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Eutrophication is a challenge to coastal waters around the globe. In many places, nutrient reductions from land-based sources have not been sufficient to achieve desired water quality improvements. Bivalve shellfish have shown promise as an in-water strategy to complement land-based nutrient management. A local-scale production model was used to estimate oyster (Crassostrea virginica) harvest and bioextraction of nitrogen (N) in Great Bay Piscataqua River Estuary (GBP), New Hampshire, USA, because a system-scale ecological model was not available. Farm-scale N removal results (0.072 metric tons acre⁻¹ year⁻¹) were up-scaled to provide a system-wide removal estimate for current (0.61 metric tons year⁻¹), and potential removal (2.35 metric tons year⁻¹) at maximum possible expansion of licensed aquaculture areas. Restored reef N removal was included to provide a more complete picture. Nitrogen removal through reef sequestration was ~ 3 times that of aquaculture. Estimated reef-associated denitrification, based on previously reported rates, removed 0.19 metric tons N year⁻¹. When all oyster processes (aquaculture and reefs) were included, N removal was 0.33% and 0.54% of incoming N for current and expanded acres, respectively. An avoided cost approach, with wastewater treatment as the alternative management measure, was used to estimate the value of the N removed. The maximum economic value for aquaculture-based removal was $105,000 and $405,000 for current and expanded oyster areas, respectively. Combined aquaculture and reef restoration is suggested to maximize N reduction capacity while limiting use conflicts. Comparison of removal based on per oyster N content suggests much lower removal rates than model results, but model harvest estimates are similar to reported harvest. Though results are specific to GBP, the approach is transferable to estuaries that support bivalve aquaculture but do not have complex system-scale hydrodynamic or ecological models.

This chapter contains sections titled: Major species in culture (oysters, clams, scallops, mussels) History Biology Culture basics Extensive versus intensive culture Spat collection: hatchery, nursery, growout Cultured algae Spawning Larval development Setting Nursery and growout scale considerations Nursery methods Growout methods Fouling Fouling control strategies Predation Harvest Food safety Shellfish diseases Disease management options Genetics: selective breeding Triploidy Harmful algal blooms Site selection Carrying capacity Permitting challenges Nonnative species References

Growth and survival of Mercenaria mercenaria seed in three marinas and a control site were compared with those in a hatchery-based upwelling system. Seed were grown in mesh bags held in cages suspended below floating docks. Growth rates varied greatly (2% to 12% per day) and survival was excellent at all sites. The biological and economic feasibility of culturing seed under floats in marinas for final grow-out in certified waters was demonstrated. The same cages were used in a 20-week study of the growth rates of three species of juvenile shellfish (Crassostrea virginica, Mercenaria mercenaria and Argopecten irradians irradians) at three locations along a food concentration gradient. Average tidal current speed was calculated for each site and temperature, total seston, particulate organic matter, and chlorophyll were measured weekly. Food-limited shellfish growth rates at the three locations were not significantly different despite a three-fold difference in chlorophyll concentrations. Higher current speeds compensated for lower food concentrations resulting in nearly identical horizontal chlorophyll fluxes at the three locations. Correlations between shellfish growth and the food flux variables were stronger than those with the food concentration variables, corroborating the Grizzle and Lutz horizontal seston flux model. A flow-through flume was constructed to study the growth response of Crassostrea virginica and Argopecten irradians exposed to varying degrees of food limitation caused by downstream depletion. The bivalves in each stage of the flume removed a constant percentage of the available food over a wide range of concentrations. Variations in growth and condition index were linearly correlated with ration consumed in the downstream compartments. Concurrent field studies showed similar growth and condition index responses to resource competition associated with varying initial stocking densities in a commercial shellfish aquaculture operation. Studies were conducted to examine the feasibility of culturing shellfish in mesh-bags held in on-bottom cages. A novel approach to shellfish aquaculture management was developed and commercialized. The approach minimizes multiple-use conflicts by avoiding the need for conventional fixed aquaculture leases by treating the cages as transient-gear. The concept and methods were described and an economic model based on four years of data was presented.

