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Stem cell exhaustion plays a major role in the ageing of different tissues. Similarly, in vitro cell ageing during expansion prior to their use in regenerative medicine can severely compromise stem cell quality through progressive declines in differentiation and growth capacity. We utilized non-destructive multispectral assessment of native cell autofluorescence to investigate the metabolic mechanisms of in vitro mesenchymal stem cell (MSC) ageing in human bone marrow MSCs over serial passages (P2–P10). The spectral signals for NAD(P)H, flavins and protein-bound NAD(P)H were successfully isolated using Robust Dependent Component Analysis (RoDECA). NAD(P)H decreased over the course of hMSC ageing in absolute terms as well as relative to flavins (optical redox ratio). Relative changes in other fluorophore levels (flavins, protein-bound NAD(P)H) suggested that this reduction was due to nicotinamide adenine dinucleotide depletion rather than a metabolic shift from glycolysis to oxidative phosphorylation. Using multispectral features, which are determined without cell fixation or fluorescent labelling, we developed and externally validated a reliable, linear model which could accurately categorize the age of culture-expanded hMSCs. The largest shift in spectral characteristics occurs early in hMSC ageing. These findings demonstrate the feasibility of applying multispectral technology for the non-invasive monitoring of MSC health in vitro. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s11357-020-00250-9) contains supplementary material, which is available to authorized users.

The preservation of cognitive ability by increasing nicotinamide adenine dinucleotide (NAD

Background Cell cycle analysis is important for cancer research. However, available methodologies have drawbacks including limited categorisation and reliance on fixation, staining or transformation. Multispectral analysis of endogenous cell autofluorescence has been shown to be sensitive to changes in cell status and could be applied to the discrimination of cell cycle without these steps. Methods Cells from the MIA-PaCa-2, PANC-1, and HeLa cell lines were plated on gridded dishes and imaged using a multispectral fluorescence microscope. They were then stained for proliferating cell nuclear antigen (PCNA) and DNA intensity as a reference standard for their cell cycle position (G1, S, G2, M). The multispectral data was split into training and testing datasets and models were generated to discriminate between G1, S, and G2 + M phase cells. A standard decision tree classification approach was taken, and a two-step system was generated for each line. Results Across cancer cell lines accuracy ranged from 68.3% (MIA-PaCa-2) to 73.3% (HeLa) for distinguishing G1 from S and G2 + M, and 69.0% (MIA-PaCa-2) to 78.0% (PANC1) for distinguishing S from G2 + M. Unmixing the multispectral data showed that the autofluorophores NADH, FAD, and PPIX had significant differences between phases. Similarly, the redox ratio and the ratio of protein bound to free NADH were significantly affected. Conclusions These results demonstrate that multispectral microscopy could be used for the non-destructive, label free discrimination of cell cycle phase in cancer cells. They provide novel information on the mechanisms of cell-cycle progression and control, and have practical implications for oncology research.

Damage and degradation of articular cartilage leads to severe pain and loss of mobility. The development of new therapies for cartilage regeneration for monitoring their effect requires further study of cartilage, ideally at a molecular level and in a minimally invasive way. Hyperspectral microscopy is a novel technology which utilises endogenous fluorophores to non-invasively assess the molecular composition of cells and tissue. In this study, we applied hyperspectral microscopy to healthy bovine articular cartilage and osteoarthritic human articular cartilage to investigate its capacity to generate informative molecular data and characterise disease state and treatment effects. We successfully demonstrated label-free fluorescence identification of collagen type I and II – isolated in cartilage here for the first time and the co-enzymes free NADH and FAD which together give the optical redox ratio that is an important measure of metabolic activity. The intracellular composition of chondrocytes was also examined. Differences were observed in the molecular ratios within the superficial and transitional zones of the articular cartilage which appeared to be influenced by disease state and treatment. These findings show that hyperspectral microscopy could be useful for investigating the molecular underpinnings of articular cartilage degradation and repair. As it is non-invasive and non-destructive, samples can be repeatedly assessed over time, enabling true time-course experiments with in-depth molecular data. Additionally, there is potential for the hyperspectral approach to be adapted for patient examination to allow the investigation of cartilage state. This could be of advantage for assessment and diagnosis as well as treatment monitoring.

Radiodynamic therapy (RDT) is a recent extension of conventional photodynamic therapy, in which visible/near infrared light irradiation is replaced by a well-tolerated dose of high-energy X-rays. This enables greater tissue penetration to allow non-invasive treatment of large, deep-seated tumors. We report here the design and testing of a drug delivery system for RDT that is intended to enhance intra- or peri-nuclear localization of the photosensitizer, leading to DNA damage and resulting clonogenic cell kill. This comprises a photosensitizer (Verteporfin, VP) incorporated into poly (lactic-co-glycolic acid) nanoparticles (PLGA NPs) that are surface-functionalized with a cell-penetrating HIV trans-activator of transcription (TAT) peptide. In addition to a series of physical and photophysical characterization studies, cytotoxicity tests in pancreatic (PANC-1) cancer cells in vitro under 4 Gy X-ray exposure from a clinical 6 MV linear accelerator (LINAC) showed that TAT targeting of the nanoparticles markedly enhances the effectiveness of RDT treatment, particularly when assessed by a clonogenic, i.e., DNA damage-mediated, cell kill.

