Clinical Outcomes and Healthcare Resource Utilization for Gastrointestinal Acute Graft-versus-Host Disease after Allogeneic Transplantation for Hematologic Malignancy: A Retrospective US Administrative Claims Database Analysis.

Graft-versus-host disease (GVHD) is the leading cause of nonrelapse mortality among patients who receive allogeneic hematopoietic cell transplantation (allo-HCT). In its acute form (aGVHD), GVHD involves the skin, liver, and gastrointestinal (GI) tract, with GI involvement most strongly associated with poor prognosis. This retrospective cohort study used US healthcare claims data for 2008 to 2015 to identify patients who developed GI aGVHD after allo-HCT performed as curative treatment for hematologic malignancy and compared them with patients who did not develop aGVHD in terms of outcomes related to survival, infections, healthcare resource utilization (HRU), and costs. Whereas the patients without aGVHD saw a 66% improvement in 1-year survival between 2009 and 2015, this effect was not observed in patients with GI aGVHD. Compared with patients without evidence of aGVHD, patients with GI aGVHD were 3.9-fold more likely to develop an infection in the year after allo-HCT. Similarly, patients who developed GI aGVHD were 4.3-fold more likely to have an inpatient admission after allo-HCT discharge, and such an admission cost on average 47% more than an admission for patients without aGVHD. Our findings confirm that GI involvement in aGVHD is associated with higher mortality, risk of infection, HRU, and cost compared with absence of aGVHD.

Safety and Effectiveness of Vedolizumab in Patients with Steroid-Refractory Gastrointestinal Acute Graft-versus-Host Disease: A Retrospective Record Review.

Allogeneic hematopoietic cell transplantation (allo-HCT) can be curative in patients with hematologic malignancies but carries a significant risk of graft-versus-host disease (GVHD). There are no standard treatments for steroid-refractory (SR) gastrointestinal (GI) acute GVHD (aGVHD). This multicenter, international, retrospective medical record review aimed to evaluate the off-label use of vedolizumab, a gut-selective immunomodulator, for treating SR GI aGVHD. Data were collected from patients' medical records; criteria for extraction included no more than 1 allo-HCT and at least 1 dose of vedolizumab as treatment for SR GI aGVHD (ie, stage 1 to 4 GI aGVHD following ≥1 previous treatment regimen(s) containing ≥1 mg/kg methylprednisolone or equivalent). Descriptive analyses of response rate, overall survival (OS), and serious adverse effects (SAEs) were performed. Twenty-nine patients were identified from 7 sites who had received 1 to 10 doses of vedolizumab 300 mg i.v. (median 3 doses) as treatment for SR GI aGVHD. The overall response rate at 6 to 10 weeks after vedolizumab initiation was 64%, and OS at 6 months was 54%. There were 29 SAEs, including 12 infections; 3 SAEs were considered possibly related to vedolizumab, 2 of which were infections. Thirteen SAEs were fatal, 1 of which was possibly vedolizumab-related. There were 8 nonserious infections and 1 serious infection with confirmed GI origin in 8 patients; there was no apparent pattern in the timing of these infections relative to the initiation of vedolizumab treatment. Further data on the efficacy and safety of vedolizumab in this setting from prospective trials are needed.

Design and construction of a recombinant lentiviral vector with specific tropism to human epidermal growth factor-overexpressed cancer cells: Developing a new retargeting system for lentivirus vectors.

BACKGROUND: Targeting of specific tissues and cells by viruses is one of the challenges faced by researchers. Lentiviral vectors (LVs) are one of the most promising gene delivery systems in cancer gene therapy. Therefore, we aimed to design a novel lentiviral delivery system that expresses anti- human epidermal growth factor 2 (HER2) designed anykrin repeat protein (DARPin) on the vector envelope to create a pseudotyped lentivirus for targeting HER2-positive cancer cells. METHODS: A helper plasmid producing the viral vector envelope containing anti-HER2 DARPin-G3 was constructed. LV was produced by transfer vector containing green fluorescent protein (GFP) gene and helper plasmids in human embryonic kidney 293 cells. The human breast cancer cell lines SKBR3 (normal and with inhibited endocytosis) (HER2-positive) and MDA-MB-231 (HER2-negative) were transduced by the recombinant viral vector. The GFP-based transduction rate was determined by flow cytometry and fluorescence microscopy. RESULTS: The anti-HER2 DARPin concentration in DARPin-LVs was significantly higher than the envelope G glycoprotein of the vesicular stomatitis virus-LVs (non-anti-HER2 control) (p < 0.0001). In flow cytometry assays, the percentage of transduction by recombinant LV was significantly higher in SKBR3 cells than in SKBR3 cells with inhibited endocytosis (p = 0.0074) and MDA-MB-231 cells (p = 0.0037). In fluorescence microscopy assays, the percentage of transduction by new LV was significantly higher in SKBR3 cells than in SKBR3 cells with inhibited endocytosis (p = 0.0026) and MDA-MB-231 cells (p = 0.0014). CONCLUSIONS: We constructed a new recombinant LV with a defect in cell entry directly, containing an anti-HER2 DARPin on the vector envelope with specific tropism to HER2 receptor on HER2-positive cancer cells. We assumed that this viral vector transduces cells via an endocytosis-dependent process.

