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Abstract Targeted alpha therapy (TAT) relies on chemical affinity or active targeting using radioimmunoconjugates as strategies to deliver α-emitting radionuclides to cancerous tissue. These strategies can be affected by transmetalation of the parent radionuclide by competing ions in vivo and the bond-breaking recoil energy of decay daughters. The retention of α-emitting radionuclides and the dose delivered to cancer cells are influenced by these processes. Encapsulating α-emitting radionuclides within nanoparticles can help overcome many of these challenges. Poly(lactic-co-glycolic acid) (PLGA) nanoparticles are a biodegradable and biocompatible delivery platform that has been used for drug delivery. In this study, PLGA nanoparticles are utilized for encapsulation and retention of actinium-225 ([225Ac]Ac3+). Encapsulation of [225Ac]Ac3+ within PLGA nanoparticles (Zave = 155.3 nm) was achieved by adapting a double-emulsion solvent evaporation method. The encapsulation efficiency was affected by both the solvent conditions and the chelation of [225Ac]Ac3+. Chelation of [225Ac]Ac3+ to a lipophilic 2,9-bis-lactam-1,10-phenanthroline ligand ([225Ac]AcBLPhen) significantly decreased its release (

Aim: This systematic review of clinical trial evidence aims to determine whether homeopathy can effectively relieve symptoms and reduce antibiotic use in patients diagnosed with otitis media (OM). Methods: Seven databases and four trial registries were searched. Eligible studies included randomised- and non-randomised-controlled-trials in patients diagnosed with OM. Studies on Individualised- and non-Individualised-Homeopathy (IH, non-IH) were included, and controls were inactive and/or active treatment. Primary outcomes were clinical-improvement and antibiotic-use. Data extraction, Risk of Bias and certainty of evidence (GRADE) were performed using established methodology. Results: Nine studies (IH = 4, non-IH = 5) comprising seven Randomised Clinical Trials (RCTs) and two non-RCTs (nRCTS) compared homeopathy with placebo (n = 2) or standard care (n = 7). 4/7 included RCTs reported statistically significant individual outcomes at relevant time points (symptom score, MEE, and antibiotic use) favouring homeopathy. However, heterogeneity of study designs, homeopathic interventions and outcome measures hindered the pooling of data for most outcomes, except for antibiotic use (non-IH). Add-on non-IH reduced filled antibiotic prescriptions by 46 % (RR = 0.54 [95%CI: 0.28, 1.06], P = 0.07, I2 = 12 %), but this did not reach statistical significance. Most studies demonstrated that the homeopathy group had less adverse events than the control group. Conclusions: The evidence base for the effectiveness of homeopathy and OM treatment is modest in study number, size, and risk of bias assessment. Individual RCTs report positive effects on clinical improvement and/or antibiotic use at relevant time points with homeopathy with no safety issues. Due to heterogeneity, the current evidence is insufficient to satisfactorily answer whether homeopathy is effective for clinical improvement and reducing antibiotic use in patients with OM. A Core Outcome Set for OM for future research is warranted to improve the potential for meta-analyses and strengthen the evidence base.

Interest in local foods, especially locally grown fruit, is increasing. High tunnel vegetable growers are strategically poised to meet this demand by growing specialty melons (Cucumis melo). Although specialty melons are commonly grown in high tunnels in other parts of the world, it is an uncommon practice in the midwestern United States. The objectives of this study were to evaluate 10 specialty melon cultivars for high tunnel production and measure fruit yield and internal quality. Fruit of the cultivar Eden’s Gem yielded the greatest number of marketable fruits per plant; however, these melons are small and have a loose cavity. Fruit of the cultivars Honey Orange and Divergent yielded the largest marketable fruit per plant with tighter cavities; however, the cavities were large. All cultivars had good to excellent internal quality in terms of sugar content. The production of specialty melons in the high tunnel was successful, resulting in the production of melons with good to excellent internal quality, and several yielded three to four marketable fruit per plant. Implementing a strong pest management plan for cucumber beetle (Diabrotica undecimpunctata howardi) and powdery mildew (Erysiphe cichoracearum, Sphaerotheca fuliginea) is recommended to prevent yield loss, especially in locations such as the Midwest, where cucumber beetles often vector bacterial wilt (Erwinia tracheiphila).

