Progress in the Study of Inflammatory Bowel Disease Patients with Primary Non-Responsiveness

Inflammatory bowel disease (IBD) is a group of chronic, nonspecific intestinal inflammatory disorders characterized by localized and systemic inflammation. The use of biologic agents in the treatment of IBD patients is widespread, and the occurrence of primary non-responsiveness during treatment is also significant. This review briefly summarizes the possible reasons for primary non-responsiveness in IBD patients, as well as predictive markers and current strategies to address it, providing a theoretical reference for early identification and management of IBD patients who do not respond to treatment.

Non-responsive celiac disease in children on a gluten free diet

BACKGROUND Non-responsive celiac disease(NRCD) is defined as the persistence of symptoms in individuals with celiac disease(CeD) despite being on a gluten-free diet(GFD). There is scant literature about NRCD in the pediatric population.AIM To determine the incidence, clinical characteristics and underlying causes of NRCD in children.METHODS Retrospective cohort study performed at Boston Children’s Hospital(BCH). Children < 18 years diagnosed with CeD by positive serology and duodenal biopsies compatible with Marsh Ⅲ histology between 2008 and 2012 were identified in the BCH’s Celiac Disease Program database. Medical records were longitudinally reviewed from the time of diagnosis through September 2015. NRCD was defined as persistent symptoms at 6 mo after the initiation of a GFD and causes of NRCD as well as symptom evolution were detailed. The children without symptoms at 6 mo(responders) were compared with the NRCD group. Additionally, presenting signs and symptoms at the time of diagnosis of CeD among the responders and NRCD patients were collected and compared to identify any potential predictors for NRCD at 6 mo of GFD therapy.RESULTS Six hundred and sixteen children were included. Ninety-one(15%) met criteria for NRCD. Most were female(77%). Abdominal pain [odds ratio(OR) 1.8 95% confidence interval(CI) 1.1-2.9], constipation(OR 3.1 95%CI 1.9-4.9) and absence of abdominal distension(OR for abdominal distension 0.4 95%CI 0.1-0.98) at diagnosis were associated with NRCD. NRCD was attributed to a wide variety of diagnoses with gluten exposure(30%) and constipation(20%) being the most common causes. Other causes for NRCD included lactose intolerance(9%), gastroesophageal reflux(8%), functional abdominal pain(7%), irritable bowel syndrome(3%), depression/anxiety(3%), eosinophilic esophagitis(2%), food allergy(1%), eating disorder(1%), gastric ulcer with Helicobacter pylori(1%), lymphocytic colitis(1%), aerophagia(1%) and undetermined(13%). 64% of children with NRCD improved on follow-up.CONCLUSION NRCD after ≥ 6 mo GFD is frequent among children, especially females, and is associated with initial presenting symptoms of constipation and/or abdominal pain. Gluten exposure is the most frequent cause.

Improved population mean estimator with exponential function under non-response

In this article,we consider a new family of exponential type estimators for estimating the unknown population mean of the study variable.We propose estimators taking advantage of the auxiliary variable information under the first and second non-response cases separately.The required theoretical comparisons are obtained and the numerical studies are conducted.In conclusion,the results show that the proposed family of estimators is the most efficient estimator with respect to the estimators in literature under the obtained conditions for both cases.

Outcome after Discharge from Hospital of Children with Complicated Severe Acute Malnutrition and Predictors Factors of Non-Response during Outpatient Treatment, in Senegal

Introduction: Malnutrition is a public health problem. It is responsible for high morbidity and mortality in children aged 6 - 59 months. The aim of this study was to determine the outcome of children with complicated severe acute malnutrition after hospital discharge. Methods: This is a descriptive and analytical cross-sectional study conducted from March 1 to November 31, 2021 at the Albert Royer Children’s Hospital. Children discharged from hospital for complicated severe acute malnutrition were included. Results: A total of 103 children were included. The mean age of children at hospitalization was 16.41 ± 10.11 months and mean duration of follow-up after hospital discharge was 29.63 ± 8.59 months. Three children (2.91%) died after hospital discharge. The mean z-score of the weight-for-current height was -1.34 ± 1.08. Almost a quarter (24.27%) of the children remain acute malnourished with 3.88% of severe acute malnutrition (SAM). The predictors’ factors associated with non-response were weaning before 2 years of age (ORaj: 12.21;95% CI [6.82 - 18.44];p = 0.04) and tuberculosis (ORaj: 21.06;95% CI [12.54 - 41.09];p = 0.03). Conclusion: The rate of recovery of nutritional status in children with complicated severe acute malnutrition is satisfactory. Ablactation before the age of two and the existence of tuberculosis are significantly associated with non-recovery of nutritional status.