Optimally preserved urinary exfoliated renal proximal tubule cells were assessed by multispectral imaging of cell autofluorescence. We demonstrated different multispectral autofluorescence signals in such cells extracted from the urine of patients with healthy or diseased kidneys. Using up to 10 features, we were able to differentiate cells from individuals with heathy kidneys and impaired renal function (indicated by estimated glomerular filtration rate (eGFR) values) with the receiver operating characteristic area under the curve (AUC) of 0.99. Using the same method, we were also able to discriminate such urine cells from patients with and without renal fibrosis on biopsy, where significant differences in multispectral autofluorescence signals (AUC = 0.90) were demonstrated between healthy and diseased patients (p

Background Metformin, a first line antihyperglycemic medication, is an AMPK activator and has been hypothesized to act as a geroprotective agent. Studies on its association with various classifications of age-related cognitive decline have shown mixed results with positive and negative findings. Objective To synthesize the best available evidence on the association of metformin-use with risk, progression, and severity of dementia. Method Eligible research investigated the effect of metformin on dementia, Alzheimer's disease, or any measure of cognitive impairment compared to any control group who were not receiving metformin. The initial search resulted in 862 citations from which 14 studies (seven cohort, four cross-sectional, two RCTs, and one case control) were included. Results Meta-analysis of three studies showed that cognitive impairment was significantly less prevalent in diabetic metformin (Odds ratio = 0.55, 95% CI 0.38 to 0.78), while six studies showed that dementia incidence was also significantly reduced (Hazard ratio = 0.76, 95% CI 0.39 to 0.88). Mini-Mental State Examination scores were not significantly affected by metformin-use, although both RCTs showed that metformin had a neuroprotective effect compared to placebo. Some studies found negative or neutral effects for metformin use by people with diabetes; the potential mechanism of metformin-induced vitamin B12 deficiency is discussed. Conclusions Metformin should continue to be used as a first line therapy for diabetes in patients at risk of developing dementia or Alzheimer's disease. The use of metformin by individuals without diabetes for the prevention of dementia is not supported by the available evidence.

Pain catastrophizing (PC), defined as an exaggerated negative cognitive-affective orientation toward pain, is one of the strongest psychological predictors of pain outcomes. Although regularly included as a process variable in clinical trials, there have been no comprehensive reviews of how it can be modified. Using a registered protocol (PROSPERO 2016 CRD42016042761), we searched MEDLINE, PsychINFO, EMBASE, CINAHL, and CENTRAL up to November 2016 for all randomized controlled trials measuring PC in adults with chronic noncancer pain. Two authors independently screened studies and assessed bias risk using the Cochrane tool. Quality of evidence was rated according to Grading of Recommendations Assessment, Development and Evaluation criteria. We included 79 studies (n = 9,914), which mostly recruited participants with musculoskeletal pain and had low risk of bias. Meta-analyses (standardized mean difference) showed 9 interventions had efficacy compared with waitlist/usual care or active control, although evidence quality was often low. The best evidence (moderate-high quality) was found for cognitive-behavioral therapy, multimodal treatment, and acceptance and commitment therapy. Effects were generally of medium strength and had questionable clinical significance. When only the 8 studies targeting people with high PC were included, effects were larger and more consistent. Multimodal treatment showed the strongest effects when all studies were considered, whereas cognitive-behavioral therapy had the best evidence among targeted studies. Perspective PC is a modifiable characteristic but most interventions produce only modest benefit unless targeted to people with high PC. More research into theory-driven interventions matched to specific patient profiles is required to improve treatment efficacy and efficiency.

REVIEW QUESTION The review question is: what is the effectiveness of primary surgery versus primary radiotherapy on disease-free survival and quality of life in adults with an unknown primary, head and neck squamous cell carcinoma?

REVIEW QUESTION The objective of this review is to investigate the association between paternal body mass index (BMI) (particularly elevated paternal BMI) and complications of conception and pregnancy as well as neonatal and childhood health.

This systematic review investigated whether the insulin sensitiser metformin has a geroprotective effect in humans. Pubmed and Embase were searched along with databases of unpublished studies. Eligible research investigated the effect of metformin on all-cause mortality or diseases of ageing relative to non-diabetic populations or diabetics receiving other therapies with adjustment for disease control achieved. Overall, 260 full-texts were reviewed and 53 met the inclusion criteria. Diabetics taking metformin had significantly lower all-cause mortality than non-diabetics (hazard ratio (HR) = 0.93, 95%CI 0.88–0.99), as did diabetics taking metformin compared to diabetics receiving non-metformin therapies (HR = 0.72, 95%CI 0.65–0.80), insulin (HR = 0.68, 95%CI 0.63–0.75) or sulphonylurea (HR = 0.80, 95%CI 0.66–0.97). Metformin users also had reduced cancer compared to non-diabetics (rate ratio = 0.94, 95%CI 0.92–0.97) and cardiovascular disease (CVD) compared to diabetics receiving non-metformin therapies (HR = 0.76, 95%CI 0.66–0.87) or insulin (HR = 0.78, 95%CI 0.73–0.83). Differences in baseline characteristics were observed which had the potential to bias findings, although statistical adjustments were made. The apparent reductions in all-cause mortality and diseases of ageing associated with metformin use suggest that metformin could be extending life and healthspans by acting as a geroprotective agent.

Integrated care is the combination of different healthcare services with the goal to provide comprehensive, seamless, effective and efficient patient care. Assessing the experiences of healthcare professionals (HCPs) is an important aspect when evaluating integrated care strategies.The aim of this rapid review was to investigate if quantitative surveys used to assess HCPs' experiences with integrated care capture all the aspects highlighted as being important in qualitative research, with a view to informing future survey development.The review considered all types of health professionals in primary care, and hospital and specialist services, with a specific focus on the provision of integrated care aimed at improving the patient journey. PubMed, CINAHL and grey literature sources were searched for relevant surveys/program evaluations and qualitative research studies. Full text articles deemed to be of relevance to the review were appraised for methodological quality using abridged critical appraisal instruments from the Joanna Briggs Institute. Data were extracted from included studies using standardized data extraction templates. Findings from included studies were grouped into domains based on similarity of meaning. Similarities and differences in the domains covered in quantitative surveys and those identified as being important in qualitative research were explored.A total of 37 studies (19 quantitative surveys, 14 qualitative studies and four mixed-method studies) were included in the review. A range of healthcare professions participated in the included studies, the majority being primary care providers. Common domains identified from quantitative surveys and qualitative studies included Communication, Agreement on Clear Roles and Responsibilities, Facilities, Information Systems, and Coordination of Care and Access. Qualitative research highlighted domains identified by HCPs as being relevant to their experiences with integrated care that have not routinely being surveyed, including Workload, Clear Leadership/Decision-Making, Management, Flexibility of Integrated Care Model, Engagement, Usefulness of Integrated Care and Collaboration, and Positive Impact/Clinical Benefits/Practice Level Benefits.There were several domains identified from qualitative research that are not routinely included in quantitative surveys to assess health professionals' experiences of integrated care. In addition, the qualitative findings suggest that the experiences of HCPs are often impacted by deeper aspects than those measured by existing surveys. Incorporation of targeted items within these domains in the design of surveys should enhance the capture of data that are relevant to the experiences of HCPs with integrated care, which may assist in more comprehensive evaluation and subsequent improvement of integrated care programs.

