A meta-ethnography of how children and young people with chronic non-cancer pain and their families experience and understand their condition, pain services, and treatments.

Chronic non-cancer pain in childhood is widespread, affecting 20% to 35% of children and young people worldwide. For a sizeable number of children, chronic non-cancer pain has considerable negative impacts on their lives and quality of life, and leads to increased use of healthcare services and medication. In many countries, there are few services for managing children's chronic non-cancer pain, with many services being inadequate. Fourteen Cochrane Reviews assessing the effects of pharmacological, psychological, psychosocial, dietary or physical activity interventions for managing children's chronic non-cancer pain identified a lack of high-quality evidence to inform pain management. To design and deliver services and interventions that meet the needs of patients and their families, we need to understand how children with chronic non-cancer pain and their families experience pain, their views of services and treatments for chronic pain, and which outcomes are important to them. 1. To synthesise qualitative studies that examine the experiences and perceptions of children with chronic non-cancer pain and their families regarding chronic non-cancer pain, treatments and services to inform the design and delivery of health and social care services, interventions and future research. 2. To explore whether our review findings help to explain the results of Cochrane Reviews of intervention effects of treatments for children's chronic non-cancer pain. 3. To determine if programme theories and outcomes of interventions match children and their families' views of desired treatments and outcomes. 4. To use our findings to inform the selection and design of patient-reported outcome measures for use in chronic non-cancer pain studies and interventions and care provision to children and their families. The review questions are: 1. How do children with chronic non-cancer pain and their families conceptualise chronic pain? 2. How do children with chronic non-cancer pain and their families live with chronic pain? 3. What do children with chronic non-cancer pain and their families think of how health and social care services respond to and manage their child's chronic pain? 4. What do children with chronic non-cancer pain and their families conceptualise as 'good' chronic pain management and what do they want to achieve from chronic pain management interventions and services? Review strategy: we comprehensively searched 12 bibliographic databases including MEDLINE, CINAHL, PsycInfo and grey literature sources, and conducted supplementary searches in 2020. We updated the database searches in September 2022. To identify published and unpublished qualitative research with children aged 3 months to 18 years with chronic non-cancer pain and their families focusing on their perceptions, experiences and views of chronic pain, services and treatments. The final inclusion criteria were agreed with a patient and public involvement group of children and young people with chronic non-cancer pain and their families. We conducted a qualitative evidence synthesis using meta-ethnography, a seven-phase, systematic, interpretive, inductive methodology that takes into account the contexts and meanings of the original studies. We assessed the richness of eligible studies and purposively sampled rich studies ensuring they addressed the review questions. Cochrane Qualitative Methods Implementation Group guidance guided sampling. We assessed the methodological limitations of studies using the Critical Appraisal Skills Programme tool. We extracted data on study aims, focus, characteristics and conceptual findings from study reports using NVivo software. We compared these study data to determine how the studies related to one another and grouped studies by pain conditions for synthesis. We used meta-ethnography to synthesise each group of studies separately before synthesising them all together. Analysis and interpretation of studies involved children with chronic non-cancer pain and their families and has resulted in theory to inform service design and delivery. Sampling, organising studies for synthesis, and analysis and interpretation involved our patient and public involvement group who contributed throughout the conduct of the review. We used the GRADE-CERQual (Confidence in the Evidence from Reviews of Qualitative research) approach to assess our confidence in each review finding. We used a matrix approach to integrate our findings with existing Cochrane Reviews on treatment effectiveness for children's chronic non-cancer pain. We synthesised 43 studies sampled from 170 eligible studies reported in 182 publications. Included studies involved 633 participants. GRADE-CERQual assessments of findings were mostly high (n = 21, 58%) or moderate (n = 12, 33%) confidence with three (8%) low or very low confidence. Poorly managed, moderate or severe chronic non-cancer pain had profound adverse impacts on family dynamics and relationships; family members' emotions, well-being, autonomy and sense of self-identity; parenting strategies; friendships and socialising; children's education and future employment prospects; and parental employment. Most children and parents understood chronic non-cancer pain as having an underlying biological cause and wanted curative treatment. However, families had difficulties seeking and obtaining support from health services to manage their child's pain and its impacts. Children and parents felt that healthcare professionals did not always listen to their experiences and expertise, or believe the child's pain. Some families repeatedly visited health services seeking a diagnosis and cure. Over time, some children and families gave up hope of effective treatment. Outcomes measured within trials and Cochrane Reviews of intervention effects did not include some outcomes of importance to children and families, including impacts of pain on the whole family and absence of pain. Cochrane Reviews have mainly neglected a holistic biopsychosocial approach, which specifies the interrelatedness of biological, psychological and social aspects of illness, when selecting outcome measures and considering how chronic pain management interventions work. We had high or moderate confidence in the evidence contributing to most review findings. Further research, especially into families' experiences of treatments and services, could strengthen the evidence for low or very low confidence findings. Future research should also explore families' experiences in low- to middle-income contexts; of pain treatments including opioid use in children, which remains controversial; and of social care services. We need development and testing of family-centred interventions and services acceptable to families. Future trials of children's chronic non-cancer pain interventions should include family-centred outcomes.

France E ，Uny I ，Turley R ，Thomson K ，Noyes J ，Jordan A ，Forbat L ，Caes L ，Silveira Bianchim M ... -  《Cochrane Database of Systematic Reviews》

Understanding how children and young people with chronic non-cancer pain and their families experience living with pain, pain management and services: a meta-ethnography.

Silveira Bianchim M ，Caes L ，Forbat L ，Jordan A ，Noyes J ，Thomson K ，Turley R ，Uny I ，France EF ... -  《-》

Folic acid supplementation and malaria susceptibility and severity among people taking antifolate antimalarial drugs in endemic areas.

