Severe drug-associated colitis with Crohn's features in setting of ixekizumab therapy for chronic plaque psoriasis.

BACKGROUND: Ixekizumab is monoclonal antibody targeted against interleukin-17 (IL-17) and has been approved for use in chronic plaque psoriasis. Despite its efficacy in treating psoriasis, concerns have been raised regarding Ixekizumab's potential to induce and exacerbate inflammatory bowel disease (IBD). CASE PRESENTATION: Here we report the new onset of severe drug-associated colitis with surgical complications in a 45-year-old male patient who was receiving Ixekizumab therapy for chronic plaque psoriasis. Review of the patient's colonic pathology demonstrated acute inflammatory changes with features of Crohn's disease. The patient remained disease-free 9-months following his hospitalization and cessation of Ixekizumab. CONCLUSIONS: This case raises suspicion for an association between Ixekizumab and IBD and calls on clinicians to have heightened awareness of potential risks before prescribing anti-IL-17 agents.

Feasibility and Performance of Elastin Trichrome as a Primary Stain in Colorectal Cancer Resection Specimens: Results of an Interobserver Variability Study.

Venous invasion (VI) is a powerful prognostic factor in colorectal cancer (CRC) that is widely underreported. The ability of elastin stains to improve VI detection is now recognized in several international CRC pathology protocols. However, concerns related to the cost and time required to perform and evaluate these stains in addition to routine hematoxylin and eosin (H&E) stains remains a barrier to their wider use. We therefore sought to determine whether an elastin trichrome (ET) stain could be used as a "stand-alone" stain in CRC resections, by comparing the sensitivity, accuracy, and reproducibility of detection of CAP-mandated prognostic factors using ET and H&E stains. Representative H&E- and ET-stained slides from 50 CRC resections, including a representative mix of stages and prognostic factors, were used to generate 2 study sets. Each case was represented by H&E slides in 1 study set and by corresponding ET slides from the same blocks in the other study set. Ten observers (3 academic gastrointestinal [GI] pathologists, 4 community pathologists, 3 fellows) evaluated each study set for CAP-mandated prognostic factors. ET outperformed H&E in the assessment of VI with respect to detection rates (50% vs. 28.6%; P<0.0001), accuracy (82% vs. 59%, P<0.0001), and reproducibility (k=0.554 vs. 0.394). No significant differences between ET and H&E were observed for other features evaluated. In a poststudy survey, most observers considered the ease and speed of assessment at least equivalent for ET and H&E for most prognostic factors, and felt that ET would be feasible as a stand-alone stain in practice. If validated by others, our findings support the use of ET, rather than H&E, as the primary stain for the evaluation of CRC resections.

Silica-Coated Nanoparticles with a Core of Zinc, l-Arginine, and a Peptide Designed for Oral Delivery.

Nanoparticle constructs for oral peptide delivery at a minimum must protect and present the peptide at the small intestinal epithelium in order to achieve oral bioavailability. In a reproducible, scalable, surfactant-free process, a core was formed with insulin in ratios with two established excipients and stabilizers, zinc chloride and l-arginine. Cross-linking was achieved with silica, which formed an outer shell. The process was reproducible across several batches, and physicochemical characterization of a single batch was confirmed in two independent laboratories. The silica-coated nanoparticles (SiNPs) entrapped insulin with high entrapment efficiency, preserved its structure, and released it at a pH value present in the small intestine. The SiNP delivered insulin to the circulation and reduced plasma glucose in a rat jejunal instillation model. The delivery mechanism required residual l-arginine in the particle to act as a permeation enhancer for SiNP-released insulin in the jejunum. The synthetic process was varied in terms of ratios of zinc chloride and l-arginine in the core to entrap the glucagon-like peptide 1 analogue, exenatide, and bovine serum albumin. SiNP-delivered exenatide was also bioactive in mice to some extent following oral gavage. The process is the basis for a platform for oral peptide and protein delivery.