A multicenter, retrospective, case-cohort study of the epidemiology and risk factors for Clostridium difficile infection among cord blood transplant recipients.

BACKGROUND: Clostridium difficile infection (CDI) is the leading cause of health-care associated infectious diarrhea. The aim of this study was to evaluate the epidemiology and risk factors for CDI in the 100 days following umbilical cord blood transplantation (UCBT) at three Boston hospitals. METHODS: We performed a multicenter, retrospective, case-cohort study of 226 UCBT recipients at Beth Israel Deaconess Medical Center, Massachusetts General Hospital, and Dana Farber/Brigham and Women's Cancer Center from 2003 to 2012. CDI was defined as diarrhea (≥3 unformed bowel movements for at least 2 days) plus a positive stool test for toxinogenic C. difficile and not attributed to any other cause. RESULTS: Among 226 UCBT recipients, 22 patients (9.7%) developed CDI within the first 100 days of transplant (corresponding to an infection rate of 10.8 cases per 10 000 person-days). The 100-day and 1-year rates were stable across the time period and between institutions. UCBT recipients with CDI were more likely than non-CDI patients to be older, with higher body mass indices, and to have received an antipseudomonal penicillin agent. In a time-dependent case-cohort analysis of the risk factors associated with CDI in the first 100 days after UCBT, bacterial infection after UCBT was the strongest risk factor for CDI (hazard ratio 2.8; 95% confidence interval 1.08-7.24; P=.03), after adjustment for transplant variables including antibiotic exposure. CONCLUSION: This study verifies the previously reported risk factors for CDI including older age and antibiotic exposure and identifies a novel association between bacterial infections and risk for CDI.

Preparation of a reproducible long-acting formulation of risperidone-loaded PLGA microspheres using microfluidic method.

The aim of the present study is to prepare risperidone-loaded poly lactic-co-glycolic acid (PLGA) microspheres within microfluidic system and to achieve a formulation with uniform size and monotonic and reproducible release profile. In comparison to batch method, T-junction and serpentine chips were utilized and optimizing study was carried out at different processing parameters (e.g. PLGA and surfactant concentration and flow rates ratio of outer to inner phase). The computational fluid dynamic (CFD) modeling was performed, and loading and release study were carried out. CFD simulation indicates that increasing the flow rate of aqueous phase cause to decrease the droplet size, while the change in size of microspheres did not follow a specific pattern in the experimental results. The most uniform microspheres and narrowest standard deviation (66.79 µm ± 3.32) were achieved using T-junction chip, 1% polyvinylalcohol, 1% PLGA and flow rates ratio of 20. The microfluidic-assisted microspheres were more uniform with narrower size distribution. The release of risperidone from microspheres produced by the microfluidic method was more reproducible and closer to zero-order kinetic model. The release profile of formulation with 2:1 drug-to-polymer ratio was the most favorable release, in which 41.85% release could be achieved during 24 days.

Socioeconomic Risk Factors for Celiac Disease Burden and Symptoms.

