Preoperative and Intraoperative Opioid-Sparing Analgesic Techniques to Reduce Postoperative Opioid Consumption in Patients Undergoing Open, Non-Emergent Abdominal Surgeries: An Educational Module

Background: Opioids have long been considered the “gold standard” of pain management; however, the significant side effects associated with opioid use make opioid-sparing analgesic methods appealing for various reasons. Reducing postoperative opioid consumption without compromising pain management is an area requiring further exploration. Objective: This study seeks to assess healthcare providers’ knowledge and confidence regarding the use of various preoperative and perioperative interventions aimed at reducing postoperative opioid consumption following non-emergent open abdominal surgeries. Based on the systematic review performed, Certified Registered Nurse Anesthetists were presented with a pre-assessment test, an educational video presentation, and a post-assessment test. Data Sources: Investigator used Pubmed, CINAHL, and EMBASE databases to answer the PICO (i.e., population, intervention, comparison, outcome) question: In patients undergoing open, nonemergent abdominal surgeries, does the use of multimodal, opioid-sparing pain management techniques during the preoperative and perioperative period reduce postoperative opioid consumption versus non-multimodal pain management? This question became the basis for the educational module by the same name. Pre-assessment and post-assessment testing were used to measure the effects of the intervention. Statistical analysis was applied to assess the effectiveness of the educational intervention. Study Selection: Nine articles were included in the systematic review and the findings were incorporated into the educational presentation. All found that their respective non-opioid interventions reduced postoperative opioid consumption to some degree. A majority reported secondary outcomes of reduced opioid-related side effects such as nausea and vomiting, decreased time to first meal, first ambulation, and foley removal, and increased patient satisfaction. Results: There were nine participants in the study and survey. The pre- and post-test gauged participants’ knowledge and confidence in non-opioid analgesic methods and implementing them in practice. The average number of correct answers in the pre-test was 4.22, compared to 7.44 in the post-test. Confidence for preoperative and intra-operative interventions improved from 44.44% and 33.33% to 88.89% and 100%, respectively. With education, participants were more likely to advocate for opioid-sparing analgesic interventions to improve postoperative outcomes for patients undergoing non-emergent abdominal surgery. All participants selected more correct answers in the post-test than pre-test. Conclusions: The evidence shows that several non-opioid analgesic interventions can reduce postoperative opioid consumption. The implementation of an educational module based on these findings led to a significant increase in providers’ knowledge and confidence of opioid-sparing analgesic methods in patients undergoing non-emergent open abdominal surgery and the benefits associated with non-opioid interventions

Bobolink (Dolichonyx oryzivorus) Declines Follow Bison (Bison bison) Reintroduction on Private Conservation Grasslands

Simple Summary North American grassland birds evolved with American bison (Bison bison), until overhunting drove bison to near-extinction > 150 years ago. Bison have now been reintroduced to many areas that provide important nesting habitat for grassland birds, which are now among the most rapidly declining birds in North America. However, little is known about bison interactions with birds such as Bobolinks (Dolichonyx oryzivorus), obligate grassland nesting songbirds of conservation concern. Using data collected over an 18-year period, we assessed the effects of bison reintroduction, together with other land management and climate factors, on Bobolinks in a private conservation area comprising 24 km(2) of native grasslands in the North American Great Plains. In grasslands where bison were reintroduced, Bobolink abundance (adult numbers) declined by 62%, and productivity (juvenile numbers) declined by 84%. By contrast, Bobolink populations remained stable over the same time period in adjacent grasslands where bison were not reintroduced. Bobolink abundance and productivity increased in years following warmer and wetter winters, but nevertheless declined over time in grasslands where the bison population doubled. Where bison are reintroduced and confined in high densities, overgrazing, trampling, and related impacts may drive severe declines in Bobolinks and other grassland birds of conservation concern. Among the most rapidly declining birds in continental North America, grassland birds evolved with American bison (Bison bison) until bison nearly became extinct due to overhunting. Bison populations have subsequently rebounded due to reintroductions on conservation lands, but the impacts of bison on grassland nesting birds remain largely unknown. We investigated how bison reintroduction, together with other land management and climate factors, affected breeding populations of a grassland bird species of conservation concern, the Bobolink (Dolichonyx oryzivorus). We quantified population changes in Bobolinks over an 18-year period in conservation grasslands where bison were reintroduced, compared with adjacent grasslands grazed by cattle and where hay was harvested after the bird breeding season. Four years after bison reintroduction, the bison population in the study area had doubled, while Bobolink abundance declined 62% and productivity declined 84%. Our findings suggest that bison reintroduction as a conservation strategy may be counterproductive in grassland fragments where overgrazing, trampling, and other negative impacts drive declines in grassland breeding birds. Where bird conservation is an objective, small grassland reserves may therefore be inappropriate sites for bison reintroduction. To maximize conservation benefits to birds, land managers should prioritize protecting grassland birds from disturbance during the bird breeding season

