To conclude the evidence from systematic reviews (SRs) and meta-analyses assessing the effectiveness of acupuncture to treat couples with subfertility undergoing ART. We searched the major databases from their inception to March 2018: PubMed, Embase, The Cochrane Library, China National Knowledge Infrastructure (CNKI), Wanfang Database, Chongqing VIP, and Sino-Med (the Chinese database). The primary outcomes of the overview were live birth and clinical pregnancy, and secondary outcomes were ongoing pregnancy, miscarriage, and adverse events. Study selection, quality assessment, and data extraction were performed independently by two review authors. Review methodological quality was assessed by using the AMSTAR tool, and the quality of the evidence was rated by GRADE methods. Eleven systematic reviews were included and published between 2009 and 2017. Our study showed that the acupuncture treatment seems to be a useful tool to improve the clinical pregnancy rate in patients who undergo assisted reproduction therapy. However, there was no evidence that acupuncture had any effect on live birth rate, ongoing pregnancy rates, or miscarriage regardless of whether acupuncture was performed around the time of oocyte retrieval or around the day of embryo transfer; this evidence is inconclusive because of the low quality of the included studies. The evidence for acupuncture to treat couples with subfertility undergoing ART remains unclear. Further research is needed, with high-quality trials undertaken and reported. With rapid development of the economy, changes in lifestyles, and aggravation of environmental pollution, the incidence of infertility has gained increased worldwide attention. According to the Centers for Disease Control and Prevention's (CDC) 2011–2015 report, 12.1% of American women aged 15–44 years have impaired ability to conceive or carry a baby to term; the majority 7.3 million) seeks fertility treatment [ million Acupuncture is an important part of traditional Chinese medicine and traces back at least 3,000 years. Recently, it has gained significant popularity in the Western world, due to its lack of side effects, convenience, and unique effect on general well-being . It reliThe increased use of acupuncture in the management of infertility has been reflected in the expansion of the number of clinical trials and systematic reviews (SRs) studying this type of treatment, but its effectiveness has remained controversial. Some studies showed that acupuncture was significant in improving ART outcomes . The speMany recent meta-analyses and SRs have analyzed the effects of acupuncture among women undergoing ART, and controversial results have been reported.The aim of this paper was to assess the effectiveness of acupuncture to treat the couples with subfertility undergoing ART by summarising the evidence from SRs and meta-analyses.We selected SRs and meta-analyses that were based on randomized controlled trials (RCT). Narrative reviews and other overviews were excluded. The language placed in any of the studies is limited to Chinese and English.Participants in eligible studies were infertile couples undergoing ART whether primary infertility or secondary infertility, and any type of acupuncture at any or all time points before, during, or after ART with the purpose to improve the ART outcome.The following studies were considered: SRs or meta-analyses comparing acupuncture treatment of participants versus no treatment, placebo or sham acupuncture during controlled ovarian stimulation (COS), in vitro fertilization (IVF), intracytoplasmic sperm injection (ICSI), and frozen-thawed embryo transfer (FET).The therapeutic intervention includes traditional needling acupuncture, electroacupuncture, and moxibustion with warming needle, auricular acupuncture, and laser acupuncture. We excluded studies that did not involve skin penetration, such as tap-pricking, scrapping, point injection, acupressure, or blood-letting puncture and cupping.Needling in the control groups could be with either placebo acupuncture or sham needle; no needling treatment is also considered. We excluded studies comparing different acupuncture treatments alone.The primary outcome of this overview was live birth rate and clinical pregnancy rate. Secondary outcomes were ongoing pregnancy, miscarriage, and side effects.We searched digital databases for relevant studies: PubMed (1977 to March 2018), Embase (1974 to March 2018), The Cochrane Library (March 2018), Chinese databases such as the China National Knowledge Infrastructure (CNKI) (1982 to March 2018), Wanfang Database (1990 to March 2018), Chongqing VIP (1989 to March 2018), and the Chinese database Sino-Med  (1990 to March 2018). The reference lists of relevant articles were examined to identify citations not captured by electronic searches. The corresponding authors were contacted for missing information.The following terms were searched as free text terms and Medical Subject Headings terms: acupuncture, acupuncture therapy, electro acupuncture, acupoint, needle, warm needling, acupuncture plus moxibustion, auricular acupuncture, auricular needle, ear acupuncture, and moxibustion; reproduce, ART, assisted reproductive, assisted conception, infertility, in vitro fertilization, IVF, embryo transfer, ICSI, and intracytoplasmic sperm injection. And the Medical Subject Headings terms were “acupuncture therapy”, “reproduction”, “reproductive Techniques, Assisted” and “infertility”. We combined these searches strategy with a filter for systematic review and meta-analysis.The following terms were searched in the Chinese database: ZHEN JIU (which means “acupuncture”), ZHEN CI(“acupuncture”), HAO ZHEN (“acupuncture”), TI ZHEN(“acupuncture”), DIAN ZHEN (“electro acupuncture”), WEN ZHEN(“warm needling”), ER ZHEN (“auricular acupuncture”), JIU (“moxibustion”) and XUE WEI (“acupoint”) and BU YUN (“infertility”), SHEN ZHI (“reproduce”), FU ZHU SHENG ZHI (“assisted reproductive”), TI WAI SHOU JING(“in vitro fertilization”), PEI TAI YI ZHI (“embryo transfer”), SHI GUAN YING ER (“in vitro fertilization”), and LUAN PAO JIANG NEI DNA JING ZI XIAN WEI ZHU SHE (“intracytoplasmic sperm injection”). (See the Appendix for details of the literature search.)The titles and abstracts of all searches, hiding the name of the study author, were independently read by two reviewers, and then the full texts of all potentially eligible articles were obtained. Two review authors independently examined these full text articles in accordance with the inclusion criteria and selected eligible studies for inclusion in the review. In cases of duplicate publication, the most recent and complete versions were selected. Any disagreement in the process was resolved by consensus or arbitration by an experienced and authoritative third reviewer.Two reviewers extracted data independently using a standardized data extraction form. The following specific characteristics were extracted from each study: the first author, year of publication, number of RCTs, number of participants, details of the acupuncture intervention, type of control, and outcome measures. The corresponding authors were contacted by email for missing information.Quality assessment of the reviews was performed by Assessment of Multiple Systematic Reviews (AMSTAR) criteria, a validated instrument with good construct validity and reliability . It contThe Grades of Recommendations, Assessment, Development and Evaluation (GRADE) approach was used to assess the level of evidence and summarise each outcome . GRADE pThe narrative description of the included studies was provided, and the network meta-analysis was not undertaken. The Forest plots were performed with StataMP 14.0.A total of 478 citations were acquired from the electronic search, and 76 duplicated articles were identified and excluded. 366 citations were excluded after screening the titles and abstracts for a variety of reasons, such as types of studies, interventions, and patients. Therefore, the full texts of the remaining 36 citations were retrieved for further evaluation. Twenty-five publications were excluded for the following reasons: six –21 were The included reviews were published between 2009 and 2017; nine were published in English and three in Chinese. The number of RCTs included in the SRs varied widely, ranging from 4 to 32 studies; the quality assessment scales of the original studies varied across the included systematic reviews: ten used the risk of bias from the Method Guidelines for Systematic Reviews in the Cochrane Review Group, and one  adopted The quality of the included reviews was rated by AMSTAR. The number of SRs meeting the criteria for these items varied widely, and six items were satisfied: all reviews that described the characteristics of the included studies; all reviews that assessed study quality; all reviews that used the scientific quality appropriately in formulating conclusions; all reviews that combined the studies using appropriate methods; all reviews that have duplicate study selection and data extraction; ten reviews that achieved a comprehensive literature search; and eight reviews that searched the grey literature. In contrast, four items accounted for the major methodological limitations: only three reviews provided an “a priori” design; three reviews listed included and excluded studies; five reviews assessed the likelihood of publication bias; five reviews included the conflict of interest. See The quality levels of evidence of all outcomes from primary studies determined by GRADE were low or very low because of the study limitations within the trials, inconsistency, and the possibility of publication bias .The outcome measures looked at by different studies include live birth rate, clinical pregnancy, ongoing pregnancy rate, miscarriage rate, and side effects. Due to the low incidence of these outcomes, some reviews use Odds Ratio (OR) instead of Relative Ratio (RR) to assess outcomes; we compare them with RR accounting from the raw data, with Forest plot.  There was no evidence that acupuncture had any effect on live birth rate regardless of whether acupuncture was performed around the time of oocyte retrieval or around the day of embryo transfer. Maybe because the quality of the transplanted embryo is most important for the outcomes of IVF, in addition, the condition of the endometrium and the systemic health status of the woman are involved. But the acupuncture treatment that is accompanied by the assisted reproductive technology cannot fundamentally affect the condition of the ovum, which is essential for the quality of the embryo. Therefore, the impact of acupuncture on overall pregnancy and childbirth outcomes is limited. (2) Most SRs of our study demonstrated that the acupuncture could improve the clinical pregnancy rate in patients who undergo assisted reproduction therapy. But some studies showed no significant difference in the CPR between the acupuncture and control group, maybe due to the low quality of the included studies. Acupuncture treatment at or around the time of IVF may increase uterine blood flow, modulate immune function, inhabit uterine motility, and relieve anxiety, depression, and stress . And theBased on the ability of acupuncture to increase the flow of Qi at needle insertion points, Chinese medicine practitioners have historically believed that acupuncture is particularly effective in increasing clinical pregnancy rates. But most reviews showed no significant improvement in outcomes of assisted reproductive technology when acupuncture was performed. The inability of our overview to provide evidence that acupuncture can be effective for female infertility may be due to the low quality of the included reviews. The lack of high-quality SRs may be due to small study populations, poorly designed RCTs, and methodological flaws. Further well-designed and sufficiently powered randomized trials to evaluate the effectiveness of acupuncture on ART outcomes should be carried out. In addition, more comprehensive outcomes should be observed, especially the live birth rate.Embryo quality is one of the most important prognostic factors in IVF and oocyte quality plays a major role in the development potential of embryo . Li J etOur study is the first summary of the effects of acupuncture on the outcomes of ART with an overview. In order to enable this overview informative for clinicians and researchers, we established strict inclusion criteria and the data were separated according to the time of treatment; however, limited to language, the study included only systematic reviews published in Chinese and English. At the same time, only the published systematic reviews were searched and may miss the unpublished literature, so there is a certain publication bias.To conclude, the evidence for acupuncture to increase the success rate of ART is unclear. Thus, physicians should apply the evidence to make decisions about acupuncture for infertile women under ART with caution in clinical practice and consider the actual situation, combined with the patient's value preferences and economic factors.