Description of the condition Malaria, an infectious disease transmitted by the bite of female mosquitoes from several Anopheles species, occurs in 87 countries with ongoing transmission (WHO 2020). The World Health Organization (WHO) estimated that, in 2019, approximately 229 million cases of malaria occurred worldwide, with 94% occurring in the WHO's African region (WHO 2020). Of these malaria cases, an estimated 409,000 deaths occurred globally, with 67% occurring in children under five years of age (WHO 2020). Malaria also negatively impacts the health of women during pregnancy, childbirth, and the postnatal period (WHO 2020). Sulfadoxine/pyrimethamine (SP), an antifolate antimalarial, has been widely used across sub-Saharan Africa as the first-line treatment for uncomplicated malaria since it was first introduced in Malawi in 1993 (Filler 2006). Due to increasing resistance to SP, in 2000 the WHO recommended that one of several artemisinin-based combination therapies (ACTs) be used instead of SP for the treatment of uncomplicated malaria caused by Plasmodium falciparum (Global Partnership to Roll Back Malaria 2001). However, despite these recommendations, SP continues to be advised for intermittent preventive treatment in pregnancy (IPTp) and intermittent preventive treatment in infants (IPTi), whether the person has malaria or not (WHO 2013). Description of the intervention Folate (vitamin B9) includes both naturally occurring folates and folic acid, the fully oxidized monoglutamic form of the vitamin, used in dietary supplements and fortified food. Folate deficiency (e.g. red blood cell (RBC) folate concentrations of less than 305 nanomoles per litre (nmol/L); serum or plasma concentrations of less than 7 nmol/L) is common in many parts of the world and often presents as megaloblastic anaemia, resulting from inadequate intake, increased requirements, reduced absorption, or abnormal metabolism of folate (Bailey 2015; WHO 2015a). Pregnant women have greater folate requirements; inadequate folate intake (evidenced by RBC folate concentrations of less than 400 nanograms per millilitre (ng/mL), or 906 nmol/L) prior to and during the first month of pregnancy increases the risk of neural tube defects, preterm delivery, low birthweight, and fetal growth restriction (Bourassa 2019). The WHO recommends that all women who are trying to conceive consume 400 micrograms (µg) of folic acid daily from the time they begin trying to conceive through to 12 weeks of gestation (WHO 2017). In 2015, the WHO added the dosage of 0.4 mg of folic acid to the essential drug list (WHO 2015c). Alongside daily oral iron (30 mg to 60 mg elemental iron), folic acid supplementation is recommended for pregnant women to prevent neural tube defects, maternal anaemia, puerperal sepsis, low birthweight, and preterm birth in settings where anaemia in pregnant women is a severe public health problem (i.e. where at least 40% of pregnant women have a blood haemoglobin (Hb) concentration of less than 110 g/L). How the intervention might work Potential interactions between folate status and malaria infection The malaria parasite requires folate for survival and growth; this has led to the hypothesis that folate status may influence malaria risk and severity. In rhesus monkeys, folate deficiency has been found to be protective against Plasmodium cynomolgi malaria infection, compared to folate-replete animals (Metz 2007). Alternatively, malaria may induce or exacerbate folate deficiency due to increased folate utilization from haemolysis and fever. Further, folate status measured via RBC folate is not an appropriate biomarker of folate status in malaria-infected individuals since RBC folate values in these individuals are indicative of both the person's stores and the parasite's folate synthesis. A study in Nigeria found that children with malaria infection had significantly higher RBC folate concentrations compared to children without malaria infection, but plasma folate levels were similar (Bradley-Moore 1985). Why it is important to do this review The malaria parasite needs folate for survival and growth in humans. For individuals, adequate folate levels are critical for health and well-being, and for the prevention of anaemia and neural tube defects. Many countries rely on folic acid supplementation to ensure adequate folate status in at-risk populations. Different formulations for folic acid supplements are available in many international settings, with dosages ranging from 400 µg to 5 mg. Evaluating folic acid dosage levels used in supplementation efforts may increase public health understanding of its potential impacts on malaria risk and severity and on treatment failures. Examining folic acid interactions with antifolate antimalarial medications and with malaria disease progression may help countries in malaria-endemic areas determine what are the most appropriate lower dose folic acid formulations for at-risk populations. The WHO has highlighted the limited evidence available and has indicated the need for further research on biomarkers of folate status, particularly interactions between RBC folate concentrations and tuberculosis, human immunodeficiency virus (HIV), and antifolate antimalarial drugs (WHO 2015b). An earlier Cochrane Review assessed the effects and safety of iron supplementation, with or without folic acid, in children living in hyperendemic or holoendemic malaria areas; it demonstrated that iron supplementation did not increase the risk of malaria, as indicated by fever and the presence of parasites in the blood (Neuberger 2016). Further, this review stated that folic acid may interfere with the efficacy of SP; however, the efficacy and safety of folic acid supplementation on these outcomes has not been established. This review will provide evidence on the effectiveness of daily folic acid supplementation in healthy and malaria-infected individuals living in malaria-endemic areas. Additionally, it will contribute to achieving both the WHO Global Technical Strategy for Malaria 2016-2030 (WHO 2015d), and United Nations Sustainable Development Goal 3 (to ensure healthy lives and to promote well-being for all of all ages) (United Nations 2021), and evaluating whether the potential effects of folic acid supplementation, at different doses (e.g. 0.4 mg, 1 mg, 5 mg daily), interferes with the effect of drugs used for prevention or treatment of malaria. To examine the effects of folic acid supplementation, at various doses, on malaria susceptibility (risk of infection) and severity among people living in areas with various degrees of malaria endemicity. We will examine the interaction between folic acid supplements and antifolate antimalarial drugs. Specifically, we will aim to answer the following. Among uninfected people living in malaria endemic areas, who are taking or not taking antifolate antimalarials for malaria prophylaxis, does taking a folic acid-containing supplement increase susceptibility to or severity of malaria infection? Among people with malaria infection who are being treated with antifolate antimalarials, does folic acid supplementation increase the risk of treatment failure? Criteria for considering studies for this review