BACKGROUND & AIMS: Celiac disease (CD) affects approximately 1% of the population and negatively affects aspects of life including physical and social function. The relationship between socioeconomic (SE) factors, symptom severity, and perceived burden of living with CD is not well understood. The objective of this study was to assess the relationships between income, symptoms, and perceived burden of CD. METHODS: In this survey study conducted at a tertiary care center, 773 patients 18 years of age or more with biopsy confirmed CD were eligible to participate. Patients completed a survey with information on SE data, the validated Celiac Symptom Index (CSI), and visual analog scales (VAS) assessing overall health, CD-related health, difficulty in following a gluten-free diet (GFD), and importance of following a GFD. RESULTS: Three hundred forty one patients completed the survey. Higher income predicted better overall health, better CD related health, and fewer symptoms. In the logistic regression model, low income was associated with greater CD symptoms (odds ratio=6.04, P=0.002). Other factors associated with greater symptoms were younger age, poor overall health state, and more physician visits. Factors associated with increased burden of CD included hospitalizations, more symptoms, poor overall health state, and burden of following a GFD. CONCLUSIONS: Patients with lower incomes have worse CD-related health and greater symptoms. Those with low income had 6 times the odds of greater symptoms compared with those with high income. Our data suggest that income is associated with perceived overall health, CD-related health, and CD symptoms.

Systematic Analysis and Critical Appraisal of the Quality of the Scientific Evidence and Conflicts of Interest in Practice Guidelines (2005-2013) for Barrett's Esophagus.

BACKGROUND: Barrett's esophagus (BE) is a condition that has a small but important risk of progressing to esophageal cancer. To date, no study has assessed the strength of evidence supporting the recommendations for BE. We sought to assess the overall quality of the recommendations and strength of the BE using the AGREE II instrument. METHODS: A PubMed search was performed to identify guidelines published pertaining to BE. Every guideline was reviewed using the AGREE II format to assess the methodological rigor and validity of the guideline. Additionally, guidelines were reviewed for the level of evidence used to support recommendations, conflicts of interest (COI), and differences in recommendations. Statistical analysis was performed using Stata (version 12). RESULTS: In total, 234 manuscripts were identified of which 8 guidelines published between 2005 and 2013 pertained to BE. Seventy-five percentage (6/8) graded the evidence used to formulate recommendations. Of the 126 recommendations with supporting evidence, 6 % were supported by level A evidence, 49 % level B evidence, and 45 % level C evidence. Using the AGREE II format, the highest overall assessment grade was the BSG BE guideline (6.5 ± 0.6) followed by the AGA (5.5 ± 0.6). The highest rated domains were scope and purpose (mean 77 range 24-96) and clarity of presentation (mean 75), while the lowest rated domains were editorial independence (mean 32 range 0-92) and applicability of the guideline (mean 35 range 7-90). There was significant variability in recommendations regarding who to screen for BE and surveillance intervals. Finally, only 50 % of the guidelines disclosed if COI were present and 75 % (3/4) reported potentially relevant COI. CONCLUSIONS: Majority of the BE guideline fail to meet the AGREE II domains, and most of the recommendations are level B or C quality evidence. Further interventions are necessary to improve the overall quality of the guidelines.

Patient perception of treatment burden is high in celiac disease compared with other common conditions.

OBJECTIVES: The only treatment for celiac disease (CD) is life-long adherence to a gluten-free diet (GFD). Noncompliance is associated with signs and symptoms of CD, yet long-term adherence rates are poor. It is not known how the burden of the GFD compares with other medical treatments, and there are limited data on the socioeconomic factors influencing treatment adherence. In this study, we compared treatment burden and health state in CD compared with other chronic illnesses and evaluated the relationship between treatment burden and adherence. METHODS: Survey was mailed to participants with CD, gastroesophageal reflux disease (GERD), irritable bowel syndrome, inflammatory bowel disease, hypertension (HTN), diabetes mellitus (DM), congestive heart failure, and end-stage renal disease (ESRD) on dialysis. Surveys included demographic information and visual analog scales measuring treatment burden, importance of treatment, disease-specific health status, and overall health status. RESULTS: We collected surveys from 341 celiac and 368 non-celiac participants. Celiac participants reported high treatment burden, greater than participants with GERD or HTN and comparable to ESRD. Conversely, patients with CD reported the highest health state of all groups. Factors associated with high treatment burden in CD included poor adherence, concern regarding food cost, eating outside the home, higher income, lack of college education, and time limitations in preparing food. Poor adherence in CD was associated with increased symptoms, income, and low perceived importance of treatment. CONCLUSIONS: Participants with CD have high treatment burden but also excellent overall health status in comparison with other chronic medical conditions. The significant burden of dietary therapy for CD argues for the need for safe adjuvant treatment, as well as interventions designed to lower the perceived burden of the GFD.