Carpal tunnel syndrome (CTS) occurs when the median nerve becomes compressed as it passes through the wrist within the carpal tunnel, resulting in pain, tingling, weakness, or numbness in the hand or the wrist. Occupational risk factors for CTS include engaging in work activities that require forceful, repetitive tasks, prolonged use of the hands or wrists in an awkward posture, or vibration , material moving (13.4), and office and administrative support (13.0) . The CenIn this examination of statewide trends in demographic and occupational risk factors for CTS during 2007–2014 using California’s workers’ compensation claims, the overall incidence of CTS was 6.3 per 10,000 FTE, and the rate was approximately three times higher in women than in men. The rate decreased over time; however, this trend also mirrors a decrease in all-cause workers’ compensation claims and could be related to delayed diagnosis and reporting of CTS to workers’ compensation insurers or insurers’ misclassification of workers’ compensation CTS claims. Improved workplace ergonomic designs and employment demographic shifts might have contributed to this trend. Industries with high rates of CTS included those that manufacture apparel, process food, and perform administrative work. The occupation groups with the highest rates included production workers, material moving workers, and office and administrative support workers. Workers in these occupations are often required to perform forceful or repetitive tasks with their hands , or maintain an awkward posture on the job , all known risk factors for CTS.These findings are consistent with those previously reported using data from the 2010 National Health Interview Survey, which estimated that the prevalence of CTS was higher among women, and that the highest ratios of CTS cases to percentage of workforce were among production, office and administrative support, and personal care and service occupations   was occupation coded because of the time and resources necessary to code occupation, even with the assistance of the NIOSH Industry and Occupation Computerized Coding System. Whether the occupations at risk for CTS changed over time is not addressed by this analysis.Analysis of workers’ compensation records is helpful for understanding the industries and occupations that are at a higher risk for CTS and for determining allocation of limited resources for prevention. Industries and occupations identified with high rates of CTS should consider implementing intervention measures, including ergonomic evaluations and development of tools and instruments that require less repetition and force and correct awkward postures. States could use their workers’ compensation data to identify cases of CTS and use this information to target prevention activities. Carpal tunnel syndrome (CTS) is an important contributor to work-related disability.Workers’ compensation claims of CTS in California during 2007–2014 overall were 6.3 per 10,000 full-time equivalent workers. Female workers and workers in industries that manufacture apparel, process food, and perform administrative work were at highest risk for CTS. The highest rates of CTS were among telephone operators; cafeteria, food concession, and coffee shop counter attendants; and electrical, electronics, and electromechanical assemblers.Industries with high rates of CTS should consider implementing intervention measures, including ergonomic evaluations and development of tools and instruments that require less repetition and force and correct awkward postures.


Cancer cells possess remarkable abilities to adapt to adverse environmental conditions. Their survival during severe nutrient and oxidative stress depends on their capacity to acquire extracellular lipids and the plasticity of their mechanisms for intracellular lipid synthesis, mobilisation, and recycling. Lipid droplets, cytosolic fat storage organelles present in most cells from yeast to men, are emerging as major regulators of lipid metabolism, trafficking, and signalling in various cells and tissues exposed to stress. Their biogenesis is induced by nutrient and oxidative stress and they accumulate in various cancers. Lipid droplets act as switches that coordinate lipid trafficking and consumption for different purposes in the cell, such as energy production, protection against oxidative stress or membrane biogenesis during rapid cell growth. They sequester toxic lipids, such as fatty acids, cholesterol and ceramides, thereby preventing lipotoxic cell damage and engage in a complex relationship with autophagy. Here, we focus on the emerging mechanisms of stress-induced lipid droplet biogenesis; their roles during nutrient, lipotoxic, and oxidative stress; and the relationship between lipid droplets and autophagy. The recently discovered principles of lipid droplet biology can improve our understanding of the mechanisms that govern cancer cell adaptability and resilience to stress. Cancer cells are often faced with an inconsistent and limited availability of nutrients due to poor vascularization . They poLipid droplets store neutral lipids, mostly triacylglycerol (TAG) and sterol esters, and balance lipid uptake, storage and use according to cellular needs . They haFirst, lipid droplets are central anti-lipotoxic organelles that control FA, diacylglycerol (DAG), cholesterol and ceramide lipotoxicity by sequestering these potentially toxic lipids into inert triglycerides, cholesterol esters and acylceramides ,39,40,41Second, lipid droplets provide FAs not only for energy production during both nutrient and oxygen deprivation, but also for the maintenance of redox homeostasis see . In cancThird, lipid droplets dynamically interact with mitochondria in response to nutrient cues and provide a network of conduits for efficient channelling of FAs, thereby enabling a homogenous distribution of FAs into tubulated mitochondria and maximizing the efficiency of FA oxidation during starvation see  25,41].,41.25,41Fourth, lipid droplets are crucial for the maintenance of membrane and ER homeostasis. They contribute to membrane and protein quality control and are involved in the removal of damaged lipids, aggregated and unfolded proteins, thereby reducing ER stress ,45,46,47Fifth, lipid droplets are engaged in a complex relationship with autophagy  and sterol-regulatory element binding proteins (SREBPs)—or they are converted into bioactive lipid mediators, such as eicosanoids, that act as paracrine and autocrine messengers affecting inflammatory signalling, metabolism, proliferation, migration, and metastasis ,64,65,66In this review, we focus on recent advances describing the involvement of lipid droplets in the protection against nutrient, lipotoxic, and oxidative stresses. We discuss the emerging mechanisms of stress-induced lipid droplet biogenesis, the roles of lipid droplets during stress, and the complex bidirectional relationship between lipid droplets and autophagy. Because studies on the role of lipid droplets in cancer are relatively scarce, we provide a broader overview of lipid droplet function in cellular stress in various tissues and pathophysiological settings. Many of these recently discovered principles of lipid droplet biology can improve our understanding of the mechanisms that govern cancer cell resistance to stress. Lipid droplets have a unique structure among organelles with a central core of neutral lipids surrounded by a phospholipid monolayer and numerous peripheral and embedded proteins ,71,72. TLipid droplets are broken down by two major mechanisms: lipolysis and lipophagy ,57,83,842 (sPLA2s) . I. I271]. A coordinated regulation of lipophagy and lipolysis has also been suggested through a direct interaction between microtubule-associated protein light chain 3 (LC3) and ATGL . Cold exThe crosstalk between lipid droplets and autophagy/lipophagy also extends to recent discoveries, suggesting that lipid droplets are necessary for the proper initiation and execution of autophagy . The con2 γ (iPLA2γ), displays PLA2 activity and preferentially hydrolyses arachidonic acid-containing membrane phospholipids [Furthermore, it has been shown recently that lipolysis mediated by ATGL (PNPLA2) may stimulate autophagy/lipophagy in the liver . It was holipids . PNPLA8 holipids ,197,279.holipids . These sholipids . As discussed above, the importance of autophagy for lipid droplet breakdown has been well established in the last decade, but autophagy also affects lipid droplet biogenesis. Studies in 3T3-L1 preadipocytes have shown that the depletion of Atg5 and Atg7 leads to a reduced lipid droplet accumulation and impaired differentiation . SimilarThe first clues for understanding the reasons for lipid droplet biogenesis in starved cells came from recent studies showing that autophagy contributes to lipid droplet biogenesis in acutely starved MEFs ,31. GeneChlamydomonas [Autophagy-induced lipid droplet biogenesis has been recently associated with the protection of mesenchymal stem cells against nutrient and oxidative stress . Carnitiydomonas . ClearlyLipid droplets have long been regarded as inert fat storage depots and we know very little about their lipid and protein composition, dynamics, and functions in the cell. Along with the increasing interest in lipid metabolism in cancer in the last decade, there is an emerging appeal for studying lipid droplets and their role in the cellular stress response. The extra- and intracellular sources of lipids used by cells for lipid droplet biogenesis and the reasons behind lipid droplet accumulation in different pathophysiological settings are only beginning to emerge. It is also not clear how different stress conditions affect the choice of lipids for lipid droplet biogenesis and how lipid droplets regulate the release of particular species of lipids from their core. Likewise, one of the outstanding questions in cancer research is which lipid sources are used by cancer cells for survival in particular stress conditions and how cells switch between them. Furthermore, it will be important to get a broader and quantifiable picture of the lipid species stored in lipid droplets in various cells and tissues and improve our ability to follow the dynamic changes in the lipid droplet lipidome and proteome. For example, it will be fascinating to discover how different stress conditions and diseases are reflected by changes in the lipidome/proteome and what the roles of the numerous fatty acid, cholesterol and ceramide species stored in lipid droplets are. The potential of lipid droplets as lipid mediator signalling hubs is also emerging and provides exciting prospects for their role in inflammation and immunity. Identification of lipid droplet-associated proteins involved in