Types of studies Inclusion criteria Randomized controlled trials (RCTs) Quasi-RCTs with randomization at the individual or cluster level conducted in malaria-endemic areas (areas with ongoing, local malaria transmission, including areas approaching elimination, as listed in the World Malaria Report 2020) (WHO 2020) Exclusion criteria Ecological studies Observational studies In vivo/in vitro studies Economic studies Systematic literature reviews and meta-analyses (relevant systematic literature reviews and meta-analyses will be excluded but flagged for grey literature screening) Types of participants Inclusion criteria Individuals of any age or gender, living in a malaria endemic area, who are taking antifolate antimalarial medications (including but not limited to sulfadoxine/pyrimethamine (SP), pyrimethamine-dapsone, pyrimethamine, chloroquine and proguanil, cotrimoxazole) for the prevention or treatment of malaria (studies will be included if more than 70% of the participants live in malaria-endemic regions) Studies assessing participants with or without anaemia and with or without malaria parasitaemia at baseline will be included Exclusion criteria Individuals not taking antifolate antimalarial medications for prevention or treatment of malaria Individuals living in non-malaria endemic areas Types of interventions Inclusion criteria Folic acid supplementation Form: in tablet, capsule, dispersible tablet at any dose, during administration, or periodically Timing: during, before, or after (within a period of four to six weeks) administration of antifolate antimalarials Iron-folic acid supplementation Folic acid supplementation in combination with co-interventions that are identical between the intervention and control groups. Co-interventions include: anthelminthic treatment; multivitamin or multiple micronutrient supplementation; 5-methyltetrahydrofolate supplementation. Exclusion criteria Folate through folate-fortified water Folic acid administered through large-scale fortification of rice, wheat, or maize Comparators Placebo No treatment No folic acid/different doses of folic acid Iron Types of outcome measures Primary outcomes Uncomplicated malaria (defined as a history of fever with parasitological confirmation; acceptable parasitological confirmation will include rapid diagnostic tests (RDTs), malaria smears, or nucleic acid detection (i.e. polymerase chain reaction (PCR), loop-mediated isothermal amplification (LAMP), etc.)) (WHO 2010). This outcome is relevant for patients without malaria, given antifolate antimalarials for malaria prophylaxis. Severe malaria (defined as any case with cerebral malaria or acute P. falciparum malaria, with signs of severity or evidence of vital organ dysfunction, or both) (WHO 2010). This outcome is relevant for patients without malaria, given antifolate antimalarials for malaria prophylaxis. Parasite clearance (any Plasmodium species), defined as the time it takes for a patient who tests positive at enrolment and is treated to become smear-negative or PCR negative. This outcome is relevant for patients with malaria, treated with antifolate antimalarials. Treatment failure (defined as the inability to clear malaria parasitaemia or prevent recrudescence after administration of antimalarial medicine, regardless of whether clinical symptoms are resolved) (WHO 2019). This outcome is relevant for patients with malaria, treated with antifolate antimalarials. Secondary outcomes Duration of parasitaemia Parasite density Haemoglobin (Hb) concentrations (g/L) Anaemia: severe anaemia (defined as Hb less than 70 g/L in pregnant women and children aged six to 59 months; and Hb less than 80 g/L in other populations); moderate anaemia (defined as Hb less than 100 g/L in pregnant women and children aged six to 59 months; and less than 110 g/L in others) Death from any cause Among pregnant women: stillbirth (at less than 28 weeks gestation); low birthweight (less than 2500 g); active placental malaria (defined as Plasmodium detected in placental blood by smear or PCR, or by Plasmodium detected on impression smear or placental histology). Search methods for identification of studies A search will be conducted to identify completed and ongoing studies, without date or language restrictions. Electronic searches A search strategy will be designed to include the appropriate subject headings and text word terms related to each intervention of interest and study design of interest (see Appendix 1). Searches will be broken down by these two criteria (intervention of interest and study design of interest) to allow for ease of prioritization, if necessary. The study design filters recommended by the Scottish Intercollegiate Guidelines Network (SIGN), and those designed by Cochrane for identifying clinical trials for MEDLINE and Embase, will be used (SIGN 2020). There will be no date or language restrictions. Non-English articles identified for inclusion will be translated into English. If translations are not possible, advice will be requested from the Cochrane Infectious Diseases Group and the record will be stored in the "Awaiting assessment" section of the review until a translation is available. The following electronic databases will be searched for primary studies. Cochrane Central Register of Controlled Trials. Cumulative Index to Nursing and Allied Health Literature (CINAHL). Embase. MEDLINE. Scopus. Web of Science (both the Social Science Citation Index and the Science Citation Index). We will conduct manual searches of ClinicalTrials.gov, the International Clinical Trials Registry Platform (ICTRP), and the United Nations Children's Fund (UNICEF) Evaluation and Research Database (ERD), in order to identify relevant ongoing or planned trials, abstracts, and full-text reports of evaluations, studies, and surveys related to programmes on folic acid supplementation in malaria-endemic areas. Additionally, manual searches of grey literature to identify RCTs that have not yet been published but are potentially eligible for inclusion will be conducted in the following sources. Global Index Medicus (GIM). African Index Medicus (AIM). Index Medicus for the Eastern Mediterranean Region (IMEMR). Latin American & Caribbean Health Sciences Literature (LILACS). Pan American Health Organization (PAHO). Western Pacific Region Index Medicus (WPRO). Index Medicus for the South-East Asian Region (IMSEAR). The Spanish Bibliographic Index in Health Sciences (IBECS) (ibecs.isciii.es/). Indian Journal of Medical Research (IJMR) (journals.lww.com/ijmr/pages/default.aspx). Native Health Database (nativehealthdatabase.net/). Scielo (www.scielo.br/). Searching other resources Handsearches of the five journals with the highest number of included studies in the last 12 months will be conducted to capture any relevant articles that may not have been indexed in the databases at the time of the search. We will contact the authors of included studies and will check reference lists of included papers for the identification of additional records. For assistance in identifying ongoing or unpublished studies, we will contact the Division of Nutrition, Physical Activity, and Obesity (DNPAO) and the Division of Parasitic Diseases and Malaria (DPDM) of the CDC, the United Nations World Food Programme (WFP), Nutrition International (NI), Global Alliance for Improved Nutrition (GAIN), and Hellen Keller International (HKI). Data collection and analysis Selection of studies Two review authors will independently screen the titles and abstracts of articles retrieved by each search to assess eligibility, as determined by the inclusion and exclusion criteria. Studies deemed eligible for inclusion by both review authors in the abstract screening phase will advance to the full-text screening phase, and full-text copies of all eligible papers will be retrieved. If full articles cannot be obtained, we will attempt to contact the authors to obtain further details of the studies. If such information is not obtained, we will classify the study as "awaiting assessment" until further information is published or made available to us. The same two review authors will independently assess the eligibility of full-text articles for inclusion in the systematic review. If any discrepancies occur between the studies selected by the two review authors, a third review author will provide arbitration. Each trial will be scrutinized to identify multiple publications from the same data set, and the justification for excluded trials will be documented. A PRISMA flow diagram of the study selection process will be presented to provide information on the number of records identified in the literature searches, the number of studies included and excluded, and the reasons for exclusion (Moher 2009). The list of excluded studies, along with their reasons for exclusion at the full-text screening phase, will also be created. Data extraction and management Two review authors will independently extract data for the final list of included studies using a standardized data specification form. Discrepancies observed between the data extracted by the two authors will be resolved by involving a third review author and reaching a consensus. Information will be extracted on study design components, baseline participant characteristics, intervention characteristics, and outcomes. For individually randomized trials, we will record the number of participants experiencing the event and the number analyzed in each treatment group or the effect estimate reported (e.g. risk ratio (RR)) for dichotomous outcome measures. For count data, we will record the number of events and the number of person-months of follow-up in each group. If the number of person-months is not reported, the product of the duration of follow-up and the number of children evaluated will be used to estimate this figure. We will calculate the rate ratio and standard error (SE) for each study. Zero events will be replaced by 0.5. We will extract both adjusted and unadjusted covariate incidence rate ratios if they are reported in the original studies. For continuous data, we will extract means (arithmetic or geometric) and a measure of variance (standard deviation (SD), SE, or confidence interval (CI)), percentage or mean change from baseline, and the numbers analyzed in each group. SDs will be computed from SEs or 95% CIs, assuming a normal distribution of the values. Haemoglobin values in g/dL will be calculated by multiplying haematocrit or packed cell volume values by 0.34, and studies reporting haemoglobin values in g/dL will be converted to g/L. In cluster-randomized trials, we will record the unit of randomization (e.g. household, compound, sector, or village), the number of clusters in the trial, and the average cluster size. The statistical methods used to analyze the trials will be documented, along with details describing whether these methods adjusted for clustering or other covariates. We plan to extract estimates of the intra-cluster correlation coefficient (ICC) for each outcome. Where results are adjusted for clustering, we will extract the treatment effect estimate and the SD or CI. If the results are not adjusted for clustering, we will extract the data reported. Assessment of risk of bias in included studies Two review authors (KSC, LFY) will independently assess the risk of bias for each included trial using the Cochrane 'Risk of bias 2' tool (RoB 2) for randomized studies (Sterne 2019). Judgements about the risk of bias of included studies will be made according to the recommendations outlined in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2021). Disagreements will be resolved by discussion, or by involving a third review author. The interest of our review will be to assess the effect of assignment to the interventions at baseline. We will evaluate each primary outcome using the RoB2 tool. The five domains of the Cochrane RoB2 tool include the following. Bias arising from the randomization process. Bias due to deviations from intended interventions. Bias due to missing outcome data. Bias in measurement of the outcome. Bias in selection of the reported result. Each domain of the RoB2 tool comprises the following. A series of 'signalling' questions. A judgement about the risk of bias for the domain, facilitated by an algorithm that maps responses to the signalling questions to a proposed judgement. Free-text boxes to justify responses to the signalling questions and 'Risk of bias' judgements. An option to predict (and explain) the likely direction of bias. Responses to signalling questions elicit information relevant to an assessment of the risk of bias. These response options are as follows. Yes (may indicate either low or high risk of bias, depending on the most natural way to ask the question). Probably yes. Probably no. No. No information (may indicate no evidence of that problem or an absence of information leading to concerns about there being a problem). Based on the answer to the signalling question, a 'Risk of bias' judgement is assigned to each domain. These judgements include one of the following. High risk of bias Low risk of bias Some concerns To generate the risk of bias judgement for each domain in the randomized studies, we will use the Excel template, available at www.riskofbias.info/welcome/rob-2-0-tool/current-version-of-rob-2. This file will be stored on a scientific data website, available to readers. Risk of bias in cluster randomized controlled trials For the cluster randomized trials, we will be using the RoB2 tool to analyze the five standard domains listed above along with Domain 1b (bias arising from the timing of identification or recruitment of participants) and its related signalling questions. To generate the risk of bias judgement for each domain in the cluster RCTs, we will use the Excel template available at https://sites.google.com/site/riskofbiastool/welcome/rob-2-0-tool/rob-2-for-cluster-randomized-trials. This file will be stored on a scientific data website, available to readers. Risk of bias in cross-over randomized controlled trials For cross-over randomized trials, we will be using the RoB2 tool to analyze the five standard domains listed above along with Domain 2 (bias due to deviations from intended interventions), and Domain 3 (bias due to missing outcome data), and their respective signalling questions. To generate the risk of bias judgement for each domain in the cross-over RCTs, we