Vedolizumab as a rescue therapy for patients with medically refractory Crohn's disease.

AIM: Vedolizumab, a monoclonal antibody resulting in gut-selective anti-inflammatory activity, was approved by the US Food and Drug Administration in 2014 for use in patients with Crohn's disease (CD). The aim of this study was to investigate the efficacy of vedolizumab as a rescue therapy when other medical therapies have failed. METHOD: A retrospective review was performed on consecutive patients with CD receiving vedolizumab at the Penn State Hershey IBD Center between May 2014 and March 2016. These patients were unresponsive or intolerant to tumour necrosis factor (TNF) antagonist therapy, and previously would have been candidates for surgery. Outcomes included surgical intervention, clinical response and endoscopic improvement. RESULTS: A total of 48 patients with medically refractory CD receiving vedolizumab were included. The median length of follow-up was 69 weeks (range 15-113 weeks). A majority (81%) of patients previously failed at least two TNF antagonists, and 77% had prior surgery for CD. Surgical intervention was required in 21 (44%) patients and 13 (27%) patients required intra-abdominal operations. At the conclusion of the study, 23 (48%) patients reported continued improvement of symptoms, and 22 of 37 (59%) patients undergoing endoscopy showed improvement. Patients with the inflammatory CD phenotype were more likely to improve clinically and avoid surgery. CONCLUSION: Vedolizumab alone or in combination with immunomodulators or steroids may be used as a rescue therapy in patients with medically refractory CD and may decrease the rate of surgical intervention. Patients with the inflammatory CD phenotype had the best clinical response and decreased need for surgery, suggesting that vedolizumab is most effective in the inflammatory phenotype.

Development of an electronic medical record based intervention to improve medical care of osteoporosis.

UNLABELLED: Osteoporosis is infrequently addressed during hospitalization for osteoporotic fractures. An EMR-based intervention (osteoporosis order set) was developed with physician and patient input. There was a trend toward greater calcium supplementation from July 2008 to April 2009 (s = 0.058); however, use of antiresorptives (13%) or discharge instructions for BMD testing and osteoporosis treatment (10%) remained low. INTRODUCTION: Osteoporosis is infrequently addressed during hospitalization for osteoporotic fractures. The study population consisted of patients over 50 years of age. METHODS: Northwestern Memorial Hospital is a tertiary care academic hospital in Chicago. This study was conducted from September 1, 2007 through June 30, 2009. RESULTS: Physicians reported that barriers to care comprised nonacute nature of osteoporosis, belief that osteoporosis should be addressed by the PCP, low awareness of recurrent fractures, and radiographs with terms such as "compression deformity", "wedge deformity", or "vertebral height loss" which in their opinion were not clearly indicative of vertebral fractures. An EMR-based intervention was developed with physician and patient input. Over the evaluation period, 295 fracture cases in individuals over the age of 50 years in the medicine floors were analyzed. Mean age was 72 ± 11 years; 74% were female. Sites of fracture included hip n = 78 (27%), vertebral n = 87 (30%), lower extremity n = 61 (21%), upper extremity n = 43 (15%) and pelvis n = 26 (9%). There was no increase in documentation of osteoporosis in the medical record from pre- to post-EMR implementation (p = 0.89). There was a trend toward greater calcium supplementation from July 2008 to April 2009 (p = 0.058); however, use of antiresorptives (13%) or discharge instructions for BMD testing and osteoporosis treatment (10%) remained low. CONCLUSION: An electronic medical record intervention without electronic reminders created with physician input achieves an increase in calcium supplementation but fails to increase diagnosis or treatment for osteoporosis at the time of hospitalization for a fragility fracture.

Towards meaningful medication-related clinical decision support: recommendations for an initial implementation.

