Progress on core outcomes sets for critical care research

Purpose of review: Appropriate selection and definition of outcome measures are essential for clinical trials to be maximally informative. Core outcome sets (an agreed, standardized collection of outcomes measured and reported in all trials for a specific clinical area) were developed due to established inconsistencies in trial outcome selection. This review discusses the rationale for, and methods of, core outcome set development, as well as current initiatives in critical care.

Recent findings: Recent systematic reviews of reported outcomes and measurement instruments relevant to the critically ill highlight inconsistencies in outcome selection, definition, and measurement, thus establishing the need for core outcome sets. Current critical care initiatives include development of core outcome sets for trials aimed at reducing mechanical ventilation duration; rehabilitation following critical illness; long-term outcomes in acute respiratory failure; and epidemic and pandemic studies of severe acute respiratory infection.

Summary: Development and utilization of core outcome sets for studies relevant to the critically ill is in its infancy compared to other specialties. Notwithstanding, core outcome set development frameworks and guidelines are available, several sets are in various stages of development, and there is strong support from international investigator-led collaborations including the International Forum for Acute Care Trialists.

The utility of animal models in developing immunosuppressive agents

The immune system comprises an integrated network of cellular interactions. Some responses are predictable, while others are more stochastic. While in vitro the outcome of stimulating a single type of cell may be stereotyped and reproducible, in vivo this is often not the case. This phenomenon often merits the use of animal models in predicting the impact of immunosuppressant drugs. A heavy burden of responsibility lies on the shoulders of the investigator when using animal models to study immunosuppressive agents. The principles of the three R׳s: refine (less suffering,), reduce (lower animal numbers) and replace (alternative in vitro assays) must be applied, as described elsewhere in this issue. Well designed animal model experiments have allowed us to develop all the immunosuppressive agents currently available for treating autoimmune disease and transplant recipients. In this review, we examine the common animal models used in developing immunosuppressive agents, focusing on drugs used in transplant surgery. Autoimmune diseases, such as multiple sclerosis, are covered elsewhere in this issue. We look at the utility and limitations of small and large animal models in measuring potency and toxicity of immunosuppressive therapies.

Safety of Spectacles for Children's Vision: A Cluster-Randomized Controlled Trial.

Purpose: To study safety of children’s glasses in rural China, where fear that glasses harm vision is an important barrier for families and policy-makers. Design: Exploratory analysis from a cluster-randomized, investigator-masked, controlled trial.Methods: Among primary schools (n=252) in western China, children were randomized by school to one of three interventions: free glasses provided in class, vouchers for free glasses at a local facility or glasses prescriptions only (Control group). The main outcome of this analysis is uncorrected visual acuity after 8 months, adjusted for baseline acuity.Results: Among 19,934 children randomly selected for screening, 5852 myopic (spherical equivalent refractive error <= -0.5 D) eyes of 3001 children (14.7%, mean age 10.5 years) had VA <= 6/12 without glasses correctable to > 6/12 with glasses, and were eligible. Among these, 1903 (32.5%), 1798 (30.7%), and 2151 (36.8%) were randomized to Control, Voucher and Free Glasses respectively. Intention-to-treat analyses were performed on all 1831 (96.2%), 1699 (94.5%), and 2007 (93.3%) eyes of children with follow-up in Control, Voucher and Free Glasses groups. Final visual acuity for eyes of children in the treatment groups (Free Glasses and Voucher) was significantly better than for Control children, adjusting only for baseline visual acuity (difference of 0.023 logMAR units [0.23 vision chart lines, 95% CI: 0.03, 0.43]) or for other baseline factors as well (0.025 logMAR units [0.25 lines, 95% CI 0.04, 0.45]). Conclusion: We found no evidence that spectacles promote decline in uncorrected vision with aging among children.