sensing and responding to nutrient and oxidative stress will improve our understanding of lipid droplet functions in the stressed cancer cell. Studies will also provide important clues on the identity of lipid droplet proteins that are specifically recognized by the lipophagic machinery. It will also be important to see how cells switch between lipolysis and lipophagy and how these complementary processes of lipid droplet breakdown are regulated. Moreover, lipid droplet biogenesis may be a general cellular response to conditions of high autophagic flux. Clearly, we are only at the beginning of our understanding of the complex network of interactions between lipid droplets and the various forms of autophagy. Finally, interfering with lipid droplet biogenesis and/or breakdown may be beneficial for reducing the ability of cancer cells to cope with stress in therapeutic settings. The inhibition of lipid droplet biogenesis could compromise lipid acquisition and usage pathways in cancer cells by concomitantly increasing lipotoxicity and shutting down critical survival mechanisms. Current studies imply that several molecular targets, such as DGAT1, ATGL and LPCAT2, hold promise for reducing the availability of lipids critical for the survival, growth, and metastatic potential of cancer cells. However, given the pleiotropic roles of lipid droplets, it will be critical to first define the dependence of particular cancer types on lipid droplet metabolism. For example, targeting lipid droplet lipolysis  may be particularly useful for the treatment of cancers that depend on and strive in the vicinity of adipose tissue, such as breast and ovarian cancer. ATGL inhibitors are currently under investigation as promising therapeutic agents for the treatment of metabolic disorders, but they may also prove to be beneficial in the prevention of cancers associated with obesity and diabetes. Future studies of the roles of lipid droplets in challenged (cancer) cells will surely provide important answers to many of these questions and will improve our ability to target the specific vulnerabilities of different cancer cells in their respective environments.


Eye care professionals should have access to high quality clinical practice guidelines that ideally are underpinned by evidence from robust systematic reviews of relevant research. The aim of this study was to identify clinical guidelines with recommendations pertaining to dietary modification and/or nutritional supplementation for age-related macular degeneration (AMD), and to evaluate the overall quality of the guidelines using the Appraisal of Guidelines for Research and Evaluation II (AGREE II) instrument. We also mapped recommendations to existing systematic review evidence. A comprehensive search was undertaken using bibliographic databases and other electronic resources for eligible guidelines. Quality appraisal was undertaken to generate scores for each of the six AGREE II domains, and mapping of extracted nutritional recommendations was performed for systematic reviews published up to March 2017. We identified 13 national and international guidelines, developed or updated between 2004 and 2019. These varied substantially in quality. The lowest scoring AGREE II domains were for ‘Rigour of Development’, ‘Applicability’ (which measures implementation strategies to improve uptake of recommendations), and ‘Editorial Independence’. Only four guidelines used evidence from systematic reviews to support their nutritional recommendations. In conclusion, there is significant scope for improving current Clinical Practice Guidelines for AMD, and guideline developers should use evidence from existing high quality systematic reviews to inform clinical recommendations. Age-related macular degeneration (AMD) is an ocular disease affecting the central area of the retina (the macula), which is responsible for high-resolution daytime vision . In the AMD is a complex disorder with several non-modifiable and modifiable risk factors . The retBased on accumulating research evidence, dietary modification and/or nutritional supplementation has been proposed as a simple and potentially cost-effective strategy for modifying the risk of AMD. Although there is a large body of research in this area, the quality of studies is highly variable and conflicting results have been reported. These factors pose challenges for clinicians, when attempting to provide evidence-based recommendations to patients about the relative risks and benefits of nutrition-based interventions. Clinical practice guidelines can be used to aid clinical decision-making in such circumstances. These documents should contain recommendations that are informed by a systematic review of the available research evidence, and a consideration of the benefits and harms of alternative interventions . In the (1) Identify clinical practice guidelines for AMD that contain nutritional recommendations, based upon a systematic literature search; (2) Evaluate the quality of these guidelines using the Appraisal of Guidelines for Research and Evaluation II (AGREE II) tool; and (3) Map clinical practice guideline recommendations, as related to nutrition and AMD, to relevant systematic reviews.We included national and international clinical practice guidelines for AMD that contained nutritional recommendations, including dietary modification or nutritional supplementation, as strategies to prevent or slow the progression of the disease. https://www.cadth.ca)  and the Turning Research into Practice (TRIP) database (https://www.tripdatabase.com/), and undertook a search of the webpages of national and international professional organisations for ophthalmology and optometry. The search was not limited by language and we used Google Translate to extract recommendations and appraise guidelines that were not written in English.We searched the Ovid MEDLINE and Embase bibliographic databases from January 1999 to January 2019 using search filters for identifying clinical guidelines that were developed by the Canadian Agency for Drugs and Technologies in Health (.ca) see . In addiFollowing removal of duplicates, two reviewers (JL/LD) independently screened the titles and abstracts identified from the bibliographic searches and resolved any discrepancies by discussion and consensus. We obtained full-text copies of potentially eligible guidelines and these were independently assessed by all three authors, working in pairs, to determine whether they met the inclusion criteria. Reasons for exclusion were documented at this stage. Two reviewers  independently extracted general characteristics of each guideline  and details of the specific nutritional recommendations.https://www.agreetrust.org/). The AGREE II instrument evaluates the process of practice guideline development, and the quality of reporting, using 21 items organised into six key domains, as follows: (1) Scope and Purpose; (2) Stakeholder Involvement; (3) Rigour of Development; (4) Clarity of Presentation; (5) Applicability; and (6) Editorial Independence. The quality of each clinical guideline was independently evaluated by two reviewers  using the Appraisal of Guidelines for Research and Evaluation (AGREE) II tool  . Five guThe overall inter-rater agreement on scoring of the individual items was excellent  0.76 to 0.84)).The quality of each guideline, across each of the AGREE II domains, is shown in We extracted individual recommendations relating to nutritional strategies for both preventing and slowing the progression of AMD   recommenOnly one guideline  guideline NG82) achieved high scores in all of the AGREE II assessment domains. This is perhaps unsurprising, since the NICE guideline development manual states that NICE guidelines “are based on internationally accepted criteria of quality as detailed in the Appraisal of Guidelines of Research and Evaluation II (AGREE II) instrument”. The development and implementation of high quality clinical practice guidelines requires substantial time, expertise and resources. Less formal guideline development groups, such as those produced by ‘expert panels’ or professional organisations, may lack the resources and/or methodological expertise to produce guidelines of the highest quality. In such circumstances, adapting existing high quality guidelines to local contexts may be an alternative to de novo development. The AMD Preferred Practice Patterns (PPP) Philippines (2016)  is an exMany robust systematic reviews have considered the merit of a variety of dietary and nutritional recommendations for AMD. In the present study, we used the systematic evidence searches performed by Lindsley et al.  and DownOf the nine guidelines that considered nutritional approaches for the primary prevention of AMD, most considered the potential merit of dietary modification, although some also made recommendations in relation to nutritional supplementation. Several epidemiological studies have investigated whether specific dietary patterns and/or foods are associated with a reduced risk of developing AMD. A meta-analysis of prospective cohort, case-control and cross-sectional studies concluded that consumption of two or more servings of oily fish per week was beneficial in the primary prevention of AMD . AnotherNutritional strategies for secondary prevention of AMD  were included in all of the clinical guidelines. Five guidelines ,28,33,34With respect to high-dose anti-oxidant vitamin and mineral supplements for managing AMD, there were divergent recommendations. Notably, only the U.K. NICE guideline  did not eporting of methodological details for clinical guideline development was poor and therefore it was not possible to make a judgement as to whether the guidelines had used an appropriate evidence-based approach in their development.A key strength of the current study was the comprehensive search to identify eligible clinical practice guidelines. Data extraction and quality appraisal were conducted independently by two reviewers, using a recognised assessment tool (AGREE II), which has established metrics of reliability and validity . OverallDespite the availability of robust systematic reviews evaluating the efficacy and safety of nutritional interventions for AMD, this study found evidence that these resources are infrequently used to support recommendations in AMD clinical practice guidelines. Consequently, guidelines often present conflicting recommendations that could lead to variations in clinical care. The AGREE II quality evaluations of the included guidelines identified several key areas that require improvement, particularly the rigour of development, managing potential conflicts of interests, and presenting strategies for implementing guideline recommendations into daily practice.


