeks to induce CP. After 4 weeks of caerulein injections, mice were administered a control or a soy-tomato enriched diet for 2 weeks. Disease severity was measured via immunohistochemical analysis of pancreata measuring loss of acini, fibrosis, inflammation, and necrosis. Serum lipase and amylase levels were analyzed at the end of the study. Inflammatory factors in the serum and pancreas, and immune populations in the spleen of mice were analyzed by cytokine multiplex detection, qRT-PCR, and flow cytometry respectively. Infra-red (IR) sensing of mice was used to monitor spontaneous activity and distress of mice. Mice fed a soy-tomato enriched diet had a significantly reduced level of inflammation and severity of CP (p = 0.032) compared to mice administered a control diet with restored serum lipase and amylase levels (p < 0.05). Mice with CP fed a soy-tomato diet had a reduction in inflammatory factors (TNF-α, IL-1β, IL-5) and suppressive immune populations (myeloid-derived suppressor cells; MDSC) compared to control diet fed mice (p < 0.05). Infra-red sensing to monitor spontaneous activity of mice showed that soy-tomato enriched diet improved total activity and overall health of mice with CP (p = 0.055) and CP mice on a control diet were determined to spend more time at rest (p = 0.053). These pre-clinical results indicate that a soy-tomato enriched diet may be a novel treatment approach to reduce inflammation and pain in patients with CP.
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http://dx.doi.org/10.1038/s41598-020-78762-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7733503PMC
December 2020

Feasibility study of a modified yoga program for chronic pain among elderly adults in assisted and independent living.

Explore (NY) 2020 Nov 23. Epub 2020 Nov 23.

Department of Family Medicine, University of Michigan Medical School, Ann Arbor, MI, United States; Department of Nutritional Sciences, University of Michigan School of Public Health, Ann Arbor, MI, United States.

Context: Yoga improves quality of life in elders ≥65 years, but studies among elders with chronic pain are limited.

Objective: Conduct a feasibility study of gentle yoga among elders in assisted and independent living.

Design: Single arm pre/post clinical trial.

Subjects: Adults (≥65 years of age) with self-identified chronic pain (≥3 on a 10-point scale, lasting for ≥3 months) and no current yoga practice.

Intervention: Ten weekly 60-min gentle yoga classes tailored to elderly adults.

Outcome Measures: At baseline, weeks 5, 10 (end of intervention), and 20 (follow-up), we collected data on feasibility (adherence, retention, safety), pain, anxiety, depression, fatigue, sleep disturbance, and physical function.

Results: Twenty-six participants enrolled (88% women, 77% white, 58% in assisted living) with average age of 86.6 ± 4.4 (Mean, STD). Twenty participants completed the intervention, with 90% adhering (completing ≥6 classes). Nine participants (45% of completers) experienced adverse events, which were non-serious and related to transient musculoskeletal pain. No adverse events resulted in study withdrawal. Participants reported being somewhat likely to recommend yoga to a friend, and quite a bit likely to do yoga again. At the end of the intervention, four of twenty participants reported practicing yoga outside of class. Anxiety significantly decreased from 5.80 (SE=0.90) to 4.44 (SE=0.74) (p = 0.014), but there were no changes in other measures.

Conclusions: Our pilot 10-week yoga study was generally safe for and suitable to assisted and independent living elderly adults. Future studies are needed to examine other effects of yoga in assisted/independent living adults with chronic pain.
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http://dx.doi.org/10.1016/j.explore.2020.11.010DOI Listing
November 2020

Use of linked administrative and laboratory data to confirm that serum 25(OH)D levels in pregnant women can be predicted from satellite estimates of ultraviolet radiation.

Int J Epidemiol 2021 Mar;50(1):303-313

University of Western Australia, Perth, Western Australia.

Background: Serum 25 hydroxyvitamin D [25(OH)D] levels of pregnant women have been linked to various health outcomes in their offspring. Satellite-derived ultraviolet radiation (UVR) data have been used as a proxy for 25(OH)D levels, as individual-level cohort studies are time-consuming, costly and only feasible for common outcomes.

