Sequential multiple assignment randomised trial to develop an adaptive mobile health intervention to increase physical activity in people poststroke in the community setting in Ireland: TAPAS trial protocol.

INTRODUCTION: Stroke is the second-leading cause of death and disability globally. Participation in physical activity (PA) is a cornerstone of secondary prevention in stroke care. Given the heterogeneous nature of stroke, PA interventions that are adaptive to individual performance are recommended. Mobile health (mHealth) has been identified as a potential approach to supporting PA poststroke. To this end, we aim to use a Sequential Multiple Assignment Randomised Trial (SMART) design to develop an adaptive, user-informed mHealth intervention to improve PA poststroke. METHODS AND ANALYSIS: The components included in the 12-week intervention are based on empirical evidence and behavioural change theory and will include treatments to increase participation in Structured Exercise and Lifestyle or a combination of both. 117 participants will be randomly assigned to one of the two treatment components. At 6 weeks postinitial randomisation, participants will be classified as responders or non-responders based on participants' change in step count. Non-responders to the initial treatment will be randomly assigned to a different treatment allocation. The primary outcome will be PA (steps/day), feasibility and secondary clinical and cost outcomes will also be included. A SMART design will be used to evaluate the optimum adaptive PA intervention among community-dwelling, ambulatory people poststroke. ETHICS AND DISSEMINATION: Ethical approval has been granted by the Health Service Executive Mid-Western Ethics Committee (REC Ref: 026/2022). The findings will be submitted for publication and presented at relevant national and international academic conferences TRIALS REGISTRATION NUMBER: NCT05606770.

OptiCogs: feasibility of a multicomponent intervention to rehabilitate people with cognitive impairment post-stroke.

BACKGROUND: Stroke is a leading cause of death and disability worldwide. Despite the prevalence and associated burden of cognitive impairment post-stroke, there is uncertainty regarding optimal cognitive rehabilitation for people post-stroke. This study aimed to assess whether a multicomponent intervention, called OptiCogs, is feasible, acceptable, and safe for people with cognitive impairment post-stroke. A secondary aim was to explore changes in cognitive function, fatigue, quality of life, physical function, and occupational performance, from pre-intervention to post-intervention. METHODS: A feasibility study was conducted where people post-stroke with cognitive impairment enrolled in a 6-week multicomponent intervention. The primary outcomes recorded included response rate, recruitment rate, retention rate, adherence to the intervention protocol, adverse events, and acceptability of the intervention to people post-stroke. Secondary outcomes included (i) change in cognitive functioning using the Addenbrooke's Cognitive Examination III, (ii) fatigue using the Fatigue Severity scale, (iii) quality of life using the Stroke Specific Quality of Life scale (iv) physical function using the patient-reported outcomes measurement information system, and (v) patient-reported occupational performance using the Canadian Occupational Performance Measure. The Consolidated Standards of Reporting Trials extension reporting guidelines were followed, for pilot and feasibility studies, to standardize the conduct and reporting of this study. RESULTS: The response rate was 10.9%. Nine eligible participants were enrolled during the 4-month recruitment period, with eight participants completing the entire 6-week intervention, as well as the pre- and post-intervention outcome measures. There were no reported adverse events. Participants were satisfied with the intervention and found it acceptable overall. Results of the secondary outcomes were promising for cognitive function (ACE III, pre: 63.3 ± 23.9 to post: 69 ± 24.6), fatigue (FSS, pre: 52.5 ± 7.3 to post: 45.6 ± 7.2), quality of life (SSQoL, pre: 131.0 ± 26.3 to post: 169.9 ± 15.3), physical function (PROMIS-PF, pre: 15.5 ± 6.3 to post: 15.8 ± 5.3), and occupational performance (COPM performance, pre: 9.3 ± 2.3 to post: 22.9 ± 4.2) and COPM satisfaction, pre: 9.9 ± 2.1 to post: 22.7 ± 3.5). CONCLUSION: Preliminary results suggest low-modest recruitment and high retention rates for the OptiCogs intervention. Changes in cognitive function, fatigue, quality of life, and self-reported occupational performance show improvement from pre- to post-intervention. These potential benefits require further testing in a larger pilot trial. TRIAL REGISTRATION: NCT05414539.

Inhaled Sargramostim (Recombinant Human Granulocyte-Macrophage Colony-Stimulating Factor) for COVID-19-Associated Acute Hypoxemia: Results of the Phase 2, Randomized, Open-Label Trial (iLeukPulm).