Review question/objective:The objective of the review is to assess the effect of metformin on the risk, progression and severity of Alzheimer's disease and other forms of dementia, as well as any measures of cognitive performance or impairment.

REVIEW OBJECTIVE The objective of this review is to systematically identify, review and synthesize relevant qualitative research on end user and implementer experiences of mobile health (mHealth) technologies developed for noncommunicable chronic disease management in young adults. "End users" are defined as young people aged 15-24 years, and "implementers" are defined as health service providers, clinicians, policy makers and administrators.The two key questions we wish to systematically explore from identified relevant qualitative studies or studies with qualitative components are.

Objectives The influence of maternal body mass index (BMI) on pregnancy and child health outcomes is well characterised, however less is known about paternal BMI. This systematic review investigated the independent effects of increased paternal BMI on conception and pregnancy as well as neonatal and childhood outcomes. Methods Our systematic search (Sept. 2018) of PubMed, Embase, Cinahl, Web of Science, ProQuest, and OpenThesis resulted in 11,045 hits from which 17 studies met the inclusion criteria (Participants: men Exposure: BMI or waist circumferences Outcomes: associations with time to pregnancy, incidence of infertility, pregnancy loss, pregnancy complications, birthweight and length, childhood weight and height, or incidence of any childhood disease). Studies had to adjust for maternal age and BMI. Results Meta-analysis was only possible for infertility which was significantly more prevalent in obese (OR = 1.49 95%CI 1.30–1.70) and overweight (OR = 1.18 95%CI 1.11–1.26) men. Individual studies showed increased likelihoods of small for gestational age and macrosomia in fathers who had increased BMI – possibly accounting for the general finding of no effect on mean birthweight in other studies. Most studies found increased BMI in fathers correlated with altered growth curves and increased BMI in childhood, while one study found a higher likelihood of autism spectrum disorder. Conclusion Our findings support increased paternal BMI negatively affecting pregnancy and child health outcomes. Future studies must include or adjust for paternal contributions, as the longstanding assumption that only maternal factors are relevant is likely to have considerably confounded prior work.

Background Western countries are increasingly using complementary and alternative medicine (CAM) to assist with relieving ailments. Turmeric, from the ginger family Zingiberaceae, has a history of use for medicinal purposes. The polyphenols found in turmeric (curcuminoids) have demonstrated anti-inflammatory and pain relieving properties. With the use of CAMs increasing, it is important for the effectiveness of curcuminoids to be established. Objectives To identify the effectiveness of the use of curcuminoids for the amelioration of musculoskeletal pain. Inclusion criteria types of participants Persons experiencing musculoskeletal pain, including experimentally induced musculoskeletal pain. Types of intervention(s)/phenomena of interest The current review considered studies that evaluated the use of curcuminoids. Types of controls Any form including placebo, treatment as usual or before and after measurements. Types of studies Both experimental and epidemiological study designs including randomized controlled trials (RCTs), non-RCTs, quasi-experimental and before and after studies were eligible for consideration in this review. Studies published in English were considered without date restriction. Outcomes The current review considered studies that included measurement of pain. Outcome measures included visual analog scales, and/or pain questionnaires. Secondary outcome measures of functionality (activities of daily living and range of motion) were included. Any data provided on adverse events were considered. Search strategy The databases PubMed, CINAHL, Embase and ProQuest were searched in March 2015 (and updated in April 2016) using the Joanna Briggs Institute (JBI) three-step search strategy. The reference lists of identified articles were reviewed for additional studies. Methodological quality Papers selected were assessed by two independent reviewers using standardized instruments from the JBI Meta-Analysis of Statistics Assessment and Review Instrument (JBI-MAStARI). Data extraction Data were extracted using the data extraction tool from JBI-MAStARI. Data extracted included details about the populations, interventions, study methods and outcomes. Data synthesis Narrative and tabular synthesis was conducted. Meta-analysis was precluded due to methodological and clinical heterogeneity across all included studies. Results Thirteen studies with a combined total of 1101 participants were included. Three studies of limited sample size examined the effects of curcuminoids compared with the use of placebo on musculoskeletal pain, with one study showing a statistically significant effect. Four studies examined the effects of curcuminoids compared with non-selective non-steroidal anti-inflammatory drugs on musculoskeletal pain. Two of these four studies were non-inferiority studies showed that the use of both curcuminoids and ibuprofen were associated with a similar significant reduction in pain over the study durations of four and six weeks, respectively, with curcuminoid use non-inferior to the use of ibuprofen over the study durations. Six studies investigated presentations of curcuminoid-containing herbomineral mixtures versus placebo or active controls. Conclusion There is insufficient evidence to recommend that curcuminoids be considered for relieving pain and improving function in musculoskeletal pain conditions. This finding needs to be considered in the context of limitations imposed by the variability in the quality of studies, small sample sizes, short duration of interventions, a gender-bias toward females, absence of long-term data extraction and small number of relevant studies.

The objective of this article is to investigate adherence to reporting standards and methodological quality in systematic reviews on burns care published in peer-reviewed journals to determine their utility for guiding evidence-based burns care. PubMed, Embase, Database of Abstracts of Reviews of Effects, Cochrane Database of Systematic Reviews, and the Joanna Briggs Institute (JBI) Database of Systematic Reviews and Implementation Reports were searched from 2009. Any systematic review on any question on therapeutic interventions in burns care was eligible for inclusion. Critical appraisal and data extraction were performed using the Assessing the Methodological Quality of Systematic Reviews (AMSTAR) tool and the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) checklist by two independent reviewers. The overall quality of the 44 included burns care systematic reviews was low, with an average methodological quality of 55% and an average compliance with reporting guidelines of 70%. Correlation analysis showed that adherence to reporting guidelines has been relatively stable, but methodological quality has deteriorated (r = -.32, P < .05). Cochrane reviews had lower citation rates than reviews published in other journals, whereas reviews that included meta-analyses had more citations. Quality did not have a significant effect on citation rate. Health professionals working in burns should be able to expect that systematic reviews published in their field are of a high standard. Unfortunately, this is not the case. To address this problem, established guidelines on the conduct and reporting of systematic reviews should be adhered to by researchers and editors.