Background: There is limited data on personal use fall prevention programs, and the relationship of race and ethnicity on fall risk awareness, personal beliefs, behavior change, and response to intervention. Objective: The aim of this study was to develop an educational program to prevent falls for ethnically diverse older adults. This program will be a culturally attuned program that values diversity and seeks to eliminate words and behaviors that might be discriminatory based on racial/ethnic or cultural identity. Methods: Three steps were used to develop the program: 1) constructing content domains; 2) generating the program draft; and 3) judging the program domain and content. The content domains were constructed based on data from a conventional content analysis of four focus groups from older participants (n=28) and their family caregivers (n=4), and individual in-depth interviews from health care providers (n=8). We generated the program outline with three response choices. Eight older participants and two health care providers rated it. Results: The program consisted of risk assessment, outreaching and raising awareness and knowledge. Risk assessment: all participants suggested that risk assessment should consists of objective and subjective measures. Outreaching: participants agreed that group-teaching and individual learning by peer coaching based on their culture, new blasts, brochures, and family-based approaches were the best outreaching methods that they preferred. They identified that raising awareness and knowledge should include the following topics: performing physical activity with fall risk awareness, medication management, visual care, behavioral adaptation with appropriate accessories /equipment, and environmental safety.


Transjugular intrahepatic portosystemic shunt (TIPS) may be placed to treat complications of portal hypertension by creating a conduit between the hepatic and portal vein. The diagnosis of hepatocellular carcinoma (HCC) is typically made by multiphasic imaging studies demonstrating arterial enhancement with washout on arterial, portal venous, and delayed phase imaging. The aim of our study was to determine how the presence of TIPS would affect the imaging diagnosis of HCC.This was a single-center electronic database review of all patients who underwent multiphasic imaging with MRI or CT scan for HCC screening between January 2000 and July 2017 and who were subsequently diagnosed with HCC. Data collected included patient demographics, liver disease characteristics including CPT score, MELD-Na, AFP, type of imaging, tumor stage, and lab values at the time of HCC diagnosis. The diagnosis of HCC was made using LI-RADS criteria on contrast-enhanced CT or MR imaging and confirmed by chart abstraction as documented by the treating clinician. Demographic and imaging characteristics for HCC patients with and without TIPS were compared.A total of 279 patients met eligibility criteria for the study, 37 (13.2%) of whom had TIPS placed prior to diagnosis of HCC. There was no significant difference in demographics or liver disease characteristics between patients with and without TIPS. Compared to cirrhotic patients with no TIPS prior to HCC diagnosis, patients with TIPS had significantly more scans with a longer duration of surveillance until HCC diagnosis. However, LI-RADS criteria and stage of HCC at diagnosis were not significantly different between both groups. There were no differences in outcomes including liver transplant and survival.The presence of TIPS does not lead to a delayed diagnosis of HCC. It is associated, however, with greater duration of time from first scan to diagnosis of HCC. Deaths from cirrhosis have increased from 1980 to 2010 ,4,5. HepPlacement of a transjugular intrahepatic portosystemic shunt (TIPS) creates a low-resistance channel between the hepatic vein and the intrahepatic portion of the portal vein, allowing venous blood to travel directly from the portal vein to the hepatic vein while bypassing the liver. TIPS placement treats complications of portal hypertension in cirrhotic patients including refractory ascites and bleeding from esophageal/gastric varices and remains the treatment of choice to decompress the portal system . In the This was a single-center electronic database retrospective review of all patients who underwent dynamic imaging with MRI or CT scan for HCC screening between January 2000 and July 2017 and who were subsequently diagnosed with HCC. The Stanford University Institutional Review Board approved the study. Subjects were identified via the Stanford University electronic data warehouse (STRIDE) by querying ICD-9 (155.0) and ICD-10 (C22.0) codes for hepatocellular carcinoma, and diagnosis of HCC made by clinicians using established imaging-based guidelines and clinical correlation. Data was not anonymized prior to accession but was fully anonymized after data extraction. The review board waived the requirement for informed consent for this study. Patients were excluded from the study if they had a lack of imaging for review or known hepatic mass at referral. Data abstracted included: (1) demographic information ; (2) presence of other medical comorbidities and risk factors ; (3) etiology of liver disease; (4) complications related to liver disease including portal vein thrombosis, esophageal variceal bleed, ascites, hepatic encephalopathy, and the indication for TIPS; (5) number, frequency, and type of contrast-enhanced imaging (triphasic CT vs MRI); (6) tumor characteristics on imaging ; (7) lab values at the time of HCC diagnosis including AFP, serum sodium, creatinine, total bilirubin, and INR; (8) whether patient was listed for liver transplant; and (9) patient survival.The diagnosis of HCC was documented by the treating clinician, using imaging results reported at the time of diagnosis by a board-certified abdominal radiologist on CT or MRI contrast-enhanced imaging or liver biopsy, and confirmed by chart abstraction where the clinician diagnosed hepatocellular cancer . SurveilSensitivity analysis for tumor size greater and less than 2 cm, and with and without PVT, showed similar results—HCC was diagnosed at similar LI-RADS scores and TNM stage regardless of the presence of TIPS Tables  and 4.In multivariable quasi-Poisson regression, TIPS was not associated with longer time to diagnosis of HCC (p = 0.08). In this model, portal vein thrombosis was an independent risk factor for delayed diagnosis (p = 0.04).Transjugular intrahepatic portosystemic shunts (TIPS) decompress the portal system to relieve complications of portal hypertension. Multiple meta-analyses and randomized controlled trials have demonstrated the effectiveness of TIPS for secondary prevention of variceal bleeding and treatment of refractory ascites and hepatic hydrothorax. Hepatocellular carcinoma (HCC) is one of the few solid tumor malignancies that does not require tissue diagnosis, but instead relies on characteristic imaging patterns on dynamic imaging. Previous studies have shown that hepatic blood flow is altered by portal vein thrombosis (PVT), resulting in atypical HCC imaging characteristics that did not meet standard diagnostic criteria for HCC, potentially causing significant delays in diagnosis ,13. MoreA TIPS procedure alters the blood supply to the liver parenchyma by directing blood flow through the stent, which could potentially alter the enhancements and imaging characteristics of the lesion and hepatic parenchyma on the arterial, portal phase, and delayed phase images—all of which are integral to the usual diagnosis of HCC –16. We pIn our study, compared to cirrhotic patients with no TIPS, patients with TIPS had significantly more scans and longer duration of surveillance until diagnosis of HCC, but this did not lead to more advanced presentation or worse clinical outcomes. The greater number of scans in the TIPS group is possibly due to the longer surveillance time. Though not significant, we did note a higher proportion of patients with LI-RADS 3 and 4 in the TIPS group. In addition, there were fewer TNM Stage 1 subjects om the HCC TIPS group though, this did not reach significance. It is possible that this study was underpowered to demonstrate differences between TIPS and non-TIPS HCC patients with lesions <2cm Tables  and 6. IOur multivariable regression model did not identify TIPS as an independent risk factor for longer time to HCC diagnosis, but it did confirm findings from prior studies that PVT is associated with delayed diagnosis of HCC . The preLimitations of the study include a relatively small sample size, as this was a retrospective analysis of patient records from a single institution, and all patients referred in for potential liver mass were excluded. Because of the size of this dataset, small differences between groups may have resulted in statistically significant findings (such as INR). In addition, we found paradoxically a lower rate of hepatic encephalopathy in our TIPS cohort, though we did not abstract for use of lactulose or other therapies in this study. However, using this sample, we were able to identify PVT as a risk factor for delayed HCC diagnosis, and did not similarly identify TIPS as an independent predictor—suggesting that the study is adequately powered. The sample is also subject to referral bias, as patients who received TIPS may be have been more closely followed over time. HCC was also diagnosed via imaging and not liver biopsy, which would provide a definitive diagnosis. However, LI-RADS has now superseded liver biopsy in the diagnosis of HCC. We abstracted data from the CT and MR reports using criteria derived LI-RADS 2014 to our entire cohort even though these criteria had not yet been defined during the earlier period of our chart abstraction (2000–2011), though we note no period effect noted. In addition, all scans were prospectively read by radiologists specialized in liver disease at our center and the final diagnosis was confirmed by the clinician evaluating the patient. Analyses involving multiple centers may lead to greater variability and could potentially lead to different results.Ongoing surveillance for HCC in patients with TIPS remains important. Clinicians may still need to maintain a higher index of suspicion in the presence of TIPS, where hepatic blood flow is altered, and there may be compensatory changes in liver parenchyma and blood supply. The criteria for diagnosis of HCC as defined by the American Association for the Study of Liver Disease (AASLD) or the Organ Procurement and Transplantation Network (OPTN), may be less applicable in cases of HCC in patients with TIPS.