The impact of phonological versus semantic repetition training on generalisation in chronic stroke aphasia reflects differences in dorsal pathway connectivity

It has been suggested that neuroimaging can be used to inform therapeutic intervention. The current study aimed to determine whether an individual would benefit more from training engaging their intact or their damaged neural pathway. Two males with chronic stroke aphasia participated, with DM showing milder disruption of connectivity along the dorsal language pathway relative to JS, according to distortion corrected diffusion-weighted magnetic resonance imaging. Each patient received two blocks of six repetition training sessions over two weeks, one of which was "phonological" and the other "semantic" in nature. Both phonological and semantic training produced significant gains for both patients for trained items. For the untrained control items, significant gains were specific to training type for each patient. Only phonological training elicited significant generalisation for DM, which was greater than that seen for JS. Conversely, only semantic training elicited significant generalisation for JS, which was greater than that seen for DM. This double dissociation in generalisation effects suggests that a restitutive approach is more effective for patients with milder damage while a compensatory approach may be more effective for those with more severe damage. These results indicate the utility of neuroimaging to optimise relearning strategies and promote generalisation to untrained items

Molecular selection of therapy in metastatic colorectal cancer: the FOCUS4 molecularly stratified RCT

Complex trials with innovative designs are becoming increasingly common and offer the potential to improve patient outcomes in a shorter time frame. There is evidence that patients with colorectal cancer fall into different subgroups with varying responsiveness to therapy, and that this variation is linked to genetic biomarkers. To the best of our knowledge, FOCUS4 was the first molecularly stratified trial in metastatic colorectal cancer and remains one of the first umbrella trial designs to be launched globally. Objectives To identify novel therapies that improve disease control within the molecular subgroup of metastatic colorectal cancer in which the novel therapies were expected to be most effective. Design This was a Phase II/III molecularly stratified umbrella trial that used adaptive statistical methodology to decide which subtrial should close early; new subtrials were added as protocol amendments. Setting The maintenance setting following 16 weeks of first-line combination chemotherapy. Participants Patients with newly diagnosed metastatic colorectal cancer were registered, and central laboratory testing was used to stratify their tumour into molecular subtypes. Following 16 weeks of first-line therapy, patients with stable or responding disease were eligible for randomisation into either a molecularly stratified subtrial or the non-stratified FOCUS4-N trial. Interventions Of the 20 drug combinations that were explored for inclusion in the platform trial, three molecularly targeted subtrials were activated: FOCUS4-B (PIK3CA mutation or PTEN overexpression) – aspirin versus placebo; FOCUS4-C (TP53 and RAS mutation) – adavosertib (AstraZeneca Ltd, Cambridge, UK) versus active monitoring; and FOCUS4-D (BRAF-PIK3CA-RAS wild type) – AZD8931 versus placebo. A non-stratified subtrial was also carried out: FOCUS4-N – capecitabine versus active monitoring. Main outcome measures The main outcome measure was progression-free survival from the time of randomisation to progression, comparing the intervention with active monitoring/placebo. Toxicity and overall survival data were collected in all randomised patients, and quality of life (using EuroQol-5 Dimensions) data were collected in FOCUS4-N only. Results Between January 2014 and October 2020, 1434 patients were registered from 88 hospitals in the UK. Successful biomarker testing was completed in 1291 out of 1382 samples (93%), and 908 out of 1315 patients (69%) completing 16 weeks of first-line therapy were eligible for randomisation, with 361 randomly allocated to a subtrial. FOCUS4-B evaluated aspirin versus placebo in the PIK3CA-mutant/ PTEN -loss subgroup, but recruited only six patients, so was closed for futility. FOCUS4-C evaluated adavosertib versus active monitoring in 67 patients in the RAS + TP53 double-mutant subgroup and met its primary end point, showing an improvement in progression-free survival (median 3.61 vs. 1.87 months; hazard ratio 0.35, 95% confidence interval 0.18 to 0.68; p = 0022). FOCUS4-D evaluated AZD8931 in 32 patients in the BRAF-PIK3CA-RAS wild-type subgroup and showed no benefit, so was discontinued after the first interim analysis. FOCUS4-N evaluated capecitabine monotherapy versus active monitoring in 254 patients and met its primary end point, showing improvement in progression-free survival (hazard ratio 0.40, 95% confidence interval 0.21 to 0.75; p < 0.0001). Limitations FOCUS4-C and FOCUS4-N were closed early owing to COVID-19, so did not accrue their planned recruitment numbers. Conclusions Adaptive stratified medicine studies are feasible in common cancers but present challenges. Capecitabine monotherapy is an effective maintenance therapy. Wee1 inhibition using adavosertib shows significant clinical activity, notably in left-sided colorectal cancer. Trial registration This trial was registered as ISRCTN90061546. Funding This project was jointly funded by the Efficacy and Mechanism Evaluation (EME) programme, a MRC and National Institute for Health and Care Research (NIHR) partnership, and Cancer Research UK. This will be published in full in Efficacy and Mechanism Evaluation; Vol. 9, No. 9. See the NIHR Journals Library website for further project information