Purpose: Methotrexate chemotherapy is associated with various toxicities which can result in the interruption or discontinuation of treatment and a subsequently raised risk of relapse. This umbrella systematic review was conducted to synthesize the results of all existing systematic reviews that investigate the pharmacogenetics of methotrexate-induced toxicity, with the aim of developing a comprehensive reference for personalized medicine. Methods: Databases searched were PubMed, Embase, JBI Database of Systematic Reviews and Implementation Reports, DARE, and ProQuest. Papers were critically appraised by two reviewers, and data were extracted using a standardized tool. Results: Three systematic reviews on methotrexate-induced toxicity were included in the review. Meta-analyses were reported across Asian, Caucasian, pediatric and adult patients for the MTHFR C677T and A1298C polymorphisms. Toxicity outcomes included different forms of hematologic, ectodermal and hepatic toxicities. Results varied considerably depending on the patient groups and subgroups investigated in the different systematic reviews, as well as the genetic models utilized. However, significant associations were found between the MTHFR C677T allele and; hepatic toxicity, myelosuppression, oral mucositis, gastrointestinal toxicity, and skin toxicity. Additionally, limited evidence suggests that the MTHFR A1298C polymorphism may be associated with decreased risk of skin toxicity and leukopenia. Conclusion: This umbrella systematic review has synthesized the best available evidence on the pharmacogenetics of methotrexate toxicity. The next step in making personalized medicine for methotrexate therapy a clinical reality is research on the effectiveness and cost-effectiveness of MTHFR genotype testing to enable the close monitoring of at-risk patients for the timely initiation of rescue therapies. Refereed/Peer-reviewed

Fluoropyrimidine (FU) and platinum-based chemotherapies are greatly complicated by their associated toxicities. This umbrella systematic review synthesized all systematic reviews that investigated associations between germline variations and toxicity, with the aim of informing personalized medicine. Systematic reviews are important in pharmacogenetics where false positives are common. Four systematic reviews were identified for FU-induced toxicity and three for platinum. Polymorphisms of DPYD and TYMS, but not MTHFR, were statistically significantly associated with FU-induced toxicity (although only DPYD had clinical significance). For platinum, GSTP1 was found to not be associated with toxicity. This umbrella systematic review has synthesized the best available evidence on the pharmacogenetics of FU and platinum toxicity. It provides a useful reference for clinicians and identifies important research gaps. Refereed/Peer-reviewed

Detecting reactive oxygen species (ROS) that play a critical role as redox modulators and signalling molecules in biological systems currently requires invasive methods such as ROS -specific indicators for imaging and quantification. We developed a non-invasive, real-time, label-free imaging technique for assessing the level of ROS in live cells and thawed cryopreserved tissues that is compatible with in-vivo imaging. The technique is based on autofluorescence multispectral imaging (AFMI) carried out in an adapted fluorescence microscope with an expanded number of spectral channels spanning specific excitation (365 nm–495 nm) and emission (420 nm–700 nm) wavelength ranges. We established a strong quantitative correlation between the spectral information obtained from AFMI and the level of ROS obtained from CellROX staining. The results were obtained in several cell types (HeLa, PANC1 and mesenchymal stem cells) and in live kidney tissue. Additioanly,two spectral regimes were considered: with and without UV excitation (wavelengths > 400 nm); the latter being suitable for UV-sensitive systems such as the eye. Data were analyzed by linear regression combined with an optimization method of swarm intelligence. This allowed the calibration of AFMI signals to the level of ROS with excellent correlation (R = 0.84, p = 0.00) in the entire spectral range and very good correlation (R = 0.78, p = 0.00) in the limited, UV-free spectral range. We also developed a strong classifier which allowed us to distinguish moderate and high levels of ROS in these two regimes (AUC = 0.91 in the entire spectral range and AUC = 0.78 for UV-free imaging). These results indicate that ROS in cells and tissues can be imaged non-invasively, which opens the way to future clinical applications in conditions where reactive oxygen species are known to contribute to progressive disease such as in ophthalmology, diabetes, kidney disease, cancer and neurodegenerative diseases.

The ISUP (Internal Society of Urologic Pathology) recently adopted a five-tiered prognostication system. There is evidence to suggest that the ISUP grade group 4 is a heterogeneous entity regarding prognosis. Our aim was to systematically examine the existing evidence to determine if outcome differences exist within the ISUP grade group 4. A systematic search of the literature for all studies examining the heterogeneity of the ISUP grade group 4 was conducted. Available studies were combined with meta-analysis to evaluate prognostic differences within the ISUP grade group 4 measured by all-cause mortality (ACM) and the prostate cancer-specific mortality (PCSM). Eight studies were identified and utilised a variety of outcome measures to answer the question of heterogeneity within the ISUP grade group 4. Four of these studies examined prognosis using both ACM and PCSM. These were combined into a meta-analysis. The combined group of 5 + 3/3 + 5 had statistically significant higher ACM (hazard ratio [HR] 1.23, 95% confidence internal [Cl] 1.08–1.41) when compared to the 4 + 4 group. There was no difference in the PCSM between the two groups (HR 1.34, 95% CI 0.89–2.01). However, heterogeneity was high for this analysis secondary to a range of methodological differences. Our meta-analysis showed that Gleason grade 3 + 5/5 + 3 had higher ACM than Gleason grade group 4 + 4. Measures of PCSM were statistically insignificant, although heterogeneity was high. Evidence suggests that heterogeneity is likely, although inconclusive. Further studies with consistent methodologies are required to answer this question.