This chapter contains sections titled: Introduction Literature review Experimental design Conclusions Acknowledgments Literature cited

Mitogen-Activated Protein Kinase (MAPK) pathway activation has been implicated in many types of human cancer. BRAF mutations that constitutively activate MAPK signalling and bypass the need for upstream stimuli occur with high prevalence in melanoma, colorectal carcinoma, ovarian cancer, papillary thyroid carcinoma, and cholangiocarcinoma. In this report we characterize the novel, potent, and selective BRAF inhibitor, dabrafenib (GSK2118436). Cellular inhibition of BRAF(V600E) kinase activity by dabrafenib resulted in decreased MEK and ERK phosphorylation and inhibition of cell proliferation through an initial G1 cell cycle arrest, followed by cell death. In a BRAF(V600E)-containing xenograft model of human melanoma, orally administered dabrafenib inhibited ERK activation, downregulated Ki67, and upregulated p27, leading to tumor growth inhibition. However, as reported for other BRAF inhibitors, dabrafenib also induced MAPK pathway activation in wild-type BRAF cells through CRAF (RAF1) signalling, potentially explaining the squamous cell carcinomas and keratoacanthomas arising in patients treated with BRAF inhibitors. In addressing this issue, we showed that concomitant administration of BRAF and MEK inhibitors abrogated paradoxical BRAF inhibitor-induced MAPK signalling in cells, reduced the occurrence of skin lesions in rats, and enhanced the inhibition of human tumor xenograft growth in mouse models. Taken together, our findings offer preclinical proof of concept for dabrafenib as a specific and highly efficacious BRAF inhibitor and provide evidence for its potential clinical benefits when used in combination with a MEK inhibitor.

Dietary restriction of sodium has been suggested to prevent fluid overload and adverse outcomes for patients with heart failure. We designed the Study of Dietary Intervention under 100 mmol in Heart Failure (SODIUM-HF) to test whether or not a reduction in dietary sodium reduces the incidence of future clinical events. SODIUM-HF is an international, open-label, randomised, controlled trial that enrolled patients at 26 sites in six countries (Australia, Canada, Chile, Colombia, Mexico, and New Zealand). Eligible patients were aged 18 years or older, with chronic heart failure (New York Heart Association [NYHA] functional class 2–3), and receiving optimally tolerated guideline-directed medical treatment. Patients were randomly assigned (1:1), using a standard number generator and varying block sizes of two, four, or six, stratified by site, to either usual care according to local guidelines or a low sodium diet of less than 1500 mg/day. The primary outcome was the composite of cardiovascular-related admission to hospital, cardiovascular-related emergency department visit, or all-cause death within 12 months in the intention-to-treat (ITT) population (ie, all randomly assigned patients). Safety was assessed in the ITT population. This study is registered with ClinicalTrials.gov, NCT02012179, and is closed to accrual. Between March 24, 2014, and Dec 9, 2020, 806 patients were randomly assigned to a low sodium diet (n=397) or usual care (n=409). Median age was 67 years (IQR 58–74) and 268 (33%) were women and 538 (66%) were men. Between baseline and 12 months, the median sodium intake decreased from 2286 mg/day (IQR 1653–3005) to 1658 mg/day (1301–2189) in the low sodium group and from 2119 mg/day (1673–2804) to 2073 mg/day (1541–2900) in the usual care group. By 12 months, events comprising the primary outcome had occurred in 60 (15%) of 397 patients in the low sodium diet group and 70 (17%) of 409 in the usual care group (hazard ratio [HR] 0·89 [95% CI 0·63–1·26]; p=0·53). All-cause death occurred in 22 (6%) patients in the low sodium diet group and 17 (4%) in the usual care group (HR 1·38 [0·73–2·60]; p=0·32), cardiovascular-related hospitalisation occurred in 40 (10%) patients in the low sodium diet group and 51 (12%) patients in the usual care group (HR 0·82 [0·54–1·24]; p=0·36), and cardiovascular-related emergency department visits occurred in 17 (4%) patients in the low sodium diet group and 15 (4%) patients in the usual care group (HR 1·21 [0·60–2·41]; p=0·60). No safety events related to the study treatment were reported in either group. In ambulatory patients with heart failure, a dietary intervention to reduce sodium intake did not reduce clinical events. Canadian Institutes of Health Research and the University Hospital Foundation, Edmonton, Alberta, Canada, and Health Research Council of New Zealand.