Navigating the Borderlands: Brian McGilloway as Contemporary Cartographer of the Liminal in the Ulster Landscape

Set in the borderlands between Letterkenny and Derry-Londonderry, a landscape scarred by geological fold, river and cartographer’s pen, the Ulster crime novelist Brian McGilloway chronicles the hopes and fears of a contemporary society unable to escape a complicated history, redolent and entwined with the voices of its ‘ghosts of its past.’ Through his choice of chief protagonist, An Garda Síochána officer Benedict Devlin, McGilloway turns detective to critically investigate the both the seemingly straightforward and the unseen dwelling in the rural Ulster landscape. Following in the footsteps of Nordic and Tartan Noir in making commentary on current societ,y McGilloway recognises the importance of the past in trying to reach an understanding of the present. His critique however goes beyond criminal behaviour motivated primarily by politics or religion, allowing a deeper and more meaningful diagnosis of the ‘state of the nation’. Place, name and event become especially important in contextualising the liminality of McGilloway’s real rural border settings. In doing so, McGilloway continues in the rich tradition of Ulster poet such as Heaney, MacNiece, Muldoon and Hewitt in trying to rationalise the man-made amidst the elemental in the land of both the ‘Planter & The Gael.’ History, language, tradition and the sacral are all instruments of investigation in helping McGilloway present a revealing pathology and atlas of our times to his readers. Turning literary investigator, the author contends that there is much to learn from this physiography, not just for the borderlands region, but for the wider countryside and society beyond. Keywords Cultural Atlas, Crime Fiction, Place, Poetry, Rural.

An interview with Manuel Salto-Tellez on diagnostic pathology: the future is morphomolecular

Professor Manuel Salto-Tellez of Queen’s University, Belfast, Northern Ireland is an expert histopathologist and molecular diagnostician. Professor Salto-Tellez is a lead investigator at the Northern Ireland Molecular Pathology Laboratory and also serves as a member of the Editorial Advisory Board for Expert Review of Molecular Diagnostics. In this interview, he proposes directions for the future of molecular pathology and molecular diagnostics, integrating all aspects of pathology toward a common goal.

Effect of providing free glasses on children's educational outcomes in China: cluster randomized controlled trial

Objective: To assess the effect of provision of free glasses on academic performance in rural Chinese children with myopia. Design: Cluster randomized, investigator masked, controlled trial.Setting 252 primary schools in two prefectures in western China, 2012-13. Participants: 3177 of 19 934 children in fourth and fifth grades (mean age 10.5 years) with visual acuity <6/12 in either eye without glasses correctable to >6/12 with glasses. 3052 (96.0%) completed the study.Interventions Children were randomized by school (84 schools per arm) to one of three interventions at the beginning of the school year: prescription for glasses only (control group), vouchers for free glasses at a local facility, or free glasses provided in class. Main outcome measures: Spectacle wear at endline examination and end of year score on a specially designed mathematics test, adjusted for baseline score and expressed in standard deviations. Results: Among 3177 eligible children, 1036 (32.6%) were randomized to control, 988 (31.1%) to vouchers, and 1153 (36.3%) to free glasses in class. All eligible children would benefit from glasses, but only 15% wore them at baseline. At closeout glasses wear was 41% (observed) and 68% (self reported) in the free glasses group, and 26% (observed) and 37% (self reported) in the controls. Effect on test score was 0.11 SD (95% confidence interval 0.01 to 0.21) when the free glasses group was compared with the control group. The adjusted effect of providing free glasses (0.10, 0.002 to 0.19) was greater than parental education (0.03, −0.04 to 0.09) or family wealth (0.01, −0.06 to 0.08). This difference between groups was significant, but was smaller than the prespecified 0.20 SD difference that the study was powered to detect. Conclusions: The provision of free glasses to Chinese children with myopia improves children’s performance on mathematics testing to a statistically significant degree, despite imperfect compliance, although the observed difference between groups was smaller than the study was originally designed to detect. Myopia is common and rarely corrected in this setting. Trial Registration: Current Controlled Trials ISRCTN03252665.

Surgical strategies for coexisting glaucoma and cataract: an evidence-based update.

OBJECTIVE:

To assess short- and long-term control of intraocular pressure (IOP) with different surgical treatment strategies for coexisting cataract and glaucoma.

DESIGN:

Systematic literature review and analysis.

METHOD:

We performed a search of the published literature to identify all eligible articles pertaining to the surgical management of coexisting cataract and glaucoma in adults. One investigator abstracted the content of each article onto a custom-designed form. A second investigator corroborated the findings. The evidence supporting different approaches was graded by consensus as good, fair, weak, or insufficient.

MAIN OUTCOME MEASURES:

Short-term (24 hours or fewer) and long-term (more than 24 hours) IOP control.