With the climate continuing to change, specialty crop growers are particularly at risk for economic loss caused by erratic weather conditions, excess heat and rain, and frost damage. Although tolerant to cold, lettuce (Lactuca sativa) is a major horticultural crop at risk for exposure to freezing temperatures in late fall or early spring in the Midwest. Exogenous applications of salicylic acid, ascorbic acid, and calcium chloride have been shown to improve abiotic stress in plants, particularly with freezing tolerance. This research investigated the effects of the exogenous application of salicylic acid, ascorbic acid, and calcium chloride, in varying concentrations, on field-grown lettuce. The study was conducted at the Iowa State University Horticulture Research Station, Ames, IA, USA. Weekly applications of salicylic acid (0.5 and 1.0 mM), ascorbic acid (0.5 and 1.0 mM), and calcium chloride (10 and 20 mM) were applied until plants were a marketable size. A control treatment (no spray) was also included. Data regarding plant size, yield, leaf area, leaf number, plant dry weight, plant nutrient analysis, and freeze tolerance were collected. Freeze tolerance assessments were conducted through laboratory-simulated freeze events and the evaluation of natural in-field freeze events. Freeze injury was quantified through the electrolyte leakage method. Marketable weights in 2020 and 2021 were statistically similar, except for 1.0 mM salicylic acid in 2020, which showed a significantly lower marketable weight and head diameter. Trends during both years showed that stress protectant applications had the most effective freeze protection at −12 °C in laboratory-simulated freeze events. Calcium chloride at 20 mM had the highest protection at −12 °C, with 13.3% and 24.0% less injury compared with the control in 2020 and 2021, respectively. Salicylic acid 1.0 mM at −12 °C had 4.7% and 23.7% less injury compared with control during these two years, respectively. Ascorbic acid 1.0 mM at −12 °C also showed 6.8% and 9.5% less injury than the control in 2020 and 2021, respectively. Similar trends were observed after in-field freezing events, with 20 mM calcium chloride providing the highest protection against frost in 2020 and 2021. These findings advance the understanding of the capabilities of stress protectants on lettuce as chemical primers after freezing events. This research highlights the benefits of ascorbic acid, salicylic acid, and calcium chloride as stress protectants and encourages future research and further exploration of concentrations, methods of application, and timing of application of products.

Introduction Delirium is a syndrome characterised by a disturbance in attention, awareness and cognition as a result of another physical condition. It occurs in up to 50% of patients after cardiac surgery and is associated with increased mortality, prolonged intensive care and hospital stay and long-term cognitive dysfunction. Identifying effective preventive interventions is important. We will therefore conduct a systematic review to identify all randomised controlled studies that have tested a pharmacological or non-pharmacological intervention to prevent delirium.Methods and analysis We will search electronic databases (CDSR (Reviews), CENTRAL (Trials), MEDLINE Ovid, Embase Ovid, PsycINFO Ovid) as well as trial registers (clinicaltrials.gov and ISCRTN) for randomised controlled trials of both pharmacological and non-pharmacological interventions designed to prevent delirium after cardiac surgery in adults. Screening of search results and data extraction from included articles will be performed by two independent reviewers using Rayyan. The primary outcome will be the incidence of delirium. Secondary outcomes include: duration of postoperative delirium, all-cause mortality, length of postoperative hospital and intensive care stay, postoperative neurological complications other than delirium, health-related quality of life and intervention-specific adverse events. Studies will be assessed for risk of bias using the Cochrane RoB2 tool. A narrative synthesis of all included studies will be presented and meta-analysis (if appropriate network meta-analysis) will be undertaken where there are sufficient studies (three or more) for pooling results. Results will be reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement.Ethics and dissemination No ethical approval is required. This review will be disseminated via peer-reviewed manuscript and conferences.PROSPERO registration number CRD42022369068.

Abstract Background The provision of palliative care is increasing, with many people dying in community-based settings. It is essential that communication is effective if and when patients transition from hospice to community palliative care. Past research has indicated that communication issues are prevalent during hospital discharges, but little is known about hospice discharges. Methods An explanatory sequential mixed methods study consisting of a retrospective review of hospice discharge letters, followed by hospice focus groups, to explore patterns in communication of palliative care needs of discharged patients and describe why these patients were being discharged. Discharge letters were extracted for key content information using a standardised form. Letters were then examined for language patterns using a linguistic methodology termed corpus linguistics. Thematic analysis was used to analyse the focus group transcripts. Findings were triangulated to develop an explanatory understanding of discharge communication from hospice care. Results We sampled 250 discharge letters from five UK hospices whereby patients had been discharged to primary care. Twenty-five staff took part in focus groups. The main reasons for discharge extracted from the letters were symptoms “managed/resolved” (75.2%), and/or the “patient wishes to die/for care at home” (37.2%). Most patients had some form of physical needs documented on the letters (98.4%) but spiritual needs were rarely documented (2.4%). Psychological/emotional needs and social needs were documented in 46.4 and 35.6% of letters respectively. There was sometimes ambiguity in “who” will be following up “what” in the discharge letters, and whether described patients’ needs were resolved or ongoing for managing in the community setting. The extent to which patients received a copy of their discharge letter varied. Focus groups conveyed a lack of consensus on what constitutes “complexity” and “complex pain”. Conclusions The content and structure of discharge letters varied between hospices, although generally focused on physical needs. Our study provides insights into patterns associated with those discharged from hospice, and how policy and guidance in this area may be improved, such as greater consistency of sharing letters with patients. A patient-centred set of hospice-specific discharge letter principles could help improve future practice.