Methods: Data on 25(OH)D levels from a public laboratory database were linked to data from the Western Australian Midwives' Notification System and daily erythemal UVR dose from NASA satellites. Regression analysis was used to identify the time period prior to venesection where daily UVR dose best predicted 25(OH)D levels. A predictive model was used to validate the use of daily UVR dose as a proxy for personal sun exposure during pregnancy.

Results: Data from 19 173 pregnancies in women aged 18-43 years in Western Australia were included. The daily UVR dose averaged over the 90 days before venesection was the strongest UVR predictor of 25(OH)D level (a 5% increase per 1000 J m-2; equal to 3.3 nmol L-1 at the median of 66 nmol L-1). Ethnicity was the strongest predictor of 25(OH)D levels (21% lower in non-Caucasian vs Caucasian: equal to 7.2 nmol L-1 difference). Other significant predictors were gestation, age, year, parity, socio-economic status, remoteness, medical conditions and season.

Conclusion: NASA-derived erythemal UVR dose in the 90 days prior to venesection is a significant predictor of 25(OH)D levels in pregnant women. Linked administrative data can be used to investigate associations between UVR during pregnancy and health outcomes in offspring.
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http://dx.doi.org/10.1093/ije/dyaa165DOI Listing
March 2021

Case report: a man with untreated rheumatoid arthritis, cryoglobulinemic vasculitis, membranous nephropathy and pulmonary sarcoidosis.

BMC Nephrol 2020 11 19;21(1):496. Epub 2020 Nov 19.

Department of Nephrology, Cook County Health, Chicago, IL, USA.

Background: Glomerular involvement in rheumatoid arthritis has been known to be associated with treatment side effects from medications and secondary amyloidosis. However, limited basic science and clinical studies have been performed to address the potential disease specific immune-mediated mechanisms causing secondary glomerular pathology, its various types of presentation, and the potential treatments.

Case Presentation: A 41-year-old man with chronic active rheumatoid arthritis presented with nephrotic syndrome and was found to have membranous nephropathy with eosinophilic intracapillary thrombi on renal biopsy. Proteinuria persisted despite complete withdrawal from non-steroidal anti-inflammatory drugs (NSAIDs) and disease-modifying anti-rheumatic drugs (DMARDs). Throughout the disease course, he developed cryoglobulinemic vasculitis and pulmonary sarcoidosis, both of which achieved clinical resolution with glucocorticoids. However, only partial improvement was observed in proteinuria with treatment of steroids and Rituximab.

Conclusion: Our case presented a unique and complicated clinical phenotype of active rheumatoid arthritis, with clinical features of cryoglobulinemic vasculitis, histopathologic features of membranous and cryoglobulinemic nephropathy in the absence of DMARDs use, as well as pulmonary sarcoidosis. We speculate that there is a wider spectrum of glomerular disease in patients with untreated rheumatoid arthritis. In addition, the potential association between rheumatoid arthritis and cryoglobulinemic vasculitis should probably be revisited and requires further studies to elucidate the underlying mechanisms and treatment options.
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http://dx.doi.org/10.1186/s12882-020-02161-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7676473PMC
November 2020

Mucosal Therapy of Multi-Drug Resistant Tuberculosis With IgA and Interferon-γ.

Front Immunol 2020 20;11:582833. Epub 2020 Oct 20.

Institute for Infection and Immunity, St. George's University, London, United Kingdom.

New evidence has been emerging that antibodies can be protective in various experimental models of tuberculosis. Here, we report on protection against multidrug-resistant (MDR-TB) infection using a combination of the human monoclonal IgA 2E9 antibody against the alpha-crystallin (Acr, HspX) antigen and mouse interferon-gamma in mice transgenic for the human IgA receptor, CD89. The effect of the combined mucosal IgA and IFN-γ; treatment was strongest (50-fold reduction) when therapy was applied at the time of infection, but a statistically significant reduction of lung bacterial load was observed even when the therapy was initiated once the infection had already been established. The protection involving enhanced phagocytosis and then neutrophil mediated killing of infected cells was IgA isotype mediated, because treatment with an IgG version of 2E9 antibody was not effective in human IgG receptor CD64 transgenic mice. The Acr antigen specificity of IgA antibodies for protection in humans has been indicated by their elevated serum levels in latent tuberculosis unlike the lack of IgA antibodies against the virulence-associated MPT64 antigen. Our results represent the first evidence for potential translation of mucosal immunotherapy for the management of MDR-TB.
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http://dx.doi.org/10.3389/fimmu.2020.582833DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7606302PMC
October 2020

Presentations and outcomes of central nervous system TB in a UK cohort: The high burden of neurological morbidity.