will use the Excel template, available at https://sites.google.com/site/riskofbiastool/welcome/rob-2-0-tool/rob-2-for-crossover-trials, for each risk of bias judgement of cross-over randomized studies. This file will be stored on a scientific data website, available to readers. Overall risk of bias The overall 'Risk of bias' judgement for each specific trial being assessed will be based on each domain-level judgement. The overall judgements include the following. Low risk of bias (the trial is judged to be at low risk of bias for all domains). Some concerns (the trial is judged to raise some concerns in at least one domain but is not judged to be at high risk of bias for any domain). High risk of bias (the trial is judged to be at high risk of bias in at least one domain, or is judged to have some concerns for multiple domains in a way that substantially lowers confidence in the result). The 'risk of bias' assessments will inform our GRADE evaluations of the certainty of evidence for our primary outcomes presented in the 'Summary of findings' tables and will also be used to inform the sensitivity analyses; (see Sensitivity analysis). If there is insufficient information in study reports to enable an assessment of the risk of bias, studies will be classified as "awaiting assessment" until further information is published or made available to us. Measures of treatment effect Dichotomous data For dichotomous data, we will present proportions and, for two-group comparisons, results as average RR or odds ratio (OR) with 95% CIs. Ordered categorical data Continuous data We will report results for continuous outcomes as the mean difference (MD) with 95% CIs, if outcomes are measured in the same way between trials. Where some studies have reported endpoint data and others have reported change-from-baseline data (with errors), we will combine these in the meta-analysis, if the outcomes were reported using the same scale. We will use the standardized mean difference (SMD), with 95% CIs, to combine trials that measured the same outcome but used different methods. If we do not find three or more studies for a pooled analysis, we will summarize the results in a narrative form. Unit of analysis issues Cluster-randomized trials We plan to combine results from both cluster-randomized and individually randomized studies, providing there is little heterogeneity between the studies. If the authors of cluster-randomized trials conducted their analyses at a different level from that of allocation, and they have not appropriately accounted for the cluster design in their analyses, we will calculate the trials' effective sample sizes to account for the effect of clustering in data. When one or more cluster-RCT reports RRs adjusted for clustering, we will compute cluster-adjusted SEs for the other trials. When none of the cluster-RCTs provide cluster-adjusted RRs, we will adjust the sample size for clustering. We will divide, by the estimated design effects (DE), the number of events and number evaluated for dichotomous outcomes and the number evaluated for continuous outcomes, where DE = 1 + ((average cluster size 1) * ICC). The derivation of the estimated ICCs and DEs will be reported. We will utilize the intra-cluster correlation coefficient (ICC), derived from the trial (if available), or from another source (e.g., using the ICCs derived from other, similar trials) and then calculate the design effect with the formula provided in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2021). If this approach is used, we will report it and undertake sensitivity analysis to investigate the effect of variations in ICC. Studies with more than two treatment groups If we identify studies with more than two intervention groups (multi-arm studies), where possible we will combine groups to create a single pair-wise comparison or use the methods set out in the Cochrane Handbook to avoid double counting study participants (Higgins 2021). For the subgroup analyses, when the control group was shared by two or more study arms, we will divide the control group (events and total population) over the number of relevant subgroups to avoid double counting the participants. Trials with several study arms can be included more than once for different comparisons. Cross-over trials From cross-over trials, we will consider the first period of measurement only and will analyze the results together with parallel-group studies. Multiple outcome events In several outcomes, a participant might experience more than one outcome event during the trial period. For all outcomes, we will extract the number of participants with at least one event. Dealing with missing data We will contact the trial authors if the available data are unclear, missing, or reported in a format that is different from the format needed. We aim to perform a 'per protocol' or 'as observed' analysis; otherwise, we will perform a complete case analysis. This means that for treatment failure, we will base the analyses on the participants who received treatment and the number of participants for which there was an inability to clear malarial parasitaemia or prevent recrudescence after administration of an antimalarial medicine reported in the studies. Assessment of heterogeneity Heterogeneity in the results of the trials will be assessed by visually examining the forest plot to detect non-overlapping CIs, using the Chi2 test of heterogeneity (where a P value of less than 0.1 indicates statistical significance) and the I2 statistic of inconsistency (with a value of greater than 50% denoting moderate levels of heterogeneity). When statistical heterogeneity is present, we will investigate the reasons for it, using subgroup analysis. Assessment of reporting biases We will construct a funnel plot to assess the effect of small studies for the main outcome (when including more than 10 trials). Data synthesis The primary analysis will include all eligible studies that provide data regardless of the overall risk of bias as assessed by the RoB2 tool. Analyses will be conducted using Review Manager 5.4 (Review Manager 2020). Cluster-RCTs will be included in the main analysis after adjustment for clustering (see the previous section on cluster-RCTs). The meta-analysis will be performed using the Mantel-Haenszel random-effects model or the generic inverse variance method (when adjustment for clustering is performed by adjusting SEs), as appropriate. Subgroup analysis and investigation of heterogeneity The overall risk of bias will not be used as the basis in conducting our subgroup analyses. However, where data are available, we plan to conduct the following subgroup analyses, independent of heterogeneity. Dose of folic acid supplementation: higher doses (4 mg or more, daily) versus lower doses (less than 4 mg, daily). Moderate-severe anaemia at baseline (mean haemoglobin of participants in a trial at baseline below 100 g/L for pregnant women and children aged six to 59 months, and below 110 g/L for other populations) versus normal at baseline (mean haemoglobin above 100 g/L for pregnant women and children aged six to 59 months, and above 110 g/L for other populations). Antimalarial drug resistance to parasite: known resistance