Background Cardiovascular disease (CVD), cancer, diabetes and chronic respiratory disease are noncommunicable diseases (NCDs) that cause extensive social and economic burden worldwide, particularly in low-income and middle-income countries. There is growing recognition of the importance of the disabilities that individuals experience as a consequence of these NCDs. Objectives This systematic review examined the prevalence of disabilities associated with cancer, CVD, chronic respiratory disease and diabetes. Methods A comprehensive literature search was conducted in PubMed, CINAHL, Embase, Web of Science, PsycINFO, CIRRIE, WHO database, LILACS and AIM. Studies were included if their samples were representative of people with at least one of these four conditions and if prevalence estimates of disability were provided. As random sampling was not feasible in the majority of cases, studies were included where they offered evidence that their sample was representative of the general population being investigated. Results A total of 105 articles were included in the review. Most studies were conducted in high-income countries. The prevalence of difficulties with activities of daily living (i.e. eating, bathing, dressing) was reported to be 10.4-34.5% amongst cancer survivors, 21.1-64.1% in those with CVD, 7.4-49.8% in those with chronic respiratory disease and 12.2-54.5% for those with diabetes. The prevalence of a range of other physical, cognitive and psychological impairments (systemic or structural) was additionally described for each disease. Conclusion Substantial proportions of people with cancer, CVD, chronic respiratory disease or diabetes experience some form of disability - although there was great variance in prevalence and definitions. The findings of this review support the evidence base of global impact associated with NCD, indicate frequency measures for specific disabilities and inabilities associated with each NCD and provide direction for future systematic reviews. What is known about the topic WHAT THIS ARTICLE ADDS.

REVIEW QUESTION / OBJECTIVE Does pancreatic enzyme replacement therapy improve nutritional status such as body mass index and fat-soluble vitamins associated with improved fat absorption and better control of gastrointestinal symptoms associated with fat malabsorption in patients with pancreatic exocrine insufficiency? Does the timing of pancreatic enzyme administration and adjuvant therapy with proton pump inhibitor influence the effectiveness of pancreatic enzyme replacement therapy for patients with pancreatic exocrine insufficiency? The objectives of this review are to identify the effect of pancreatic enzyme replacement therapy on: Fat absorption in patients with pancreatic exocrine insufficiency Nutritional impact such as weight change and nutritional markers Improvement in gastrointestinal symptoms Treatment related adverse events in patients with pancreatic exocrine insufficiency. In addition to these, the timing of pancreatic enzyme administration and adjuvant therapy with proton pump inhibitors will also be investigated for its effectiveness in pancreatic enzyme replacement therapy. INCLUSION CRITERIA Types of participants This review will consider studies that include all patients with pancreatic exocrine insufficiency, including patients with chronic pancreatitis, pancreatic cancer, and a history of pancreatic surgical resection and cystic fibrosis in acute and community settings. Studies on patients with celiac disease, diabetes mellitus, human immunodeficiency virus, irritable bowel syndrome, post gastric and bowel resections will not be included as the use of pancreatic enzyme replacement therapy in these populations has not been fully accepted. Studies on patients of any age will be included. Types of intervention(s)/phenomena of interest This review will consider studies that evaluate pancreatic enzyme replacement therapy without TRUNCATED AT 250 WORDS

This systematic review investigated the effect of paternal obesity on reproductive potential. Databases searched were Pubmed, Ovid, Web of Science, Scopus, Cinahl and Embase. Papers were critically appraised by two reviewers, and data were extracted using a standardized tool. Outcomes were: likelihood of infertility, embryo development, clinical pregnancy, live birth, pregnancy viability, infant development, sperm; concentration, morphology, motility, volume, DNA fragmentation, chromatin condensation, mitochondrial membrane potential (MMP), and seminal plasma factors. Thirty papers were included, with a total participant number of 115,158. Obese men were more likely to experience infertility (OR = 1.66, 95% CI 1.53-1.79), their rate of live birth per cycle of assisted reproduction technology (ART) was reduced (OR = 0.65, 95% CI 0.44-0.97) and they had a 10% absolute risk increase of pregnancy non-viability. Additionally, obese men had an increased percentage of sperm with low MMP, DNA fragmentation, and abnormal morphology. Clinically significant differences were not found for conventional semen parameters. From these findings it can be concluded that male obesity is associated with reduced reproductive potential. Furthermore, it may be informative to incorporate DNA fragmentation analysis and MMP assessment into semen testing, especially for obese men whose results suggest they should have normal fertility.

BACKGROUND Primary research, including qualitative research, as well as experts working in social services and aged care have identified the mixed feelings carers experience when the person they have been caring for is admitted into a residential aged care facility permanently. They have raised the importance of understanding these experiences as a means to implementing policies and programs that enhance carers’ well-being. This systematic review was motivated by the need to use evidence to inform effective and feasible interventions to support carers, and the absence of a systematic review synthesizing the qualitative evidence on how carers experience this transition. OBJECTIVES The objective of this qualitative systematic review was to identify and synthesize the evidence on the experiences of carers of older people when the person they had been providing care for is admitted permanently into a residential aged care facility, and to draw recommendations from the synthesis of the evidence on these experiences to enhance policy and programming aimed at supporting affected caregivers. INCLUSION CRITERIA Types of participants: All carers of people who had experienced the person they had been caring for at home being moved into a residential aged care facility permanently. Phenomena of interest: Experiences of the caregiver of the older person when the person they have been caring for at home is admitted into a residential aged care facility permanently. Types of studies: The review considered qualitative studies, including but not limited to designs such as phenomenology, grounded theory, ethnography and action research. Types of outcomes: The outcomes are in the form of synthesized findings pertaining to carers’ experiences when the person they have been caring for is admitted into a residential aged care facility permanently. SEARCH STRATEGY A comprehensive search of leading databases which are sources of qualitative published and unpublished studies was conducted between 18 September 2013 and 10 November 2013. The search considered studies reported in English and published from the database inception to 10 November 2013. METHODOLOGICAL QUALITY Papers selected for retrieval were assessed by two independent reviewers for methodological validity prior to inclusion in the review using the Joanna Briggs Institute Qualitative Assessment and Review Instrument. DATA EXTRACTION Data were extracted from identified papers using the standardized data extraction tool from the Joanna Briggs Institute Qualitative Assessment and Review Instrument. The data extracted included descriptive details about the phenomena of interest, populations and study methods. DATA SYNTHESIS The Joanna Briggs Institute meta-aggregative approach for synthesizing qualitative evidence was used. Research findings were pooled using the Joanna Briggs Institute Qualitative Assessment and Review Instrument. Study findings that were supported by the data in primary studies were organized into categories on the basis of similarity of meaning. These categories were then subjected to a meta-synthesis to produce a set of synthesized findings. RESULTS Fourteen studies matched the inclusion criteria and were included in the review. From these 14 studies a total of 71 study findings about how carers experience the transition when the person they have been caring for is TRUNCATED AT 500 WORDS