Population pharmacokinetic modeling of vedolizumab for graft-versus-host disease prophylaxis in adults with allogeneic hematopoietic stem cell transplant.

We aimed to characterize the population pharmacokinetics (PK) of vedolizumab for acute graft-versus-host disease prophylaxis in adults undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT) and assess potential clinically relevant covariates. Dosing, patient characteristics, and PK from a phase 1b, open-label, dose-finding study of vedolizumab 75 mg initial dose escalated to 300 mg and a phase 3 study of vedolizumab 300 mg in patients receiving allo-HSCT were analyzed using a two-compartment population PK model with linear elimination. Covariates included age, race, weight, sex, albumin, lymphocyte count, GvHD type, and concomitant medications. Weight, albumin, and lymphocyte count were time-varying covariates. Model selection was driven by goodness-of-fit criteria, precision of parameter estimates, and visual predictive checks. In 193 patients undergoing allo-HSCT, vedolizumab PK were well described by a two-compartment, linear PK model. Using reference covariate values, final parameter estimates (95% confidence intervals [CI]) were: clearance, 0.148 (0.136, 0.162) L/day; central volume of distribution, 3.12 (3.03, 3.21) L; intercompartmental clearance, 0.500 (0.408, 0.612) L/day; and peripheral volume of distribution, 3.95 (3.52, 4.44) L. Weight and albumin were the most important predictors of vedolizumab PK, with clearance decreasing by ≈20% for low body weight/high albumin and increasing by ≈30% for high body weight/low albumin. There was an inverse relationship between vedolizumab clearance and age, but no detectable effect for lymphocyte count or GvHD type. Post hoc analyses did not detect any relationship between vedolizumab PK and concomitant medications. In summary, the covariates studied did not have a clinically meaningful effect on the PK of vedolizumab.

Prevalence and lifetime risk of endoscopy-related complications among patients with inflammatory bowel disease.

BACKGROUND & AIMS: Few studies have analyzed the safety of endoscopy in patients with inflammatory bowel disease (IBD). We aimed to determine the prevalence of procedure-related complications among these patients, compared with the general population, and estimate the lifetime risk of colonoscopy-related complications. METHODS: We collected data on complications in 685 patients with IBD and 17,000 patients without IBD (controls) using an automated system to track all emergency department visits to the Beth Israel Deaconess Medical Center within 14 days of an endoscopic procedure, from March 1, 2007, to November 30, 2007. We reviewed charts of all IBD patients to determine health care use (telephone calls or visits to a gastroenterologist or primary care physician and visits to other emergency departments or hospitals) after endoscopy. The lifetime risk of procedure-related complications was estimated using a Markov Monte Carlo model. RESULTS: Rates of complications were 1.17% among patients with IBD and 0.96% among controls (P = .55). The chart review showed that 3.8% of the IBD cohort received medical care within 14 days of the endoscopic procedure. Based on a Markov Monte Carlo simulation model, the lifetime risk of complications after a surveillance colonoscopy protocol was 12.7% among patients with IBD and 2.0% in the general population undergoing screening colonoscopy (P < .001). CONCLUSIONS: Although the risk of adverse events after each endoscopic procedure was similar for patients with IBD and the general population, IBD patients have an increased lifetime risk of complications after colonoscopies. A higher percentage of patients with IBD also seek medical care after endoscopic procedures than controls.

Systematic analysis underlying the quality of the scientific evidence and conflicts of interest in gastroenterology practice guidelines.