In accordance with Liaison Committee on Medical Education (LCME) curriculum content standards, medical schools are expected to teach physician communication skills and cultural competence. Given the sustained U.S. Spanish-speaking population growth, importance of language in diagnosis, and benefits of patient–physician language concordance, addressing LCME standards equitably should involve linguistic preparedness education. The authors present strategies for implementation of linguistic preparedness education in medical schools by discussing (1) examples of institutional approaches to dedicated medical Spanish courses that meet best practice guidelines and (2) a partnership model with medical interpreters to implement integrated global linguistic competencies in undergraduate medical curricula. Given the heterogeneous and dynamic linguistic profile of U.S. patients, communication skills education in medical schools should address these demographic realities to ensure health equity for all. Further, the Association of American Medical Colleges (AAMC) includes within its diversity and inclusion mission the objective to grow a diverse and culturally prepared health workforce by improving integration of public health concepts into medical education, supporting inclusion of social factors in health within medical education programs.2The Liaison Committee on Medical Education (LCME) sets curriculum content standards for undergraduate medical education to ensure standardization of educational content for United States (U.S.) medical school graduates. In accordance with standards pertaining to communication skills and cultural competence of graduating medical students,3 and linguistic differences have been shown to lead to exacerbation of health disparities for the underserved Hispanic/Latino population.4–7 Prior national regulations and efforts have primarily focused on interpreter services only9 rather than on simultaneously enhancing language-concordant, direct patient–physician communication through medical education and assessment.10 Moreover, U.S. population trends demonstrate continued growth of Spanish use nationwide,11 yet patient–physician communication in languages besides English and the non-English linguistic proficiency of medical students are not routinely included in medical education curricula or assessment processes.Language alone, through medical history taking, has long been demonstrated to be sufficient in making a diagnosis in a majority (75%) of cases,We propose that meeting LCME curricular content standards for communication and cultural competence in medical education within a public health context should include two primary elements of linguistic preparedness for physicians: global linguistic competence education and dedicated medical Spanish courses, outlined in 12 although methods of implementation are variable, most reported courses lack assessment of student skills, posing patient safety risks,13 and a standardized curriculum tested at multiple centers has never been attempted. We will illustrate several examples of institutional approaches to dedicated medical Spanish courses that can form the basis of a standardized curricular model and propose a partnership model with professional medical interpreters to implement the concept of integrated global linguistic competencies in undergraduate medical education.Multiple examples exist of curricula for medical Spanish education, and a majority of medical schools report medical Spanish courses according to the most recent survey;14 and represent variations in execution that can be replicated at other centers. A comparison of the programs is illustrated in In the absence of an existing standardized curricular structure or list of learner competencies or objectives, individual schools and/or instructors typically design their own medical Spanish programs. This presents a challenge for schools without existing programs since creating a course from scratch is a significant academic endeavor, and the lack of standardization results in a lack of uniformity at different institutions. We provide examples of curricular structure at three academic institutions that were designed according to best practice guiding principles established by Reuland et al.At the University of Texas Medical Branch (UTMB), a multidisciplinary hybrid course was designed to provide the student with basic structures of the Spanish language and the specialized medical vocabulary needed to communicate effectively with Spanish-speaking patients in a variety of clinical scenarios. Students actively self-manage their learning; the course is online, therefore modules can be completed during flexible times at the students' convenience. The course is divided into four main sections: (1) learning resource center, which provides a variety of learning experiences to help the student understand and apply course concepts, such as Spanish basics, grammar, anatomy, medical terminology, and culture. (2) Clinical modules, which contain the essentials of the Spanish language, culture, and the vocabulary needed to communicate effectively in a variety of health care situations, including greeting the patient, taking a full medical history, review of systems, physical examination, diagnosis, patient medication instructions, and special populations. (3) The third section provides the student easy access to basic language tools existing online. (4) The fourth component of the course is interactive, where students have to produce four taped encounters and, finally, a complete full medical history. Student assessment during the course includes self-reflection, peer and faculty feedback on videos, language assessment by faculty, and scoring on 15 inline components from the learning resource center and from the clinical modules.15 Due to student popularity, the course is now accessible outside of UTMB through the Visiting Student Application Service (VSAS) of the AAMC.16The Clinical Conversational Spanish for Healthcare Professionals UTMB course has been in existence for 5 years, a total of 129 students have enrolled, and 100% have achieved successful course completion. Students report that course content is useful and relevant to clinics (72%), and 52% believe that clinical Spanish should be a mandatory course.17 patient interview requirements, mid- and end-course objective structured clinical examinations with trained standardized patients (SPs), and cultural research spread out over the course.18At the University of Illinois College of Medicine (UICOM), students hold peer-led faculty-supervised workshops on medical Spanish vocabulary and conversational skills during lunch as a preparatory step in first and second years of medical school. This initial exposure helps some students self-identify a need to improve their basic Spanish skills before qualifying for the third- and fourth-year Clinical Medical Spanish elective, for which an intermediate Spanish language requirement is implemented. The formal elective is designed to provide 2 weeks (80 h) of official credit spread out over a 10-week longitudinal elective, in which students have a 2-h evening lecture weekly, but have multiple self-study multimedia and grammar/vocabulary exercise components,18 To accommodate student need, a new 2-week intensive course will be piloted in the near future at UICOM, in which the curriculum will be condensed into a shorter time period, but students will dedicate to medical Spanish material full-time for the 2 weeks of the course.The course is organized by organ–system  with each week focusing on one subject and addressing class role-play, patient interviews, case write-ups, and development of culturally appropriate patient education materials. In the 10-week course, students are expected to overlap the medical Spanish elective with other clinical clerkships. In 4 years since course initiation, 158 students have enrolled and completed the Clinical Medical Spanish elective. Data analyzed for the first 2 years of implementation  showed that the self-rated comfort level with interviewing and examining Spanish-speaking patients significantly improved after the course, and the improvement in comfort level was sustained 1 year into residency training based on a follow-up survey completed by 64% of students. Eighty-nine percent of follow-up respondents reported that the elective was useful for their intern year, and 97.3% reported that they would recommend the course to other fourth-year medical students.At the Washington University School of Medicine in St. Louis, the medical Spanish curriculum is designed for advanced Spanish speakers, defined as native speakers or those with strong conversational skills. The goals of the program are for students to develop proficiency in conducting a clinical encounter in Spanish, emphasize the importance of both language and culture in patient–physician interactions, and obtain certification as a bilingual provider. The program is designed as a comprehensive and longitudinal experience to span all 4 years of medical school, with the classroom component primarily in year 1, certification in the summer after year 2, and clinical opportunities to serve Spanish-speaking patients in years 3 and 4. In the first semester of year 1, a 10-week selective is offered for clinical credit with weekly, 1-h, peer-led faculty-supervised classes to learn medical Spanish vocabulary and practice speaking during role-play. Two SP sessions in Spanish are included in this selective. During the second semester of year 1, a 10-week selective is offered as humanities credit with weekly 1-h classes to discuss cultural aspects of medical interaction, ethics, and professionalism. In year 2, students continue to practice their medical Spanish by required participation in a few of the following roles: teaching assistant for year 1 sessions, organizer for student group conversation sessions, on-call interpreter for a Spanish-speaking clinic, additional SP session participation, or grand rounds Spanish case presentations. At the end of year 2, students take the Clinical Cultural and Linguistic Assessment examination as part of their certification process. Years 3 and 4 have clerkships with incorporated bilingual components for eligible students.The elements of global linguistic competence, which should be included as part of a longitudinal communication skills curriculum for all students regardless of Spanish proficiency or desire to enroll in a formal Spanish elective, should be as follows: understanding of linguistic diversity and the impact of language on population health; self-awareness of language proficiency and limitations in medical settings; competency in the use of a professional medical interpreter; and cultural issues in health that may confound successful medical communication. Critical communication elements related to language include cultural health beliefs, variations in health literacy, and patient distrust or other barriers to full communication with physicians, as well as the possibility of errors in communication due to limited physician Spanish skills or misunderstandings.Medical school curricula pertaining to clinical communication skills may consider integration of global linguistic competence elements throughout existing programming without the need to add a separate course. If these components are only included in elective, dedicated medical Spanish courses, there would be a significant missed opportunity to expose students who do not qualify or desire to enroll in medical Spanish to these critical communication skills. For example, segments that can be considered throughout the curriculum include demonstration of correct and incorrect usage of professional interpreters, inclusion of readings or faculty lectures pertaining to linguistic minority patient populations relevant to a particular module , discussion of cultural health beliefs or practices that may defy literal interpretation, and incorporation of SP cases that reflect underserved patients' social circumstances, including linguistic realities, and allow students to practice clinical skills and troubleshoot challenges.promotores de salud.19It may be helpful to identify existing sources of expertise such as certified medical interpreters who could assist with specific components of linguistic competence education using an interdisciplinary approach. Similar partnerships could be sought with public health institutions, university foreign languages departments, or community organizations with educational missions such as 21 are skilled in medical vocabulary in source and target