Climate vulnerability assessment for Pacific salmon and steelhead in the California Current Large Marine Ecosystem.

Major ecological realignments are already occurring in response to climate change. To be successful, conservation strategies now need to account for geographical patterns in traits sensitive to climate change, as well as climate threats to species-level diversity. As part of an effort to provide such information, we conducted a climate vulnerability assessment that included all anadromous Pacific salmon and steelhead (Oncorhynchus spp.) population units listed under the U.S. Endangered Species Act. Using an expert-based scoring system, we ranked 20 attributes for the 28 listed units and 5 additional units. Attributes captured biological sensitivity, or the strength of linkages between each listing unit and the present climate; climate exposure, or the magnitude of projected change in local environmental conditions; and adaptive capacity, or the ability to modify phenotypes to cope with new climatic conditions. Each listing unit was then assigned one of four vulnerability categories. Units ranked most vulnerable overall were Chinook (O. tshawytscha) in the California Central Valley, coho (O. kisutch) in California and southern Oregon, sockeye (O. nerka) in the Snake River Basin, and spring-run Chinook in the interior Columbia and Willamette River Basins. We identified units with similar vulnerability profiles using a hierarchical cluster analysis. Life history characteristics, especially freshwater and estuary residence times, interplayed with gradations in exposure from south to north and from coastal to interior regions to generate landscape-level patterns within each species. Nearly all listing units faced high exposures to projected increases in stream temperature, sea surface temperature, and ocean acidification, but other aspects of exposure peaked in particular regions. Anthropogenic factors, especially migration barriers, habitat degradation, and hatchery influence, have reduced the adaptive capacity of most steelhead and salmon populations. Enhancing adaptive capacity is essential to mitigate for the increasing threat of climate change. Collectively, these results provide a framework to support recovery planning that considers climate impacts on the majority of West Coast anadromous salmonids

Variation of organic matter quantity and quality in streams at Critical Zone Observatory watersheds

The quantity and chemical composition of dissolved organic matter (DOM) in surface waters influence ecosystem processes and anthropogenic use of freshwater. However, despite the importance of understanding spatial and temporal patterns in DOM, measures of DOM quality are not routinely included as part of large-scale ecosystem monitoring programs and variations in analytical procedures can introduce artifacts. In this study, we used consistent sampling and analytical methods to meet the objective of defining variability in DOM quantity and quality and other measures of water quality in streamflow issuing from small forested watersheds located within five Critical Zone Observatory sites representing contrasting environmental conditions. Results show distinct separations among sites as a function of water quality constituents. Relationships among rates of atmospheric deposition, water quality conditions, and stream DOM quantity and quality are consistent with the notion that areas with relatively high rates of atmospheric nitrogen and sulfur deposition and high concentrations of divalent cations result in selective transport of DOM derived from microbial sources, including in-stream microbial phototrophs. We suggest that the critical zone as a whole strongly influences the origin, composition, and fate of DOM in streams. This study highlights the value of consistent DOM characterization methods included as part of long-term monitoring programs for improving our understanding of interactions among ecosystem processes as controls on DOM biogeochemistry

