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Objectives: This article is part of a series on methods for living guidelines, consolidating practical experiences from developing living guidelines. It focuses on methods for identification, selection, and prioritization of clinical questions for a living approach to guideline development., Study Design and Setting: Members of the Australian Living Evidence Consortium, the National Institute of Health and Care Excellence and the US Grading of Recommendations, Assessment, Development and Evaluations Network, convened a working group. All members have expertize and practical experience in the development of living guidelines. We collated methods, documents on prioritization from each organization's living guidelines, conducted interviews and held working group discussions. We consolidated these to form best practice principles which were then edited and agreed on by the working group members., Results: We developed best practice principles for (1) identification, (2) selection, and (3) prioritization, of questions for a living approach to guideline development. Several different strategies for undertaking prioritizing questions are explored., Conclusion: The article provides guidance for prioritizing questions in living guidelines. Subsequent articles in this series explore consumer involvement, search decisions, and methods decisions that are appropriate for questions with different priority levels., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Competing Interests: The authors declare no conflicts of interest.

This paper examines three common critiques of 'resilience': (i) that it is a 'top-down' policy discourse that pays too little regard to local specificities; (ii) that resilience policy represents a neoliberal shift towards the responsibilisation of communities and a retreat of the state from its role in providing protection; and (iii) that the focus on resilience tends to divert attention from the underlying causes of vulnerability. Using data collected after the 2015 earthquake in Nepal, the paper argues that these critiques have mixed salience in this context, but that (i) and (iii) in particular point to important problems in how the central government and its international partners have approached enhancing the resilience of communities. While there are benefits to considering resilience at the local level, it is important to recognise the inequalities within communities, how these might be reflected in differential degrees of vulnerability, and how they might be reinforced through resilience-building programmes., (© 2021 The Authors Disasters © 2021 ODI.)

Chemical thinning of apple fruitlets is an important practice as it reduces the natural fruit load and, therefore, increases the size of the final fruit for commercial markets. In apples, one chemical thinner used is Metamitron, which is sold as the commercial product Brevis ® (Adama, Ashdod, Israel). This thinner inhibits the electron transfer between Photosystem II and Quinone-b within light reactions of photosynthesis. In this study, we investigated the responses of two apple cultivars-Golden Delicious and Top Red-and photosynthetic light reactions after administration of Brevis ® . The analysis revealed that the presence of the inhibitor affects both cultivars' energetic status. The kinetics of the photoprotective mechanism's sub-processes are attenuated in both cultivars, but this seems more severe in the Top Red cultivar. State transitions of the antenna and Photosystem II repair cycle are decreased substantially when the Metamitron concentration is above 0.6% in the Top Red cultivar but not in the Golden Delicious cultivar. These attenuations result from a biased absorbed energy distribution between photochemistry and photoprotection pathways in the two cultivars. We suggest that Metamitron inadvertently interacts with photoprotective mechanism-related enzymes in chloroplasts of apple tree leaves. Specifically, we hypothesize that it may interact with the kinases responsible for the induction of state transitions and the Photosystem II repair cycle.

Background and Objective: This article explores the need for conceptual advances and practical guidance in the application of the GRADE approach within public health contexts., Methods: We convened an expert workshop and conducted a scoping review to identify challenges experienced by GRADE users in public health contexts. We developed this concept article through thematic analysis and an iterative process of consultation and discussion conducted with members electronically and at three GRADE Working Group meetings., Results: Five priority issues can pose challenges for public health guideline developers and systematic reviewers when applying GRADE: (1) incorporating the perspectives of diverse stakeholders; (2) selecting and prioritizing health and "nonhealth" outcomes; (3) interpreting outcomes and identifying a threshold for decision-making; (4) assessing certainty of evidence from diverse sources, including nonrandomized studies; and (5) addressing implications for decision makers, including concerns about conditional recommendations. We illustrate these challenges with examples from public health guidelines and systematic reviews, identifying gaps where conceptual advances may facilitate the consistent application or further development of the methodology and provide solutions., Conclusion: The GRADE Public Health Group will respond to these challenges with solutions that are coherent with existing guidance and can be consistently implemented across public health decision-making contexts., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)