Abstract Background Specialist palliative care (SPC) providers tend to use the term ‘complex’ to refer to the needs of patients who require SPC. However, little is known about complex needs on first referral to a SPC service. We examined which needs are present and sought the perspectives of healthcare professionals on the complexity of need on referral to a hospice service. Methods Multi-site sequential explanatory mixed method study consisting of a case-note review and focus groups with healthcare professionals in four UK hospices. Results Documentation relating to 239 new patient referrals to hospice was reviewed; and focus groups involving 22 healthcare professionals conducted. Most patients had two or more needs documented on referral (96%); and needs were recorded across two or more domains for 62%. Physical needs were recorded for 91% of patients; psychological needs were recorded for 59%. Spiritual needs were rarely documented. Referral forms were considered limited for capturing complex needs. Referrals were perceived to be influenced by the experience and confidence of the referrer and the local resource available to meet palliative care needs directly. Conclusions Complexity was hard to detail or to objectively define on referral documentation alone. It appeared to be a term used to describe patients whom primary or secondary care providers felt needed SPC knowledge or support to meet their needs. Hospices need to provide greater clarity regarding who should be referred, when and for what purpose. Education and training in palliative care for primary care nurses and doctors and hospital clinicians could reduce the need for referral and help ensure that hospices are available to those most in need of SPC input.

Abstract Background Weight loss maintenance is a challenge for people with type 2 diabetes mellitus (T2DM), which attenuates the long-term benefits of weight loss for diabetes management. Medication, specific dietary requirements and the psychosocial burden of T2DM signify that weight loss maintenance designed for obesity may not suit people with T2DM. The primary objective of this review is to comprehensively evaluate existing weight maintenance interventions for people with or at high risk of T2DM. Methods We registered a protocol for the systematic review and meta-analysis of randomised and non-randomised weight maintenance interventions for T2DM. Studies included will have been carried out in adults with clinical diagnosis of T2DM or pre-diabetes. All intervention types will be accepted (e.g. behavioural/lifestyle change and pharmacological). The primary outcomes will be weight control, glycaemic control and adverse effects. Secondary outcomes will include cardiovascular risk factors (e.g. total cholesterol, LDL-cholesterol, blood pressure control), psychological wellbeing (including health-related quality of life), change in glucose medication and waist circumference. Multiple electronic databases will be searched such as MEDLINE, EMBASE, Web of Science, PsychINFO and international registers (e.g. Cochrane Central Register of Controlled Trials, WHO ICTRP). OpenGrey will be searched for grey literature. Two researchers will screen all citations and abstracts. This process will also be conducted by an additional researcher using a semi-automated tool to reduce human error. Full-text articles will be further examined by the researchers to select a final set for further analysis, and a narrative synthesis of the evidence will be presented. Potential sources of heterogeneity will be assessed, and a meta-analysis will be conducted if feasible. Risk of bias will be evaluated using the Cochrane risk of bias tool and the certainty of evidence using the GRADE (grading of recommendations, assessment, development and evaluation) approach. Discussion This review will critically appraise existing weight maintenance interventions targeting T2DM. Findings will inform future intervention development to support people with T2DM delay weight regain and prolong successful diabetes management. Systematic review registration PROSPERO CRD42020168032

Objectives This review examined the evidence arising from randomised controlled trials regarding the impact of nutrition therapy on glycaemic control in people living with type 2 diabetes mellitus (T2DM) in low/middle-income countries (LMICs).Design Systematic review and meta-analysis using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) Approach.Data sources MEDLINE, EMBASE, Web of Science, OpenGrey and the International Clinical Trials Registry were searched (up to July 3 2020).Eligibility criteria Trials were included if they evaluated nutrition therapy in adults diagnosed with T2DM, were conducted in LMICs, measured glycaemic control and the trial included a 3-month post-intervention assessment. Nutrition therapy was defined according to American Diabetes Association recommendations.Data extraction and synthesis Two independent reviewers screened the database. Study characteristics and outcome data were extracted using a data collection form. Meta-analyses were conducted for glycated haemoglobin (HbA1c) and fasting blood glucose. Trials were assessed for risk of bias (Cochrane Risk-of-Bias, Version 2.0) and overall certainty of evidence (GRADE).Results Four trials met inclusion criteria (total n=463), conducted in Malaysia, Iran and South Africa. All trials focused on nutrition education with no direct prescription or manipulation of diet. Mean differences between intervention and standard care were −0.63% (95% CI −1.47% to 0.21%) for HbA1c and −13.63 mg/dL (95% CI −37.61 to 10.34) for fasting blood glucose in favour of the intervention. Given the small number of eligible trials, moderate to high risk of publication bias and serious concerns regarding consistency and precision of the evidence, certainty of evidence was deemed to be very low.Conclusions There is a lack of well-conducted randomised controlled trials that examine the long-term impact of nutrition therapy in LMICs, preventing firm conclusions to be made on their effectiveness. Further research is essential to discover realistic, evidence-based solutions.PROSPERO registration number CRD42020188435.