INTRODUCTION: Granulocyte-macrophage colony-stimulating factor (GM-CSF), a protein produced in the lung, is essential for pulmonary host defense and alveolar integrity. Prior studies suggest potential benefits in several pulmonary conditions, including acute respiratory distress syndrome and viral infections. This trial evaluated the effect of the addition of inhaled sargramostim (yeast-derived, glycosylated recombinant human GM-CSF) to standard of care (SOC) on oxygenation and clinical outcomes in patients with COVID-19-associated acute hypoxemia. MATERIALS AND METHODS: A randomized, controlled, open-label trial of hospitalized adults with COVID-19-associated hypoxemia (oxygen saturation <93% on ≥2 L/min oxygen supplementation and/or PaO2/FiO2 <350) randomized 2:1 to inhaled sargramostim (125 mcg twice daily for 5 days) plus SOC versus SOC alone. Institutional SOC before and during the study was not limited. Primary outcomes were change in the alveolar-arterial oxygen gradient (P(A-a)O2) by day 6 and the percentage of patients intubated within 14 days. Safety evaluations included treatment-emergent adverse events. Efficacy analyses were based on the modified intent-to-treat population, the subset of the intent-to-treat population that received ≥1 dose of any study treatment (sargramostim and/or SOC). An analysis of covariance approach was used to analyze changes in oxygenation measures. The intubation rate was analyzed using the chi-squared test. All analyses are considered descriptive. The study was institutional review board approved. RESULTS: In total, 122 patients were treated (sargramostim, n = 78; SOC, n = 44). The sargramostim arm experienced greater improvement in P(A-a)O2 by day 6 compared to SOC alone (least squares [LS] mean change from baseline [SE]: -102.3 [19.4] versus -30.5 [26.9] mmHg; LS mean difference: -71.7 [SE 33.2, 95% CI -137.7 to -5.8]; P = .033; n = 96). By day 14, 11.5% (9/78) of sargramostim and 15.9% (7/44) of SOC arms required intubation (P = .49). The 28-day mortality was 11.5% (9/78) and 13.6% (6/44) in the sargramostim and SOC arms, respectively (hazard ratio 0.85; P = .76). Treatment-emergent adverse events occurred in 67.9% (53/78) and 70.5% (31/44) on the sargramostim and SOC arms, respectively. CONCLUSIONS: The addition of inhaled sargramostim to SOC improved P(A-a)O2, a measure of oxygenation, by day 6 in hospitalized patients with COVID-19-associated acute hypoxemia and was well tolerated. Inhaled sargramostim is delivered directly to the lung, minimizing systemic effects, and is simple to administer making it a feasible treatment option in patients in settings where other therapy routes may be difficult. Although proportionally lower rates of intubation and mortality were observed in sargramostim-treated patients, this study was insufficiently powered to demonstrate significant changes in these outcomes. However, the significant improvement in gas exchange with sargramostim shows this inhalational treatment enhances pulmonary efficiency in this severe respiratory illness. These data provide strong support for further evaluation of sargramostim in high-risk patients with COVID-19.

Sargramostim in acute radiation syndrome.

INTRODUCTION: Since 1944, nearly 400 radiologic accidents/incidents have exposed about 3,000 people to substantial doses of ionizing radiation, with more than 125 deaths. Known are the Chernobyl and Fukushima nuclear power facility accidents, but the recent war in Ukraine has refocused attention on this issue. Therapy of acute, high-dose, whole-body exposures to ionizing radiation includes transfusions, antimicrobial drugs, molecularly cloned hematopoietic growth factors, and hematopoietic cell transplants (HCT). AREAS COVERED: We focus on approved therapies including recombinant human granulocyte-macrophage colony-stimulating factor (rhu GM-CSF, sargramostim). Animal data indicate sargramostim accelerates marrow recovery and increases survival. In 2018, the United States Food and Drug Administration approved sargramostim for persons acutely exposed to myelosuppressive radiation doses based on two large nonhuman primate studies. In seven radiation accidents since 1986, 28 victims exposed to acute high-dose ionizing radiation received rhu GM-CSF alone or with other hematopoietic growth factors. Therapy appeared effective with few, if any, adverse events; 18 survived. EXPERT OPINION: This favorable benefit-to-risk ratio suggests giving sargramostim soon after exposure and is favored over HCT based on greater safety and fewer resource requirements, especially in the context of large-scale exposures which might occur after use of a tactical nuclear weapon or nuclear terrorism.

Exploring the perspectives of key stakeholders on the design and delivery of a cognitive rehabilitation intervention for people post-stroke.

PURPOSE: Stroke is a leading cause of death and disability worldwide. Despite the prevalence and associated burden of post-stroke cognitive impairment, there is uncertainty regarding optimum interventions to improve cognitive function in people post-stroke. The aim of this study is to explore the perspectives of key stakeholders on the design and development of a multidisciplinary intervention to rehabilitate cognitive deficits in people post-stroke. MATERIALS AND METHODS: Audio-recorded, semi-structured interviews were employed with people post-stroke, caregivers, healthcare professionals and academics. All transcribed interviews were exported to NVivo software and analysed using reflexive thematic analysis. RESULTS: Thirty interviews were conducted across stakeholder groups including people post-stroke (n = 10), caregivers (n = 5), healthcare professionals (n = 14) and academics (n = 1). Four themes relevant to the design and development of the intervention were identified (i) engagement in the intervention must be meaningful, (ii) the point of readiness to engage, (iii) a familiar but flexible setting is key (iv) pragmatics of intervention delivery. CONCLUSIONS: These findings present new perspectives across stakeholder groups on the design and delivery of an intervention to rehabilitate cognitive deficits in people post-stroke. Taken together with existing quantitative evidence, these findings will inform the development of a feasibility trial, examining patient and process outcomes, to rehabilitate cognitive deficits post-stroke.