SUMMARY: Clinical decision support (CDS) can improve safety, quality, and cost-effectiveness of patient care, especially when implemented in computerized provider order entry (CPOE) applications. Medication-related decision support logic forms a large component of the CDS logic in any CPOE system. However, organizations wishing to implement CDS must either purchase the computable clinical content or develop it themselves. Content provided by vendors does not always meet local expectations. Most organizations lack the resources to customize the clinical content and the expertise to implement it effectively. In this paper, we describe the recommendations of a national expert panel on two basic medication-related CDS areas, specifically, drug-drug interaction (DDI) checking and duplicate therapy checking. The goals of this study were to define a starter set of medication-related alerts that healthcare organizations can implement in their clinical information systems. We also draw on the experiences of diverse institutions to highlight the realities of implementing medication decision support. These findings represent the experiences of institutions with a long history in the domain of medication decision support, and the hope is that this guidance may improve the feasibility and efficiency CDS adoption across healthcare settings.

Association of the dopamine receptor D4 (DRD4) gene 7-repeat allele with children with attention-deficit/hyperactivity disorder (ADHD): an update.

Polymorphisms of the dopamine receptor D4 gene DRD4, 11p15.5, have previously been associated with attention-deficit/hyperactivity disorder (ADHD) [Bobb et al., 2005; Am J Med Genet B Neuropsychiatr Genet 132:109-125; Faraone et al., 2005; Biol Psychiatry 57:1313-1323; Thapar et al., 2005; Hum Mol Genet 14 Spec No. 2:R275-R282]. As a follow up to a pilot study [see Castellanos et al., 1998; Mol Psychiatry 3:431-434] consisting of 41 probands and 56 controls which found no significant association between the DRD4 7-repeat allele in exon 3 and ADHD, a greatly expanded study sample (cases n = 166 and controls n = 282) and long term follow-up (n = 107, baseline mean age n = 9, follow-up mean age of n = 15) prompted reexamination of this gene. The DRD4 7-repeat allele was significantly more frequent in ADHD cases than controls (OR = 1.2; P = 0.028). Further, within the ADHD group, the 7-repeat allele was associated with better cognitive performance (measured by the WISC-III) (P = 0.013-0.07) as well as a trend for association with better long-term outcome. This provides further evidence of the role of the DRD4 7-repeat allele in the etiology of ADHD and suggests that this allele may be associated with a more benign form of the disorder.

Active surveillance using electronic triggers to detect adverse events in hospitalized patients.

BACKGROUND: Adverse events (AEs) occur with alarming frequency in health care and can have a significant impact on both patients and caregivers. There is a pressing need to understand better the frequency, nature, and etiology of AEs, but currently available methodologies to identify AEs have significant limitations. We hypothesized that it would be possible to design a method to conduct real time active surveillance and conducted a pilot study to identify adverse events and medical errors. METHODS: Records were selected based on 21 electronically obtained triggers, including abnormal laboratory values and high risk and antidote medications. Triggers were chosen based on their expected potential to signal AEs occurring during hospital admissions. Each AE was rated for preventability and severity and categorized by type of event. Reviews were performed by an interdisciplinary patient safety team. RESULTS: Over a 3 month period 327 medical records were reviewed; at least one AE or medical error was identified in 243 (74%). There were 163 preventable AEs (events in which there was a medical error that resulted in patient harm) and 138 medical errors that did not lead to patient harm. Interventions to prevent or ameliorate harm were made following review of the medical records of 47 patients. CONCLUSIONS: This methodology of active surveillance allows for the identification and assessment of adverse events among hospitalized patients. It provides a unique opportunity to review events at or near the time of their occurrence and to intervene and prevent harm.

Acute and subacute dermal toxicity of Break-Free CLP: a weapons cleaning and maintenance compound.