Predictors of non-response to cardiac resynchronization therapy implantation in patients with class Ⅰ indications: the markedly dilated left ventricular end-diastolic dimension and the presence of fragmented QRS

Background Cardiac resynchronization therapy(CRT)is a highly effective treatment in patients with a class I recommendation.However,a small proportion of the strictly selected patients still fail to respond.This study was designed to identify predictors of non-response in patients with class I indications for CRT and determine the non-response probability of the patients.Methods A total of 296 consecutive patients with a class I recommendation received CRT from January 2009 to January 2017 were retrospectively analyzed.Multivariate logistic regression analysis was performed to identify predictors for non-response(defined as cardiac death,heart transplantation,or HF hospitalization during 1-year follow-up).Results Among 296 patients,30(10.1%)met non-response.Multivariate analysis demonstrated that non-response to CRT was associated with a fragmented QRS(odd ratio(OR)=2.86,95%CI:1.14–7.12;P=0.025)and left ventricular end-diastolic dimension(LVEDD)≥77 mm(OR=3.02,95%CI:1.17–7.82;P=0.022).Patients with both of the predictors had a non-response probability of 46.2%(95%CI:19.1%–73.3%).Conclusion In patients with left bundle branch block and wider QRS duration,the proportion of non-response to CRT is not low in real world.The presence of the dilated LVEDD or fragmented QRS is a strong predictor of non-response to CRT.The probability of non-response in the patients with the two predictors was 46.2%.

Estimating a Finite Population Mean under Random Non-Response in Two Stage Cluster Sampling with Replacement

Non-response is a regular occurrence in Sample Surveys. Developing estimators when non-response exists may result in large biases when estimating population parameters. In this paper, a finite population mean is estimated when non-response exists randomly under two stage cluster sampling with replacement. It is assumed that non-response arises in the survey variable in the second stage of cluster sampling. Weighting method of compensating for non-response is applied. Asymptotic properties of the proposed estimator of the population mean are derived. Under mild assumptions, the estimator is shown to be asymptotically consistent.

Exponential Ratio Type Estimators of Population Mean under Non-Response

This paper proposes some exponential ratio type estimators of population mean under the situations when certain observations for some sampling units are missing. These missing observations may be for either auxiliary variable or study variable. The biases and mean square errors of the proposed estimators have been derived, up to the first order of approximation. The proposed estimators are compared theoretically with that of the existing ratio type estimators defined by [1]. It has been found that the proposed exponential ratio type estimators perform better than the mean per unit estimator even for the low positive correlation between study variable and auxiliary variable. Moreover, we obtained the conditions for which our proposed estimators are better than the corresponding ratio type estimators of [1]. To verify the theoretical results obtained, a simulation study is carried out finally.

Compromise Allocation for Combined Ratio Estimates of Population Means of a Multivariate Stratified Population Using Double Sampling in Presence of Non-Response

This paper is an attempt to work out a compromise allocation to construct combined ratio estimates under multivariate double sampling design in presence of non-response when the population mean of the auxiliary variable is unknown. The problem has been formulated as a multi-objective integer non-linear programming problem. Two solution procedures are developed using goal programming and fuzzy programming techniques. A numerical example is also worked out to illustrate the computational details. A comparison of the two methods is also carried out.

Fuzzy Geometric Programming in Multivariate Stratified Sample Surveys in Presence of Non-Response with Quadratic Cost Function

In this paper, the problem of non-response with significant travel costs in multivariate stratified sample surveys has been formulated of as a Multi-Objective Geometric Programming Problem (MOGPP). The fuzzy programming approach has been described for solving the formulated MOGPP. The formulated MOGPP has been solved with the help of LINGO Software and the dual solution is obtained. The optimum allocations of sample sizes of respondents and non respondents are obtained with the help of dual solutions and primal-dual relationship theorem. A numerical example is given to illustrate the procedure.