languages and adhere to a strict code of ethics founded on precision, boundaries, objectivity, confidentiality, and respect.22 In health care, the dynamic interdisciplinary partnership between interpreters and providers can also be extended to an educational partnership.Certified medical interpreters already serve as communication conduits in health care settings, assisting with verbal communication between providers and patients where language discordance is identified. Interpreters certified by accredited certification processes in the U.S.23The certified medical interpreter's role is to maintain transparency, set boundaries, and recognize and intervene when a miscommunication may be taking place in a patient–provider encounter. Likewise, interpreters can help providers assess their needs and skills through observational progress assessments for medical Spanish learners as well as constructive feedback for medical students using interpreter services to improve the students' skills in effectively using language assistance tools, including onsite interpreters and remote interpreter devices. Although such technological advances are helpful in increasing access to professional interpreting, they require training to minimize perceived barriers to utilization and maximize effective communication.24 In the case of intermediate or advanced proficiency, determining if the encounters will be general in scope or specialty-driven is also a fundamental consideration since the latter vocabulary may be out of the scope of even an advanced or native Spanish speaker. In addition, interpreters can participate in longitudinal, integrated global linguistic competence training in partnership with medical school faculty by acting as the interpreter during select SP encounters, providing sample clinical scenarios of culturally or linguistically complex cases, identifying materials that can be used for problem-based learning or role-play challenges  in multilingual encounters, or giving guest lectures on cultural topics that may influence communication.During dedicated medical Spanish courses, interpreters can potentially contribute during in-class role-play encounters, provide feedback on recorded or real-time simulated or SP interviews, or observe live clinical encounters in which the interpreter can serve as a safety net by intervening if miscommunication occurs. Medical interpreters can help students and providers determine their need for language assistance services in varying situations. For instance, providers with basic proficiency may be safely encouraged to engage in greetings and casual conversations as trust- and rapport-building opportunities; however, conversations about treatment plans, procedures, and informed consent require a much higher degree of medical Spanish skill and therefore a much lower threshold for utilization of a trained medical interpreter.Medical schools should consider strategies to incorporate the linguistic realities of U.S. patients as part of public health-conscious medical education. Addressing linguistic skills for medical students is supported by LCME core content standards and must adapt to demographic trends to ensure health equity for linguistic minorities and to address physician public health preparedness in an increasingly global U.S. population. Institutional endorsement of courses that address non-English language competencies is critical to the success and sustainability of educational programs and can be justified as part of existing medical education standards.We propose that schools focus on two complementary approaches to linguistic needs of physicians in training: (1) dedicated medical Spanish courses for eligible students who desire to achieve and assess competency in direct patient–physician communication with Spanish-speaking patients and (2) integrated global linguistic competence education for all medical students within communication and clinical skills courses. Replication of an accepted curricular methodology that has been previously established should be considered to reduce the need for recreating new curricula for dedicated medical Spanish courses. Furthermore, interdisciplinary partnerships, such as collaboration with professional medical interpreters, can contribute to the cultural and self-awareness components critical for multilingual and monolingual physicians alike and should form part of a comprehensive longitudinal approach to linguistic competence in medical education.Next steps should consider interinstitutional collaboration on curricular implementation and evaluation by means of data collection regarding student comfort, confidence, and skill demonstration. Varying aspects of implementation such as course duration, curricular placement, course faculty qualifications, and successful interdisciplinary partnership models should be studied to better understand best practices. In addition, continued engagement of institutional stakeholders such as administrators and leadership is important in assessing institutional priorities and considering integration of both dedicated medical Spanish and global linguistic competence curricula as part of health equity-conscious undergraduate medical education.


Objectives: Given the increasing prevalence of Alzheimer’s disease and related dementia (ADRD) in the United States and the rapid growth of the older Chinese American population, many older Chinese Americans are expected to need intensive care because of cognitive impairment. Prior studies on Chinese ADRD caregivers lack comprehensive examinations from a life course perspective that emphasizes the importance of time, context, process and meaning on human development. Using the life course perspective, this study aims to identify challenges and strength of caregiving experience for this population. Methods: We conducted semi-structured face-to-face interviews with 28 Chinese family caregivers of persons with ADRD in New York City. Thematic analysis method was used to assess the interview data. Results: Seven life-course themes emerged from the data. In the domain of challenges, four themes were identified: (1) physical and emotional exhaustion, (2) limited understanding on cognitive health, (3) difficulty in accessing effective and culturally-sensitive health care services for care recipients, and (4) caregivers’ inability to do self-care. Other three themes were found in the domain of strengths: (1) commitment to care due to cultural and religious values, (2) emotional closeness as resource to sustain caregiving, and (3) family support and cohesion. Conclusion: This study indicates that the life course perspective is an important lens to understand challenges and strengths of Chinese American caregivers. This study also suggests that health professionals could incorporate the life course perspective into assessment and intervention development when working with minority and immigrant ADRD family caregivers.


Early studies of technology adoption and computer use identified a “digital divide” between older adults and the general population. As that gap has narrowed, other demographic variables have been identified as continuing to foster disparities in access to and use of computers and related technologies. For example, gender, socioeconomic status, education, and ethnicity have been recognized as predictors of computer use among community living older adults. The ORCATECH Collaborative Aging (In Place) Research Using Technology (CART) initiative was designed to develop and validate an infrastructure for research utilizing technologies to facilitate healthy and independent aging. The CART program tests innovative technology applications in four diverse populations: residents in low income, section 202 housing in Portland; isolated, rural veterans in the Pacific Northwest; urban African American seniors in Chicago; and socially isolated, ethnically diverse low income seniors in Miami. As part of their participation in the CART project, older adults complete an annual survey of health and technology use. A total of 214 participants were enrolled and agreed to have their homes instrumented with the CART platform of monitoring technologies. Across all four cohorts 166 answered the technology survey thus far: 82 - 97% of participants own a cell phone; 64 - 78% perform some online banking activities. There were no differences among cohorts in computer use or cell phone ownership, or in other measures of technology use. Inclusion of ethnically and economically diverse populations in future technology research will be critical in the development of effective digital health interventions.


Predicting adverse drug reactions (ADRs) has become very important owing to the huge global health burden and failure of drugs. This indicates a need for prior prediction of probable ADRs in preclinical stages which can improve drug failures and reduce the time and cost of development thus providing efficient and safer therapeutic options for patients. Though several approaches have been put forward for in silico ADR prediction, there is still room for improvement.In the present work, we have used machine learning based approach for cardiovascular (CV) ADRs prediction by integrating different features of drugs, biological , chemical (substructure fingerprints) and phenotypic (therapeutic indications and other identified ADRs), and their two and three level combinations. To recognize quality and important features, we used minimum redundancy maximum relevance approach while synthetic minority over-sampling technique balancing method was used to introduce a balance in the training sets.This is a rigorous and comprehensive study which involved the generation of a total of 504 computational models for 36 CV ADRs using two state-of-the-art machine-learning algorithms: random forest and sequential minimization optimization. All the models had an accuracy of around 90% and the biological and chemical features models were more informative as compared to the models generated using chemical features.The results obtained demonstrated that the predictive models generated in the present study were highly accurate, and the phenotypic information of the drugs played the most important role in drug ADRs prediction. Furthermore, the results also showed that using the proposed method, different drugs properties can be combined to build computational predictive models which can effectively predict potential ADRs during early stages of drug development.The online version of this article (10.1186/s12967-019-1918-z) contains supplementary material, which is available to authorized users. Adverse drug reactions (ADRs) are unpleasant, harmful, or unwanted effects caused by a drug and are one of the main reasons for the failure of drugs and their withdrawal from the market . AlthougIn recent years, prediction of potential ADRs has become of extreme importance and several machine learning based methods have been proposed for the prediction of potential ADRs in pre-clinical stages using the chemical features of compounds, drug targets, enzymes, transporters and pathways and information on drug side effects and therapeutic indications. Azuaje et al. , 6 generAlthough numerous computational methods have been projected so far for ADR prediction problems, a lot can still be improved. The data used for generating the models is severely imbalanced, and imbalanced data classification would lead to predictions biased towards the negative class which is typically the dominating class. Another problem is with the large number of features associated with the drugs: some may be redundant, and not all would be related to ADRs. Recently, feature selection techniques have been increasingly used to identify significantly contributing features from high dimensional feature data sets for improving upon the prediction performances –15. The In the present study, we have tried to solve the problem of data imbalance using the synthetic minority over-sampling technique (SMOTE) balancing method , and undThe dataset of approved drugs was retrieved from the DrugBank  databasehttp://sideeffects.embl.de/. The 2141 approved DrugBank drugs were mapped to SIDER using PubChem compound IDs (CID) as SIDER uses STITCH compounds IDs which were converted to PubChem CIDs according to the rule mentioned in . The SIDER database was also used to collect data on therapeutic indications of drugs. We obtained information for a total of 970 drugs, which comprised data for 5497 side effects and 1840 therapeutic indications.SIDER   and enzymes (for drug metabolism). We obtained data for 1264 drug targets, 