Break-Free CLP((R)) is a commercial cleaning, lubricating and preserving compound used in both the military and civilian sectors for maintenance of small- and large-caliber weapons. Like many commercial mixtures, there is very little information available on the toxicity of Break-Free CLP. Studies were conducted to characterize the biological effects of single or repeat dermal application of Break-Free CLP to the clipped backs of CD-1 mice. Break-Free CLP was applied neat, 50 microl three times of week for up to 2 weeks. Foci of epithelial ulceration were observed in skin sections from 22% of Break-Free CLP-treated animals in conjunction with markedly thickened epithelium suggesting that robust epithelial regeneration was occurring in these animals. Skin histopathology of Break-Free CLP-treated animals closely matched the histopathology from mice treated repeatedly with 2% croton oil in acetone (dermal irritation positive control). Serum alkaline phosphatase activity was significantly (P < 0.05) lower for mice treated with Break-Free CLP, 2% croton oil or 7,12-dimethylbenz[a]anthracene (DMBA) compared with negative and vehicle control mice. Skin nitric oxide (NO) levels were not significantly elevated for mice treated with Break-Free CLP but were significantly elevated for mice treated with dermal irritation positive control compound DMBA. The cumulative skin changes in Break-Free CLP-treated animals support conducting a subchronic dermal application study. The observed decreases in serum alkaline phosphatase activity suggest that future studies should include the liver and bone as possible target organs. Additionally, dermal penetration studies could provide key health risk assessment information for characterizing the potential health risks associated with chronic dermal exposure to Break-Free CLP.

GAD1 (2q31.1), which encodes glutamic acid decarboxylase (GAD67), is associated with childhood-onset schizophrenia and cortical gray matter volume loss.

Postmortem brain studies have shown deficits in the cortical gamma-aminobutyric acid (GABA) system in schizophrenic individuals. Expression studies have shown a decrease in the major GABA-synthesizing enzyme (glutamic acid decarboxylase (GAD67) mRNA levels in neurons in dorsolateral prefrontal cortex in schizophrenics relative to controls. In the present study, SNPs in and around the GAD1 gene, which encodes the protein GAD67, were tested on a rare, severely ill group of children and adolescents with childhood-onset schizophrenia (COS) (n=72), in a family-based association analysis. Compared to adult-onset samples, the COS sample has evidence for more salient familial, and perhaps genetic, risk factors for schizophrenia, as well as evidence for frontal cortical hypofunction, and greater decline in cortical gray matter volume on anatomic brain MRI scans during adolescence. We performed family-based TDT and haplotype association analyses of the clinical phenotype, as well as association analyses with endophenotypes using the QTDT program. Three adjacent SNPs in the 5' upstream region of GAD1 showed a positive pairwise association with illness in these families (P=0.022-0.057). Significant transmission distortion of 4-SNP haplotypes was also observed (P=0.003-0.008). Quantitative trait TDT analyses showed an intriguing association between several SNPs and increased rate of frontal gray matter loss. These observations, when taken together with the positive results reported recently in two independent adult-onset schizophrenia pedigree samples, suggest that the gene encoding GAD67 may be a common risk factor for schizophrenia.

Conserved RY-repeats mediate transactivation of seed-specific promoters by the developmental regulator PvALF.

Transcription of genes DLEC2 and PHSbeta is specifically and coordinately regulated during maturation of Phaseolus embryos. Over-expression of the seed- specific factor PvALF in cotyledon cells results in transactivation of either promoter. PvALF is related to the VP1 protein of maize, which transactivates gene expression via G-boxes, Sph elements and AT-rich sequences. We used deletions and base substitutions in the DLEC2 and PHSbeta promoters to demonstrate that several conserved RY-repeats were necessary for PvALF induction of both genes. A comprehensive mutational and transactivation analysis was used to define functionally the sequence of the DLEC2 repeat RY3 asG/CCATGCxxG/C. We also found that an interaction between RY3 and the 3'-flanking tetranucleotide CCAC increased PvALF transactivation. A preferred spacing and phasing requirement for the RY3 and CCAC motifs suggested the possibility of interactions between cellular factors that recognize either element. The high conservation of Sph-RY motifs in seed-specific promoters from monocots and dicots indicates that organ and temporal specification by factors similar to VP1 and PvALF is common among seed plants.