Meroterpenoid Synthesis via Sequential Polyketide Aromatization and Cationic Polyene Cyclization: Total Syntheses of (+)-Hongoquercin A and B and Related Meroterpenoids.

(+)-Hongoquercin A and B were synthesized from commercially available trans, trans-farnesol in six and eleven steps, respectively, using dual biomimetic strategies with polyketide aromatization and subsequent polyene functionalization from a common farnesyl-resorcylate intermediate. Key steps involve Pd(0)-catalyzed decarboxylative allylic rearrangement of a dioxinone ß,δ-diketo ester to a ß,δ-diketo dioxinone, which was readily aromatized into the corresponding resorcylate, and subsequent polyene cyclization via enantioselective protonation or regioselective terminal alkene oxidation and cationic cyclization of enantiomerically enriched epoxide to furnish the tetracyclic natural product cores. Analogues of the hongoquercin were synthesized via halonium-induced polyene cyclizations, and the meroterpenoid could be further functionalized via saponification, hydrolytic decarboxylation, reduction, and amidation reactions.

Human papillomavirus testing versus cytology in primary cervical cancer screening: End-of-study and extended follow-up results from the Canadian cervical cancer screening trial.

The Canadian Cervical Cancer Screening Trial was a randomized controlled trial comparing the performance of human papillomavirus (HPV) testing and Papanicolaou cytology to detect cervical intraepithelial neoplasia of grades 2 or worse (CIN2+) among women aged 30-69 years attending routine cervical cancer screening in Montreal and St. John's, Canada (n = 10,154). We examined screening and prognostic values of enrollment cytologic and HPV testing results. Extended follow-up data were available for St. John's participants (n = 5,754; 501,682.6 person-months). HPV testing detected more CIN2+ than cytology during protocol-defined (82.9 vs. 44.4%) and extended (54.2 vs. 19.3%) follow-up periods, respectively. Three-year risks ranged from 0.87% (95% CI: 0.37-2.05) for HPV-/Pap- women to 35.77% (95% CI: 25.88-48.04) for HPV+/Pap+ women. Genotype-specific risks ranged from 0.90% (95% CI: 0.40-2.01) to 43.84% (95% CI: 32.42-57.24) among HPV- and HPV16+ women, respectively, exceeding those associated with Pap+ or HPV+ results taken individually or jointly. Ten-year risks ranged from 1.15% (95% CI: 0.60-2.19) for HPV-/Pap- women to 26.05% (95% CI: 15.34-42.13) for HPV+/Pap+ women and genotype-specific risks ranged from 1.13% (95% CI: 0.59-2.14) to 32.78% (95% CI: 21.15-48.51) among women testing HPV- and HPV16+, respectively. Abnormal cytology stratified risks most meaningfully for HPV+ women. Primary HPV testing every 3 years provided a similar or greater level of reassurance against disease risks as currently recommended screening strategies. HPV-based cervical screening may allow for greater disease detection than cytology-based screening and permit safe extensions of screening intervals; genotype-specific testing could provide further improvement in the positive predictive value of such screening.

Heavier alkaline earth catalyzed ene-yne cyclizations: atom-efficient access to tetrahydroisoquinoline frameworks.

Tetrahydroisoquinoline frameworks may be accessed with 100% atom efficiency through the alkaline earth catalyzed addition of primary amines to ene-yne substrates through a sequence of intermolecular alkene and intramolecular alkyne hydroamination steps.

Effect of fundamental frequency at voice onset on vocal attack time.

OBJECTIVE: To examine vocal attack time (VAT) values associated with the production of low, mid, and high rates of vocal fold vibration in normal speakers. STUDY DESIGN: Sound pressure (SP) and electroglottographic (EGG) recordings were obtained for eight female and five male subjects while producing multiple tokens of the sustained vowels /ɑ/, /i/, and /u/ at comfortable loudness and at mid, low (-3 semitones), and high (+6 semitones) rates of vocal fold vibration. METHODS: Generalized sinusoidal models of the SP and EGG signals were computed to compare rates of amplitude change. VAT was computed from the time lag of the cross-correlation function. RESULTS: Adjusted mean VAT for the high frequency condition was smaller than the adjusted mean VAT values for the low- and mid-frequency conditions. There was no significant difference between the mid and low frequency conditions. CONCLUSIONS: Findings reveal an association of the VAT measure with increases in vocal fold tension associated with the production of high rates of vocal fold vibration.