Review question/objective The objective of this review is to identify the effectiveness of curcumin on musculoskeletal pain. More specifically, the objectives are to identify the effectiveness of the use of turmeric, turmeric extract, and/or curcuminoids to modulate musculoskeletal pain. Inclusion criteria Types of participants This review will consider studies that include any humans (children, adults and older people) experiencing musculoskeletal pain, including experimentally induced pain. Types of intervention(s) This review will consider studies that evaluate the use of turmeric, turmeric extract or curcuminoids on subjects experiencing pain of clinical or experimental origin. Where turmeric or curcumin is delivered as one component of a combination of bioactive agents and is not individually controlled for; studies will be included but considered separately. Types of controls Studies with any form of control including placebo, treatment as usual and before and after measurements will be considered in this review. Types of outcomes This review will consider studies that include the following outcome measures: pain diaries, visual analogue scales, or pain questionnaires. As a secondary outcome measures of functionality including activities of daily living and range of motion will be included. Additionally, any reports or data in selected studies on adverse events will be included.

BACKGROUND Pain management is a significant issue in health facilities in Ghana. For burn patients, this is even more challenging as burn pain has varied facets. Despite the existence of pharmacological agents for pain management, complaints of pain still persist. OBJECTIVES The aim of this project was to identify pain management practices in the burns units of Komfo Anokye Teaching Hospital, compare these approaches to best practice, and implement strategies to enhance compliance to standards. METHODS Ten evidence-based audit criteria were developed from evidence summaries. Using the Joanna Briggs Institute Practical Application of Clinical Evidence Software (PACES), a baseline audit was undertaken on a convenience sample of ten patients from the day of admission to the seventh day. Thereafter, the Getting Research into Practice (GRiP) component of PACES was used to identify barriers, strategies, resources and outcomes. After implementation of the strategies, a follow-up audit was undertaken using the same sample size and audit criteria. RESULTS The baseline results showed poor adherence to best practice. However, following implementation of strategies, including ongoing professional education and provision of assessment tools and protocols, compliance rates improved significantly. Atlhough the success of this project was almost disrupted by an industrial action, collaboration with external bodies enabled the successful completion of the project. CONCLUSION Pain management practices in the burns unit improved at the end of the project which reflects the importance of an audit process, education, providing feedback, group efforts and effective collaboration.

REVIEW QUESTION/OBJECTIVE The objective of this systematic review is to assess the effectiveness of aggressive treatment of oligometastatic breast cancer (OMBC) on survival outcomes by conducting a meta-analysis of current available evidence.More specifically, the objectives are to identify the effectiveness of intensified multidisciplinary treatment with aggressive locoregional therapies on survival time, five-year survival rates and disease free survival. The population is adult women (18 years and over) with OMBC defined as single or few (five or less) metastases limited to a single organ and the comparative group is conventional palliative treatment aimed at disease control. Secondary objectives to be assessed will be adverse outcomes associated with intensified treatment regimes.

REVIEW QUESTION/OBJECTIVE The gold standard for the diagnosis of pre-diabetes is the measurement of fasting plasma glucose and the oral glucose tolerance test. The objective of this systematic review is to identify all alternative tests currently in use for the diagnosis of type 2 pre-diabetes mellitus in children and establish their accuracy relative to this gold standard.

REVIEW OBJECTIVE The objective of this systematic review is to synthesize the best available evidence on the predictors of change in the severity of untreated lower urinary tract symptoms in men in a non-hospital setting.

Background Prostate cancer can be treated with several different modalities, including radiation treatment. Various prognostic tools have been developed to aid decision making by providing estimates of the probability of different outcomes. Such tools have been demonstrated to have better prognostic accuracy than clinical judgment alone. Methods A systematic review was undertaken to identify papers relating to the prediction of clinical outcomes (biochemical failure, metastasis, survival) in patients with prostate cancer who received radiation treatment, with the particular aim of identifying whether published tools are adequately developed, validated, and provide accurate predictions. PubMed and EMBASE were searched from July 2007. Title and abstract screening, full text review, and critical appraisal were conducted by two reviewers. A review protocol was published in advance of commencing literature searches. Results The search strategy resulted in 165 potential articles, of which 72 were selected for full text review and 47 ultimately included. These papers described 66 models which were newly developed and 31 which were external validations of already published predictive tools. The included studies represented a total of 60,457 patients, recruited between 1984 and 2009. Sixty five percent of models were not externally validated, 57% did not report accuracy and 31% included variables which are not readily accessible in existing datasets. Most models (72, 74%) related to external beam radiation therapy with the remainder relating to brachytherapy (alone or in combination with external beam radiation therapy). Conclusions A large number of prognostic models (97) have been described in the recent literature, representing a rapid increase since previous reviews (17 papers, 1966–2007). Most models described were not validated and a third utilised variables which are not readily accessible in existing data collections. Where validation had occurred, it was often limited to data taken from single institutes in the US. While validated and accurate models are available to predict prostate cancer specific mortality following external beam radiation therapy, there is a scarcity of such tools relating to brachytherapy. This review provides an accessible catalogue of predictive tools for current use and which should be prioritised for future validation. Electronic supplementary material The online version of this article (doi:10.1186/s13014-017-0786-z) contains supplementary material, which is available to authorized users.