J Infect 2021 Jan 31;82(1):90-97. Epub 2020 Oct 31.

Infection Care Group, St George's University Hospitals NHS Foundation Trust, London, UK; Institute for Infection & Immunity, St George's, University of London, London SW17 0RE, UK. Electronic address:

Objectives: Most data for Central Nervous System Tuberculosis (CNS-TB) derive from high-incidence, resource-limited countries. We sought to determine the presentation, management and outcomes of CNS-TB in a low-incidence setting with accessible healthcare.

Methods: We undertook a retrospective, observational study of CNS-TB in adults at a single tertiary-referral London hospital (2001-2017). Cases were categorised as either TB meningitis (TBM) or TB mass lesions without meningitis (TBML), applying novel criteria for definite, probable, and possible TBML.

Results: We identified sixty-two cases of TBM (37% definite; 31% probable; 32% possible) alongside 14 TBML cases (36% definite; 29% probable; and 36% possible). Clinical presentation was highly variable. Among CSF parameters, hypoglycorrhachia proved most discriminatory for "definite" TBM. Neurosurgical intervention was required for mass-effect or hydrocephalus in 16%. Mortality was higher in TBM versus TBML (16% vs. 0%) but overall morbidity was significant; 33% of TBM and 29% of TBML survivors suffered persisting neurological disability at 12-months. In TBM, hydrocephalus, infarct, basal enhancement and low CSF white cell count were independently associated with worse neurological outcomes.

Conclusion: Although mortality was lower than previously reported in other settings, morbidity was significant, highlighting the need for improved CNS-TB diagnostics, therapeutics and interventions to mitigate neurological sequelae.
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http://dx.doi.org/10.1016/j.jinf.2020.10.028DOI Listing
January 2021

Health-Related Quality of Life, Depressive Symptoms, and Kidney Transplant Access in Advanced CKD: Findings From the Chronic Renal Insufficiency Cohort (CRIC) Study.

Kidney Med 2020 Sep-Oct;2(5):600-609.e1. Epub 2020 Aug 11.

Department of Medicine, Loyola University Medical Center, Maywood, IL.

Rationale & Objective: Among individuals with chronic kidney disease (CKD), poor self-reported health is associated with adverse outcomes including hospitalization and death. We sought to examine the association between health-related quality-of-life (HRQoL) and depressive symptoms in advanced CKD and subsequent access to the kidney transplant waiting list.

Study Design: Prospective cohort study.

Setting & Population: 1,676 Chronic Renal Insufficiency Cohort (CRIC) study participants with estimated glomerular filtration rates ≤ 30 mL/min/1.73 m at study entry or during follow-up.

Exposures: HRQoL ascertained by 5 scales of the Kidney Disease Quality of Life-36 Survey (Physical Component Summary [PCS], Mental Component Summary, Symptoms, Burdens, and Effects), with higher scores indicating better HRQoL, and depressive symptoms ascertained using the Beck Depression Inventory.

Outcomes: Time to kidney transplant wait-listing and time to pre-emptive wait-listing.

Analytic Approach: Time-to-event analysis using Cox proportional hazards regression.

Results: During a median follow-up of 5.1 years, 652 (39%) participants were wait-listed, of whom 304 were preemptively wait-listed. Adjusted for demographics, comorbid conditions, estimated glomerular filtration rate slope, and cognitive function, participants with the highest scores on the Burden and Effects scales, respectively, had lower rates of wait-listing than those with the lowest scores on the Burden (wait-listing adjusted hazard ratio [aHR], 0.70; 95% CI, 0.57-0.85;  < 0.001) and Effects scales (wait-listing aHR, 0.74; 95% CI, 0.59-0.92;  = 0.007). Participants with fewer depressive symptoms (ie, Beck Depression Inventory score < 14) had lower wait-listing rates than those with more depressive symptoms (aHR, 0.81; 95% CI, 0.66-0.99;  = 0.04). Participants with lower Burden and Effects scale scores and those with higher Symptoms and PCS scores had higher pre-emptive wait-listing rates (aHR in highest tertile of PCS relative to lowest tertile, 1.58; 95% CI, 1.12-2.23;  = 0.01).

