Amphiregulin from regulatory T cells promotes liver fibrosis and insulin resistance in non-alcoholic steatohepatitis.

Production of amphiregulin (Areg) by regulatory T (Treg) cells promotes repair after acute tissue injury. Here, we examined the function of Treg cells in non-alcoholic steatohepatitis (NASH), a setting of chronic liver injury. Areg-producing Treg cells were enriched in the livers of mice and humans with NASH. Deletion of Areg in Treg cells, but not in myeloid cells, reduced NASH-induced liver fibrosis. Chronic liver damage induced transcriptional changes associated with Treg cell activation. Mechanistically, Treg cell-derived Areg activated pro-fibrotic transcriptional programs in hepatic stellate cells via epidermal growth factor receptor (EGFR) signaling. Deletion of Areg in Treg cells protected mice from NASH-dependent glucose intolerance, which also was dependent on EGFR signaling on hepatic stellate cells. Areg from Treg cells promoted hepatocyte gluconeogenesis through hepatocyte detection of hepatic stellate cell-derived interleukin-6. Our findings reveal a maladaptive role for Treg cell-mediated tissue repair functions in chronic liver disease and link liver damage to NASH-dependent glucose intolerance.

The Impact of Molecular Subtyping on Pathological Staging of Pancreatic Cancer.

BACKGROUND: The long-term outcomes following surgical resection for pancreatic ductal adenocarcinoma (PDAC) remains poor, with only 20% of patients surviving 5 years after pancreatectomy. Patient selection for surgery remains suboptimal largely due to the absence of consideration of aggressive tumor biology. OBJECTIVE: The aim of this study was to evaluate traditional staging criteria for PDAC in the setting of molecular subtypes. METHODS: Clinicopathological data were obtained for 5 independent cohorts of consecutive unselected patients, totaling n = 1298, including n = 442 that underwent molecular subtyping. The main outcome measure was disease-specific survival following surgical resection for PDAC stratified according to the American Joint Commission for Cancer (TNM) staging criteria, margin status, and molecular subtype. RESULTS: TNM staging criteria and margin status confers prognostic value only in tumors with classical pancreatic subtype. Patients with tumors that are of squamous subtype, have a poor outcome irrespective of favorable traditional pathological staging [hazard ratio (HR) 1.54, 95% confidence interval (CI) 1.04-2.28, P = 0.032]. Margin status has no impact on survival in the squamous subtype (16.0 vs 12.1 months, P = 0.374). There were no differences in molecular subtype or gene expression of tumors with positive resection margin status. CONCLUSIONS: Aggressive tumor biology as measured by molecular subtype predicts poor outcome following pancreatectomy for PDAC and should be utilized to inform patient selection for surgery.

New guidance for self-harm: an opportunity not to be missed.

In this editorial we, as members of the 2022 NICE Guideline Committee, highlight and discuss what, in our view, are the key guideline recommendations (generated through evidence synthesis and consensus) for mental health professionals when caring for people after self-harm, and we consider some of the implementation challenges.

Active travelling to school is not associated with increased total daily physical activity levels, or reduced obesity and cardiovascular/pulmonary health parameters in 10-12-year olds: a cross-sectional cohort study.

BACKGROUND/OBJECTIVES: Childhood obesity has increased enormously. Several lifestyle factors have been implicated, including decreased physical activity, partially involving a decline in active travel to school. We aimed to establish the association between school transport mode and physical activity levels of primary 6 and 7 children (aged 10-12). Secondary outcomes were body mass index standard deviation scores, blood pressure levels and lung function. SUBJECTS/METHODS: A cross-sectional study was conducted with a total number of 432 children from three primary schools in North East Scotland. Actigraph accelerometers were used to provide objective measures of physical activity. Ninety-two children in primary 6 and 90 children in primary 7 (40 in common) had adequate data. Modes of transport to school were assessed by a questionnaire. Two hundred and seventeen children in primary 6 and one hundred and sixty-five in primary 7 returned adequate questionnaires. Children who used active transport modes for >70% of their journeys to school over the week were coded as active travellers and <30% were coded as passive travellers. All children also had height, weight, blood pressure levels and lung function measured. RESULTS: Children who lived further away from school, and in more expensive properties were more likely to travel passively to school. Actively commuting children (70% walking) had significantly higher activity levels than passive commuters during the 30 min that encompassed their journey to and from school. However, there were no significant differences between active and passive school travellers in total daily physical activity, BMI SDS, and both systolic and diastolic blood pressure and lung function. CONCLUSIONS: There was no evidence that more days of active travel to school had a significant influence on total physical activity, obesity and related health parameters. Public health interventions promoting active travel to school may have limited success in quelling the childhood obesity epidemic.