OBJECTIVES: The practice guidelines published by the American Gastroenterological Association (AGA) and the American College of Gastroenterology (ACG) are used to establish standards of care and improve patient outcomes. We examined the guidelines for quality of evidence, methods of grading evidence, and conflicts of interest (COIs). METHODS: All 81 (AGA and ACG) guidelines available online on 26 July 2012 were reviewed for the presence of grading of evidence and COIs. In total, 570 recommendations were evaluated for level of evidence and methods used to grade the evidence. The data were evaluated in aggregate and by society. RESULTS: Only 31% (n=25) of the guidelines graded the levels of evidence. A total of 12 systems were used to grade the quality of evidence in these 25 guidelines. Of the 570 recommendations reviewed, only 29% (n=165) were supported by the highest quality of evidence, level A; 37% (n=210) level B, 29% (n=165) level C, and 5% (n=30) level D. Since 2007, 87% (n=13/15) of the ACG guidelines graded the evidence compared with only 33% of the AGA guidelines (n=4/12). Furthermore, 70% (n=57/81) of the guidelines failed to disclose any information regarding COIs. Of the 24 articles commenting on COIs, 67% reported COIs. CONCLUSIONS: Although the majority of the gastroenterology guidelines fail to grade the quality of evidence, more recent ACG guidelines grade majority of their recommendations. When the evidence is graded, most of the supporting evidence is based on lower-quality evidence. In addition, most of the guidelines fail to comment on COIs, and when disclosed, numerous COIs were present. This study highlights the critical need to revise the guideline development process. Future guidelines should clearly state the quality of evidence for their recommendations, utilize a standard grading system, and be transparent regarding all COIs.

Primary renal osteosarcoma: A case report and review of literature.

Primary renal osteosarcoma is an exceedingly rare tumor with poor prognosis. It tends to spread to distant sites and has a low survival rate. In this report, we present a case of a 43-year-old female patient presented with flank pain, gross hematuria, weakness, and weight loss. The patient was diagnosed with primary renal osteogenic sarcoma. This case report aimed to describe the clinical and pathological features, pathogenesis, and treatment modalities of this neoplasm.

Chitosan/tripolyphosphate nanoparticles in active and passive microchannels.

BACKGROUND AND PURPOSE: In recent years, the interest in chitosan nanoparticles has increased due to their application, especially in drug delivery. The main aim of this work was to find a suitable method for simulating pharmaceutical nanoparticles with computational fluid dynamics (CFD) modeling and use it for understanding the process of nanoparticle formation in different types of microchannels. EXPERIMENTAL APPROACH: Active and passive microchannels were compared to find the advantages and disadvantages of each system. Twenty-eight experiments were done on microchannels to quantify the effect of 4 parameters and their interactions on the size and polydispersity index (PDI) of nanoparticles. CFD was implemented by coupling reactive kinetics and the population balance method to simulate the synthesis of chitosan/tripolyphosphate nanoparticles in the microchannel. FINDINGS/RESULTS: The passive microchannel had the best performance for nanoparticle production. The most uniform microspheres and the narrowest standard deviation (124.3 nm, PDI = 0.112) were achieved using passive microchannel. Compared to the active microchannel, the size and PDI of the nanoparticles were 28.7% and 70.5% higher for active microchannels, and 55.43% and 105.3% higher for simple microchannels, respectively. Experimental results confirmed the validity of CFD modeling. The growth and nucleation rates were determined using the reaction equation of chitosan and tripolyphosphate. CONCLUSION AND IMPLICATIONS: CFD modeling by the proposed method can play an important role in the prediction of the size and PDI of chitosan/tripolyphosphate nanoparticles in the same condition and provide a new perspective for studying the production of nanoparticles by numerical methods.

A phase 2a randomized clinical trial of intravenous vedolizumab for the treatment of steroid-refractory intestinal acute graft-versus-host disease.

Steroid-refractory (SR) acute graft-versus-host disease (aGvHD) remains a significant complication after allogeneic hematopoietic cell transplantation. Systemic corticosteroids are first-line therapy for aGvHD, but apart from ruxolitinib, there are no approved treatments for SR aGvHD. Vedolizumab is approved for treatment of ulcerative colitis and Crohn's disease, and may be effective for treatment of SR intestinal aGvHD. We conducted a phase 2a trial (NCT02993783) to evaluate the clinical efficacy, tolerability, and safety of vedolizumab 300 and 600 mg for SR intestinal aGvHD. This study was terminated before full enrollment was completed because early results failed to demonstrate positive proof-of-concept in efficacy. Before termination, 17 participants had enrolled and an early response in intestinal aGvHD was observed in 11 and eight participants at days 15 and 28, respectively. All adverse events observed were consistent with those expected in a population with SR intestinal aGvHD. Overall, vedolizumab did not meet the primary efficacy endpoint (overall response at day 28), likely owing to premature study drug discontinuation, lack of efficacy, and the competing risks inherent with a population with advanced SR intestinal aGvHD. Nevertheless, this study provides valuable insights into the considerations needed when conducting studies in patients with SR intestinal aGvHD.