Experiences of running a stratified medicine adaptive platform trial: Challenges and lessons learned from 10 years of the FOCUS4 trial in metastatic colorectal cancer

BACKGROUND: Complex innovative design trials are becoming increasingly common and offer potential for improving patient outcomes in a faster time frame. FOCUS4 was the first molecularly stratified trial in metastatic colorectal cancer and it remains one of the first umbrella trial designs to be launched globally. Here, we aim to describe lessons learned from delivery of the trial over the last 10 years. METHODS: FOCUS4 was a Phase II/III molecularly stratified umbrella trial testing the safety and efficacy of targeted therapies in metastatic colorectal cancer. It used adaptive statistical methodology to decide which sub-trial should close early, and new therapies were added as protocol amendments. Patients with newly diagnosed metastatic colorectal cancer were registered, and central laboratory testing was used to stratify their tumour into molecular subtypes. Following 16 weeks of first-line therapy, patients with stable or responding disease were eligible for randomisation into either a molecularly stratified sub-trial (FOCUS4-B, C or D) or non-stratified FOCUS4-N. The primary outcome for all studies was progression-free survival comparing the intervention with active monitoring/placebo. At the close of the trial, feedback was elicited from all investigators through surveys and interviews and consolidated into a series of recommendations and lessons learned for the delivery of similar future trials. RESULTS: Between January 2014 and October 2020, 1434 patients were registered from 88 UK hospitals. Of the 20 drug combinations that were explored for inclusion in the platform trial, three molecularly targeted sub-trials were activated: FOCUS4-D (February 2014-March 2016) evaluated AZD8931 in the BRAF-PIK3CA-RAS wildtype subgroup; FOCUS4-B (February 2016-July 2018) evaluated aspirin in the PIK3CA mutant subgroup and FOCUS4-C (June 2017-October 2020) evaluated adavosertib in the RAS+TP53 double mutant subgroup. FOCUS4-N was active throughout and evaluated capecitabine monotherapy versus a treatment break. A total of 361 (25%) registered patients were randomised into a sub-trial. Feedback on the experiences of delivery of FOCUS4 could be grouped into three main areas of challenge: funding/infrastructure, biomarker testing procedures and trial design efficiencies within which 20 recommendations are summarised. CONCLUSION: Adaptive stratified medicine platform studies are feasible in common cancers but present challenges. Our stakeholder feedback has helped to inform how these trial designs can succeed and answer multiple questions efficiently, providing resource is adequate

Characterization of COPD in U.S. Primary Care : Data from a Real-Life COPD Registry

Peer reviewedPostprin

Childhood socioeconomic position and objectively measured physical capability levels in adulthood: a systematic review and meta-analysis

<p><b>Background:</b> Grip strength, walking speed, chair rising and standing balance time are objective measures of physical capability that characterise current health and predict survival in older populations. Socioeconomic position (SEP) in childhood may influence the peak level of physical capability achieved in early adulthood, thereby affecting levels in later adulthood. We have undertaken a systematic review with meta-analyses to test the hypothesis that adverse childhood SEP is associated with lower levels of objectively measured physical capability in adulthood.</p> <p><b>Methods and Findings:</b> Relevant studies published by May 2010 were identified through literature searches using EMBASE and MEDLINE. Unpublished results were obtained from study investigators. Results were provided by all study investigators in a standard format and pooled using random-effects meta-analyses. 19 studies were included in the review. Total sample sizes in meta-analyses ranged from N = 17,215 for chair rise time to N = 1,061,855 for grip strength. Although heterogeneity was detected, there was consistent evidence in age adjusted models that lower childhood SEP was associated with modest reductions in physical capability levels in adulthood: comparing the lowest with the highest childhood SEP there was a reduction in grip strength of 0.13 standard deviations (95% CI: 0.06, 0.21), a reduction in mean walking speed of 0.07 m/s (0.05, 0.10), an increase in mean chair rise time of 6% (4%, 8%) and an odds ratio of an inability to balance for 5s of 1.26 (1.02, 1.55). Adjustment for the potential mediating factors, adult SEP and body size attenuated associations greatly. However, despite this attenuation, for walking speed and chair rise time, there was still evidence of moderate associations.</p> <p><b>Conclusions:</b> Policies targeting socioeconomic inequalities in childhood may have additional benefits in promoting the maintenance of independence in later life.</p&gt