Rehabilitation of Cognitive Deficits Poststroke: Systematic Review and Meta-Analysis of Randomized Controlled Trials.

BACKGROUND: Despite the prevalence of cognitive impairment poststroke, there is uncertainty regarding interventions to improve cognitive function poststroke. This systematic review and meta-analysis evaluate the effectiveness of rehabilitation interventions across multiple domains of cognitive function. METHODS: Five databases were searched from inception to August 2019. Eligible studies included randomized controlled trials of rehabilitation interventions for people with stroke when compared with other active interventions or standard care where cognitive function was an outcome. RESULTS: Sixty-four randomized controlled trials (n=4005 participants) were included. Multiple component interventions improved general cognitive functioning (MD, 1.56 [95% CI, 0.69-2.43]) and memory (standardized MD, 0.49 [95% CI, 0.27-0.72]) compared with standard care. Physical activity interventions improved neglect (MD, 13.99 [95% CI, 12.67-15.32]) and balance (MD, 2.97 [95% CI, 0.71-5.23]) compared with active controls. Noninvasive brain stimulation impacted neglect (MD, 20.79 [95% CI, 14.53-27.04) and functional status (MD, 14.02 [95% CI, 8.41-19.62]) compared with active controls. Neither cognitive rehabilitation (MD, 0.37 [95% CI, -0.94 to 1.69]) nor occupational-based interventions (MD, 0.45 [95% CI, -1.33 to 2.23]) had a significant effect on cognitive function compared with standard care. CONCLUSIONS: There is some evidence to support multiple component interventions, physical activity interventions, and noninvasive brain stimulation improving cognitive function poststroke. Findings must be interpreted with caution given the overall moderate to high risk of bias, heterogeneity of interventions, and outcome measures across studies.

Audit of inpatient acute stroke services in a university teaching hospital, 2020.

BACKGROUND: We aimed to assess stroke care at an Irish university teaching hospital and benchmark against national (Irish National Audit of Stroke 2019) and international (6th SSNAP Annual Report; American Heart Association, 2013) practice to inform a quality improvement strategy. METHODS: All patients with a HIPE discharge diagnosis of Cerebral Infarction or Cerebral Haemorrhage (1 January to 31 December 2019) were identified through both the HIPE database and the institutional Stroke Portal. RESULTS: A total of 419 patients were included (56.6% male, mean age 72). The following were comparable/better than findings from the Irish National Audit of Stroke: median duration of symptoms-3 h 6 min; 10% received thrombolysis; median door to needle time-60 min; 78.5% admitted to the stroke unit; 81.1% had a swallow assessment; in-patient mortality rate-10.5%; rates of institutionalisation-3.8%. The following areas were below the national average: overall door to imaging time-median 104 min; rate of thrombectomy-4%; 11.5% had mood screening; median length of stay- 12 days. DISCUSSION: Using national and international audit data as an institutional benchmark provides a standard with which a service can be compared to highlight areas for improvement. We identified mood screening, swallow screening, thrombectomy rates, length of stay and time to neuroimaging as key areas for development in our centre. We are currently completing a process map to determine cause, effect, and solutions, and we will implement change using PDSA methodology as per SQUIRE 2.0 guidelines. The results of the re-audit cycle for 2020 will be available in 2021 to inform our progress. Ongoing quality improvement is essential for stroke care, which is a leading cause of death and disability in Ireland.

Assessment of Colorimetric Reporter Enzymes in the PURE System.

Colorimetric reporter enzymes are useful for generating eye-readable biosensor readouts that do not require a device to interpret, an attractive property for applications in remote or developing parts of the world. The use of cell-free gene expression further facilitates such applications via amenability to lyophilization and incorporation into materials like paper. Currently, detection of multiple analytes simultaneously with these systems requires multiple reactions or a device. Here we evaluate seven enzymes and 15 corresponding substrates for functionality in a particular cell-free expression system known as PURE. We report eight enzyme/substrate pairs spanning four enzymes that are compatible with PURE. Of the four enzymes, three pairings exhibit no cross-reactivity. We finally show that at least one pairing can be used to create a third color when both are present, highlighting the potential use of these reporters for multiplex sensing.

Rapid Characterization of Genetic Parts with Cell-free Systems.

