Impact of infliximab therapeutic drug level monitoring on outcomes of patients with inflammatory bowel disease: A real-world experience from a Middle Eastern cohort

Background and study aimTherapeutic drug monitoring (TDM) through measurement of infliximab (IFX) trough levels and antibodies to infliximab (ATI) is performed to guide IFX intensification strategies and improve its efficacy. We conducted this study to explore the relationship between clinical and endoscopic/radiological remission and IFX and ATI levels in patients with inflammatory bowel disease (IBD) treated with IFX and to evaluate the appropriateness of treatment decision post TDM.Patients and methodsThis was a cross-sectional study of a cohort of adult patients with IBD. Serum IFX trough concentrations and ATI were measured.ResultsA total of 129 patients [104] with ulcerative colitis (UC) and 25 with Crohn’s disease (CD)] were included in this study, of whom 61.2% were men. The mean disease duration was 6.7 years, and 72% of patients with UC had extensive colitis. The mean serum IFX trough level was 4.1 µg/mL; the IFX trough levels were subtherapeutic in 75 patients (58%), therapeutic in 37 patients (29%), and supratherapeutic in 17 patients (13%). Positivity to ATI was found in 16 patients (12.4%). Only 43 patients (33.3%) underwent an appropriate change in therapy after TDM, patients with penetrating CD disease had low IFX levels and higher C-reactive protein levels at 12 months before TDM.ConclusionsPatients with IBD with therapeutic IFX levels tend to have increased endoscopic/radiological remission rates. However, an appropriate change in management based on TDM was absent in the majority of patients, potentially reflecting the need to have a dashboard to support and guide clinicians in decision-making.     

Cas9-expressing chickens and pigs as resources for genome editing in livestock

Genetically modified animals continue to provide important insights into the molecular basis of health and disease. Research has focused mostly on genetically modified mice, although other species like pigs resemble the human physiology more closely. In addition, cross-species comparisons with phylogenetically distant species such as chickens provide powerful insights into fundamental biological and biomedical processes. One of the most versatile genetic methods applicable across species is CRISPR-Cas9. Here, we report the generation of transgenic chickens and pigs that constitutively express Cas9 in all organs. These animals are healthy and fertile. Functionality of Cas9 was confirmed in both species for a number of different target genes, for a variety of cell types and in vivo by targeted gene disruption in lymphocytes and the developing brain, and by precise excision of a 12.7-kb DNA fragment in the heart. The Cas9 transgenic animals will provide a powerful resource for in vivo genome editing for both agricultural and translational biomedical research, and will facilitate reverse genetics as well as cross-species comparisons.

Chickens and pigs are the most important livestock species worldwide. They are not only important sources of food, but also valuable models for evolutionary biology and biomedical science. Pigs share a high anatomical and physiological similarity with humans and are an important species for translational biomedical research, for example, in the areas of cancer, diabetes, neurodegenerative, and cardiovascular diseases (1–3). They also resemble the human pathophenotype more closely than rodents. For example, pig models for familial adenomatous polyposis (FAP) develop polyps in the large intestine as observed in human patients (4), whereas mouse FAP models develop them in the small intestine (5). In contrast to mammals, chickens are phylogenetically distant vertebrates from humans, but they were instrumental in the field of developmental biology due to the easy access to the embryonated egg. They are used for studying neurological and cardiovascular functions (6–8) and provided key findings in B cell development and graft versus host responses (9–11). Genetically modified livestock species also hold great promise for agriculture by offering new approaches for disease control, such as genome-edited pigs resistant to Porcine Reproductive and Respiratory Syndrome or Avian Leucosis Virus (ALV)-resistant chickens (12–15).Due to the lack of fully functional embryonic stem cells, genetic engineering in pigs and chickens has been a laborious, inefficient, and time-consuming procedure (16). The generation of pigs with precise germline modifications required gene targeting in somatic cells followed by somatic cell nuclear transfer. This also is not practical in chickens, where precise alteration of the genome only became possible with recent improvements in the cultivation and manipulation of germline-competent primordial germ cells (PGCs) (17–19). These modified PGCs can be injected into the blood vessel system of stage 13 to 15 (Hamburger−Hamilton [HH]) embryos to produce germline chimeras and, by further breeding, genetically modified chickens.With the advent of synthetic endonucleases such as CRISPR-Cas9 efficiency of targeted germline modification has improved in both species (20–23). It still requires the generation and breeding of new founder lines, which is time consuming in large animals. To circumvent the need for generating germline-modified animals, attempts have been made to carry out genome editing directly in specific organs or tissues (24–27). But this has been hampered by the need to deliver both Cas9 and the required guide RNA (gRNA) and by the limited cargo capacity of viral vectors. To bypass this drawback, Cas9 transgenic mice have been generated, requiring delivery of only the respective gRNAs (28).Here, we describe the generation of both Cas9 transgenic pigs and chickens that ubiquitously express Cas9 endonuclease and provide proof of its function in vitro and in vivo. These animals provide an innovative and efficient model for in vivo genome editing to assess gene function in health and disease.     