The aim of this study was to observe after following a routine change in the feeding protocol whether the earlier introduction of nutrient supplements improved nutritional outcomes in moderately preterm to late preterm low birth weight (LBW) babies. In this prospective observational study, LBW babies between 31 and 39 weeks' gestation admitted to a Special Care Nursery were assigned to two groups (F80, n = 45, F160, n = 42) upon commencing nutrient supplement at total fluid intake achievement of 80 or 160 mL/kg/day. Outcomes included weight, protein intake, biochemical markers, feeding intolerance, and length of stay (LOS). F80 nutrient supplements commenced before F160 (2.8 vs. 6.7 days, p < 0.0001) and lasted longer (15.2 vs. 12.2 days, p < 0.03). Weight gain velocity and LOS were similar. F80 mean protein intake during the first 10 days was higher (3.38 vs. 2.74 g/kg/day, p < 0.0001). There were fewer infants with protein intake <3 g/kg/day in the F80 group (8% vs. 65%, p < 0001). F80 babies regained birthweight almost two days earlier (7.5 vs. 9.4 days, p < 0.01). Weight gain Z-scores revealed an attenuation of the trend towards lower weight percentiles in the F80 group. Feeding intolerance was decreased for F80 (24.4% vs. 47.6%, p < 0.03). There were no adverse outcomes. Earlier nutrient supplementation for LBW babies lifts mean protein intake to above 3 g/kg/day and reduces both the duration of post-birth weight loss and incidence of feeding intolerance.

Prescription opioid misuse is an ongoing and escalating epidemic. Although these pharmacological agents are highly effective analgesics prescribed for different types of pain, opioids also induce euphoria, leading to increasing diversion and misuse. Opioid use and related mortalities have developed in spite of initial claims that OxyContin, one of the first opioids prescribed in the USA, was not addictive in the presence of pain. These claims allayed the fears of clinicians and contributed to an increase in the number of prescriptions, quantity of drugs manufactured, and the unforeseen diversion of these drugs for non-medical uses. Understanding the history of opioid drug development, the widespread marketing campaign for opioids, the immense financial incentive behind the treatment of pain, and vulnerable socioeconomic and physical demographics for opioid misuse give perspective on the current epidemic as an American-born problem that has expanded to global significance. In light of the current worldwide opioid epidemic, it is imperative that novel opioids are developed to treat pain without inducing the euphoria that fosters physical dependence and addiction. We describe insights from preclinical findings on the properties of opioid drugs that offer insights into improving abuse-deterrent formulations. One finding is that the ability of some agonists to activate one pathway over another, or agonist bias, can predict whether several novel opioid compounds bear promise in treating pain without causing reward among other off-target effects. In addition, we outline how the pharmacokinetic profile of each opioid contributes to their potential for misuse and discuss the emergence of mixed agonists as a promising pipeline of opioid-based analgesics. These insights from preclinical findings can be used to more effectively identify opioids that treat pain without causing physical dependence and subsequent opioid abuse.

Information and Communication Technologies (ICTs) are increasingly recognized for their potential contributions to health service delivery in Low-and Middle-Income Countries (LMICs). As well as playing a role in improving the provision of health services under everyday 'normal' circumstances, ICTs can also be important in preparing for, mitigating, responding to and recovering from disasters. This research explores the use of ICTs in a natural disaster situation in Nepal, a country affected by a series of strong earthquakes in 2015. In March and April 2016, in-depth semi-structured interviews (n = 24) and focus group discussions (n = 4) were conducted with key informants: those affected by the earthquake, and those forming part of the formal or informal health system responses. Data were collected and analysed across three levels, from the bottom 'upwards', namely: (1) village level; (2) district level and (3) central/national level. Perceptions of the role and value of ICTs varied greatly-as did patterns of use. While access and capability were found to be key barriers to use rurally, ICTs were nevertheless an important part of the informal response, helping people to gather information, express needs and cope emotionally. They also helped relief agencies in allowing for networking and coordination among actors. Use of ICTs in the formal health system response, however, was severely lacking in many areas, relying more on traditional methods of disaster management. This reflects a general deficiency in, and underuse of, ICTs in the pre-earthquake Nepali healthcare system. We conclude by calling for a redoubling of efforts to improve and increase the adoption, diffusion, integration and regular use of ICTs within the Nepali health system-an approach that will assist with day-to-day service delivery but also provide a crucial platform upon which to build during future crises., (© The Author 2017. Published by Oxford University Press in association with The London School of Hygiene and Tropical Medicine. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

In many perennial fruit trees, flowering in the year following a year with heavy fruit load can be quite limited. This biennial cycle of fruiting, termed alternate bearing, was described 170 years ago in apple (Malus domestica). Apple inflorescences are mainly found on short branches (spurs). Bourse shoots (BS) develop from the leaf axils of the spur. BS apices may terminate ~100 days after flowering, with formation of next year's inflorescences. We sought to determine how developing fruit on the spur prevents the adjacent BS apex from forming an inflorescence. The presence of adjacent fruit correlated with reaccumulation of transcript encoding a potential flowering inhibitor, MdTFL1-2, in BS apices prior to inflorescence initiation. BS apices without adjacent fruit that did not flower due to late fruitlet removal, neighbouring fruit on the tree, or leaf removal, also reaccumulated the MdTFL1-2 transcript. Fruit load and gibberellin (GA) application had similar effects on the expression of MdTFL1-2 and genes involved in GA biosynthesis and metabolism. Some apple cultivars are less prone to alternate bearing. We show that the response of a BS apex to different numbers of adjacent fruit differs among cultivars in both MdTFL1-2 accumulation and return flowering. These results provide a working model for the further study of alternate bearing, and help clarify the need for cultivar-specific approaches to reach stable fruit production., (© 2016 The Authors The Plant Journal © 2016 John Wiley & Sons Ltd.)