Service Users perspectives in PROMISE and research.

Since its inception in 2013, PROMISE (PROactive Management of Integrated Services and Environments) has been supporting service users and staff at the Cambridgeshire and Peterborough NHS Foundation Trust (CPFT) on a journey to reduce reliance on force. The author's own personal experiences led to the founding of PROMISE and illustrates how individual experiences can influence a patient to lead change. Coproduction is actively embedded in PROMISE. Patients have been meaningfully involved because they are innovators and problem solvers who bring an alternative viewpoint by the very nature of their condition. A patient is more than just a person who needs to be 'fixed' they are individuals with untapped skills and added insight. There have been 2 separate Patient Advisory Groups (PAGs) since the project was first established. The first Patient Advisory Group was recruited to work with the PROMISE researchers on a study which used a participatory qualitative approach. Drawing on their lived experience and different perspectives the PAG was instrumental in shaping the qualitative study, including the research questions. Their active involvement helped to ensure that that the study was sensitively designed, methodologically robust and ethically sound. The 2nd PAG was formed in 2016 to give the project an overall steer. Patients in this group contributed to the work on the 'No' Audit and reviewed several CPFT policies such as the Seclusion and Segregation policy which has impacted on frontline practice. They also made a significant contribution to the study design for a funding application that was submitted by the PROMISE team to the National Institute for Health Research (NIHR). Both PAGs were supported by funding from East of England Collaboration for Leadership in Applied Health Research and Care (CLAHRC EoE) and were influential in different ways. An evaluation of the 2nd PAG which was conducted in June 2017 showed very high satisfaction levels. The free text comments also revealed how many of the patients valued their involvement and were glad to have worked alongside the PROMISE team. The impact of this PAG has been recognised by CPFT who have agreed to support the group financially and are keen to widen its remit to ensure that more patients are actively involved in Trust activities.

PROMISE. Beyond frontiers.

The concepts underlying the PROMISE initiative are described. This initiative to implement more humane healthcare is now developing from a local initiativein Cambridge to a global movement.

Towards a better understanding of mental health care delivery systems: From stories to system components.

The growing demand for better quality of care, together with an increasing awareness of limited resources, is bringing attention to the need for design in healthcare. In mental health, considered the largest single cause of disability in the UK, the need is great. Existing services often fail to meet current levels of demand and do not consistently deliver good quality care for all service users. The design of better delivery systems has the potential to improve service user experience and care outcomes. This paper reports how through the interactive and participatory method of storytelling, the key components of a mental health delivery system were identified. We explain each of the ten components and discuss their implications for system understanding and service design. A model of a mental health delivery system has also been proposed.

Parent involvement in child anthropometric measurement.

BACKGROUND: Young children are often accompanied by their parent/caregiver when attending primary healthcare visits, where clinical procedures such as anthropometric measurements are conducted. Parents are not typically involved in their child's anthropometric measurement collection, and there are no recommendations for parental involvement during visits. The objective of this study was to describe parents' experiences with being involved in their child's anthropometric measurements. METHODS: A 10-question survey comprised of scaled and open-ended questions was self-administered to participants after child anthropometric measurement collection including length/height, weight, head, arm, and waist circumference. Survey data were analyzed using a general inductive approach and thematic analysis. Surveys were collected in participating TARGet Kids! primary care practice sites in Toronto, Canada. Survey respondents included 30 parents of children < 2 years of age, and 30 parents of children 2-5 years of age. RESULTS: 76% of parents with children aged < 2 years and 93% of those with children aged 2-5 years rated their overall experience in being involved in their child's anthropometric measurement as enjoyable or thoroughly enjoyable. Analysis of open-ended survey questions revealed five themes: [1] parent interest in child growth; [2] ease of anthropometric measurement; [3] extended clinic visit; [4] child discomfort; and [5] interest in participating in research. CONCLUSION: Parents reported a high degree of enjoyment in being involved in their child's anthropometric measurements. Parent participation in anthropometric measurement may improve parental satisfaction with children's primary healthcare. Future research may include assessing the reliability of measurements taken with the support of a parent/caregiver.