Characterizing and cataloging genetic parts are critical to the design of useful genetic circuits. Having well-characterized parts allows for the fine-tuning of genetic circuits, such that their function results in predictable outcomes. With the growth of synthetic biology as a field, there has been an explosion of genetic circuits that have been implemented in microbes to execute functions pertaining to sensing, metabolic alteration, and cellular computing. Here, we show a rapid and cost-effective method for characterizing genetic parts. Our method utilizes cell-free lysate, prepared in-house as a medium to evaluate parts via the expression of a reporter protein. Template DNA is prepared by PCR amplification using inexpensive primers to add variant parts to the reporter gene, and the template is added to the reaction as linear DNA without cloning. Parts that can be added in this way include promoters, operators, ribosome binding sites, insulators, and terminators. This approach, combined with the incorporation of an acoustic liquid handler and 384-well plates, allows the user to carry out high-throughput evaluations of genetic parts in a single day. By comparison, cell-based screening approaches require time-consuming cloning and have longer testing times due to overnight culture and culture density normalization steps. Further, working in cell-free lysate allows the user to exact tighter control over the expression conditions through the addition of exogenous components and DNA at precise concentrations. Results obtained from cell-free screening can be used directly in applications of cell-free systems or, in some cases, as a way to predict function in whole cells.

Coeliac disease enteropathy and symptoms may be aggravated by angiotensin receptor blockers in patients on a gluten-free diet.

BACKGROUND: Angiotensin receptor blocker-associated enteropathy (ARB-e) is an increasingly recognised clinical entity with symptoms and histological findings identical to coeliac disease (CD). There is evidence to suggest immune-mediated mucosal injury in ARB-e with a high prevalence of DQ2/DQ8; however, as IgA anti-tissue transglutaminase (anti-TTG) is usually negative, an insult other than TTG-mediated injury is suspected. The impact of ARBs on disease activity in patients with CD is not known. OBJECTIVE: To assess the effect of ARB exposure on patients with established CD. METHODS: A patient record search of 1142 individual patients attending a dedicated coeliac clinic from 2010 to the present identified 59 patients treated with ARB. Those with CD confirmed by serology (TTG + ve/EMA + ve) and histopathology (Marsh criteria) were included (n = 40, 0.52%). Data collected included disease duration, compliance with gluten-free diet (GFD), reported symptoms (diarrhoea, weight loss and abdominal pain), surrogate markers of absorption (Vitamin D, Iron, Calcium and Haemoglobin), in addition to anti-TTG titre and histological grade at last follow up. Patients were age and sex-matched in a 1:2 ratio with CD patients not taking ARBs (controls), with comparable rates of disease duration and compliance with GFD. RESULTS: The ARB and control groups were matched in terms of age (mean 66.2 years) and gender (female 63%). Strict compliance with GFD was reported in 55% and 56%, respectively. Persistent symptoms were reported in 10/40 (25%) of the ARB group compared with 7/82 (9%) of controls (p = 0.0181). There were lower rates of mucosal healing (Marsh grade 0) in the ARB group (36% n = 11) compared to controls (55%, n = 33). There was no significant difference in anti-TTG titres. Surrogate markers of absorption were comparable across the groups, except for Vitamin D which was lower in those taking olmesartan (p = 0.0015). CONCLUSIONS: ARBs may aggravate the enteropathy and lead to increased symptoms in patients with bone fide diagnosed CD following a GFD.

Visceral adiposity and inflammatory bowel disease.