Policy Points More rigorous methodologies and systematic approaches should be encouraged in the science of scaling. This will help researchers better determine the effectiveness of scaling, guide stakeholders in the scaling process, and ultimately increase the impacts of health innovations. The practice and the science of scaling need to expand worldwide to address complex health conditions such as noncommunicable and chronic diseases. Although most of the scaling experiences described in the literature are occurring in the Global South, most of the authors publishing on it are based in the Global North. As the science of scaling spreads across the world with the aim of reducing health inequities, it is also essential to address the power imbalance in how we do scaling research globally. Context Scaling of effective innovations in health and social care is essential to increase their impact. We aimed to synthesize the evidence base on scaling and identify current knowledge gaps. Methods We conducted an umbrella review according to the Joanna Briggs Institute Reviewers’ Manual. We included any type of review that 1) focused on scaling, 2) covered health or social care, and 3) presented a methods section. We searched MEDLINE (Ovid), Embase, PsycINFO (Ovid), CINAHL (EBSCO), Web of Science, The Cochrane Library, Sociological s (ProQuest), Academic Search Premier (EBSCO), and ProQuest Dissertations & Theses Global from their inception to August 6, 2020. We searched the gray literature using, e.g., Google and WHO‐ExpandNet. We assessed methodological quality with AMSTAR2. Paired reviewers independently selected and extracted eligible reviews and assessed study quality. A narrative synthesis was performed. Findings Of 24,269 records, 137 unique reviews were included. The quality of the 58 systematic reviews was critically low (n = 42). The most frequent review type was systematic review (n = 58). Most reported on scaling in low‐ and middle‐income countries (n = 59), whereas most first authors were from high‐income countries (n = 114). Most reviews concerned infectious diseases (n = 36) or maternal–child health (n = 28). They mainly focused on interventions (n = 37), barriers and facilitators (n = 29), frameworks (n = 24), scalability (n = 24), and costs (n = 14). The WHO/ExpandNet scaling definition was the definition most frequently used (n = 26). Domains most reported as influencing scaling success were building scaling infrastructure (e.g., creating new service sites) and human resources (e.g., training community health care providers). Conclusions The evidence base on scaling is evolving rapidly as reflected by publication trends, the range of focus areas, and diversity of scaling definitions. Our study highlights knowledge gaps around methodology and research infrastructures to facilitate equitable North–South research relationships. Common efforts are needed to ensure scaling expands the impacts of health and social innovations to broader populations.

Background There is a growing interest in scaling effective health innovations to promote equitable access to high-quality health services worldwide. However, multiple challenges persist in scaling innovations. In this study, we aim to summarize the scaling evidence in the health and social care literature and identify current knowledge gaps. Methods We will conduct a living umbrella review according to the Joanna Briggs Institute Reviewers’ Manual. We will consider all knowledge syntheses addressing scaling in health or social care (e.g., any setting, any clinical area) and conducted in a systematic way. We will search the following electronic databases: MEDLINE (Ovid), Embase, PsychINFO (Ovid), CINAHL (EBSCO), Web of Science, The Cochrane Library, Sociological Abstract (Proquest), Academic Search Premier (EBSCO), and Proquest Dissertations & Theses Global, from inception. Furthermore, we will conduct searches of the grey literature. No restriction regarding date or language will be applied. Each phase of the review will be processed by two independent reviewers. We will develop a data extraction form on Covidence. We will assess the methodological quality of the included reviews using AMSTAR2 and the risk of bias using ROBIS. Results will be presented in tabular form and accompanied by a narrative synthesis covering the traditional themes of scaling science that emerge from the analysis, such as coverage, range, and sustainability, as well as themes less covered in the literature, including reporting guidance, models, tools, barriers, and/or facilitators to scaling innovations, evidence regarding application in high-income or low-income countries, and end-user engagement. We will disseminate the findings via publications and through relevant networks. Discussion The findings of the umbrella review will facilitate access to scaling evidence in the literature and help strengthen the science of scaling for researchers, policy makers, and program managers. Finally, this work will highlight important knowledge gaps and help prioritize future research questions. Systematic review registration This protocol was registered with the International Prospective Register of Systematic Reviews (PROSPERO) on November 11, 2020 (registration number: CRD42020183774 ).