Randomized controlled trial evaluating a virtual parenting intervention for young children at risk of obesity: study protocol for Parenting Addressing Early Years Intervention with Coaching Visits in Toronto (PARENT) trial.

BACKGROUND: The prevalence of overweight (15%) and obesity (6%) in children under 5 years of age in Canada are high, and young children with overweight and obesity are at increased risk of the development of chronic disease(s) in adulthood. Prior research has demonstrated very few published trials on effective obesity prevention interventions in young children at risk of obesity, within primary healthcare settings. The aim of this study is to determine if 18-48-month-old children at risk for obesity, who are randomized to receive the Parents Together program (i.e., intervention group), have reduced body mass index z-score (zBMI), compared to those not receiving the intervention, at a 12-month follow-up. Secondary clinical outcomes between the intervention and control groups will be compared at 12 months. METHODS: A pragmatic, parallel group, 1:1, superiority, randomized control trial (RCT) through the TARGetKids! Practice Based Research Network will be conducted. Young children (ages 18-48 months) who are at increased risk for childhood obesity will be invited to participate. Parents who are enrolled in the intervention group will participate in eight weekly group sessions and 4-5 coaching visits, facilitated by a trained public health nurse. Children and parents who are enrolled in the control group will receive the usual health care. The primary outcome will be compared between intervention arms using an analysis of covariance (ANCOVA). Feasibility and acceptability will be assessed by parent focus groups and interviews, and fidelity to the intervention will be measured using nurse-completed checklists. A cost-effectiveness analysis (CEA) will be conducted. DISCUSSION: This study will aim to reflect the social, cultural, and geographic diversity of children in primary care in Toronto, Ontario, represented by an innovative collaboration among applied child health researchers, community health researchers, and primary care providers (i.e., pediatricians and family physicians in three different models of primary care). Clinical and implementation outcomes will be used to inform future research to test this intervention in a larger number, and diverse practices across diverse geographic settings in Ontario. TRIAL REGISTRATION: ClinicalTrials.gov NCT03219697. Registered on June 27, 2017.

Chemokines expressed by engineered bacteria recruit and orchestrate antitumor immunity.

Tumors use multiple mechanisms to actively exclude immune cells involved in antitumor immunity. Strategies to overcome these exclusion signals remain limited due to an inability to target therapeutics specifically to the tumor. Synthetic biology enables engineering of cells and microbes for tumor-localized delivery of therapeutic candidates previously unavailable using conventional systemic administration techniques. Here, we engineer bacteria to intratumorally release chemokines to attract adaptive immune cells into the tumor environment. Bacteria expressing an activating mutant of the human chemokine CXCL16 (hCXCL16K42A) offer therapeutic benefit in multiple mouse tumor models, an effect mediated via recruitment of CD8+ T cells. Furthermore, we target the presentation of tumor-derived antigens by dendritic cells, using a second engineered bacterial strain expressing CCL20. This led to type 1 conventional dendritic cell recruitment and synergized with hCXCL16K42A-induced T cell recruitment to provide additional therapeutic benefit. In summary, we engineer bacteria to recruit and activate innate and adaptive antitumor immune responses, offering a new cancer immunotherapy strategy.

What interventions should we implement in England's mental health services? The mental health implementation network (MHIN) mixed-methods approach to rapid prioritisation.

Introduction: Setting mental health priorities helps researchers, policy makers, and service funders improve mental health services. In the context of a national mental health implementation programme in England, this study aims to identify implementable evidence-based interventions in key priority areas to improve mental health service delivery. Methods: A mixed-methods research design was used for a three step prioritisation approach involving systematic scoping reviews (additional manuscript under development), expert consultations and data triangulation. Groups with diverse expertise, including experts by experience, worked together to improve decision-making quality by promoting more inclusive and comprehensive discussions. A multi-criteria decision analysis (MCDA) model was used to combine participants' varied opinions, data and judgments about the data's relevance to the issues at hand during a decision conferencing workshop where the priorities were finalised. Results: The study identified mental health interventions in three mental health priority areas: mental health inequalities, child and adolescent mental health, comorbidities with a focus on integration of mental and physical health services and mental health and substance misuse problems. Key interventions in all the priority areas are outlined. The programme is putting some of these evidence-based interventions into action nationwide in each of these three priority mental health priority areas. Conclusion: We report an inclusive attempt to ensure that the list of mental health service priorities agrees with perceived needs on the ground and focuses on evidence-based interventions. Other fields of healthcare may also benefit from this methodological approach if they need to make rapid health-prioritisation decisions.