Limitations: Unmeasured confounders.

Conclusions: Self-reported health in late-stage CKD may influence the timing of kidney transplantation.
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http://dx.doi.org/10.1016/j.xkme.2020.06.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7568061PMC
August 2020

Narrowband UVB phototherapy reduces TNF production by B-cell subsets stimulated via TLR7 from individuals with early multiple sclerosis.

Clin Transl Immunology 2020 15;9(10):e1197. Epub 2020 Oct 15.

Telethon Kids Institute University of Western Australia Perth WA Australia.

Objectives: At the end of a 60-day course of narrowband UVB phototherapy, administered to individuals with early multiple sclerosis, there were changes in the relative proportions of circulating B-cell subsets. This study investigated phototherapy-associated changes to cytokine responses of B cells when exposed to a TLR7 ligand.

Methods: PBMCs from participants of the PhoCIS (Phototherapy for Clinically Isolated Syndrome) trial taken before (day 1) and after phototherapy for 8 weeks (day 60) were incubated with, or without, the TLR7 ligand, R848, for 18 h. Production of TNF and IL-10 in seven B-cell subsets was examined, with cytokine responses in each individual at day 60, adjusted for responses at day 1. Paired PBMCs were from participants administered phototherapy ( = 7) or controls ( = 6).

Results: At day 60, significantly fewer B cells, particularly marginal zone-like B cells (CD27/IgD), from participants administered phototherapy produced TNF in response to TLR7 stimulation. When responses by seven B-cell subsets were analysed together using multivariate methods, a phototherapy-specific signature was observed. An increased responsiveness from day 1 to day 60 in IgM-only memory B cells (CD27/IgD/IgM) after TLR7 stimulation also predicted slower progression from CIS to MS. Phototherapy was without significant effect on B-cell IL-10 production.

Conclusions: Reduced TNF responses after TLR7 stimulation in marginal zone-like B cells from participants administered phototherapy suggested treatment-associated priming effects that were detected upon subsequent polyclonal B-cell activation. Changes in responsiveness to TLR7 stimulation also suggested that IgM-only memory B cells may be important in conversion from CIS to MS.
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http://dx.doi.org/10.1002/cti2.1197DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7561518PMC
October 2020

Structure Based Design of Bicyclic Peptide Inhibitors of RbAp48.

Angew Chem Int Ed Engl 2021 01 24;60(4):1813-1820. Epub 2020 Nov 24.

Department of Chemical Biology, Max Planck Institute of Molecular Physiology, Otto-Hahn-Strasse 11, 44227, Dortmund, Germany.

The scaffolding protein RbAp48 is part of several epigenetic regulation complexes and is overexpressed in a variety of cancers. In order to develop tool compounds for the study of RbAp48 function, we have developed peptide inhibitors targeting the protein-protein interaction interface between RbAp48 and the scaffold protein MTA1. Based on a MTA1-derived linear peptide with low micromolar affinity and informed by crystallographic analysis, a bicyclic peptide was developed that inhibits the RbAp48/MTA1 interaction with a very low nanomolar K value of 8.56 nM, and which showed appreciable stability against cellular proteases. Design included exchange of a polar amide cyclization strategy to hydrophobic aromatic linkers enabling mono- and bicyclization by means of cysteine alkylation, which improved affinity by direct interaction of the linkers with a hydrophobic residue on RbAp48. Our results demonstrate that stepwise evolution of a structure-based design is a suitable strategy for inhibitor development targeting PPIs.
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http://dx.doi.org/10.1002/anie.202009749DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7894522PMC
January 2021

How C-Reactive Protein Structural Isoforms With Distinctive Bioactivities Affect Disease Progression.

Front Immunol 2020 10;11:2126. Epub 2020 Sep 10.

Roosevelt University College of Pharmacy, Schaumburg, IL, United States.