Objective To determine the impact of perioperative thoracic epidural analgesia (TEA) on acute and late outcomes following transapical transcatheter aortic valve implantation (TA-TAVI). Patients and intervention A total of 135 consecutive patients who underwent TA-TAVI were included. All patients received catheter-based pain control, either via TEA (TEA group, n=74) or intercostal local analgesia with a catheter placed at the surgical incision site (non-TEA group, n=61), depending on the preference of the anaesthesiologist responsible for the case. Main outcome measures Pain level during early postoperative period (verbal rating scale from 1 to 10), 30-day/in-hospital complications and mortality, and 1-year mortality. Results There were no differences in baseline or procedural characteristics between groups except for a lower left ventricular ejection fraction in the TEA group. The maximal pain score related to thoracotomy in the postoperative period was higher in the non-TEA group as compared with the TEA group (4 (IQR: 3–5)) vs 2 (IQR: 1–3), p<0.001). Non-TEA was associated with a higher rate of pulmonary complications (p<0.05 for nosocomial pneumonia, reintubation and tracheostomy). The 30-day/in-hospital mortality rate was higher in the non-TEA group (22.9% vs 2.7% in the TEA group, p<0.001). At 1-year follow-up, overall mortality remained higher in the non-TEA group (31.1%) compared with the TEA group (10.8%), p=0.005. Similar periprocedural and late results were obtained in a propensity score-matched analysis that included 100 matched patients. In the multivariable analysis, STS score (p=0.027) and absence of TEA (p=0.039) were independent predictors of increased cumulative late mortality. Conclusions TEA provided superior analgesia following TA-TAVI, and was associated with a dramatic reduction in periprocedural respiratory complications, and both, short- and long-term mortality. These results highlight the importance of obtaining optimal analgesia following TA-TAVI to improve the results associated with this procedure.

Background The lack of a reporting guideline for scaling of evidence-based practices (EBPs) studies has prompted the registration of the Standards for reporting studies assessing the impact of scaling strategies of EBPs (SUCCEED) with EQUATOR Network. The development of SUCCEED will be guided by the following main steps recommended for developing health research reporting guidelines. Methods Executive Committee. We established a committee composed of members of the core research team and of an advisory group. Systematic review . The protocol was registered with the Open Science Framework on 29 November 2019 ( https://osf.io/vcwfx/ ). We will include reporting guidelines or other reports that may include items relevant to studies assessing the impact of scaling strategies. We will search the following electronic databases: EMBASE, PsycINFO, Cochrane Library, CINAHL, Web of Science, from inception. In addition, we will systematically search websites of EQUATOR and other relevant organizations. Experts in the field of reporting guidelines will also be contacted. Study selection and data extraction will be conducted independently by two reviewers. A narrative analysis will be conducted to compile a list of items for the Delphi exercise. Consensus process . We will invite panelists with expertise in: development of relevant reporting guidelines, methodologists, content experts, patient/member of the public, implementers, journal editors, and funders. We anticipated that three rounds of web-based Delphi consensus will be needed for an acceptable degree of agreement. We will use a 9-point scale (1 = extremely irrelevant to 9 = extremely relevant). Participants’ response will be categorized as irrelevant (1–3), equivocal (4–6) and relevant (7–9). For each item, the consensus is reached if at least 80% of the participants’ votes fall within the same category. The list of items from the final round will be discussed at face-to-face consensus meeting. Guideline validation . Participants will be authors of scaling studies. We will collect quantitative (questionnaire) and qualitative (semi-structured interview) data. Descriptive analyses will be conducted on quantitative data and constant comparative techniques on qualitative data. Discussion Essential items for reporting scaling studies will contribute to better reporting of scaling studies and facilitate the transparency and scaling of evidence-based health interventions.