Codesigning a systemic discharge intervention for inpatient mental health settings (MINDS): a protocol for integrating realist evaluation and an engineering-based systems approach.

INTRODUCTION: Transition following discharge from mental health hospital is high risk in terms of relapse, readmission and suicide. Discharge planning supports transition and reduces risk. It is a complex activity involving interacting systemic elements. The codesigning a systemic discharge intervention for inpatient mental health settings (MINDS) study aims to improve the process for people being discharged, their carers/supporters and staff who work in mental health services, by understanding, co-designing and evaluating implementation of a systemic approach to discharge planning. METHODS AND ANALYSIS: The MINDS study integrates realist research and an engineering-informed systems approach across three stages. Stage 1 applies realist review and evaluation using a systems approach to develop programme theories of discharge planning. Stage 2 uses an Engineering Better Care framework to codesign a novel systemic discharge intervention, which will be subjected to process and economic evaluation in stage 3. The programme theories and resulting care planning approach will be refined throughout the study ready for a future clinical trial. MINDS is co-led by an expert by experience, with researchers with lived experience co-leading each stage. ETHICS AND DISSEMINATION: MINDS stage 1 has received ethical approval from Yorkshire & The Humber-Bradford Leeds (Research Ethics Committee (22/YH/0122). Findings from MINDS will be disseminated via high-impact journal publications and conference presentations, including those with service user and mental health professional audiences. We will establish routes to engage with public and service user communities and National Health Service professionals including blogs, podcasts and short videos. TRIAL REGISTRATION NUMBER: MINDS is funded by the National Institute of Health Research (NIHR 133013) https://fundingawards.nihr.ac.uk/award/NIHR133013. The realist review protocol is registered on PROSPERO. PROSPERO REGISTRATION NUMBER: CRD42021293255.

The World Hypertension League Science of Salt: a regularly updated systematic review of salt and health outcomes studies (Sept 2019 to Dec 2020).

The World Hypertension League Science of Salt health outcomes review series highlights high-quality publications relating to salt intake and health outcomes. This review uses a standardised method, outlined in previous reviews and based on methods developed by WHO, to identify and critically appraise published articles on dietary salt intake and health outcomes. We identified 41 articles published between September 2019 to December 2020. Amongst these, two studies met the pre-specified methodological quality criteria for critical appraisal. They were prospective cohort studies and examined physical performance and composite renal outcomes as health outcomes. Both found an association between increased/higher sodium intake and poorer health outcomes. Few studies meet criteria for high-quality methods. This review adds further evidence that dietary salt reduction has health benefits and strengthens evidence relating to health outcomes other than blood pressure and cardiovascular disease. We observe that most studies on dietary sodium do not have adequate methodology to reliably assess sodium intake and its association with health outcomes.

Folates, folic acid and preconception care - a review.

The link between folate deficiency and congenital spina bifida defects was first suggested in the 1960s. Although the prevention of these defects by preconception folic acid supplementation was confirmed in a large multi-centre controlled trial in 1991, its subsequent implementation as health education advice has made very little difference. North America's policy of folic acid fortification of flour and bread has had a beneficial impact. No European country has implemented fortification due to concern over possible adverse effects on older subjects, but a recent review shows these to be largely hypothetical and far outweighed by beneficial effects. Recent research by Menezo et al. has, however, shown that folic acid is ineffective for some women with severe fertility problems including recurrent miscarriage and failed in vitro fertilisation. There is a genetically determined bottleneck (677TT) in their folate metabolism that can be successfully overridden by going straight to the next step in the metabolic pathway and taking 5-methylytetrahydrofolate, as a preconception supplement. Menezo suggests that all women with fertility problems should be tested for 677TT. If fortification of flour and bread is to be implemented in the UK, there should be monitoring for possible adverse effects including the incidence of colorectal cancers and cognitive decline. In conclusion, whilst there are concerns that fortification could have a detrimental effect on these conditions, there is sound evidence that it would have much greater beneficial effects.

Further evidence that methods based on spot urine samples should not be used to examine sodium-disease relationships from the Science of Salt: A regularly updated systematic review of salt and health outcomes (November 2018 to August 2019).