Celiac disease:Management of persistent symptoms in patients on a gluten-free diet

AIM:To investigate all patients referred to our center with non-responsive celiac disease (NRCD),to establish a cause for their continued symptoms.METHODS:We assessed all patients referred to our center with non-responsive celiac disease over an 18-mo period.These individuals were investigated to establish the eitiology of their continued symptoms.The patients were first seen in clinic where a thorough history and examination were performed with routine blood work including tissue transglutaminase antibody measurement.They were also referred to a specialist gastroenterology dietician to try to identift any lapses in the diet and sources of hidden gluten ingestion.A repeat small intestinal biopsy was also performed and compared to biopsies from the referring hospital where possible.Colonoscopy,lactulose hydrogen breath testing,pancreolauryl testing and computed tomography scan of the abdomen were undertaken if the symptoms persisted.Their clinical progress was followed over a minimum of 2 years.RESULTS:One hundred and twelve consecutive patients were referred with NRCD.Twelve were found not to have celiac disease (CD).Of the remaining 100 patients,45% were not adequately adhering to a strict gluten-free diet,with 24 (53%) found to be inadvertently ingesting gluten,and 21 (47%) admitting noncompliance.Microscopic colitis was diagnosed in 12% and small bowel bacterial overgrowth in 9%.Refractory CD was diagnosed in 9%.Three of these were diagnosed with intestinal lymphoma.After 2 years,78 patients remained well,eight had continuing symptoms,and four had died.CONCLUSION:In individuals with NRCD,a remediable cause can be found in 90%:with continued gluten ingestion as the leading cause.We propose an algorithm for investigation.

Limited Efficacy of Aspirin in Patients with Peripheral Arterial Occlusive Disease

Antiplatelet drugs represent one of the basic options for management of patients with different atherosclerotic diseases. Aspirin is the oldest and most often prescribed antiplatelet drug. It seems that it is most effective in coronary patients with clinically unstable disease, less effective in prevention of cerebrovascular incidents, and its efficacy is uncertain in peripheral artery disease （PAD） patients. One of the first meta-analysis indicated that antiplatelet drugs also significantly reduce cardiovascular events in patients with PAD. However, latest meta-analysis of randomized control trials of aspirin therapy involving patients with diabetes and PAD demonstrated no benefit of aspirin in reducing cardiovascular events. Also in patients with preclinical PAD aspirin did not result in a significant reduction of vascular events. The new anti-platelet drugs prasugrel, ticagrelol, picotamide seem to be more effective than aspirin in PAD patients, particularly in diabetic patients with PAD. However, evidence based data are scanty. New studies on PAD patients are necessary to better define the role of anti-platelet agents in these patient and one of the promising ways of access to anti-platelet treatment would be personalized anti-platelet therapy.

Elevated serum interleukin-38 level at baseline predicts virological response in telbivudine-treated patients with chronic hepatitis B

AIM: To investigate serum interleukin(IL)-38 level and its clinical role in predicting virological response(VR) to telbivudine(Ld T) in patients with chronic hepatitis B(CHB).METHODS: The study participants were divided into two groups; one group consisted of 43 healthy controls(HCs) and the other group consisted of 46 patients with hepatitis B e antigen-positive CHB. All patients were administered 600 mg of oral Ld T daily for 52 wk, and they visited physicians every 12 wk for physical examination and laboratory tests. Serum IL-38 levels were determined using ELISA. The concentrations of serum Th1- and Th2-type cytokines were measured using the cytometric bead array(CBA) method. RESULTS: Serum levels of IL-38 at baseline in all patients were higher than those in HCs [306.97(123.26-492.79) pg/m L vs 184.50(135.56-292.16) pg/m L, P = 0.019]; the levels returned to normal after the first 12 wk of treatment with Ld T [175.51(103.90-331.91) pg/m L vs 184.50(135.56-292.16) pg/m L, P > 0.05]. Serum IL-38 levels at baseline were positively associated with serum aspartate aminotransferase levels in patients with CHB(r = 0.311, P = 0.036). Higher levels of serum IL-38 at baseline were associated with a greater probability of VR to Ld T treatment at 24 wk(48.15% vs 15.79%, P = 0.023) and 52 wk(66.67% vs 36.84%, P = 0.044). The levels of serum IL-38 in patients with primary nonresponse at week 12 after treatment initiation were lower than those in patients with primary response [64.44(49.85-172.08) pg/m L vs 190.54(121.35-355.28) pg/m L, P = 0.036]. Serum IL-38 levels were correlated with serum IL-6 and IL-12 levels in patients with CHB during treatment with Ld T. CONCLUSION: Elevated serum IL-38 levels in untreated CHB patients reflect ongoing liver injury. Higher serum IL-38 levels before treatment indicate a greater probability of VR to Ld T treatment.