Objective To determine the benefits and harms of pre-admission interventions (prehabilitation) on postoperative outcomes in patients undergoing major elective surgery.Design Systematic review and meta-analysis of randomised controlled trials (RCTs) (published or unpublished). We searched Medline, Embase, CENTRAL, DARE, HTA and NHS EED, The Cochrane Library, CINAHL, PsychINFO and ISI Web of Science (June 2020).Setting Secondary care.Participants Patients (≥18 years) undergoing major elective surgery (curative or palliative).Interventions Any intervention administered in the preoperative period with the aim of improving postoperative outcomes.Outcomes and measures Primary outcomes were 30-day mortality, hospital length of stay (LoS) and postoperative complications. Secondary outcomes included LoS in intensive care unit or high dependency unit, perioperative morbidity, hospital readmission, postoperative pain, heath-related quality of life, outcomes specific to the intervention, intervention-specific adverse events and resource use.Review methods Two authors independently extracted data from eligible RCTs and assessed risk of bias and the certainty of evidence using Grading of Recommendations, Assessment, Development and Evaluation. Random-effects meta-analyses were used to pool data across trials.Results 178 RCTs including eight types of intervention were included. Inspiratory muscle training (IMT), immunonutrition and multimodal interventions reduced hospital LoS (mean difference vs usual care: −1.81 days, 95% CI −2.31 to −1.31; −2.11 days, 95% CI −3.07 to −1.15; −1.67 days, 95% CI −2.31 to −1.03, respectively). Immunonutrition reduced infective complications (risk ratio (RR) 0.64 95% CI 0.40 to 1.01) and IMT, and exercise reduced postoperative pulmonary complications (RR 0.55, 95% CI 0.38 to 0.80, and RR 0.54, 95% CI 0.39 to 0.75, respectively). Smoking cessation interventions reduced wound infections (RR 0.28, 95% CI 0.12 to 0.64).Conclusions Some prehabilitation interventions may reduce postoperative LoS and complications but the quality of the evidence was low.PROSPERO registration number CRD42015019191.

Abstract Background Infantile colic is a distressing condition characterised by excessive crying in the first few months of life. The aim of this research was to update the synthesis of evidence of complementary and alternative medicine (CAM) research literature on infantile colic and establish what evidence is currently available. Methods Medline, Embase and AMED (via Ovid), Web of Science and Central via Cochrane library were searched from their inception to September 2018. Google Scholar and OpenGrey were searched for grey literature and PROSPERO for ongoing reviews. Published systematic reviews that included randomised controlled trials (RCTs) of infants aged up to 1 year, diagnosed with infantile colic using standard diagnostic criteria, were eligible. Reviews of RCTs that assessed the effectiveness of any individual CAM therapy were included. Three reviewers were involved in data extraction and quality assessment using the AMSTAR-2 scale and risk of bias using the ROBIS tool. Results Sixteen systematic reviews were identified. Probiotics, fennel extract and spinal manipulation show promise to alleviate symptoms of colic, although some concerns remain. Acupuncture and soy are currently not recommended. The majority of the reviews were assessed as having high or unclear risk of bias and low confidence in the findings. Conclusion There is clearly a need for larger and more methodologically sound RCTs to be conducted on the effectiveness of some CAM therapies for IC. Particular focus on probiotics in non-breastfed infants is pertinent. Systematic review registration PROSPERO: CRD42018092966.

Abstract Background Childhood adiposity has increased dramatically in the last few decades and is an important predictor of adulthood chronic disease. Later eating rhythm, termed night eating (NE), is increasingly prevalent in adults; however, the prevalence of NE in children and relationship between NE and adiposity in children still remains uncertain. The aim of this work is to review the association between adiposity in children and adolescents and NE, in terms of calorie intake, timing and meal frequency in the evening/night. Methods The Cochrane library, CINAHL, Embase, MEDLINE (via OVID) and Web of Science databases will be searched from inception to November 2019 for randomised controlled trials (RCTs) and observational studies (cohort, cross-sectional and case-control studies) which investigate the association between later vs. earlier timing of food intake at night or relatively more vs. less energy intake in any eating occasions or time period after 4 pm on adiposity in children and adolescents (4–18 years). The outcomes will be body mass index (BMI)/BMI standard deviation score (BMI-SDS or BMI Z-score), waist circumference (WC), fat mass index (FMI)/percentage of body fat (%BF) or waist to hip ratio (WHR). No language restriction will be applied. Screening for eligibility from the title and abstracts and data extraction from the full texts will be carried out by two reviewers independently. References listed in the included studies will be hand-searched for any additional articles. The quality of included RCT studies will be assessed using Revised Cochrane Risk of Bias tool (RoB 2), and of observational studies using Newcastle Ottawa scale. A qualitative synthesis of the results will be presented, and meta-analysis will be conducted, where appropriate. Discussion The planned systematic review will investigate the association between later eating rhythm and adiposity in children and adolescents. Understanding the best meal size, timing of energy intake and meal frequency across the evening time for maintaining healthy weight in children is important in order to give parents the best advice to help prevent adulthood obesity and associated chronic diseases in their children. Systematic review registration PROSPERO CRD42019134187.