This systematic review investigated the effectiveness and safety of intensive insulin therapy (IIT), insulin secretagogues and sensitisers in burn patients. PubMed, Embase, clinicaltrials.gov and Cochrane central were searched from 1990 to 2016. Title/abstract screening, full-text review, critical appraisal and data extraction were carried out by two independent reviewers. Inclusion criteria were hospitalised burn patients, IIT, insulin sensitisers or secretagogues and the outcomes mortality, length of stay, resting energy expenditure, blood glucose, catabolism, or complications. We identified 594 potential studies of which 13 were included. Five studies investigated IIT in paediatric patients, 3 investigated IIT in adults and 5 investigated sensitisers or secretagogues. Glycaemic targets differed with age group - paediatric studies compared IIT to loose glycaemic control while adult studies compared IIT to more moderate control. Meta-analyses were limited by differences in outcome reporting, however mortality was increased in children by loose glycaemic control (OR=3.78, 95%CI 1.19-12.02) but not significantly affected in adults by moderate compared to tight control. Meta-analyses could not be performed for sensitisers or secretagogues. These findings support recommendations that moderate insulin administration (130-150mg/dL) is the prudent approach in burn patients. The evidence is relatively sparse and further research is warranted.

Prostate cancer is a heterogeneous disease whose therapies frequently have adverse effects. Informed patient counseling regarding likely clinical outcomes is therefore important. In this systematic review we aimed to identify all external validations of tools that are used to predict clinical outcomes in patients undergoing radical prostatectomy and evaluate which are optimum for clinical implementation. PubMed and EMBASE were searched from 2007 to 2016. Search terms related to the inclusion criteria were: prostate cancer, clinical outcomes, radical prostatectomy, and prognosis. Titles and abstracts were screened and relevant studies were advanced to full-text review. Reference lists were reviewed for further studies. The Centre for Evidence Based Medicine prognostic tool was used for critical appraisal. Seventy-three studies externally validated 13 pre- and 41 postoperative tools for the prediction of biochemical recurrence (BCR), aggressive BCR, metastasis, and prostate cancer-specific mortality (PCSM). Recommendations for clinical implementation were made on the basis of accuracy, cohort sizes, and consistency. The accuracy of recommended tools ranged from 68% to 79% and 72% to 92% among the largest validation cohorts for pre- and postoperative tools. For preoperative prognosis we recommended the Cancer of the Prostate Risk Assessment (CAPRA) and Stephenson nomograms for BCR, the CAPRA nomogram for aggressive BCR as well as metastasis, and the D'Amico criteria for PCSM. For postoperative prognosis we recommended the CAPRA-Surgery (CAPRA-S), Stephenson, Kattan, Duke prostate cancer (DPC), and the Suardi nomograms for the prediction of BCR, the DPC nomogram for aggressive BCR, the CAPRA-S and Eggener nomograms for metastasis, and the Eggener nomogram for PCSM. Use of these tools should help clinicians deliver accurate, evidence-based counseling to patients undergoing prostatectomy. Refereed/Peer-reviewed

Background:Radical prostatectomy is a common surgical procedure performed to treat prostate cancer. Patient-reported outcomes after surgery include urinary incontinence, erectile dysfunction, decreased quality of life and psychological effects. Predictive tools to assess the likelihood of an individual experiencing various patient-reported outcomes have been developed to aid decision-making when selecting treatment. METHODS: A systematic review was undertaken to identify all papers describing tools for the prediction of patient-reported outcome measures in men with prostate cancer treated with radical prostatectomy. To be eligible for inclusion, papers had to provide a summary measure of accuracy. PubMed and EMBASE were searched from July 2007. Title/abstract screening, and full-text review were undertaken by two reviewers, while data extraction and critical appraisal was performed by a single reviewer. RESULTS: The search strategy identified 3217 potential studies, of which 191 progressed to full-text review and 14 were included.From these studies, 27 tools in total were identified, of which 18 predicted urinary symptoms, six predicted erectile function and one predicted freedom from a group of three outcomes (‘trifecta’) (biochemical recurrence, incontinence and erectile dysfunction). On the basis of tool accuracy (470%) and external validation, two tools predicting incontinence and two tools predicting erectile dysfunction are ready for implementation CONCLUSIONS: A small number of tools for the prediction of patient-reported outcomes following radical prostatectomy have been developed. Four tools were found to have adequate accuracy and validation and are ready for implementation for the prediction of urinary incontinence and erectile dysfunction Refereed/Peer-reviewed

Irinotecan chemotherapy toxicities can be severe, and may result in treatment delay, morbidity and in some rare cases death. This systematic review of systematic reviews synthesises all meta-analyses on biomarkers for irinotecan toxicity across all genetic models for Asians, Caucasians, low dose, medium/high dose and regimens with and without fluorouracil. False-positive findings are a problem in pharmacogenetics, increasing the importance of systematic reviews. Four systematic reviews that investigated the effect of the polymorphisms UGT1A1∗6 and/or∗28 on neutropenia or diarrhoea toxicity were included. Both UGT1A1∗6 and ∗28 were reliably demonstrated to be risk factors for irinotecan-induced neutropenia, with tests for both polymorphisms potentially being particularly useful in Asian cancer patients. UGT1A1∗6 and ∗28 were also related to diarrhoea toxicity; however, at low doses of irinotecan there was evidence that UGT1A1∗28 was not. In synthesising the best available evidence, this umbrella systematic review provides a novel reference for clinicians applying personalised medicine and identifies important research gaps. Refereed/Peer-reviewed

Human embryos donated for embryonic stem cell (ESC) derivation have often been cryopreserved for 5–10 years. As a consequence, many of these embryos have been cultured in media now known to affect embryo viability and the number of ESC progenitor epiblast cells. Historically, these conditions supported only low levels of blastocyst development necessitating their transfer or cryopreservation at the 4–8-cell stage. As such, these embryos are donated at the cleavage stage and require further culture to the blastocyst stage before hESC derivation can be attempted. These are generally of poor quality, and, consequently, the efficiency of hESC derivation is low. Recent work using a mouse model has shown that the culture of embryos from the cleavage stage with insulin to day 6 increases the blastocyst epiblast cell number, which in turn increases the number of pluripotent cells in outgrowths following plating, and results in an increased capacity to give rise to ESCs. These findings suggest that culture with insulin may provide a strategy to improve the efficiency with which hESCs are derived from embryos donated at the cleavage stage.