New treatment options for alcoholic hepatitis

The burden of alcoholic liver disease has rapidly grown in the past two decades and is expected to increase further in the coming years. Alcoholic hepatitis, the most florid presentation of alcoholic liver disease, continues to have high morbidity and mortality, with significant financial and healthcare burden with limited treatment options. Steroids remain the current standard of care in severe alcoholic hepatitis in carefully selected patients. No specific treatments are available for those patients who are steroid ineligible, intolerant or unresponsive. Liver transplant has shown good short-term outcome; however, feasibility, ethical and economic concerns remain. Modification of gut microbiota composition and their products, such as lipopolysaccharide, nutritional interventions, immune modulation, increasing steroid sensitivity, genetic polymorphism and epigenetic modification of alcohol induced liver damage, augmenting hepatic regeneration using GCSF are potential therapeutic avenues in steroid non-responsive/ineligible patients. With better understanding of the pathophysiology, using &#x0201c;Omics&#x0201d; platforms, newer options for patients with alcoholic hepatitis are expected soon.

Choosing a Method to Reduce Selection Bias: A Tool for Researchers

Selection bias is well known to affect surveys and epidemiological studies. There have been numerous methods proposed to reduce its effects, so many that researchers may be unclear which method is most suitable for their study;the wide choice may even deter some researchers, for fear of choosing a sub-optimal approach. We propose a straightforward tool to inform researchers of the most promising methods available to reduce selection bias and to assist the search for an appropriate method given their study design and details. We demonstrate the tool using three examples where selection bias may occur;the tool quickly eliminates inappropriate methods and guides the researcher towards those to consider implementing. If more studies consider selection bias and adopt methods to reduce it, valuable time and resources will be saved, and should lead to more focused research towards disease prevention or cure.

Potential predictors of non-response and super-response to cardiac resynchronization therapy

Background Although cardiac resynchronization therapy （CRT） is already an established treatment, the characteristics of patients who have an excellent response to CRT and those who get no benefit remain to be determined. The purpose of this study was to search for potential predictors of both non-response and super-response to CRT.Methods Seventy-six consecutive patients who received CRT treatment were divided into group A （non-responders）,group C （super-responders） and group B （responders exclusive of super-responders）. Student＇s t test, Mann-Whitney test, Logistic regression and receiver operating characteristic curve were employed to identify potential predictors among the patients＇ demographic characteristics, clinical features, several electrocardiographic parameters before and after CRT implantation, and their pre-implant echocardiographic parameters.Results Group A had the lowest 3-month left ventricular ejection fraction （LVEF）. Group C had the smallest pre-implant left ventricular end-diastolic dimension （LVEDD）, the shortest post-implant QRS duration, the smallest 3-month LVEDD and the highest 3-month LVEF. In addition, there was a trend of gradual change in percent of left bundle branch block,severity of pre-implant mitral regurgitation, pre-implant QRS dispersion, post-implant QRS duration as well as post-implant QRS dispersion from group A to group B and from group B to group C. Multivariable Logistic analysis revealed that only pre-implant LVEDD could predict CRT super-response. A pre-implant LVEDD of 68.5 mm was the cut-off value that identified super-responders with 87.5% sensitivity and 79.7% specificity. A pre-implant LVEDD of 62.5mm identified super-responders with 50.0% sensitivity and 89.8% specificity.Conclusions Predictors of a CRT non-response remain unclear at present. But it is credible that patients with a smaller left ventricle would have a better chance to become super-responders to CRT.

Nomogram to predict primary non-response to infliximab in patients with Crohn’s disease:a multicenter study