Summary: Four boys with Pelizaeus-Merzbacher disease, an X-linked leukodystrophy, underwent transplantation with human allogeneic central nervous system stem cells (HuCNS-SC). Subsequently, all subjects were followed for an additional 4 years in this separate follow-up study to evaluate safety, neurologic function, magnetic resonance imaging (MRI) data, and immunologic response. The neurosurgical procedure, immunosuppression, and HuCNS-SC transplantation were well tolerated and all four subjects were alive at the conclusion of the study period. At year 2, all subjects exhibited diffusion MRI changes at the implantation sites as well as in more distant brain regions. There were persistent, increased signal changes in the three patients who were studied up to year 5. Two of four subjects developed donor-specific HLA alloantibodies, demonstrating that neural stem cells can elicit an immune response when injected into the CNS, and suggesting the importance of monitoring immunologic parameters and identifying markers of engraftment in future studies. : Gupta and colleagues show that transplantation with allogeneic central nervous system stem cells can be performed safely in humans with minimal morbidity. Immunologic data, however, show that neural stem cells can elicit an immune response following transplantation, suggesting the importance of monitoring immunologic parameters. Keywords: Pelizaeus-Merzbacher disease, neural stem cells, leukodystrophy, myelin, oligodendrocyte, transplantation, pediatric, neurodegenerative disease

Abstract Background Diets that restrict energy or macronutrient intake (e.g. fasting/ketogenic diets (KDs)) may selectively protect non-tumour cells during cancer treatment. Previous reviews have focused on a subset of dietary restrictions (DR) or have not performed systematic searches. We conducted a systematic scoping review of DR at the time of cancer treatment. Methods MEDLINE, Embase, CINAHL, AMED and Web of Science databases were searched for studies of adults undergoing DR alongside treatment for cancer. Search results were screened against inclusion/exclusion criteria. Data from included studies were extracted by two independent reviewers. Results were summarised narratively. Results Twenty-three independent studies (34 articles), with small sample sizes, met the inclusion criteria. Four categories were identified: KDs (10 studies), fasting (4 studies), protein restriction (5 studies) and combined interventions (4 studies). Diets were tolerated well, however adherence was variable, particularly for KDs. Biomarker analysis in KDs and fasting resulted in the expected increase in ketones or reduction in insulin-like growth factors, respectively, however they did not reduce glucose. Conclusions Future research with adequately powered studies is required to test the effects of each DR intervention on treatment toxicities and outcomes. Further research into improving adherence to DR may improve the feasibility of larger trials.

Objective To explore the perceived reasons underlying high mortality rates among people with multiple and complex needs.Design Qualitative study using peer research.Setting North East of England.Participants Three focus group discussions were held involving (1) people with lived experience of multiple and complex needs (n=5); (2) front-line staff from health, social care and voluntary organisations that support multiple and complex needs groups (n=7); and (3) managers and commissioners of these organisations (n=9).Results Findings from this study provide valuable perspectives of people with multiple complex needs and those that provide them with support on what may be perceived factors underlying premature mortality. Mental ill health and substance misuse (often co-occurring dual diagnosis) were perceived as influencing premature mortality among multiple and complex needs groups. Perceptions of opportunities to identify people at risk included critical life events (eg, bereavement, relationship breakdown) and transitions (eg, release from prison, completion of drug treatment). Early prevention, particularly supporting young people experiencing adverse childhood experiences, was also highlighted as a priority.Conclusion High mortality in multiple and complex needs groups may be reduced by addressing dual diagnosis, providing more support at critical life events and investing in early prevention efforts. Future interventions could take into consideration the intricate nature of multiple and complex needs and improve service access and navigation.

Background and study aims Endoscopic ultrasound (EUS) has been used for portal vein sampling in patients with pancreaticobiliary cancers for enumerating circulating tumor cells but is not yet a standard procedure. Further evaluation is needed to refine the methodology. Therefore, we evaluated the feasibility and safety of 19-gauge (19G) versus a 22-gauge (22 G) EUS fine-needle aspiration needles for portal vein sampling in a swine model. Methods Celiotomy was performed on two farm pigs. Portal vein sampling occurred transhepatically. We compared 19 G and 22 G needles coated interiorly with saline, heparin or ethylenediaminetetraacetic acid (EDTA). Small- (10 mL) and large- (25 mL) volume blood collections were evaluated. Two different collection methods were tested: direct-to-vial and suction syringe. A bleeding risk trial for saline-coated 19 G and 22 G needles was performed by puncturing the portal vein 20 times. Persistent bleeding after 3 minutes was considered significant. Results All small-volume collection trials were successful except for 22 G saline-coated needles with direct-to-vial method. All large-volume collection trials were successful when using suction syringe; direct-to-vial method for both 19 G and 22 G needles were unsuccessful. Collection times were shorter for 19 G vs. 22 G needles for both small and large-volume collections (P

Abstract Background Electrically assisted bicycles (e-bikes) have been highlighted as a method of active travel that could overcome some of the commonly reported barriers to cycle commuting. The objective of this systematic review was to assess the health benefits associated with e-cycling. Method A systematic literature review of studies examining physical activity, cardiorespiratory, metabolic and psychological outcomes associated with e-cycling. Where possible these outcomes were compared to those from conventional cycling and walking. Seven electronic databases, clinical trial registers, grey literature and reference lists were searched up to November 2017. Hand searching occurred until June 2018. Experimental or observational studies examining the impact of e-cycling on physical activity and/or health outcomes of interest were included. E-bikes used must have pedals and require pedalling for electric assistance to be provided. Results Seventeen studies (11 acute experiments, 6 longitudinal interventions) were identified involving a total of 300 participants. There was moderate evidence that e-cycling provided physical activity of at least moderate intensity, which was lower than the intensity elicited during conventional cycling, but higher than that during walking. There was also moderate evidence that e-cycling can improve cardiorespiratory fitness in physically inactive individuals. Evidence of the impact of e-cycling on metabolic and psychological health outcomes was inconclusive. Longitudinal evidence was compromised by weak study design and quality. Conclusion E-cycling can contribute to meeting physical activity recommendations and increasing physical fitness. As such, e-bikes offer a potential alternative to conventional cycling. Future research should examine the long-term health impacts of e-cycling using rigorous research designs.