BACKGROUND: Rates of obesity are increasing worldwide, as is the incidence of inflammatory bowel disease (IBD). Obesity is now considered an inflammatory state. Visceral adiposity in particular may be associated with a more severe inflammatory phenotype in IBD. AIM: The aim of this review article is to summarise the current literature on the association between visceral adiposity and outcomes in inflammatory bowel disease METHODS: To collect relevant articles, PubMed/MEDLINE and Embase searches were performed using Boolean search phrases. Grey literature and manual searches were also performed. Abstracts were selected by two independent reviewers based on pre-determined criteria. Full text articles were reviewed, and data extracted and assessed. RESULTS: One hundred twenty-seven abstracts were obtained through the initial search, with 85 abstracts reviewed and 22 full text articles included. Characteristics are included in Table 1. Most of these were retrospective studies and of moderate or weak quality. Studies suggested visceral fat content is higher in Crohn's disease than in healthy controls. Visceral adiposity was associated with an increased risk of complex Crohn's disease phenotype (OR 26.1 95% CI 2-75.4; p = 0.02). Post-operative recurrence was higher in patients with higher visceral fat indices (RR 2.1; CI 1.5-3; p = 0.012). There were conflicting data regarding the effect of visceral adiposity on post-operative complications and the efficacy of medical therapy. Table 1 Study characteristics Author Year Country Study type Study numbers Control group Disease type Methodology e.g. CT Body composition measurements Results Argeny [24] 2018 Austria Retrospective cohort N = 95 N/A Crohn's disease CT; L3 level Visceral fat area (cm2) Visceral fat index (VFA/m2) No association between VFA or VFI and short-term post-operative outcomes Bryant [30] 2018 Australia Prospective cohort N = 110 N/A Crohn's disease and UC DXA Visceral adipose tissue (VAT) (cm3) Visceral adipose tissue (grams) VAT/height index (cm3/m2) VAT:subcutaneous adipose tissue ratio Fat mass index (kg/m2) VAT and VHI increased significantly over 24 months Bryant [13] 2018 Australia Prospective cohort N = 72 N/A Crohn's disease; female DXA Visceral adipose tissue (VAT) (cm3) Visceral adipose tissue (grams) VAT/height index (cm3/m2) VAT:subcutaneous adipose tissue ratio VAT:SAT positively associated with stricturing disease Adiposity not associated with fistulising disease phenotype VAT:SAT significantly associated with faecal calprotectin in L3 phenotype VAT:SAT significantly negatively associated with VHI and QoL over 24 months Buning [25] 2015 Germany Case control N = 50 N = 19 healthy controls Crohn's disease MRI US VAT Thickness of abdominal fat Distance to posterior wall of aorta Area of inferior part of perirenal fat VAT accumulation was higher in CD patients vs healthy controls VAT and VAT/fat mass ratio higher in patients in short-term remission vs long-term remission VAT/FM higher in stricturing/fistulising disease vs inflammatory subtype No association between VAT/FM and CDAI, HBI or anti-TNF treatment Connolly [26] 2014 US Retrospective cohort N = 143 N/A Crohn's disease CT (L1-L5 level) Visceral/intra-abdominal adiposity (VA) Subcutaneous adiposity (SA) VA not associated with post-operative morbidity Decreased SA and increased visceral/subcutaneous ratio were predictive of post-op complications. (p = 0.02; p < 0.001) Cravo [27] 2017 Portugal Retrospective cohort N = 71 N/A Crohn's disease CT (L3 level) Smooth muscle area (cm2) Visceral fat area (cm2) Subcutaneous fat area (cm2) Visceral fat index Muscle radiation attenuation L2 phenotype associated with lower muscle attenuation and higher visceral fat index (non-significant) B2/B3/surgery - significantly lower muscle attenuation. VFI associated with increased risk of complicated phenotype. (OR 26.1; 95% CI 1-75; p = 0.02) Ding [17] 2016 US Retrospective cohort N = 164 N/A Crohn's disease CT (L3 level) Visceral fat area (cm2) Subcutaneous fat area Total fat area Visceral obesity associated with longer duration of surgery, increased intra-operative blood loss and longer length of bowel resected Higher complication rates in patients with visceral obesity (p < 0.001) VFA independent risk factor of adverse post-op outcomes Ding [14] 2017 Retrospective cohort N = 106 N/A Crohn's disease CT (L3 level) Visceral fat area Subcutaneous fat area Skeletal muscle area Skeletal muscle index Visceral obesity and myopenic obesity not significantly associated with risk of primary non-response Body composition factors not associated with secondary loss of response Erhayiem [18] 2011 UK Retrospective cohort N = 50 N/A Crohn's disease CT (L4 level) Mesenteric fat index (visceral:subcutaneous area ratio)N = 50 Mesenteric fat index was significantly higher in complicated Crohn's disease. ROC analysis for MFI in identifying complicated Crohn's disease: AUC = 0.95 (95% CI 0.89-1.0) Feng [28] 2018 China Retrospective cohort N = 80 Non-IBD GI patients Crohn's disease CT-energy spectral Visceral fat area (cm2) Subcutaneous fat area (cm2) Mesenteric fat index No significant difference in VFA between Crohn's disease cohort and control group. (p = 0.669). ROC analysis: detection of disease based on VFA and MFI: AUC 0.776 Sensitivity 77.5% Specificity 67.5% Hafraoui [16] 1998 France/Belgium Prospective N = 43 Healthy volunteers n = 13 Intestinal resection n = 9 Crohn's disease MRI (umbilicus) Total abdominal fat (cm2) Intra-abdominal fat (cm2) Subcutaneous fat (cm2) Ratio of intra-abdominal:total fat area was significantly higher in patients with Crohn's vs controls. (p = 0.012) No correlation between abdominal fat tissue and disease activity, duration or steroid therapy Holt [29] 2017 Australia/New Zealand RCT N = 44 N = 11 placebo group Crohn's disease CT/MRI (L3, L4-5 levels) Visceral adipose tissue area Subcutaneous adipose tissue area Skeletal muscle area Visceral adipose tissue/height index VHI > 1.5 times gender mean was specific for endoscopic recurrence (100%) with sensitivity of 29%. PPV = 1 (0.59-1.00) There was no significant difference in disease activity at 18 months post-resection based on VHI > 1.5 gender mean Li [31] 2015 China Retrospective cohort N = 72 N/A Crohn's disease CT (umbilicus) Visceral fat area (cm2) Subcutaneous fat area (cm2) Mesenteric fat index Post-op recurrence was more frequent with high VFA values. (p = 0.019) VFA and MFI were independent risk factors for post-operative recurrence. (p = 0.013 and p = 0.028, respectively) High VFA and high MFI were significantly higher in patients with endoscopic activity (p = 0.023) Liu [32] 2016 Retrospective case-control N = 59 N = 30 (< 15% increase VFA) IBD with IPAA CT (L3) Visceral fat area Subcutaneous fat area No difference in pouchitis, pouch sinus formation and composite adverse pouch outcomes between the 2 groups with and without VFA increase > 15%. Excessive VAT gain was an independent risk factor for the composite adverse pouch outcomes. (OR 12.6 (95% CI 1.19-133.5) Magro [33] 2018 Brazil Cross-sectional study N = 78 N = 28 Health control Crohn's disease DEXA Fat and lean masses Visceral fat (kg) Visceral fat/BMI Visceral fat per %body fat VF was higher in Crohn's disease group (p = 0.004) compared to controls Parmentier-Decrucq [34] 2009 Prospective study N = 132 N/A Crohn's disease MRI Subcutaneous fat Visceral fat Total abdominal fat increased 18% in Crohn's disease patients treated with infliximab induction therapy Shen [35] 2018 China Retrospective N = 97 N/A Crohn's disease CT (umbilicus) Subcutaneous fat area Visceral fat area Mesenteric fat index VFA and MFI were significantly lower in patients with mucosal healing (post-infliximab). (p < 0.0001) SFA was not significantly different VFA correlated with CDAI (p < 0.001) and was an independent predictive factor for mucosal healing Stidham [15] 2015 Retrospective N = 269 N/A Crohn's disease CT(T10-L5) Subcutaneous fat volume Visceral fat volume No significant difference in visceral fat volume between patients with surgical complications Thiberge [36] 2018 France Retrospective N = 149 N/A Crohn's disease CT (L3 level) Skeletal muscle index Visceral adiposity index Subcutaneous adiposity index SAI and VAI were significantly lower in patients who underwent surgery or who died in 6 months post-CT(p = 0.009 and p < 0.001) VanDerSloot [37] 2017 Cohort study N/A Crohn's disease CT (T11-S5) Visceral adipose tissue volume Non-significant trend toward increased risk of surgery and penetrating disease with increasing VAT Wei [38] 2018 China Retrospective N = 86 N/A IBD post-resection CT (L3 level) Visceral adipose volume Subcutaneous adipose volume Increased visceral:subcutaneous fat ratio was associated with increased procalcitonin levels on post-op days 1, 3 and 5 Yadav [39] 2017 India Prospective N = 97 N/A IBD CT (L4 level) Visceral fat area Subcutaneous fat area No statistically significant correlation between visceral fat and disease behaviour in Crohn's disease N/A not applicable, VFA visceral fat area, VFI visceral fat index, VAT visceral adipose tissue, VHI visceral adipose tissue to height index, SAT subcutaneous adipose tissue, DXA dual-energy X-ray absorptiometry, CT computer tomography, MRI magnetic resonance imaging, US ultrasound, CDAI Crohn's disease activity index, HBI Harvey-Bradshaw Index, anti-TNF anti-tumour necrosis factor, SA subcutaneous adiposity, ROC receiver operating curve, AUC area under the curve, MFI mesenteric fat index, SAI subcutaneous adiposity index, PPV positive predictive value CONCLUSION: Visceral adiposity appears to be increased in Crohn's disease with some evidence that it is also associated with more complex disease phenotypes. There is also a signal that post-operative recurrence rates are affected by increasing mesenteric adiposity. There is a relative lack of data in UC patients and furtherhigh-quality studies are necessary to elucidate the relationship between visceral adiposity and IBD and the implications for patient outcomes.