Grapevine bud fruitfulness is determined by the differentiation of uncommitted meristem (UCM) into either tendril or inflorescence. Since tendril and inflorescence differentiation have long been considered sequential steps in inflorescence development, factors that control the progression of floral meristem development may regulate the final outcome of UCM differentiation, and thus affect fruitfulness. A comparison of the expression profiles of the master regulators of floral meristem identity (FMI) during development of fruitful and non-fruitful buds along the same cane allowed associating the expression of a homolog of terminal flower 1 (TFL1, a negative regulator of FMI) to fruitful buds, and the expression of positive FMI regulators to non-fruitful buds. Combined with (a) cytokinin-induced upregulation of VvTFL1A expression in cultured tendrils, which accompanied cytokinin-derived tendril transformation into branched, inflorescence-like structures, (b) positive regulation of VvTFL1A expression by cytokinin, which was demonstrated in transgenic embryonic culture expressing GUS reporter under the control of VvTFL1A promoter, and (c) a significantly higher level of active cytokinins in fruitful positions, the data may support the assumption of cytokinin-regulated VvTFL1A activity's involvement in the control of inflorescence development. Such activity may delay acquisition of FMI and allow an extended branching period for the UCM, resulting in the differentiation of inflorescence primordia.

The detection of genes having similar expression profiles following the application of different stimuli that trigger bud break may constitute potent tools for the identification of pathways with a central role in dormancy release. We compared the effects of heat shock (HS) and hydrogen cyanamide (HC) and demonstrated that HS leads to earlier and higher bud-break levels. Changes in transcript levels of catalase, alcohol dehydrogenase and pyruvate decarboxylase were induced following both treatments. However, timing and extent of changes in transcript level differed. Changes occurred earlier in HS-treated buds and were more intense in HC-treated buds. The changes in transcript levels after both treatments were temporary. The rapid and short-lasting changes in gene expression following HS treatment correlated with the faster and higher level of bud-break that this treatment exerted. This correlation may propose that the reported molecular events are mechanistically involved in dormancy release. To test the hypothesis that temporary oxidative stress is part of the mechanism inducing dormancy release, we analyzed the effect of HS and HC treatments on the expression of ascorbate peroxidase, glutathione reductase, thioredoxin h, glutathione S-transferase and sucrose synthase genes and found that they were induced by both treatments in a similar pattern. Taken together, these findings propose that similar cellular processes might be triggered by different stimuli that lead to dormancy release, and are consistent with the hypothesis that temporary oxidative stress and respiratory stress might be part of the mechanism that leads to bud break.

Artificial induction of grape bud dormancy release by hydrogen cyanamide (HC) serves as a reliable model system to explore the events occurring shortly after the induction of dormancy release. Recently, a group of genes with remarkable differences in expression level between HC-treated and control buds was identified. The identification of several calcium signalling-related genes within that group raised the hypothesis of the involvement of Ca(2+) signalling in grape bud dormancy release. Therefore, the effects of HC treatment on the expression profiles of several calcium sensors, the effect of the plasma membrane calcium channel blocker LaCl(3) and the calcium chelator EGTA on HC-induced and chilling-induced bud-break, and the effect of HC application on calcium-dependent protein phosphorylation activities in the bud tissue were studied. Here the HC-induced expression of Ca(2+)-ATPase is described, indicating that this treatment might evoke an increase in [Ca(2+)]cyt. Similar induction was confirmed for calmodulin, calmodulin-binding protein, and calcium-dependent protein kinase (CDPK). Both LaCl(3) and EGTA blocked the inducing effect of HC on bud-break, and their inhibitory effects were removed by supplying exogenous Ca(2+). Calcium-dependent histone phosphorylation was up to 70% higher in HC-treated buds. Endogenous protein phosphorylation assays detected four proteins exhibiting increased phosphorylation following HC treatment, of which two were phosphorylated in a calcium-dependent manner. One of these, a 47 kDa protein, presented strong and Ca(2+)-dependent phosphorylation only in HC-treated buds. The potential role of CDPK in the phosphorylation of this protein was supported by an immunoprecipitation assay. The data suggest, for the first time, that calcium signalling is involved in the mechanism of bud dormancy release.