versus no resistance versus unknown/mixed/unreported parasite resistance. Folate status at baseline: Deficient (e.g. RBC folate concentration of less than 305 nmol/L, or serum folate concentration of less than 7nmol/L) and Insufficient (e.g. RBC folate concentration from 305 to less than 906 nmol/L, or serum folate concentration from 7 to less than 25 nmol/L) versus Sufficient (e.g. RBC folate concentration above 906 nmol/L, or serum folate concentration above 25 nmol/L). Presence of anaemia at baseline: yes versus no. Mandatory fortification status: yes, versus no (voluntary or none). We will only use the primary outcomes in any subgroup analyses, and we will limit subgroup analyses to those outcomes for which three or more trials contributed data. Comparisons between subgroups will be performed using Review Manager 5.4 (Review Manager 2020). Sensitivity analysis We will perform a sensitivity analysis, using the risk of bias as a variable to explore the robustness of the findings in our primary outcomes. We will verify the behaviour of our estimators by adding and removing studies with a high risk of bias overall from the analysis. That is, studies with a low risk of bias versus studies with a high risk of bias. Summary of findings and assessment of the certainty of the evidence For the assessment across studies, we will use the GRADE approach, as outlined in (Schünemann 2021). We will use the five GRADE considerations (study limitations based on RoB2 judgements, consistency of effect, imprecision, indirectness, and publication bias) to assess the certainty of the body of evidence as it relates to the studies which contribute data to the meta-analyses for the primary outcomes. The GRADEpro Guideline Development Tool (GRADEpro) will be used to import data from Review Manager 5.4 (Review Manager 2020) to create 'Summary of Findings' tables. The primary outcomes for the main comparison will be listed with estimates of relative effects, along with the number of participants and studies contributing data for those outcomes. These tables will provide outcome-specific information concerning the overall certainty of evidence from studies included in the comparison, the magnitude of the effect of the interventions examined, and the sum of available data on the outcomes we considered. We will include only primary outcomes in the summary of findings tables. For each individual outcome, two review authors (KSC, LFY) will independently assess the certainty of the evidence using the GRADE approach (Balshem 2011). For assessments of the overall certainty of evidence for each outcome that includes pooled data from included trials, we will downgrade the evidence from 'high certainty' by one level for serious (or by two for very serious) study limitations (risk of bias, indirectness of evidence, serious inconsistency, imprecision of effect estimates, or potential publication bias).

Crider K ，Williams J ，Qi YP ，Gutman J ，Yeung L ，Mai C ，Finkelstain J ，Mehta S ，Pons-Duran C ，Menéndez C ，Moraleda C ，Rogers L ，Daniels K ，Green P ... -  《Cochrane Database of Systematic Reviews》

Beyond the black stump: rapid reviews of health research issues affecting regional, rural and remote Australia.

CHAPTER 1: RETAIL INITIATIVES TO IMPROVE THE HEALTHINESS OF FOOD ENVIRONMENTS IN RURAL, REGIONAL AND REMOTE COMMUNITIES: Objective: To synthesise the evidence for effectiveness of initiatives aimed at improving food retail environments and consumer dietary behaviour in rural, regional and remote populations in Australia and comparable countries, and to discuss the implications for future food environment initiatives for rural, regional and remote areas of Australia. Rapid review of articles published between January 2000 and May 2020. We searched MEDLINE (EBSCOhost), Health and Society Database (Informit) and Rural and Remote Health Database (Informit), and included studies undertaken in rural food environment settings in Australia and other countries. Twenty-one articles met the inclusion criteria, including five conducted in Australia. Four of the Australian studies were conducted in very remote populations and in grocery stores, and one was conducted in regional Australia. All of the overseas studies were conducted in rural North America. All of them revealed a positive influence on food environment or consumer behaviour, and all were conducted in disadvantaged, rural communities. Positive outcomes were consistently revealed by studies of initiatives that focused on promotion and awareness of healthy foods and included co-design to generate community ownership and branding. Initiatives aimed at improving rural food retail environments were effective and, when implemented in different rural settings, may encourage improvements in population diets. The paucity of studies over the past 20 years in Australia shows a need for more research into effective food retail environment initiatives, modelled on examples from overseas, with studies needed across all levels of remoteness in Australia. Several retail initiatives that were undertaken in rural North America could be replicated in rural Australia and could underpin future research. CHAPTER 2: WHICH INTERVENTIONS BEST SUPPORT THE HEALTH AND WELLBEING NEEDS OF RURAL POPULATIONS EXPERIENCING NATURAL DISASTERS?: Objective: To explore and evaluate health and social care interventions delivered to rural and remote communities experiencing natural disasters in Australia and other high income countries. We used systematic rapid review methods. First we identified a test set of citations and generated a frequency table of Medical Subject Headings (MeSH) to index articles. Then we used combinations of MeSH terms and keywords to search the MEDLINE (Ovid) database, and screened the titles and abstracts of the retrieved references. We identified 1438 articles via database searches, and a further 62 articles via hand searching of key journals and reference lists. We also found four relevant grey literature resources. After removing duplicates and undertaking two stages of screening, we included 28 studies in a synthesis of qualitative evidence. Four of us read and assessed the full text articles. We then conducted a thematic analysis using the three phases of the natural disaster response cycle. There is a lack of robust evaluation of programs and interventions supporting the health and wellbeing of people in rural communities affected by natural disasters. To address the cumulative and long term impacts, evidence suggests that continuous support of people's health and wellbeing is needed. By using a lens of rural adversity, the complexity of the lived experience of natural disasters by rural residents can be better understood and can inform development of new models of community-based and integrated care services. CHAPTER 3: THE IMPACT OF BUSHFIRE ON THE WELLBEING OF CHILDREN LIVING IN RURAL AND REMOTE AUSTRALIA: Objective: To investigate the impact of bushfire events on the wellbeing of children living in rural and remote Australia. Literature review completed using rapid realist review methods, and taking into consideration the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) statement for systematic reviews. We