Background:Infliximab(IFX)is effective at inducing and maintaining clinical remission and mucosal healing in patients with Crohn’s disease(CD);however,9%–40%of patients do not respond to primary IFX treatment.This study aimed to construct and validate nomograms to predict IFX response in CD patients.Methods:A total of 343 patients diagnosed with CD who had received IFX induction from four tertiary centers between September 2008 and September 2019 were enrolled in this study and randomly classified into a training cohort(n=240)and a validation cohort(n=103).The primary outcome was primary non-response(PNR)and the secondary outcome was mucosal healing(MH).Nomograms were constructed from the training cohort using multivariate logistic regression.Performance of nomograms was evaluated by area under the receiver-operating characteristic curve(AUC)and calibration curve.The clinical usefulness of nomograms was evaluated by decision-curve analysis.Results:The nomogram for PNR was developed based on four independent predictors:age,C-reactive protein(CRP)at week 2,body mass index,and non-stricturing,non-penetrating behavior(B1).AUC was 0.77 in the training cohort and 0.76 in the validation cohort.The nomogram for MH included four independent factors:baseline Crohn’s Disease Endoscopic Index of Severity,CRP at week 2,B1,and disease duration.AUC was 0.79 and 0.72 in the training and validation cohorts,respectively.The two nomograms showed good calibration in both cohorts and were superior to single factors and an existing matrix model.The decision curve indicated the clinical usefulness of the PNR nomogram.Conclusions:We established and validated nomograms for the prediction of PNR to IFX and MH in CD patients.This graphical tool is easy to use and will assist physicians in therapeutic decision-making.

Binomial Proportion Estimation in Longitudinal Data with Non-ignorable Non-response

Non-random missing data poses serious problems in longitudinal studies. The binomial distribution parameter becomes to be unidentifiable without any other auxiliary information or assumption when it suffers from ignorable missing data. Existing methods are mostly based on the log-linear regression model. In this article, a model is proposed for longitudinal data with non-ignorable non-response. It is considered to use the pre-test baseline data to improve the identifiability of the post-test parameter. Furthermore, we derive the identified estimation （IE）, the maximum likelihood estimation （MLE） and its associated variance for the post-test parameter. The simulation study based on the model of this paper shows that the proposed approach gives promising results.

An atlas of immune cell transcriptomes in human immunodeficiency virus-infected immunological non-responders identified marker genes that control viral replication

Background:Previous studies have examined the bulk transcriptome of peripheral blood immune cells in acquired immunodeficiency syndrome patients experiencing immunological non-responsiveness.This study aimed to investigate the characteristics of specific immune cell subtypes in acquired immunodeficiency syndrome patients who exhibit immunological non-responsiveness.Methods:A single-cell transcriptome sequencing of peripheral blood mononuclear cells obtained from both immunological responders(IRs)(CD4^(+)T-cell count>500)and immunological non-responders(INRs)(CD4^(+)T-cell count<300)was conducted.The transcriptomic profiles were used to identify distinct cell subpopulations,marker genes,and differentially expressed genes aiming to uncover potential genetic factors associated with immunological non-responsiveness.Results:Among the cellular subpopulations analyzed,the ratios of monocytes,CD16^(+)monocytes,and exhausted B cells demonstrated the most substantial differences between INRs and IRs,with fold changes of 39.79,11.08,and 2.71,respectively.In contrast,the CD4^(+)T cell ratio was significantly decreased(0.39-fold change)in INRs compared with that in IRs.Similarly,the ratios of natural killer cells and terminal effector CD8^(+)T cells were also lower(0.37-fold and 0.27-fold,respectively)in the INRs group.In addition to several well-characterized immune cell-specific markers,we identified a set of 181 marker genes that were enriched in biological pathways associated with human immunodeficiency virus(HIV)replication.Notably,ISG15,IFITM3,PLSCR1,HLA-DQB1,CCL3L1,and DDX5,which have been demonstrated to influence HIV replication through their interaction with viral proteins,emerged as significant monocyte marker genes.Furthermore,the differentially expressed genes in natural killer cells were also enriched in biological pathways associated with HIV replication.Conclusions:We generated an atlas of immune cell transcriptomes in HIV-infected IRs and INRs.Host genes associated with HIV replication were identified as markers of,and were found to be differentially expressed in,different types of immune cells.

Semiparametric fractional imputation using empirical likelihood in survey sampling

The empirical likelihood method is a powerful tool for incorporating moment conditions in statistical inference.We propose a novel application of the empirical likelihood for handling itemnonresponse in survey sampling.The proposed method takes the form of fractional imputation but it does not require parametric model assumptions.Instead,only the first moment condition based on a regression model is assumed and the empirical likelihood method is applied to the observed residuals to get the fractional weights.The resulting semiparametric fractional imputation provides√n-consistent estimates for various parameters.Variance estimation is implemented using a jackknifemethod.Two limited simulation studies are presented to compare several imputation estimators.