86 transporters, and 182 enzymes, for a total of 970 drugs directly from DrugBank database.PaDEL  softwareTanimoto coefficient (TC) was calculated to measure the similarity between two drug molecules using the ChemmineR  platformIn classification models generation, one of the most important steps is to generate features which are a quantifiable property of an instance being classified. In case where the instance is a molecule, the chemical information of the molecule is converted to molecular descriptors, which are the mathematical depictions of chemical compounds. In the present study, we have used six types of features which include the molecular 2D fingerprints denoting chemical features, biological targets, transporters, enzymes associated with drugs representing biological information, therapeutic indications, and other known side effects comprising phenotypic properties of drugs. Each drug, associated with three types of properties, chemical, biological and phenotypic, was represented as a binary matrix, the elements of which were either 1 or 0, respectively indicating the presence or absence of each feature: drug targets, transporters, enzymes, 881 PubChem substructures, remaining known ADRs, and therapeutic indication. To this end, we had a 5497 × 1840 dimensional binary matrix representing phenotypic properties, a 1264 × 86 × 182 dimensional binary matrix demonstrating biological features, and an 881 dimensional binary matrix denoting chemical features for each of the total 965 drugs.RemoveUseless filter available from Weka  and phenotypic features [accuracy 93.83% (RF) and 93.83% (SMO)] alone were better in comparison to chemical feature [accuracy 91.41% (RF) and 88.75% (SMO)] models. The results showed that the chemical feature models were least informative in cases of both, RF and SMO models; however, the performance of the models improved upon integration of biological and phenotypic features to chemical features. To show the real-life application, efficiency and significance of the computational models, we also performed ADR prediction for uncharacterized drugs and already existing CV drugs, which were not a part of the training set used for generating the models.The present work focused on generating machine-learning based computational models for the prediction of cardiovascular ADRs. In this study, we have investigated three levels of information: biological properties including drug targets, enzymes and transporters; chemical features represented by PubChem substructures; and phenotypic properties that include drugs therapeutic indications and other known ADRs. Two machine-learning algorithms, sequential minimization optimization (SMO) and random forest (RF), were used to generate computational models trained using chemical, biological and phenotypic properties as well as their two and three level combinations for 36 CV ADRs. In conclusion, the proposed machine learning based data-integration approach could be a promising method for the prediction of potential ADRs prior to preclinical testing stages.Additional file 1. Provides the list of the top 50 features ranked by mRMR.Additional file 2. Provide the ten-fold cross-validation performance measures for the RF and SVM models for each cardiovascular ADR using biological, chemical, phenotypic features and their two and three level combinations.Additional file 3. Provide the performance measures for the RF and SVM models for each cardiovascular ADR using fifty biological, chemical, phenotypic features and their two and three level combinations on non-redundant testing dataset using SMOTE data balancing method.Additional file 4. Provide the performance measures for the RF and SVM models for each cardiovascular ADR using fifty biological, chemical, phenotypic features and their two and three level combinations on non-redundant testing dataset using SpreadSubsample data balancing method.Additional file 5. Provide the performance measures for the RF and SVM models for each cardiovascular ADR using eighty features biological, chemical, phenotypic features and their two and three level combinations on non-redundant testing dataset.


There is mixed evidence to support current ambitions for mobile health  apps to improve chronic health and well-being. One proposed explanation for this variable effect is that users do not engage with apps as intended. The application of analytics, defined as the use of data to generate new insights, is an emerging approach to study and interpret engagement with mHealth interventions.This study aimed to consolidate how analytic indicators of engagement have previously been applied across clinical and technological contexts, to inform how they might be optimally applied in future evaluations.We conducted a scoping review to catalog the range of analytic indicators being used in evaluations of consumer mHealth apps for chronic conditions. We categorized studies according to app structure and application of engagement data and calculated descriptive data for each category. Chi-square and Fisher exact tests of independence were applied to calculate differences between coded variables.P=.04), and engagement with hybrid apps was mostly measured by the number of measures recorded . A total of 24 studies presented, described, or summarized the data generated from applying analytic indicators to measure engagement. The remaining 17 studies used or planned to use these data to infer a relationship between engagement patterns and intended outcomes.A total of 41 studies met our inclusion criteria. The average mHealth evaluation included for review was a two-group pretest-posttest randomized controlled trial of a hybrid-structured app for mental health self-management, had 103 participants, lasted 5 months, did not provide access to health care provider services, measured 3 analytic indicators of engagement, segmented users based on engagement data, applied engagement data for descriptive analyses, and did not report on attrition. Across the reviewed studies, engagement was measured using the following 7 analytic indicators: the number of measures recorded , the frequency of interactions logged , the number of features accessed , the number of log-ins or sessions logged , the number of modules or lessons started or completed , time spent engaging with the app , and the number or content of pages accessed . Engagement with unstructured apps was mostly measured by the number of features accessed (8/10, Although researchers measured on average 3 indicators in a single study, the majority reported findings descriptively and did not further investigate how engagement with an app contributed to its impact on health and well-being. Researchers are gaining nuanced insights into engagement but are not yet characterizing effective engagement for improved outcomes. Raising the standard of mHealth app efficacy through measuring analytic indicators of engagement may enable greater confidence in the causal impact of apps on improved chronic health and well-being. There is mixed evidence to support current ambitions for mobile health  apps to improve chronic health and well-being . While seffective engagement, defined as sufficient engagement with an intervention to achieve intended outcomes [Recently, scholars sought to further the conceptualization of engagement by proposing that it may be more valuable to identify the mechanisms that underlie outcomes ,15. The outcomes . Sieverioutcomes . We propoffline interactions with the behavior change mediated by a digital health intervention. Yardley et al have been instrumental in furthering this conceptualization of engagement by suggesting that there are 2 levels of engagement: (1) the micro level of immediate engagement with the digital health intervention and (2) the macro level of engagement with the wider intervention-mediated behavior change [There has been recognition that the definition of engagement has evolved to include r change . They poThe application of analytics, defined as the use of data to generate new insights , is an eindicate that users may be engaging effectively with a digital health intervention but do not definitively confirm a relationship between engagement and intended outcomes. Establishing this relationship requires adopting a mixed-methods multidimensional approach to measure effective engagement using multiple assessment strategies [Motivated by the proven value of analytics to study engagement with mHealth apps, we sought to compile and catalog a library of analytic indicators of engagement with consumer mHealth apps for self-managing chronic conditions. We defined analytic indicators as proxy measures of engagement with an mHealth app based on objective usage that generates log data ,22. Whenrategies ,25.While many researchers have included analytic indicators as a study measure when evaluating apps, they are not consistent or systematic in their selection . We propwhat analytic indicators of engagement are being used in evaluations of consumer mHealth apps for chronic conditions?This scoping review was guided by the methodological framework developed by Arksey and O’Malley  and advaJournal of Medical Internet Research and its sister journals were independently searched given their frequent and high-impact publication of mHealth research. A combination of different keywords for the constructs “engagement” and “mHealth” was used. No search terms for chronic conditions were defined a priori to broaden search results. We adopted the World Health Organization’s definition of a chronic condition as a “non-communicable disease of long duration and slow progression [A literature search was conducted in the MEDLINE, PsycINFO, CINAHL, and EMBASE databases. In addition, the gression .” MultimTitles and abstracts retrieved from the search strategy were screened for inclusion against the following criteria: (1) the article described an evaluation or a protocol for an evaluation of a consumer mHealth app for self-managing a chronic condition; (2) the study included operationalization of an engagement-related construct—Studies were excluded if (1) the mHealth app was solely an appointment reminder service; (2) the primary app technology was short message service or interactive voice response; (3) the app was for an acute condition or preventive health purposes; (4) the app was a support tool for a patient’s circle of care; (5) the app did not require user input through active or passive (sensor) data entry; (6) the app only delivered educational content; and (7) the article primarily described the design, development, or usability testing of the app.The first author conducted the electronic searches with support from a faculty-affiliated librarian and reviewed the reference lists of relevant articles. All identified titles and abstracts were downloaded and merged using Mendeley (Elsevier)  and duplGeneral information regarding the study title, authors, journal, year, and country.App information, specifically the public name, chronic condition addressed, and accessibility of health care provider services.Study information, specifically the purpose, duration, sample size, and design.App structure : “Structured” apps contained locked, sequential components  that users had to complete before moving forward. “Hybrid” apps contained both fixed core components and variable components for free use. “Unstructured” apps contained variable components that users could access and use at will.Analytic indicators used to measure engagement, specifically the number of log-ins or sessions logged, the number of modules or lessons started or completed, the number of features accessed, the number of measures recorded, the number or content of pages accessed, the frequency of interactions logged, and total time spent engaging with the app.Engagement-based segmentation: studies that segmented users based on engagement data  were assigned this code.Application of engagement data : a “descriptive” code was assigned to studies that presented, described, or summarized engagement data. An “inferential” code was assigned to studies that used engagement data to predict the intended outcome. Outcome types were coded for studies that applied engagement data inferentially.Attrition type (dropout or nonusage) and statistical method of analysis: dropout attrition is the phenomenon of users not returning to complete follow-up study activities. Nonusage attrition is the phenomenon of users losing interest in a digital health intervention and ceasing to use it .A data extraction form was developed by the first author to extract relevant study information. We