C-reactive protein (CRP) is a widely known, hepatically synthesized protein whose blood levels change rapidly and pronouncedly in response to any tissue damaging event associated with an inflammatory response. The synthesis and secretion of CRP is stimulated by interleukin-6, an early pleiotropic cytokine released by macrophages, endothelial, and other cells that are activated when localized normal tissue structures are compromised by trauma or disease. Serum CRP levels can change rapidly and robustly from 10-100-fold within 6-72 h of any tissue damaging event. Elevated blood levels correlate with the onset and extent of both activated inflammation and the acute phase biochemical response to the tissue insult. Because its functional bioactivity as the prototypic acute phase reactant has eluded clear definition for decades, diagnosticians of various conditions and diseases use CRP blood levels as a simple index for ongoing inflammation. In many pathologies, which involves many different tissues, stages of disease, treatments, and responses to treatments, its interpretive diagnostic value requires a deeper understanding of the localized tissue processes and events that contribute signals which regulate protective or pathological host defense bioactivities. This report presents concepts that describe how local tissue activation events can lead to a non-proteolytic, conformational rearrangement of CRP into a unique isoform with distinctive solubility, antigenicity, binding reactivities and bioactivities from that protein widely known and measured in serum. By describing factors that control the expression, tissue localization, half-life and pro-inflammatory amplification activity of this CRP isoform, a unifying explanation for the diagnostic significance of CRP measurement in disease is advanced.
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http://dx.doi.org/10.3389/fimmu.2020.02126DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7511658PMC
September 2020

Hypercoagulability following COVID-19 infection: at what stage is it safe to do a free flap?

Br J Oral Maxillofac Surg 2020 12 20;58(10):e232-e233. Epub 2020 Aug 20.

Department of Oral and Maxillofacial Surgery, Technische Universität München, Klinikum Rechts der Isar, Germany; Department of Oral and Maxillofacial Surgery, Malteser Krankenhaus St. Josefshospital, Krefeld-Uerdingen, Germany. Electronic address:

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http://dx.doi.org/10.1016/j.bjoms.2020.08.092DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7439826PMC
December 2020

Relationship between fitness performance and a newly developed continuous body composition score in U.S. adolescent boys.

Authors:
Peter Hart

Int J Adolesc Med Health 2020 Sep 23. Epub 2020 Sep 23.

Health Promotion Research, Health Demographics, 930 4th Ave, Havre, 59501,MT, USA.

Objectives Body composition (BC) assessment typically requires the administration of a single test and can have different evaluation outcomes depending on the selected test and the specific population. The purpose of this study was twofold. Firstly, to develop and validate a novel continuous body composition (CBC) score using the continuous response model (CRM). Secondly, to examine the relationship between CBC scores and fitness performance. Methods Data from the 2012 NHANES National Youth Fitness Survey (NNYFS) were used and consisted of n=212 adolescent boys 12-15 years of age. CBC scale variables included body mass (BM), body mass index (BMI), arm circumference (AC), waist circumference (WC), calf circumference (CC), calf skinfold (CSF), triceps skinfold (TSF), and subscapular skinfold (SSF). Fitness performance variables included cardiorespiratory fitness (CRF, mL/kg/min), leg strength (LS, lb), modified pull-ups (MPU, #), grip strength (GS, kg), and plank (PL, sec). Samejima's CRM, factor analysis, convergent validity coefficients and score reliability were used to validate the CBC scale. Multinomial logistic regression and multiple linear regression were used to examine the relationship between CBC scores and fitness performance variables. Results Factor analysis of the CBC scale variables retained a single factor (loadings >0.81, 88% explained variance) with strong internal consistency (α=0.96). The CRM analysis indicated all CBC scale variables fit a unidimensional construct with adequate discrimination (as: 0.71-2.16) and difficulty (bs: -0.04-1.44). CBC scores (Mean=0, SD=1.00) displayed strong reliability (SEE.θ=0.22, r.θ=0.95) with lower values representing smaller-more-lean individuals and higher values representing larger-less-lean individuals. All fully adjusted regression models showed significant (ps<0.05) negative relationships between CBC scores and CRF, MPU, and PL and positive relationships between CBC scores and LS and GS. Conclusion The CRM-derived CBC score is a novel measure of BC and found to be positively associated with strength performance and negatively associated with endurance performance in U.S. adolescent boys.
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http://dx.doi.org/10.1515/ijamh-2020-0198DOI Listing
September 2020