Abstract Background Heterozygous familial hypercholesterolaemia (FH) is a genetic disorder characterised by elevated levels of low density lipoprotein (LDL) cholesterol from birth, estimated to affect 1 in 250 of the UK population. Left untreated, FH substantially increases an individual’s risk of premature coronary heart disease (CHD) and associated mortality. This risk can be minimised with timely diagnosis and successful treatment with medication and lifestyle changes, as advocated in national and international guidelines. Despite these recommendations, the limited research available suggests adherence to treatment may be sub-optimal. This review will identify and synthesise the available qualitative research regarding the experiences and beliefs of adults and children with FH in relation to their condition and its treatment, and the influence of these upon treatment adherence. Methods The following electronic databases will be searched from their inception: Cochrane library, MEDLINE, Embase, PsycINFO (via OVID) and CINAHL. Studies available in English and reporting primary qualitative data will be included. Database searching will be supplemented with searches in relevant specialist websites. The references of identified papers will also be hand searched. Two reviewers will independently screen titles and abstracts of identified studies, with full texts of potentially relevant papers retrieved for review against pre-defined inclusion and exclusion criteria. The Critical Appraisal Skills Programme (CASP) Qualitative Research checklist will be used to assess quality of the included studies, and the results will be taken into consideration when reporting the findings. A data extraction tool will be created for use in this review to extract study findings relevant to the review questions. A thematic synthesis approach will be taken to analyse the results. Discussion Adherence to treatment recommendations is crucial for the successful management of FH and subsequent decrease in risk of CHD later in life. Common identified themes could provide an understanding of the beliefs and experiences which influence adherence to treatment recommendations and provide an insight into perceived barriers and facilitators. The findings are intended to be used in the development of future interventions or guidelines regarding treatment of children and adults with FH. Systematic review registration PROSPERO registration number: CRD42018085946

Abstract Background Glucose abnormalities in cystic fibrosis (CF) are common, but there is limited evidence to guide their dietary management. Progressive impaired glucose tolerance eventually leads to cystic fibrosis-related diabetes (CFRD), the most prevalent complication of CF, which is associated with increased morbidity and mortality. Optimising glycaemic control improves clinical status and reduces mortality; insulin therapy is the primary means of controlling glycaemia in CFRD, but its role in managing pre-diabetes is less clear. CF dietary therapy requires a high calorie diet due to increased energy expenditure and malabsorption, but this energy-dense diet is typically high in fat and sugar, and high sugar intakes often result in hyperglycaemia in individuals who have impaired glucose handling. Current guidelines for the dietary management of glucose abnormalities in CF are based on clinical consensus rather than empirical evidence. A systematic review conducted in 2012 on the effects of low glycaemic index dietary intervention in CF concluded that there is a dearth of evidence in this area. This review will update the systematic review by Balzer et al. in 2012 and will broaden the scope of their review to include any type of dietary intervention for managing glucose abnormalities in CF. Methods Quantitative studies of dietary interventions to manage glucose abnormalities in individuals aged over 5 years with CF and glucose abnormalities will be reviewed. No limits will be placed on language or study design. The comparator will be standard CF dietary therapy (energy dense, high-fat diet) in addition to insulin therapy for individuals with CFRD. Electronic databases will be searched for completed quantitative studies published in peer-review journals that focus on dietary interventions for managing glucose abnormalities in CF. Searches will be conducted from 2000 up to the present day to reflect the evolving improvements in CF management. No restrictions will be placed on study design or language. Duration of the dietary intervention must be a minimum of 2 months and only interventions in out-patient or community settings will be included. Studies must report on dietary intervention, glycaemic control, anthropometry and lung function. Evidence will be assessed for heterogeneity and a narrative review or meta-analysis conducted as appropriate. Discussion This systematic review will elucidate current knowledge of the effects of dietary interventions for managing glucose abnormalities in the vulnerable CF clinical population. Systematic review registration PROSPERO registration number: CRD42018085569 www.crd.york.ac.uk/prospero/

Abstract Background Head and neck cancers include malignancies of the mouth, larynx and oropharynx. Tobacco use and alcohol consumption are associated with increased risks of developing and dying from head and neck cancer. The aim of this review is to examine the effectiveness of smoking and alcohol cessation interventions on disease-related outcomes, quality of life and behavioural change in adults with head and neck cancer and oral dysplasia. Methods The Cochrane library, CINAHL, Embase, MEDLINE, PsycINFO and Web of Science databases will be searched for randomised controlled trials investigating the effects of smoking or alcohol interventions on patients with either head and neck cancer or oral dysplasia. The primary outcomes are disease-free survival and, for participants with oral dysplasia, malignant transformation to cancer. Secondary outcomes are disease recurrence and progression, quality of life and behavioural change. The quality of included studies will be assessed using the ‘Cochrane Collaborations tool for assessing risk of bias’. A qualitative synthesis of the results will be reported, and a meta-analysis of the outcome data conducted, where appropriate. Discussion This systematic review will identify the extent of the current research on smoking and alcohol cessation interventions in patients with head and neck cancer and oral epithelial dysplasia. The findings have the potential to inform which interventions have been successful and how future behavioural change interventions should be conducted within these populations. Systematic review registration PROSPERO CRD42016038237