Analysis of Caenorhabditis elegans acetylcholine synthesis mutants reveals a temperature-sensitive requirement for cholinergic neuromuscular function.

In Caenorhabditis elegans, the cha-1 gene encodes choline acetyltransferase (ChAT), the enzyme that synthesizes the neurotransmitter acetylcholine. We have analyzed a large number of cha-1 hypomorphic mutants, most of which are missense alleles. Some homozygous cha-1 mutants have approximately normal ChAT immunoreactivity; many other alleles lead to consistent reductions in synaptic immunostaining, although the residual protein appears to be stable. Regardless of protein levels, neuromuscular function of almost all mutants is temperature-sensitive, i.e., neuromuscular function is worse at 25° than at 14°. We show that the temperature effects are not related to acetylcholine release, but specifically to alterations in acetylcholine synthesis. This is not a temperature-dependent developmental phenotype, because animals raised at 20° to young adulthood and then shifted for 2 h to either 14° or 25° had swimming and pharyngeal pumping rates similar to animals grown and assayed at either 14° or 25°, respectively. We also show that the temperature-sensitive phenotypes are not limited to missense alleles; rather, they are a property of most or all severe cha-1 hypomorphs. We suggest that our data are consistent with a model of ChAT protein physically, but not covalently, associated with synaptic vesicles; and there is a temperature-dependent equilibrium between vesicle-associated and cytoplasmic (i.e., soluble) ChAT. Presumably, in severe cha-1 hypomorphs, increasing the temperature would promote dissociation of some of the mutant ChAT protein from synaptic vesicles, thus removing the site of acetylcholine synthesis (ChAT) from the site of vesicular acetylcholine transport. This, in turn, would decrease the rate and extent of vesicle-filling, thus increasing the severity of the behavioral deficits.

Synthesis and characterisation of thin-film platinum disulfide and platinum sulfide.