The aim of this eighth Science of Salt outcomes review is to identify, summarize, and critically appraise studies on dietary sodium and health outcomes published between November 1, 2018, and August 31, 2019, to extend this series published in the Journal since 2016. The standardized Science of Salt search strategy was conducted. Studies were screened based on a priori defined criteria to identify publications eligible for detailed critical appraisal. The search strategy resulted in 2621 citations with 27 studies on dietary sodium and health outcomes identified. Two studies met the criteria for detailed critical appraisal and commentary. We report more evidence that high sodium intake has detrimental health effects. A post hoc analysis of the Dietary Approaches to Stop Hypertension (DASH) sodium trial showed that lightheadedness occurred at a greater frequency with a high sodium DASH diet compared to a low sodium DASH diet. In addition, evidence from a post-trial analysis of the Trials of Hypertension (TOHP) I and II cohorts showed that estimates of sodium intake from methods based on spot urine samples are inaccurate and this method alters the linearity of the sodium-mortality association. Compared to measurement of 24-hour sodium excretion using three to seven 24-hour urine collections, estimation of average 24-hour sodium excretion with the Kawasaki equation appeared to change the mortality association from linear to J-shaped. Only two high-quality studies were identified during the review period, both were secondary analyses of previously conducted trials, highlighting the lack of new methodologically sound studies examining sodium and health outcomes.

Paucity of high-quality studies reporting on salt and health outcomes from the science of salt: A regularly updated systematic review of salt and health outcomes (April 2017 to March 2018).

The purpose of this review is to identify, summarize, and critically appraise studies on dietary salt and health outcomes that were published from April 2017 to March 2018. The search strategy was adapted from a previous systematic review on dietary salt and health. Identified studies were screened based on a priori defined criteria to identify publications eligible for detailed critical appraisals. Overall, 6747 citations were identified by the search strategy, and 42 health outcome studies were identified. Three of the 42 studies met the criteria for methodological quality and health outcomes and underwent detailed critical appraisals and commentary. In addition, a systematic review and meta-analysis was critically appraised, although it did not strictly meet our methodological criteria. All four of the studies critically appraised found that sodium reduction improved blood pressure, especially in individuals with hypertension. In addition, sodium reduction reduced albuminuria in patients with stage 1-3 chronic kidney disease. Examination of the time course of blood pressure responses to sodium reduction revealed lowering sodium in the context of an average American diet may not produce maximal blood pressure reductions within a 4-week intervention period. This review provides further evidence of the benefit of sodium reduction for blood pressure lowering and gives insights into the subgroups of the population that may derive the greatest benefit from sodium reduction and the time course required to see benefit. Only three high-quality studies were identified during this 12-month review period, highlighting the critical need for more well-conducted rigorous studies in this area.

Science of Salt: A regularly updated systematic review of salt and health outcomes studies (April to October 2018).

The Science of Salt reviews identify, summarize, and critically appraise published studies on dietary salt and health outcomes according to pre-specified methods. This review covers the period April 3 to October 30, 2018. Here, nineteen studies that fit pre-specified criteria for review and summary are included. Three of these, one prospective cohort study, one randomized controlled trial, and a post hoc analysis of the Dietary Approaches to Stop Hypertension (DASH) sodium trial fulfilled the quality criteria for detailed critical appraisal, including risk of bias assessment, and commentary. Two trials demonstrated a positive association between salt intake and blood pressure. In a cohort of older Italians, increased risk of total mortality was observed with salt intake less than ~16 g/d (6300 mg sodium/d) at baseline; no association existed for incident cardiovascular disease (CVD) or CVD mortality. The paucity of published studies which met our criteria for methodological quality is of concern.

The HARMONIC trial: study protocol for a randomised controlled feasibility trial of Shaping Healthy Minds-a modular transdiagnostic intervention for mood, stressor-related and anxiety disorders in adults.