The correction of ETV6/RUNX1 translocation in acute lymphocytic leukemia cells: a new gene targeting system by homologous recombination mechanism.

Regarding the uncertainty of the exact cause of the acute lymphocytic leukemia (ALL) caused by ETV6-RUNX1t(12;21) translocation, correcting genes of the ETV6 and RUNX1 in ETV6/RUNX1 fusion gene simultaneously on chromosome 12 may be effective in reducing leukemia malignancy. Thus, we designed an homologous recombination (HR) plasmid to target of the ETV6/RUNX1 fusion gene in the REH cell line containing the ETV6-RUNX1t(12;21) translocation. Cells were cultured and transfected by HR plasmid. The presence of the replacement cassette at specific location in the ETV6/RUNX1 fusion gene was verified by PCR and sequencing method. A quantitative gene expression assay was performed to evaluate changes in expression of ETV6, RUNX1, and ETV6/RUNX1 genes following editing. The cell viability was measured by trypan blue staining. The expression of the ETV6 gene was significantly increased in modified cells than unmodified cells by 10.9-fold. In contrast, the expression of the ETV6-RUNX1 fusion gene was significantly decreased in the modified cells compared with unmodified cells by 0.26-fold. The expression of the RUNX1 gene had no significant difference between modified and unmodified cells. The survival rate of edited cells was significantly decreased than unedited cells (p = 013). We designed a gene targeting system based on HR method to correct genes of ETV6 and RUNX1 simultaneously in ETV6/RUNX1 fusion gene on chromosome 12 containing ETV6-RUNX1t(12;21) translocation. The modification of this translocation may lead to reducing effects of the fusion gene's damaging and the dosage compensation related to ETV6 and RUNX1 genes and subsequently reduce the effects of leukemia. This targeting system may open a window for treating leukemia as ex vivo.

Salivary profile and dental status of patients with multiple sclerosis.

BACKGROUND: Multiple sclerosis (MS) is a chronic autoimmune disease of the central nervous system. The MS patients may display biochemical changes in their cerebrospinal fluid, peripheral blood and saliva. Since the salivary profile plays a critical role in maintaining oral health and function, the analysis of saliva in the MS patients would be beneficial to prevent oral diseases, such as dental caries. OBJECTIVES: The aim of this study was to evaluate the dental status and salivary profile of the MS patients. MATERIAL AND METHODS: The study involved 25 MS patients and 25 healthy controls who were examined with regard to the calcium and phosphorus level, pH and flow rate of saliva as well as the decayed, missing and filled teeth (DMFT) index for permanent first molars. Student's t-test, the χ2 test and the Mann-Whitney test were utilized to compare the study groups. RESULTS: Significantly lower salivary flow rates were observed in the MS patients as compared to the controls. The salivary calcium and phosphorus levels were significantly higher in the case group during the first 6 years of the disease and 6-11 years after the onset of the disease, respectively, in comparison with the controls; however, there was no significant difference between the groups in terms of pH. The DMFT index for permanent first molars was higher in the MS patients than in the healthy controls, but not significantly. The number of carious and missing permanent first molars was significantly higher in the MS patients. CONCLUSIONS: Multiple sclerosis appears to significantly change the salivary profile and dental status of the patients.

The Insulin-like Growth Factor-1 (G>A) and 5,10-methylenetetrahydrofolate Reductase (C677T) Gene Variants and the Serum Levels of Insulin-like Growth Factor-1, Insulin, and Homeostasis Model Assessment in Patients with Acne Vulgaris.

BACKGROUND & OBJECTIVE: To find an association between gene variants of insulin-like growth factor-1 (IGF-1) and 5,10-methylenetetrahydrofolate reductase (MTHFR) with the risk of acne vulgaris (AV). METHODS: In a case-control study, we investigated 150 AV patients and 148 healthy individuals (aged 18-25 years) for the IGF-1 G>A and MTHFR C677T polymorphisms, as well as the serum levels of IGF-1, insulin, and the homeostasis model assessment of insulin resistance (HOMA-IR). The serum biochemical parameters and the genotypes of IGF-1 G>A and MTHFR C677T were detected by using appropriate kits and polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) methods, respectively. RESULTS: The frequencies of IGF-1 and the MTHFR polymorphisms were not significantly different comparing patients and controls. The serum level of IGF-1 was 179.8±72.8 µg/L in AV patients compared to 164.6±63.7 µg/L in controls (P=0.056). The serum level of insulin in female patients was significantly higher than controls. The HOMA was 3.54±5.6 in patients compared to 1.16±1.4 (P<0.001) in controls. Significantly higher levels of fasting blood sugar (FBS), total cholesterol, and low-density lipoprotein-cholesterol (LDL-C) were detected in female patients than controls. However, the level of estradiol was significantly lower in female patients than in controls. In females, the presence of the MTHFR T allele was associated with significantly higher levels of FBS and LDL-C, as well as a significantly lower level of estradiol compared to those carriers of the C allele. CONCLUSION: We found the absence of an association between IGF-1 and MTHFR polymorphisms with the risk of AV. However, increased insulin, IGF-1, and HOMA levels in AV patients indicated the effect of insulin and insulin resistance in the risk of AV and its severity.