Group-10 transition metal dichalcogenides (TMDs) are rising in prominence within the highly innovative field of 2D materials. While PtS2 has been investigated for potential electronic applications, due to its high charge-carrier mobility and strongly layer-dependent bandgap, it has proven to be one of the more difficult TMDs to synthesise. In contrast to most TMDs, Pt has a significantly more stable monosulfide, the non-layered PtS. The existence of two stable platinum sulfides, sometimes within the same sample, has resulted in much confusion between the materials in the literature. Neither of these Pt sulfides have been thoroughly characterised as-of-yet. Here we utilise time-efficient, scalable methods to synthesise high-quality thin films of both Pt sulfides on a variety of substrates. The competing nature of the sulfides and limited thermal stability of these materials is demonstrated. We report peak-fitted X-ray photoelectron spectra, and Raman spectra using a variety of laser wavelengths, for both materials. This systematic characterisation provides a guide to differentiate between the sulfides using relatively simple methods which is essential to enable future work on these interesting materials.

Sargramostim (rhu GM-CSF) Improves Survival of Non-Human Primates with Severe Bone Marrow Suppression after Acute, High-Dose, Whole-Body Irradiation.

Exposure to acute, high-dose, whole-body ionizing radiation results in bone marrow failure (hematopoietic acute radiation syndrome with resultant infection, bleeding, anemia, and increased risk of death). Sargramostim (yeast-derived rhu GM-CSF), a yeast-derived, molecularly cloned, hematopoietic growth factor and pleiotropic cytokine supports proliferation, differentiation, maturation and survival of cells of several myeloid lineages. We evaluated the efficacy of sargramostim in non-human primates (rhesus macaques) exposed to whole-body ionizing radiation at a 50-60% lethal dose. The primary end point was day 60 survival. Non-human primates received daily subcutaneous sargramostim (7 mcg/kg/day) or control. To reflect the anticipated setting of a nuclear or radiologic event, treatment began 48 h postirradiation, and non-human primates received only moderate supportive care (no whole blood transfusions or individualized antibiotics). Sargramostim significantly increased day 60 survival to 78% (95% confidence interval, 61-90%) vs. 42% (26-59%; P = 0.0018) in controls. Neutrophil, platelet and lymphocyte recovery rates were accelerated and infection rates decreased. Improved survival when sargramostim was started 48 h postirradiation, without use of intensive supportive care, suggests sargramostim may be effective in treating humans exposed to acute, high-dose whole-body, ionizing radiation in a scenario such as a mass casualty event.

Pandemic influenza and major disease outbreak preparedness in US emergency departments: A survey of medical directors and department chairs.

STUDY OBJECTIVES: To quantify the readiness of individual academic emergency departments (EDs) in the United States for an outbreak of pandemic influenza. Methods, design, and setting: Cross-sectional assessment of influenza pandemic preparedness level of EDs in the United States via survey of medical directors and department chairs from the 135 academic emergency medicine departments in the United States. Preparedness assessed using a novel score of 15 critical preparedness indicators. Data analysis consisted of summary statistics, χ2, and ANOVA. PARTICIPANTS: ED medical directors and department chairs. RESULTS: One hundred and thirty academic emergency medicine departments contacted; 66 (50.4 percent) responded. Approximately half (56.0 percent) stated their ED had a written plan for pandemic influenza response. Mean preparedness score was 7.2 (SD = 4.0) out of 15 (48.0 percent); only one program (1.5 percent) achieved a perfect score. Respondents from programs with larger EDs (=30 beds) were more likely to have a higher preparedness score (p < 0.035), an ED pandemic preparedness plan (p = 0.004) and a hospital pandemic preparedness plan (p = 0.007). Respondents from programs with larger EDs were more likely to feel that their ED was prepared for a pandemic or other major disease outbreak (p = 0.01). Only one-third (34.0 percent) felt their ED was prepared for a major disease outbreak, and only 27 percent felt their hospital was prepared to respond to a major disease outbreak. CONCLUSIONS: Significant deficits in preparedness for pandemic influenza and other disease outbreaks exist in US EDs, relative to HHS guidelines, which appear to be related in part to ED size. Further study should be undertaken to determine the barriers to appropriate pandemic preparedness, as well as to develop and validate preparedness metrics.

Prefibrotic Myelofibrosis Presenting with Multiple Cerebral Embolic Infarcts and the Rare MPL W515S Mutation.

Acquired, activating mutations of MPL W515 are recognised driver mutations of the myeloproliferative neoplasms (MPN), namely, essential thrombocythemia and primary myelofibrosis. The most common mutation at this codon is W515L with several other mutations also described at a lower frequency. Of these less common mutations, MPL W515S has only been reported sporadically with limited information on clinicopathological associations. We describe the case of an elderly man with persistent thrombocytosis presenting with an ischemic cerebral event. Bone marrow biopsy showed evidence of prefibrotic myelofibrosis with targeted sequencing demonstrating the presence of the rare MPL W515S mutation. Thrombolytic and cytoreductive therapies resulted in a favorable outcome and follow-up. This case provides additional, necessary, and phenotypic data for the rare MPN-associated MPL W515S mutation.