The utility of serum receptor-binding cancer antigen expressed on SiSo cells in gastrointestinal tract cancers.

BACKGROUND: Receptor-binding cancer antigen expressed on SiSo cells (RCAS1) is a novel tumour marker that has been described in various kinds of cancer. The majority of observations include immunohistochemical studies; however, there are not enough data about the utility of this antigen as a serum tumour marker and its tumour specificity. AIM: To measure the serum levels of RCAS1 in patients with gastrointestinal (GI) tract cancers and compare them with other GI tract tumour markers. PATIENTS AND METHODS: Sera collected from patients with GI cancers (14 esophagus, 32 gastric and 36 colon) and from healthy volunteers (30 individuals) were analyzed for RCAS1 and compared with carcinoembryonic antigen (CEA) and cancer antigen 19-9. The relationship between serum RCAS1, tumour stage and tumour grade was also evaluated. RESULTS: Mean serum RCAS1 level was higher in patients with GI tract cancers compared with the control group (P=0.001). Among GI tract cancers, RCAS1 had lowest and highest sensitivity for esophagus and colon cancer diagnosis, respectively. Serum RCAS1 had a higher sensitivity for malignancy, except in the colon, and lower specificity in all groups compared with CEA. In comparison with cancer antigen 19-9, serum RCAS1 was more sensitive but less specific for all GI cancer groups. Mean serum RCAS1 levels were not statistically significant among histopathological tumour types (P>0.05). Although serum RCAS1 levels were significantly higher in cases with lymph node involvement compared with lymph node-negative cases (P=0.009), there was no difference between cases with and without serosal involvement, vascular invasion and distant metastasis; no correlation was found between tumour size and RCAS1 levels. CONCLUSIONS: RCAS1 may be used and combined with CEA as a tumour marker in GI tract cancers.     

Trust in government and support for governmental regulation: the case of electronic health records

Background

This paper presents results from a public engagement effort in Nebraska, USA, which measured public opinions about governmental involvement in encouraging the use of electronic health records (EHRs).

Objective

We examine the role of trust in government in contributing to public support for government involvement in the development of EHR technologies. We hypothesize that trust in government will lead to support for federal and state governmental encouragement of the use of EHRs among doctors and insurance companies. Further, because individual experiences with health‐care professionals will reduce perceptions of risk, we expect that support for governmental involvement will be tempered by greater personal experience with the health‐care industry.

Design and Results

Examining a small survey of individuals on the issue, we find general support for both of our hypotheses. The findings suggest that trust in government does have a positive relationship with support for government involvement in the policy domain, but that the frequency of personal experiences with health‐care providers reduces the extent to which the public supports governmental involvement in the development of EHR technology.

Discussion and Conclusion

This inquiry contributes to our understanding of public attitudes towards government involvement in EHRs in the United States specifically and contributes to social science examining links between trust in government and support for governmental activity in the emerging policy domain regarding electronic health records systems.     

Topical analgesia following excisional haemorrhoidectomy: a systematic review and meta-analysis of randomised controlled trials

International Journal of Colorectal Disease - Post-operative pain following excisional haemorrhoidectomy poses a particular challenge for patient recovery, as well as a burden on hospital...     

Variability in Temperature-Related Mortality Projections under Climate Change

Background: Most studies that have assessed impacts on mortality of future temperature increases have relied on a small number of simulations and have not addressed the variability and sources of uncertainty in their mortality projections.Objectives: We assessed the variability of temperature projections and dependent future mortality distributions, using a large panel of temperature simulations based on different climate models and emission scenarios.Methods: We used historical data from 1990 through 2007 for Montreal, Quebec, Canada, and Poisson regression models to estimate relative risks (RR) for daily nonaccidental mortality in association with three different daily temperature metrics (mean, minimum, and maximum temperature) during June through August. To estimate future numbers of deaths attributable to ambient temperatures and the uncertainty of the estimates, we used 32 different simulations of daily temperatures for June–August 2020–2037 derived from three global climate models (GCMs) and a Canadian regional climate model with three sets of RRs (one based on the observed historical data, and two on bootstrap samples that generated the 95% CI of the attributable number (AN) of deaths). We then used analysis of covariance to evaluate the influence of the simulation, the projected year, and the sets of RRs used to derive the attributable numbers of deaths.Results: We found that < 1% of the variability in the distributions of simulated temperature for June–August of 2020–2037 was explained by differences among the simulations. Estimated ANs for 2020–2037 ranged from 34 to 174 per summer (i.e., June–August). Most of the variability in mortality projections (38%) was related to the temperature–mortality RR used to estimate the ANs.Conclusions: The choice of the RR estimate for the association between temperature and mortality may be important to reduce uncertainty in mortality projections.Citation: Benmarhnia T, Sottile MF, Plante C, Brand A, Casati B, Fournier M, Smargiassi A. 2014. Variability in temperature-related mortality projections under climate change. Environ Health Perspect 122:1293–1298; http://dx.doi.org/10.1289/ehp.1306954     

Does concomitant vaginal prolapse repair affect the outcomes of the transobturator tape procedure in the long term?