Microfluidic-assisted preparation of PLGA nanoparticles for drug delivery purposes: experimental study and computational fluid dynamic simulation.

This study, for the first time, tries to provide a simultaneous experimental and computational fluid dynamic (CFD) simulation investigation for production of uniform, reproducible, and stable polylactic-co-glycolic acid (PLGA) nanoparticles. CFD simulation was carried out to observe fluid flow behavior and micromixing in microfluidic system and improve our understanding about the governing fluid profile. The major objective of such effort was to provide a carrier for controlled and sustained release profile of different drugs. Different experimental parameters were optimized to obtain PLGA nanoparticles with proper size and minimized polydispersity index. The particle size, polydispersity, morphology, and stability of nanoparticles were compared. Microfluidic system provided a platform to control over the characteristics of nanoparticles. Using microfluidic system, the obtained particles were more uniform and harmonious in size, more stable, monodisperse and spherical, while particles produced by batch method were non-spherical and polydisperse. The best size and polydispersity index in the microfluidic method was obtained using 2% PLGA and 0.0625% (w/v) polyvinyl alcohol (PVA) solutions, and the flow rate ratio of 10:0.6 for PVA and PLGA solutions. CFD simulation demonstrated the high mixing intensity of about 0.99 at optimum condition in the microfluidic system, which is the possible reason for advantageous performance of this system. Altogether, the results of microfluidic-assisted method were found to be more reproducible, predictable, and controllable than batch method for producing a nanoformulation for delivery of drugs.

Association between CYP19A

Acne vulgaris (AV) is a common skin disease that causes physical and psychological problems for the affected individual. In addition to systemic changes in hormone levels, overproduction of local steroids, especially androgens are associated with AV. Cytochrome (CYP) 19 is involved in the synthesis of estrogens. The aim of the present study was to investigate the influence of CYP19A

Vedolizumab for prevention of graft-versus-host disease after allogeneic hematopoietic stem cell transplantation.

Acute graft-versus-host disease (aGVHD) remains a significant complication of allogeneic hematopoietic stem cell transplantation (allo-HSCT). Vedolizumab could help prevent aGVHD by inhibiting the migration of both naive and activated lymphocytes into gut-associated lymphoid tissues and the lamina propria. We carried out a phase 1b, open-label, dose-finding study in adults undergoing allo-HSCT to evaluate the tolerability, safety, and pharmacokinetics of vedolizumab, and its effectiveness in reducing aGVHD. IV vedolizumab was administered on day -1, +13, and +42 with respect to allo-HSCT, starting at 75 mg and with dose escalation guided by tolerability and pharmacokinetics. A total of 24 participants was enrolled, and no dose-limiting toxicities were observed in either the 75-mg cohort (n = 3) or the dose-escalated 300-mg cohort (n = 21). Treatment-emergent adverse events related to vedolizumab occurred in 8 participants. Overall, 4 deaths occurred during the 12 months following allo-HSCT. No participants in the 75-mg cohort developed modified Glucksberg grade II to IV aGVHD by 100 days after allo-HSCT. Four participants (19.0%) in the 300-mg cohort developed grade II to IV aGVHD by 100 days after allo-HSCT, including 3 participants who developed stage 1 aGVHD of the lower-intestinal tract. Vedolizumab IV 300 mg was well tolerated as aGVHD prevention, and the incidence of overall and lower-intestinal aGVHD was low. These findings support further evaluation of vedolizumab in this patient population. This trial was registered at www.clinicaltrials.gov as #NCT02728895.