The regulator of MAT2 (ROM2) protein binds to early maturation promoters and represses PvALF-activated transcription.

The regulation of maturation (MAT)- and late embryogenesis (LEA)-specific gene expression in dicots involves factors related to ABI3, a seed-specific component of the abscisic acid signal transduction pathways from Arabidopsis. In French bean (Phaseolus vulgaris), the ABI3-like factor, PvALF, activates transcription from MAT promoters of phytohemagglutinin (DLEC2) and beta-phaseolin (PHS beta) genes. We describe the regulator of MAT2 (ROM2) as a basic leucine zipper (bZIP) DNA binding protein that recognizes motifs with symmetric (ACGT) and asymmetric (ACCT) core elements present in both MAT promoters. ROM2 antagonizes trans-activation of the DLEC2 promoter by PvALF in transient expression assays. Repression was abolished by mutations that prevented binding of ROM2 to the DLEC2 seed enhancer region. Moreover, a hybrid protein composed of a PvALF activation domain and the DNA binding and dimerization domain of ROM2 activated gene expression, indicating that ROM2 recognizes the DLEC2 enhancer in vivo; consequently, ROM2 functions as a DNA binding site-dependent repressor. Supershift analysis of nuclear proteins, using a ROM2-specific antibody, revealed an increase in ROM2 DNA binding activity during seed desiccation. A corresponding increase in ROM2 mRNA coincided with the period when DLEC2 mRNA levels declined in embryos. These results demonstrate developmental regulation of the ROM2 repressor and point to a role for this factor in silencing DLEC2 transcription during late embryogenesis.

PvAlf, an embryo-specific acidic transcriptional activator enhances gene expression from phaseolin and phytohemagglutinin promoters.

Mutations in Vp1 and ABl3 genes of maize and Arabidopsis lead to drastic reductions in the synthesis of a subset of maturation-specific products including seed storage proteins. Gene Phaseolus vulgaris ABl3-like factor (PvAlf), whose protein product is similar to the ABl3 and Vp1 proteins, has been cloned. Here, it is shown that PvAlf positively regulates phaseolin and phytohemagglutinin (PHA-L) promoters in particle bombardment assays. PvAlf mRNA expression is embryo-specific and temporally complex. PvAlf mRNA abundance is highest during two periods (9-14 and 22-35 days after flowering) that precede the onsets of seed maturation and seed abscission, respectively. Protein fusions with the DNA-binding domain of the yeast transcriptional activator GAL4 demonstrated that the N-terminal 243 amino acids of PvAlf function as a strong transcriptional activation domain in yeast (Saccharomyces cerevisiae) and plant cells. This domain consists of a central cluster rich in serine, threonine and proline (STP cluster) flanked by two negatively charged regions containing bulky hydrophobic residues similar to acidic activation domains of Vp1, the herpes simplex virus virion protein VP16 and transcription factors GCN4 and HAP4 from yeast. Together with the Vp1 proteins of maize and rice and ABl3, PvAlf constitutes a class (Vp1/ABl3-like factors or VAlfs) of regulatory factors that are pivotal for the promotion of seed maturation and dormancy in angiosperms.

Lacrimal system complications in trachoma.

A clinical study of the lacrimal complications of trachoma was conducted in the eastern province of Saudi Arabia. Of the 579 Saudi Arabian patients examined, 446 (77%) showed clinical evidence of trachoma, 62 of whom had severe inactive trachoma. In this last group the following lacrimal complications were observed: dry eye syndrome, punctal phimosis, punctal occlusion, canalicular occlusion, nasolacrimal-duct obstruction, dacryocystitis, dacryocystocele, and dacryocutaneous fistula. Histopathologic examination of seven lacrimal-sac biopsies showed the same cicatrizing changes seen in 14 conjunctival biopsies.