Green tea or green tea extract (GT/GTE) has been demonstrated to reduce insulin resistance and improve glycemic control. However, evidence for this health beneficial effect is inconsistent. This systematic review evaluated the effect of GT/GTE on insulin resistance and glycemic control in people with pre-diabetes/type 2 diabetes mellitus (T2DM). Ovid MEDLINE, Embase, AMED, Web of Science, and the Cochrane Library were searched up to April 2017 for randomised controlled trials of participants with pre-diabetes or T2DM, where the intervention was GT/GTE. Meta-analysis was performed to assess the standardised mean difference (SMD) in biomarkers of insulin resistance and glycemic control between GT/GTE and placebo groups. Six studies (n=382) were pooled into random-effects meta-analysis. Overall, no differences were found between GT/GTE and the placebo for glycosylated hemoglobin (HbA1c: SMD, −0.32; 95% confidence interval [CI], −0.86 to 0.23), homeostatic model assessment for insulin resistance (HOMA-IR: SMD, 0.10; 95% CI, −0.17 to 0.38), fasting insulin (SMD, −0.25; 95% CI, −0.64 to 0.15), and fasting glucose (SMD, −0.10; 95% CI, −0.50 to 0.30). No evidence support the consumption of GT/GTE could reduce the levels of HbA1c, HOMA-IR, fasting insulin, or fasting glucose in people with pre-diabetes/T2DM. However, the studies included were small and of varying quality.

Abstract Background Fibromyalgia (FM) is a chronic, debilitating pain disorder. Dissatisfaction with conventional medicine can lead people with FM to turn to complementary and alternative medicine (CAM). Two previous overviews of systematic reviews of CAM for FM have been published, but they did not assessed for risk of bias in the review process. Methods Five databases Medline, Embase, AMED (via OVID), Web of Science and Central were searched from their inception to December 2015. Reference lists were hand-searched. We had two aims: the first was to provide an up-to-date and rigorously conducted synthesis of systematic reviews of CAM literature on FM; the second was to evaluate the quality of the available systematic review evidence using two different tools: AMSTAR (Shea et al. BMC Med Res Methodol 15; 7:10, 2007) and a more recently developed tool ROBIS (Whiting et al. J Clin Epidemiol 69:225-34, 2016) specifically designed to assess risk of bias in systematic reviews. Any review that assessed one of eight CAM therapies for participants diagnosed with FM was considered. The individual studies had to be randomised controlled trials where the intervention was compared to placebo, treatment as usual or waitlist controls to be included. The primary outcome measure was pain, and the secondary outcome measure was adverse events. Results We identified 15 reviews that met inclusion criteria. There was low-quality evidence that acupuncture improves pain compared to no treatment or standard treatment, but good evidence that it is no better than sham acupuncture. The evidence for homoeopathy, spinal manipulation and herbal medicine was limited. Conclusions Overall, five reviews scored 6 or above using the AMSTAR scale and the inter-rater agreement was good (83.6%), whereas seven reviews achieved a low risk of bias rating using ROBIS and the inter-rater agreement was fair (60.0%). No firm conclusions were drawn for efficacy of either spinal manipulation or homoeopathy for FM. There is limited evidence for topical Capsicum, but further research is required. There is some evidence to support the effectiveness of acupuncture for FM, but further high-quality trials are needed to investigate its benefits, harms and mechanisms of action, compared with no or standard treatment. Systematic review registration PROSPERO CRD42016035846 .

Objective Using meta-regression this paper sets out the minimum change in body mass index-SD score (BMI-SDS) required to improve adiposity as percentage body fat for children and adolescents with obesity.Design Meta-regression.Setting Studies were identified as part of a large-scale systematic review of the following electronic databases: AMED, Embase, MEDLINE via OVID, Web of Science and CENTRAL via Cochrane library.Participants Individuals aged 4–19 years with a diagnosis of obesity according to defined BMI thresholds.Interventions Studies of lifestyle treatment interventions that included dietary, physical activity and/or behavioural components with the objective of reducing obesity were included. Interventions of

Jean Dubuffet made his dramatic breakthrough into the art world in the spring of 1946 with what would become his signature innovation, the hautes pâtes (thick or high pastes). Experimenting with unorthodox materials and techniques, he loaded his canvases with materials so heavy and unstable that even before their public debut in the exhibition Mirobolus, Macadam et Cie., his unwieldy pastes began cracking, crumbling, and melting off the canvas and onto the floor. According to Dubuffet’s apologists, he welcomed these 'modifications', delighting in mutable, mutant materials that succumbed to the forces of gravity and entropy. Revisiting the story of Dubuffet’s meltdowns, this article highlights the uneasy double bind Dubuffet found himself in at the beginning of his career, as his theoretical interest in ephemerality gave way to his clients’ and dealers’ well-founded practical concerns over the longevity and material durability of his work.