sourced data from six databases: EBSCOhost (Education), EBSCOhost (Health), EBSCOhost (Psychology), Informit, MEDLINE and PsycINFO. We developed search terms to identify articles that could address the research question based on the inclusion criteria of peer reviewed full text journal articles published in English between 1983 and 2020. We initially identified 60 studies and, following closer review, extracted data from eight studies that met the inclusion criteria. Children exposed to bushfires may be at increased risk of poorer wellbeing outcomes. Findings suggest that the impact of bushfire exposure may not be apparent in the short term but may become more pronounced later in life. Children particularly at risk are those from more vulnerable backgrounds who may have compounding factors that limit their ability to overcome bushfire trauma. We identified the short, medium and long term impacts of bushfire exposure on the wellbeing of children in Australia. We did not identify any evidence-based interventions for supporting outcomes for this population. Given the likely increase in bushfire events in Australia, research into effective interventions should be a priority. CHAPTER 4: THE ROLE OF NATIONAL POLICIES TO ADDRESS RURAL ALLIED HEALTH, NURSING AND DENTISTRY WORKFORCE MALDISTRIBUTION: Objective: Maldistribution of the health workforce between rural, remote and metropolitan communities contributes to longstanding health inequalities. Many developed countries have implemented policies to encourage health care professionals to work in rural and remote communities. This scoping review is an international synthesis of those policies, examining their effectiveness at recruiting and retaining nursing, dental and allied health professionals in rural communities. Using scoping review methods, we included primary research - published between 1 September 2009 and 30 June 2020 - that reported an evaluation of existing policy initiatives to address workforce maldistribution in high income countries with a land mass greater than 100 000 km . We searched MEDLINE, Ovid Embase, Ovid Emcare, Informit, Scopus, and Web of Science. We screened 5169 articles for inclusion by title and abstract, of which we included 297 for full text screening. We then extracted data on 51 studies that had been conducted in Australia, the United States, Canada, United Kingdom and Norway. We grouped the studies based on World Health Organization recommendations on recruitment and retention of health care workers: education strategies (n = 27), regulatory change (n = 11), financial incentives (n = 6), personal and professional support (n = 4), and approaches with multiple components (n = 3). Considerable work has occurred to address workforce maldistribution at a local level, underpinned by good practice guidelines, but rarely at scale or with explicit links to coherent overarching policy. To achieve policy aspirations, multiple synergistic evidence-based initiatives are needed, and implementation must be accompanied by well designed longitudinal evaluations that assess the effectiveness of policy objectives. CHAPTER 5: AVAILABILITY AND CHARACTERISTICS OF PUBLICLY AVAILABLE HEALTH WORKFORCE DATA SOURCES IN AUSTRALIA: Objective: Many data sources are used in Australia to inform health workforce planning, but their characteristics in terms of relevance, accessibility and accuracy are uncertain. We aimed to identify and appraise publicly available data sources used to describe the Australian health workforce. We conducted a scoping review in which we searched bibliographic databases, websites and grey literature. Two reviewers independently undertook title and abstract screening and full text screening using Covidence software. We then assessed the relevance, accessibility and accuracy of data sources using a customised appraisal tool. We searched for potential workforce data sources in nine databases (MEDLINE, Embase, Ovid Emcare, Scopus, Web of Science, Informit, the JBI Evidence-based Practice Database, PsycINFO and the Cochrane Library) and the grey literature, and examined several pre-defined websites. During the screening process we identified 6955 abstracts and examined 48 websites, from which we identified 12 publicly available data sources - eight primary and four secondary data sources. The primary data sources were generally of modest quality, with low scores in terms of reference period, accessibility and missing data. No single primary data source scored well across all domains of the appraisal tool. We identified several limitations of data sources used to describe the Australian health workforce. Establishment of a high quality, longitudinal, linked database that can inform all aspects of health workforce development is urgently needed, particularly for rural health workforce and services planning. CHAPTER 6: RAPID REALIST REVIEW OF OPIOID TAPERING IN THE CONTEXT OF LONG TERM OPIOID USE FOR NON-CANCER PAIN IN RURAL AREAS: Objective: To describe interventions, barriers and enablers associated with opioid tapering for patients with chronic non-cancer pain in rural primary care settings. Rapid realist review registered on the international register of systematic reviews (PROSPERO) and conducted in accordance with RAMESES standards. English language, peer-reviewed articles reporting qualitative, quantitative and mixed method studies, published between January 2016 and July 2020, and accessed via MEDLINE, Embase, CINAHL Complete, PsycINFO, Informit or the Cochrane Library during June and July 2020. Grey literature relating to prescribing, deprescribing or tapering of opioids in chronic non-cancer pain, published between January 2016 and July 2020, was identified by searching national and international government, health service and peek organisation websites using Google Scholar. Our analysis of reported approaches to tapering conducted across rural and non-rural contexts showed that tapering opioids is complex and challenging, and identified several barriers and enablers. Successful outcomes in rural areas appear likely through therapeutic relationships, coordination and support, by using modalities and models of care that are appropriate in rural settings and by paying attention to harm minimisation. Rural primary care providers do not have access to resources available in metropolitan centres for dealing with patients who have chronic non-cancer pain and are taking opioid medications. They often operate alone or in small group practices, without peer support and access to multidisciplinary and specialist teams. Opioid tapering approaches described in the literature include regulation, multimodal and multidisciplinary approaches, primary care provider support, guidelines, and patient-centred strategies. There is little research to inform tapering in rural contexts. Our review provides a synthesis of the current evidence in the form of a conceptual model. This preliminary model could inform the development of a model of care for use in implementation research, which could test a variety of mechanisms for supporting decision making, reducing primary care providers' concerns about potential harms arising from opioid tapering, and improving patient outcomes.