INTRODUCTION: Anxiety, mood and trauma-related disorders are common, affecting up to 20% of adults. Many of these individuals will experience symptoms of more than one disorder as diagnostically defined. However, most psychological treatments focus on individual disorders and are less effective for those who experience comorbid disorders. The Healthy and Resilient Mind Programme: Building Blocks for Mental Wellbeing (HARMONIC) trial introduces a novel transdiagnostic intervention (Shaping Healthy Minds (SHM)), which synthesises several evidence-based treatment techniques to address the gap in effective interventions for people with complex and comorbid difficulties. This early phase trial aims to estimate the efficacy and feasibility of the transdiagnostic intervention in preparation for a later-phase randomised controlled trial, and to explore mechanisms of change. METHODS/ANALYSIS: We outline a patient-level two-arm randomised controlled trial (HARMONIC) that compares SHM to treatment-as-usual for individuals aged >18 years (n=50) with comorbid mood, anxiety, obsessive-compulsive or trauma/stressor disorders diagnoses, recruited from outpatient psychological services within the UK National Health Service (NHS). The co-primary outcomes will be 3-month follow-up scores on self-report measures of depressive symptoms, anxiety symptoms, and disability and functional impairment. Secondary outcomes include changes in symptoms linked to individual disorders. We will assess the feasibility and acceptability of SHM, the utility of proposed outcome measures, and refine the treatment manuals in preparation for a later-phase trial. ETHICS AND DISSEMINATION: This trial protocol has been approved by the Health Research Authority of the NHS of the UK (East of England, Reference: 16/EE/0095). We anticipate that trial findings will inform future revisions of clinical guidelines for numerous forms of mood, anxiety and stressor-related disorders. Findings will be disseminated broadly via peer-reviewed empirical journal articles, conference presentations, clinical workshops and a trial website. TRIAL REGISTRATION: NCT03143634; Pre-results.

PROGRESS: the PROMISE governance framework to decrease coercion in mental healthcare.

Reducing physical intervention in mental health inpatient care is a global priority. It is extremely distressing both to patients and staff. PROactive Management of Integrated Services and Environments (PROMISE) was developed within Cambridgeshire and Peterborough NHS Foundation Trust (CPFT) to bring about culture change to decrease coercion in care. This study evaluates the changes in physical intervention numbers and patient experience metrics and proposes an easy-to-adopt and adapt governance framework for complex interventions. PROMISE was based on three core values of: providing a caring response to all distress; courage to challenge the status quo; and coproduction of novel solutions. It sought to transform daily front-line interactions related to risk-based restrictive practice that often leads to physical interventions. PROactive Governance of Recovery Settings and Services, a five-step governance framework (Report, Reflect, Review, Rethink and Refresh), was developed in an iterative and organic fashion to oversee the improvement journey and effectively translate information into knowledge, learning and actions. Overall physical interventions reduced from 328 to 241and210 across consecutive years (2014, 2015-2016 and 2016-2017, respectively). Indeed, the 2016-2017 total would have been further reduced to 126 were it not for the perceived substantial care needs of one patient. Prone restraints reduced from 82 to 32 (2015-2016 and 2016-2017, respectively). During 2016-2017, each ward had a continuous 3-month period of no restraints and 4 months without prone restrains. Patient experience surveys (n=4591) for 2014-2017 rated overall satisfaction with care at 87%. CPFT reported fewer physical interventions and maintained high patient experience scores when using a five-pronged governance approach. It has a summative function to define where a team or an organisation is relative to goals and is formative in setting up the next steps relating to action, learning and future planning.

High sodium intake increases blood pressure and risk of kidney disease. From the Science of Salt: A regularly updated systematic review of salt and health outcomes (August 2016 to March 2017).

The purpose of this review was to identify, summarize, and critically appraise studies on dietary salt and health outcomes that were published from August 2016 to March 2017. The search strategy was adapted from a previous systematic review on dietary salt and health. Studies that meet standards for methodological quality criteria and eligible health outcomes are reported in detailed critical appraisals. Overall, 47 studies were identified and are summarized in this review. Two studies assessed all-cause or disease-specific mortality outcomes, eight studies assessed morbidity reduction-related outcomes, three studies assessed outcomes related to symptoms/quality of life/functional status, 25 studies assessed blood pressure (BP) outcomes and other clinically relevant surrogate outcomes, and nine studies assessed physiologic surrogate outcomes. Eight of these studies met the criteria for outcomes and methodological quality and underwent detailed critical appraisals and commentary. Five of these studies found adverse effects of salt intake on health outcomes (BP; death due to kidney disease and initiation of dialysis; total kidney volume and composite of kidney function; composite of cardiovascular disease (CVD) events including, and risk of mortality); one study reported the benefits of salt restriction in chronic BP and two studies reported neutral results (BP and risk of CKD). Overall, these articles confirm the negative effects of excessive sodium intake on health outcomes.