Anticoagulant Reversal Strategies in the Emergency Department Setting: Recommendations of a Multidisciplinary Expert Panel.

Bleeding is the most common complication of anticoagulant use. The evaluation and management of the bleeding patient is a core competency of emergency medicine. As the prevalence of patients receiving anticoagulant agents and variety of anticoagulants with different mechanisms of action, pharmacokinetics, indications, and corresponding reversal agents increase, physicians and other clinicians working in the emergency department require a current and nuanced understanding of how best to assess, treat, and reverse anticoagulated patients. In this project, we convened an expert panel to create a consensus decision tree and framework for assessment of the bleeding patient receiving an anticoagulant, as well as use of anticoagulant reversal or coagulation factor replacement, and to address controversies and gaps relevant to this topic. To support decision tree interpretation, the panel also reached agreement on key definitions of life-threatening bleeding, bleeding at a critical site, and emergency surgery or urgent invasive procedure. To reach consensus recommendations, we used a structured literature review and a modified Delphi technique by an expert panel of academic and community physicians with training in emergency medicine, cardiology, hematology, internal medicine/thrombology, pharmacology, toxicology, transfusion medicine and hemostasis, neurology, and surgery, and by other key stakeholder groups.

A method for cost-effective and rapid characterization of engineered T7-based transcription factors by cell-free protein synthesis reveals insights into the regulation of T7 RNA polymerase-driven expression.

The T7 bacteriophage RNA polymerase (T7 RNAP) serves as a model for understanding RNA synthesis, as a tool for protein expression, and as an actuator for synthetic gene circuit design in bacterial cells and cell-free extract. T7 RNAP is an attractive tool for orthogonal protein expression in bacteria owing to its compact single subunit structure and orthogonal promoter specificity. Understanding the mechanisms underlying T7 RNAP regulation is important to the design of engineered T7-based transcription factors, which can be used in gene circuit design. To explore regulatory mechanisms for T7 RNAP-driven expression, we developed a rapid and cost-effective method to characterize engineered T7-based transcription factors using cell-free protein synthesis and an acoustic liquid handler. Using this method, we investigated the effects of the tetracycline operator's proximity to the T7 promoter on the regulation of T7 RNAP-driven expression. Our results reveal a mechanism for regulation that functions by interfering with the transition of T7 RNAP from initiation to elongation and validates the use of the method described here to engineer future T7-based transcription factors.

Ultrafast Carrier Dynamics and Bandgap Renormalization in Layered PtSe2.

Carrier interactions in 2D nanostructures are of central importance not only in condensed-matter physics but also for a wide range of optoelectronic and photonic applications. Here, new insights into the behavior of photoinduced carriers in layered platinum diselenide (PtSe2 ) through ultrafast time-resolved pump-probe and nonlinear optical measurements are presented. The measurements reveal the temporal evolution of carrier relaxation, chemical potential and bandgap renormalization in PtSe2 . These results imply that few-layer PtSe2 has a semiconductor-like carrier relaxation instead of a metal-like one. The relaxation follows a triple-exponential decay process and exhibits thickness-dependent relaxation times. This occurs along with a band-filling effect, which can be controlled based on the number of layers and may be applied in saturable absorption for generating ultrafast laser pulses. The findings may provide means to study many-body physics in 2D materials as well as potentially leading to applications in the field of optoelectronics and ultrafast photonics.

Convergent evolution of hetero-oligomeric cellulose synthesis complexes in mosses and seed plants.

In seed plants, cellulose is synthesized by rosette-shaped cellulose synthesis complexes (CSCs) that are obligate hetero-oligomeric, comprising three non-interchangeable cellulose synthase (CESA) isoforms. The moss Physcomitrella patens has rosette CSCs and seven CESAs, but its common ancestor with seed plants had rosette CSCs and a single CESA gene. Therefore, if P. patens CSCs are hetero-oligomeric, then CSCs of this type evolved convergently in mosses and seed plants. Previous gene knockout and promoter swap experiments showed that PpCESAs from class A (PpCESA3 and PpCESA8) and class B (PpCESA6 and PpCESA7) have non-redundant functions in secondary cell wall cellulose deposition in leaf midribs, whereas the two members of each class are redundant. Based on these observations, we proposed the hypothesis that the secondary class A and class B PpCESAs associate to form hetero-oligomeric CSCs. Here we show that transcription of secondary class A PpCESAs is reduced when secondary class B PpCESAs are knocked out and vice versa, as expected for genes encoding isoforms that occupy distinct positions within the same CSC. The class A and class B isoforms co-accumulate in developing gametophores and co-immunoprecipitate, suggesting that they interact to form a complex in planta. Finally, secondary PpCESAs interact with each other, whereas three of four fail to self-interact when expressed in two different heterologous systems. These results are consistent with the hypothesis that obligate hetero-oligomeric CSCs evolved independently in mosses and seed plants and we propose the constructive neutral evolution hypothesis as a plausible explanation for convergent evolution of hetero-oligomeric CSCs.