RESULTS:

The evidence was good that long-term IOP is lowered more by combined glaucoma and cataract operations than by cataract operations alone. On average, the IOP was 3 to 4 mmHg lower in the combined groups with fewer medications required. The evidence was weak that extracapsular cataract extraction (ECCE) alone results in short-term increase in IOP and was insufficient to determine the short-term impact of phacoemulsification cataract extraction (PECE) on IOP in glaucoma patients. The evidence was weak that short-term IOP control was better with ECCE or PECE combined with an incisional glaucoma procedure compared with ECCE or PECE alone. The evidence was also weak (but consistent) that long-term IOP is lowered by 2 to 4 mmHg after ECCE or PECE. Finally, there was weak evidence that combined PECE and trabeculectomy produces slightly worse long-term IOP control than trabeculectomy alone, and there was fair evidence that the same is true for ECCE combined with trabeculectomy.

CONCLUSIONS:

There is strong evidence for better long-term control of IOP with combined glaucoma and cataract operations compared with cataract surgery alone. For other issues regarding surgical treatment strategies for cataract and glaucoma, the available evidence is limited or conflicting.

ARB: Phase II window of opportunity study of short-term preoperative treatment with enzalutamide in ER-positive and triple-negative breast cancer

The androgen receptor (AR) is expressed in 60-80% of breast cancers (BC) across all molecular phenotypes, with a higher incidence in oestrogen receptor positive (ER+) BC compared to ER negative tumours. In ER+ disease, AR-expression has been linked to endocrine resistance which might be reversed with combined treatment targeting ER and AR. In triple negative BCs (TNBC), preclinical and clinical investigations have described a subset of patients that express the AR and are sensitive to androgen blockade, providing a novel therapeutic target. Enzalutamide, a potent 2nd generation anti-androgen, has demonstrated substantial preclinical and clinical anti-tumour activity in AR+ breast cancer. Short-term preoperative window of opportunity studies are a validated strategy for novel treatments to provide proof-of-concept and define the most appropriate patient population by directly assessing treatment effects in tumour tissue before and after treatment. The ARB study aims to assess the anti-tumour effects of enzalutamide in early ER+ breast cancer and TNBC, to identify the optimal target population for further studies and to directly explore the biologic effects of enzalutamide on BC and stromal cells. Methods: ARB is an international, investigator sponsored WOO phase II study in women with newly diagnosed primary ER+ BC or AR+ TNBC of ≥ 1cm. The study has two cohorts. In the ER+ cohort, postmenopausal patients will be randomised 2:1 to receive either enzalutamide (160mg OD) plus exemestane (50mg OD) or exemestane (25mg OD). In the TNBC cohort, AR+ will receive single agent treatment with enzalutamide (160mg OD). Study treatment is planned for 15–29 days, followed by surgery or neo-adjuvant therapy. Tissue and blood samples are collected before treatment and on the last day of study treatment. The primary endpoint is inhibition of tumour-cell proliferation, as measured by change in Ki67 expression, determined centrally by 2 investigators. Secondary endpoints include induction of apoptosis (Caspase3), circulating hormone levels and safety. ARB aims to recruit ≈235 patients from ≈40 sites in the UK, Germany, Spain and USA. The study is open to recruitment.

Graphene-MoS2 Hybrid Technology for Large-Scale Two-Dimensional Electronics

Two-dimensional (2D) materials have generated great interest in the last few years as a new toolbox for electronics. This family of materials includes, among others, metallic graphene, semiconducting transition metal dichalcogenides (such as MoS2) and insulating Boron Nitride. These materials and their heterostructures offer excellent mechanical flexibility, optical transparency and favorable transport properties for realizing electronic, sensing and optical systems on arbitrary surfaces. In this work, we develop several etch stop layer technologies that allow the fabrication of complex 2D devices and present for the first time the large scale integration of graphene with molybdenum disulfide (MoS2) , both grown using the fully scalable CVD technique. Transistor devices and logic circuits with MoS2 channel and graphene as contacts and interconnects are constructed and show high performances. In addition, the graphene/MoS2 heterojunction contact has been systematically compared with MoS2-metal junctions experimentally and studied using density functional theory. The tunability of the graphene work function significantly improves the ohmic contact to MoS2. These high-performance large-scale devices and circuits based on 2D heterostructure pave the way for practical flexible transparent electronics in the future. The authors acknowledge financial support from the Office of Naval Research (ONR) Young Investigator Program, the ONR GATE MURI program, and the Army Research Laboratory. This research has made use of the MI.