The systematic review was undertaken to investigate the effectiveness of physical therapy interventions for improving gross motor skills (GMSs) in people with an intellectual disability aged 6 years and older. There is a lack of physical therapy research for GMSs in this population, and no prior systematic review. People with an intellectual disability may require specific teaching approaches within therapy interventions to accommodate their cognitive and learning needs. People with an intellectual disability who suffer from GMS deficits can benefit from physical therapy to help improve their GMSs.Data sources were PubMed, CINAHL, Embase, and ProQuest. Reference lists of relevant identified articles were also hand searched. Papers published in English from 1 January 2008 to 22 October 2014 were considered for inclusion. This start date was chosen to reflect the tenets of the United Nations Convention on the Rights of Persons with Disabilities which was ratified in 2008.Eligible study designs for inclusion were randomized controlled trial (RCT), pseudo-RCT, repeated measures, and case report. Overall, 887 potential articles were identified, of which 42 were retrieved for full-text review, and seven were finally included. Critical appraisal was independently conducted by two reviewers using the Joanna Briggs Institute appraisal checklists; no articles were excluded following critical appraisal. Data extraction was performed using Joanna Briggs Institute Meta-Analysis of Statistics Assessment and Review Instrument data extraction instruments.High heterogeneity between the studies precluded meta-analysis of the results; a narrative synthesis was completed instead. Two RCTs, two pseudo-RCTs, two repeated measures studies, and one case report were included. Studies varied in regard to participants' intellectual disability, and the clinical interventions used. Interventions were well tolerated with negligible adverse effects. Significant improvements were reported for cadence and nondimensionalized gait velocity following body-weight-supported gait training; cadence following lower limb strengthening exercises; and the Gross Motor Function Measure-88 measures following adapted judo training. These results suggest that task-specific training may be useful. However, the overall quality of evidence was low.The evidence identified by this systematic review supporting physical therapy for improving GMSs in people with an intellectual disability was limited because of the low quality of studies (only two were RCTs) and only three statistically significant findings. Given the current paucity of evidence, a future systematic review, which sought to identify evidence regarding interventions used by a range of health and education professionals for improving GMSs in people with an intellectual disability, could provide a broader evidence base for clinical interventions which may be utilized by physical therapists.

Systematic reviews are carried out to provide an answer to a clinical question based on all available evidence (published and unpublished), to critically appraise the quality of studies, and account for and explain variations between the results of studies. The Joanna Briggs Institute specializes in providing methodological guidance for the conduct of systematic reviews and has developed methods and guidance for reviewers conducting systematic reviews of studies of diagnostic test accuracy. Diagnostic tests are used to identify the presence or absence of a condition for the purpose of developing an appropriate treatment plan. Owing to demands for improvements in speed, cost, ease of performance, patient safety, and accuracy, new diagnostic tests are continuously developed, and there are often several tests available for the diagnosis of a particular condition. In order to provide the evidence necessary for clinicians and other healthcare professionals to make informed decisions regarding the optimum test to use, primary studies need to be carried out on the accuracy of diagnostic tests and the results of these studies synthesized through systematic review. The Joanna Briggs Institute and its international collaboration have updated, revised, and developed new guidance for systematic reviews, including systematic reviews of diagnostic test accuracy. This methodological article summarizes that guidance and provides detailed advice on the effective conduct of systematic reviews of diagnostic test accuracy.

Clinicians and other healthcare professionals need access to summaries of evidence-based information in order to provide effective care to their patients at the point-of-care. Evidence-based practice (EBP) point-of-care resources have been developed and are available online to meet this need. This study aimed to develop a comprehensive list of available EBP point-of-care resources and evaluate their processes and policies for the development of content, in order to provide a critical analysis based upon rigor, transparency and measures of editorial quality to inform healthcare providers and promote quality improvement amongst publishers of EBP resources.A comprehensive and systematic search (Pubmed, CINAHL, and Cochrane Central) was undertaken to identify available EBP point-of-care resources, defined as "web-based medical compendia specifically designed to deliver predigested, rapidly accessible, comprehensive, periodically updated, and evidence-based information (and possibly also guidance) to clinicians."A pair of investigators independently extracted information on general characteristics, content presentation, editorial quality, evidence-based methodology, and breadth and volume.Twenty-seven summary resources were identified, of which 22 met the predefined inclusion criteria for EBP point-of-care resources, and 20 could be accessed for description and assessment. Overall, the upper quartile of EBP point-of-care providers was assessed to be UpToDate, Nursing Reference Centre, Mosby's Nursing Consult, BMJ Best Practice, and JBI COnNECT+.The choice of which EBP point-of-care resources are suitable for an organization is a decision that depends heavily on the unique requirements of that organization and the resources it has available. However, the results presented in this study should enable healthcare providers to make that assessment in a clear, evidence-based manner, and provide a comprehensive list of the available options.

Androgen deprivation therapy (ADT) can result in a range of adverse symptoms that reduce patients' quality of life. Careful patient counseling on the likely clinical outcomes and adverse effects is therefore vital. The present systematic review was undertaken to identify and characterize all the tools used for the prediction of clinical and patient-reported outcome measures (PROMs) in patients with prostate cancer undergoing ADT. PubMed and EMBASE were systematically searched from 2007 to 2016. Search terms related to the inclusion criteria were: prostate cancer, clinical outcomes, PROMs, ADT, and prognosis. Titles and abstracts were reviewed to find relevant studies, which were advanced to full-text review. The reference lists were screened for additional studies. The Centre for Evidence Based Medicine critical appraisal of prognostic studies tool was applied. The search strategy identified 8755 studies. Of the 8755 studies, 22 on clinical outcomes were identified. However, no studies of PROMs were found. Nine tools could be used to predict clinical outcomes in treatment-naive patients and 10 in patients with recurrence. The Japan Cancer of the Prostate Risk Assessment (J-CAPRA) nomogram was the best performing and validated tool for the prediction of clinical outcomes in treatment-naive patients, and the Chi and Shamash prognostic indexes have been validated for use in patients with castration-resistant disease in different clinical contexts. Using the J-CAPRA nomogram should help clinicians deliver accurate, evidence-based counseling to patients undergoing primary ADT. A strong need exists for primary studies that derive and validate tools for the prediction of PROMs in patients undergoing ADT under any circumstance because these are currently absent from the literature. Refereed/Peer-reviewed