Objectives Individuals with heterozygous familial hypercholesterolaemia (FH) are at high risk of developing cardiovascular disease (CVD). This risk can be substantially reduced with lifelong pharmacological and lifestyle treatment; however, research suggests adherence is poor. We synthesised the qualitative research to identify enablers and barriers to treatment adherence.Design This study conducted a thematic synthesis of qualitative studies.Data sources MEDLINE, Embase, PsycINFO via OVID, Cochrane library and CINAHL databases and grey literature sources were searched through September 2018.Eligibility criteria We included studies conducted in individuals with FH, and their family members, which reported primary qualitative data regarding their experiences of and beliefs about their condition and its treatment.Data extraction and synthesis Quality assessment was undertaken using the Critical Appraisal Skills Programme for qualitative studies. A thematic synthesis was conducted to uncover descriptive and generate analytical themes. These findings were then used to identify enablers and barriers to treatment adherence for application in clinical practice.Results 24 papers reporting the findings of 15 population samples (264 individuals with FH and 13 of their family members) across 8 countries were included. Data captured within 20 descriptive themes were considered in relation to treatment adherence and 6 analytical themes were generated: risk assessment; perceived personal control of health; disease identity; family influence; informed decision-making; and incorporating treatment into daily life. These findings were used to identify seven enablers (eg, ‘commencement of treatment from a young age’) and six barriers (eg, ‘incorrect and/or inadequate knowledge of treatment advice’) to treatment adherence. There were insufficient data to explore if the findings differed between adults and children.Conclusions The findings reveal several enablers and barriers to treatment adherence in individuals with FH. These could be used in clinical practice to facilitate optimal adherence to lifelong treatment thereby minimising the risk of CVD in this vulnerable population.PROSPERO registration number CRD42018085946.

Periodontal disease can be treated in several ways. This paper reviewed whether antimicrobial photodynamic therapy (aPDT) in addition to scaling and root planing (SRP) produces improved clinical results over systemic antibiotics (ABs) in conjunction with SRP in adults with periodontitis. Studies were searched using the following electronic databases: MEDLINE, the Cochrane Database of Systematic Reviews, and the Web of Science Core Collection up to and including November 2018. Four randomized controlled trials (RCTs) were reviewed to maximise the reliability of the evidence. All participants suffered from either chronic or aggressive periodontitis and each study contained SRP as an adjunct to ABs or aPDT. To determine whether groups showed improvement after treatment, the outcome parameters chosen were probing depth (PD), clinical attachment level (CAL), and bleeding on probing (BOP). Despite finding significant improvements in all groups, the differences among groups were not consistently statistically significant. The lack of homogeneity in the results among these studies indicates that it was not possible to determine a conclusion about whether aPDT or AB as an adjunct to SRP provides better improvements in periodontitis as measured by PD, CAL, and BOP. Further studies with more similar study designs are required before firm conclusions can be deduced.

Cerebrospinal fluid (CSF) 42 amino acid species of amyloid beta (Aβ42) and tau levels are strongly correlated with the presence of Alzheimer's disease (AD) neuropathology including amyloid plaques and neurodegeneration and have been successfully used as endophenotypes for genetic studies of AD. Additional CSF analytes may also serve as useful endophenotypes that capture other aspects of AD pathophysiology. Here we have conducted a genome-wide association study of CSF levels of 59 AD-related analytes. All analytes were measured using the Rules Based Medicine Human DiscoveryMAP Panel, which includes analytes relevant to several disease-related processes. Data from two independently collected and measured datasets, the Knight Alzheimer's Disease Research Center (ADRC) and Alzheimer's Disease Neuroimaging Initiative (ADNI), were analyzed separately, and combined results were obtained using meta-analysis. We identified genetic associations with CSF levels of 5 proteins (Angiotensin-converting enzyme (ACE), Chemokine (C-C motif) ligand 2 (CCL2), Chemokine (C-C motif) ligand 4 (CCL4), Interleukin 6 receptor (IL6R) and Matrix metalloproteinase-3 (MMP3)) with study-wide significant p-values (p

The aim of this systematic review is to examine the efficacy of Garcinia extract, hydroxycitric acid (HCA) as a weight reduction agent, using data from randomised clinical trials (RCTs). Electronic and nonelectronic searches were conducted to identify relevant articles, with no restrictions in language or time. Two independent reviewers extracted the data and assessed the methodological quality of included studies. Twenty-three eligible trials were identified and twelve were included. Nine trials provided data suitable for statistical pooling. The meta-analysis revealed a small, statistically significant difference in weight loss favouring HCA over placebo (MD: −0.88 kg; 95% CI: −1.75, −0.00). Gastrointestinal adverse events were twice as common in the HCA group compared with placebo in one included study. It is concluded that the RCTs suggest that Garcinia extracts/HCA can cause short-term weight loss. The magnitude of the effect is small, and the clinical relevance is uncertain. Future trials should be more rigorous and better reported.