Introduction and hypothesis

Little information is available on the effects of concomitant vaginal prolapse repair on the outcomes of the transobturator tape (TOT) procedure. The purpose of this study is to assess the results and complications of TOT when combined with vaginal prolapse repair with a long-term follow-up.

Methods

We conducted a retrospective cohort study of 232 female patients who underwent the TOT procedure at two institutions. There were two groups: group 1 consisted of patients who had undergone TOT alone and group 2 consisted of patients who had undergone concomitant vaginal prolapse repair. The outcomes were analyzed considering four postoperative parameters: objective cure, subjective cure, resolution of urgency urinary incontinence (UUI), and patient satisfaction. The mean follow-up was 66.3 months (range 60–85).

Results

A total of 117 patients in group 1 and 104 patients in group 2 were documented in this study. The subjective and objective cure rates were 87.17 %, 64.95 % in group 1 and 89.42 %, 68.26 % in group 2. Patient satisfaction rates (visual analog scale [VAS] score ≥80) were 71.79 and 83.65 % in groups 1 and 2 respectively (p?=?0.035). Complications were reported according to the Clavien–Dindo classification with grade I 7.7 %, grade II 69.2 %, grade IIIa 7.7 %, and grade IIIb 15.4 %, and grade I 9.5 %, grade II 47.6 %, grade IIIa 42.8 %, and grade IIIb 0 % in groups 1 and 2 respectively.

Conclusions

Concomitant vaginal prolapse repair with TOT does not have any negative effects on continence outcomes; on the contrary, it increases patient satisfaction.     

Clinicopathologic and molecular features of intracranial desmoplastic small round cell tumors

Desmoplastic small round cell tumors (DSRCTs) are highly aggressive sarcomas that most commonly occur intra‐abdominally, and are defined by EWSR1‐WT1 gene fusion. Intracranial DSRCTs are exceptionally rare with only seven previously reported fusion‐positive cases. Herein, we evaluate the clinical, morphologic, immunohistochemical and molecular features of five additional examples. All patients were male (age range 6–25 years; median 11 years), with four tumors located supratentorially and one within the posterior fossa. The histologic features were highly variable including small cell, embryonal, clear cell, rhabdoid, anaplastic and glioma‐like appearances. A prominent desmoplastic stroma was seen in only two cases. The mitotic index ranged from <1 to 12/10 HPF (median 5). While all tumors showed strong desmin positivity, epithelial markers such as EMA, CAM 5.2 and other keratins were strongly positive in only one, focally positive in two and negative in two cases. EWSR1‐WT1 gene fusion was present in all cases, with accompanying mutations in the TERT promoter or STAG2 gene in individual cases. Given the significant histologic diversity, in the absence of genetic evaluation these cases could easily be misinterpreted as other entities. Desmin immunostaining is a useful initial screening method for consideration of a DSRCT diagnosis, prompting confirmatory molecular testing. Demonstrating the presence of an EWSR1‐WT1 fusion provides a definitive diagnosis of DSRCT. Genome‐wide methylation profiles of intracranial DSRCTs matched those of extracranial DSRCTs. Thus, despite the occasionally unusual histologic features and immunoprofile, intracranial DSRCTs likely represent a similar, if not the same, entity as their soft tissue counterpart based on the shared fusion and methylation profiles.     

Myxoid glioneuronal tumor,PDGFRA p.K385‐mutant: clinical,radiologic, and histopathologic features

“Myxoid glioneuronal tumor, PDGFRA p.K385‐mutant” is a recently described tumor entity of the central nervous system with a predilection for origin in the septum pellucidum and a defining dinucleotide mutation at codon 385 of the PDGFRA oncogene replacing lysine with either leucine or isoleucine (p.K385L/I). Clinical outcomes and optimal treatment for this new tumor entity have yet to be defined. Here, we report a comprehensive clinical, radiologic, and histopathologic assessment of eight cases. In addition to its stereotypic location in the septum pellucidum, we identify that this tumor can also occur in the corpus callosum and periventricular white matter of the lateral ventricle. Tumors centered in the septum pellucidum uniformly were associated with obstructive hydrocephalus, whereas tumors centered in the corpus callosum and periventricular white matter did not demonstrate hydrocephalus. While multiple patients were found to have ventricular dissemination or local recurrence/progression, all patients in this series remain alive at last clinical follow‐up despite only biopsy or subtotal resection without adjuvant therapy in most cases. Our study further supports “myxoid glioneuronal tumor, PDGFRA p.K385‐mutant” as a distinct CNS tumor entity and expands the spectrum of clinicopathologic and radiologic features of this neoplasm.