Osborne SR ，Alston LV ，Bolton KA ，Whelan J ，Reeve E ，Wong Shee A ，Browne J ，Walker T ，Versace VL ，Allender S ，Nichols M ，Backholer K ，Goodwin N ，Lewis S ，Dalton H ，Prael G ，Curtin M ，Brooks R ，Verdon S ，Crockett J ，Hodgins G ，Walsh S ，Lyle DM ，Thompson SC ，Browne LJ ，Knight S ，Pit SW ，Jones M ，Gillam MH ，Leach MJ ，Gonzalez-Chica DA ，Muyambi K ，Eshetie T ，Tran K ，May E ，Lieschke G ，Parker V ，Smith A ，Hayes C ，Dunlop AJ ，Rajappa H ，White R ，Oakley P ，Holliday S ... -  《-》

Survivor, family and professional experiences of psychosocial interventions for sexual abuse and violence: a qualitative evidence synthesis.

It is well-established that experiencing sexual abuse and violence can have a range of detrimental impacts; a wide variety of interventions exist to support survivors in the aftermath. Understanding the experiences and perspectives of survivors receiving such interventions, along with those of their family members, and the professionals who deliver them is important for informing decision making as to what to offer survivors, for developing new interventions, and enhancing their acceptability. This review sought to: 1. identify, appraise and synthesise qualitative studies exploring the experiences of child and adult survivors of sexual abuse and violence, and their caregivers, regarding psychosocial interventions aimed at supporting survivors and preventing negative health outcomes in terms of benefits, risks/harms and barriers; 2. identify, appraise and synthesise qualitative studies exploring the experiences of professionals who deliver psychosocial interventions for sexual abuse and violence in terms of perceived benefits, risks/harms and barriers for survivors and their families/caregivers; 3. develop a conceptual understanding of how different factors influence uptake, dropout or completion, and outcomes from psychosocial interventions for sexual abuse and violence; 4. develop a conceptual understanding of how features and types of interventions responded to the needs of different user/survivor groups (e.g. age groups; types of abuse exposure; migrant populations) and contexts (healthcare/therapeutic settings; low- and middle-income countries (LMICs)); 5. explore how the findings of this review can enhance our understanding of the findings from the linked and related reviews assessing the effectiveness of interventions aimed at supporting survivors and preventing negative health outcomes. In August 2021 we searched MEDLINE, Embase, PsycINFO and nine other databases. We also searched for unpublished reports and qualitative reports of quantitative studies in a linked systematic review, together with reference checking, citation searches and contacting authors and other researchers to identify relevant studies. We included qualitative and mixed-methods studies (with an identifiable qualitative component) that were linked to a psychosocial intervention aimed at supporting survivors of sexual abuse and violence. Eligible studies focused on at least one of three participant groups: survivors of any age, gender, sexuality, ethnicity or [dis]ability who had received a psychosocial intervention; their carers, family members or partners; and professionals delivering such interventions. We placed no restrictions in respect of settings, locations, intervention delivery formats or durations. Six review authors independently assessed the titles, abstracts and full texts identified. We extracted data using a form designed for this synthesis, then used this information and an appraisal of data richness and quality in order to stratify the studies using a maximum variation approach. We assessed the methodological limitations using the Critical Skills Appraisal Programme (CASP) tool. We coded directly onto the sampled papers using NVivo and synthesised data using a thematic synthesis methodology and used the GRADE-CERQual (Confidence in the Evidence from Reviews of Qualitative research) approach to assess our confidence in each finding. We used a narrative synthesis and matrix model to integrate our qualitative evidence synthesis (QES) findings with those of intervention review findings. We identified 97 eligible studies and sampled 37 of them for our analysis. Most sampled studies were from high-income countries, with four from middle-income and two from low-income countries. In 27 sampled studies, the participants were survivors, in three they were intervention facilitators. Two included all three of our stakeholder groups, and five included two of our groups. The studies explored a wide range of psychosocial interventions, with only one type of intervention explored in more than one study. The review indicates that features associated with the context in which interventions were delivered had an impact on how individuals accessed and experienced interventions. This included organisational features, such as staff turnover, that could influence survivors' engagement with interventions; the setting or location in which interventions were delivered; and the characteristics associated with who delivered the interventions. Studies that assess the effectiveness of interventions typically assess their impact on mental health; however, as well as finding benefits to mental health, our QES found that study participants felt interventions also had positive impacts on their physical health, mood, understanding of trauma, interpersonal relationships and enabled them to re-engage with a wide range of areas in their lives. Participants explained that features of interventions and their contexts that best enabled them to benefit from interventions were also often things that could be a barrier to benefiting from interventions. For example, the relationship with the therapist, when open and warm was a benefit, but if such a relationship could not be achieved, it was a barrier. Survivors' levels of readiness and preparedness to both start and end interventions could have positive (if they were ready) or negative (if they were not) impacts. Study participants identified the potential risks and harms associated with completing interventions but felt that it was important to face and process trauma. Some elements of interventions were specific to the intervention type (e.g. faith-based interventions), or related to an experience of an intervention that held particular relevance to subgroups of survivors (e.g. minority groups); these issues could impact how individuals experienced delivering or receiving interventions. We had high or moderate confidence in all but one of our review findings. Further research in low- and middle-income settings, with male survivors of sexual abuse and violence and those from minority groups could strengthen the evidence for low and moderate confidence findings. We found that few interventions had published quantitative and qualitative evaluations. Since this QES has highlighted important aspects that could enable interventions to be more suitable for survivors, using a range of methodologies would provide valuable information that could enhance intervention uptake, completion and effectiveness. This study has shown that although survivors often found interventions difficult, they also appreciated that they needed to work through trauma, which they said resulted in a wide range of benefits. Therefore, listening to survivors and providing appropriate interventions, at the right time for them, can make a significant difference to their health and well-being.

Brown SJ ，Carter GJ ，Halliwell G ，Brown K ，Caswell R ，Howarth E ，Feder G ，O'Doherty L ... -  《Cochrane Database of Systematic Reviews》