Enhancement of cisplatin cytotoxicity by disulfiram involves activating transcription factor 3.

BACKGROUND: Activating transcription factor 3 (ATF3), a stress-inducible gene, is a regulator of cisplatin-induced cytotoxicity, and enhancement of the ATF3 expression potentiates this cytotoxicity. MATERIALS AND METHODS: ATF3 expression and its binding to the transcription target CHOP were evaluated by western blot and chromatin immunoprecipitation (ChIP), respectively, in a panel of five cell lines (WI38, MCF7, PC3, A549). MTT assays were employed to assess the effects of many drugs, including disulfiram, on cell viability. RESULTS: ATF3 protein expression was up-regulated after cytotoxic doses of cisplatin treatment and it directly bound to the CHOP gene promoter, increasing this pro-apoptotic protein's expression. In a library screen of 1200 compounds, disulfiram, a dithiocarbamate drug, was identified as an enhancer of the cytotoxic effects of cisplatin. This increased cytotoxic action was synergistic and likely due to their ability to induce ATF3 independently. CONCLUSION: Understanding the role of ATF3 in cisplatin-induced cytotoxicity will lead to novel therapeutic approaches that could improve this drug's efficacy.

Learning curve analysis of a patient lift-assist device.

One of the challenges facing ergonomists in the implementation of an ergonomic solution is addressing the concerns related to their impact on productivity. The focus of the current study was to (1) apply standard learning curve analysis to the learning that takes place as an individual works with a patient handling device and (2) compare the effects of two different training protocols on measures of learning. Eighteen subjects completed 11 replications of a patient transfer task after participating in either an "interactive" training protocol or "see-one-do-one" training protocol. The results show that the learning rate for this task was 83% with no difference as a function of training protocol. The results do indicate that the effect of Training Method was significant (p<0.05) for time to complete the first patient lift task (370s for the interactive training vs. 475s for see-one-do-one training). The results of the analysis of the survey data supported the objective results in that the only measure that was responsive to training type (p<0.05) was related to comfort level in performing the patient lift task for the first time. The results emphasize the importance in considering learning when introducing an intervention in the workplace, and showed that in this instance, training type had an immediate impact on productivity, but that this effect diminished over time.

A study of lifting tasks performed on laterally slanted ground surfaces.

Lifting in most industrial environments is performed on a smooth, level ground surface. There are, however, many outdoor work environments (e.g. agriculture and construction) that require manual material handling activities on variable grade ground surfaces. Quantifying the biomechanical response while lifting under these conditions may provide insight into the aetiology of lifting-related injury. The aim of the current study was to quantify the effect of laterally slanted ground surfaces on the biomechanical response. Ten subjects performed both isometric weight-holding tasks and dynamic lifting exertions (both using a 40% of max load) while standing on a platform that was laterally tilted at 0, 10, 20 and 30 degrees from horizontal. As the subject performed the isometric exertions, the electromyographic (EMG) activity of trunk extensors and knee extensors were collected and during the dynamic lifting tasks the whole body kinematics were collected. The whole body kinematics data were used in a dynamic biomechanical model to calculate the time-dependent moment about L5/S1 and the time-dependent lateral forces acting on the body segments. The results of the isometric weight-holding task show a significant (p < 0.05) effect of slant angle on the normalized integrated EMG values in both the left (increase by 26%) and right (increase by 70%) trunk extensors, indicating a significant increase in the protective co-contraction response. The results of the dynamic lifting tasks revealed a consistent reduction in the peak dynamic L5/S1 moment (decreased by 9%) and an increase in the instability producing lateral forces (increased by 111%) with increasing slant angle. These results provide quantitative insight into the response of the human lifter under these adverse lifting conditions.