referenced work by Sieverink  and KeldA total of 1873 articles were identified through the database search. Of the 60 full texts screened, 19 were excluded, 8 of which did not include objective, quantifiable measurements using log data analytics. In total, 41 articles comprising 33 studies and 8 protocols met the eligibility criteria and were included for review. The first authors of reviewed studies were affiliated with institutions in the United States , Canada , the United Kingdom , Australia , Germany , the Netherlands , France , India , Singapore , Spain , Sweden , and Switzerland .Researchers reported log data analytics across 14 different engagement-related constructs: engagement , adherence , usage , use , feasibility , acceptability , utilization , attrition , participation , activity , adoption , compliance , fidelity , and retention . There was significant variation in how constructs were defined across studies, which limited our ability to (1) extract reliable definitions for each construct, (2) map analytic indicators to specific constructs, and (3) conduct cross-construct comparisons of analytic indicators.Journal of Medical Internet Research or its sister journals .The majority of reviewed studies were experimental , with the two-group pretest-posttest randomized controlled trial (RCT) as the most prevalent experimental study design , followed by the one-group pretest-posttest design . Quasi-experimental design selection  was more diverse and included cohort , interrupted time-series , and single case  studies. The remaining 13 studies included for review were observational in design . Studies were on average 5 months long , with a sample size of over 100 participants . The longest reviewed observational study conducted by Serrano et al was 7 years long with over 1 million participants . A totalA wide range of chronic conditions were targeted through the apps under study, with mental health , chronic pain , asthma , cardiovascular disease , and diabetes  leading the clinical charge. Researchers also evaluated apps for cancer , hypertension , obesity , chronic kidney disease , chronic obstructive pulmonary disease , cystic fibrosis and inflammatory bowel disease , Parkinson disease , and sleep apnea . Over half of the apps had a hybrid structure , 10 apps were unstructured (24%), and 7 apps were structured (17%). Nearly half of all structured apps were aimed at improving mental health . Health care provider services were accessible to users to support managing their condition in nearly half of all reviewed apps . Characteristics of the included studies are presented in P=.04), and engagement with hybrid apps was mostly measured by the number of measures recorded . Across the reviewed studies, engagement was measured using the following 7 analytic indicators in order of prevalence: the number of measures recorded , the frequency of interactions logged , the number of features accessed , the number of log-ins or sessions logged , the number of modules or lessons started or completed , time spent engaging with the app , and the number or content of pages accessed . Of the analytic indicators identified in this review, the number of measures recorded by users on an app was the most commonly used indicator of engagement with mHealth apps for chronic conditions. Researchers evaluated a range of measures that aligned with their target chronic condition, such as blood glucose ,61,64,73The frequency of interactions logged was the second most prevalent analytic indicator of engagement. Researchers often chose to complement assessing the number of measures recorded on an app with the frequency by which the measures were recorded. Stratifying frequency of interactions by specific date ranges was also common; Davies et al measured the number of users who used a mental health app at least once after 1 week, 4 weeks, and 20 weeks . They alThe range of features accessed by users in an app was frequently measured as an analytic indicator of engagement. Researchers primarily logged (1) the number of features accessed and (2) the number of times each feature was accessed. In their trial of the Veterans Affairs' Comprehensive Assistance for Family Caregivers Program where users were provided with access to a suite of 6 apps for posttraumatic stress disorder (PTSD) self-management, Frisbee et al measured the number of unique apps used in the suite . To bettThe number of log-ins or sessions logged by users continues to be a commonly used analytic indicator of engagement. This indicator was often coupled with the frequency of interactions logged to standardize counts. Researchers also frequently measured the number of users who opened an app at least once to segment them from users who had downloaded the app but never logged any subsequent activity. Owen et al made both these associations by measuring the number of sessions logged by users on their PTSD self-management app, as well as the number of users who logged at least one session on the first day, week, and month post download . Researcnumber of measures and coded studies reporting restricted data collection as number of modules. A range of studies measured the number of outcome surveys completed from those assigned [When defining analytic indicators for categorization, we differentiated between unrestricted and restricted data collection. Unrestricted data collection was defined as data that could be entered into an app at a frequency or volume dictated by the user, such as the number of blood glucose readings or medications recorded . Restricassigned ,68,75. Oassigned ,55, educassigned , or selfassigned . OverallThe amount of time that users engaged with an app was considered by a subset of researchers to be an analytic indicator of engagement. Researchers measured the time spent on unique sections of an app , the timThe number of pages accessed by users was logged by researchers to reflect overall patterns of app engagement and discoverability of specific content. Kuhn et al measured the number and content of pages visited by users in their app for PTSD self-management, as did other researchers ,41,71. TWe sought to conceptually clarify the 7 identified analytic indicators by grouping them according to the 4 categories that constitute the quantitative conceptualization of engagement: amount, duration, breadth, and depth ,12. TablOf the 41 studies included for review, 24 presented, described, or summarized the data generated from applying analytic indicators to measure engagement. The remaining 17 studies used or planned to use these data to infer a relationship between engagement patterns and intended outcomes.Over half of all researchers assessed the relationship between engagement and clinical outcomes . Toro-Ramos et al measured the number of weeks users engaged with their hypertension self-management app and found that users with sustained usage across 19 weeks experienced significant reductions in systolic blood pressure and weight . In theiMany researchers sought to investigate the effect of engagement behaviors on other engagement outcomes . In their study examining engagement with a weight loss app, Serrano et al applied classification and regression tree methods to identify subgroups with unique engagement behaviors . They weTwo studies proposed to evaluate the impact of engagement patterns on health care utilization outcomes . Kaplan et al plan to examine the impact of sustained engagement over time with an app for pediatric cystic fibrosis and inflammatory bowel disease self-management on the number of hospitalizations and emergency department visits . HoweverP=.04). In addition, most studies that applied inferential statistics also measured the frequency of interactions logged . Most researchers who did not segment users into cohorts based on engagement data only reported descriptive statistics on their engagement data , while researchers who segmented their users into cohorts were more likely to conduct subgroup analyses and infer properties of the larger clinical population . The Fisher exact test of independence indicated that studies of structured apps were more likely to only report descriptive statistics on engagement data . Of the 10 studies that did, 5 reported on dropout attrition (50%), 4 reported on nonusage attrition (40%), and 1 reported on both phenomena (10%). Researchers were more likely to descriptively summarize raw attrition proportions than statistically analyze them . Those that conducted comparisons across attrition curves used Kaplan-Meier survival curves , Cox regression models , and latent class growth models .In conducting this scoping review, we sought to catalog the range of analytic indicators being used in evaluations of consumer mHealth apps for chronic conditions. We applied Arksey and O’Malley’s methods of reporting and provided a descriptive analysis of the extent, nature, and distribution of analytic indicators across 41 studies, as well as a narrative and thematic summary of collected data . The aveOur results indicate that researchers are measuring engagement across 7 analytic indicators, specifically: (1) the number of measures recorded, (2) the frequency of interactions logged, (3) the number of features accessed, (4) the number of log-ins or sessions logged, (5) the number of modules or lessons started or completed, (6) time spent engaging with the app, and (7) the number or content of pages accessed. We found that the researchers favored evaluating the number of measures recorded on an app as an indicator of engagement, closely followed by the frequency of interactions logged. We also found that both these indicators were most often used to assess hybrid and unstructured apps; these 2 app structures also made up the majority of apps under review.We noted that researchers were least likely to measure the number of pages accessed and time spent engaging with the app; the latter indicator was mostly reported descriptively . This finding was surprising given the historical popularity of these indicators for measuring engagement with Web-based interventions ,23,80. TOur identification of the number of measures recorded on an app as an analytic indicator of engagement deviates from previous research by Sieverink et al on usage and adherence to eHealth interventions , which fWe did not observe any significant differences between the number or type of analytic indicators used to measure engagement across chronic conditions. Researchers applied indicators that were relevant to the features and functionality of their app. For example, studies of apps for diabetes self-management often measured the number of blood glucose readings due to the popularity of this feature but never measured the number of modules or lessons because these features were not offered to users. In a recent review on the barriers and facilitators of engagement with remote measurement technology for managing health, Simblett et al found that studies were reporting idiosyncratic measures of engagement and adherence that were not comparable across studies . Their fAlthough researchers measured, on average, 3 indicators in a single study, the majority reported findings descriptively and did not further investigate how engagement with an app contributed to its impact on health and well-being. This finding suggests that researchers are gaining nuanced insights into how users are engaging with their apps but are not conducting inferential analyses to characterize effective engagement for improved outcomes. Relating analytic engagement patterns to behavior change and intended outcomes has been advocated across the behavioral and computational sciences ,24,85,86In their systematic review, Sieverink et al found that over half of all reviewed studies measured adherence to eHealth interventions using a single analytic indicator, and a quarter used 2 indicators . The autIn contrast to Sieverink et al’s findings, the majority of our reviewed studies applied between 2 and 4 analytic indicators to measure engagement. This variance suggests that researchers are starting to recognize a conceptual and methodological distinction between the constructs of engagement and adherence. From these findings, we make the following recommendation: researchers seeking to gain a preliminary understanding of how users are engaging with their app are encouraged to apply all relevant analytic indicators from those identified in this review. During our full-text review, we excluded a large number of studies because they did not include objective, quantifiable measurements using log data analytics. Some studies had users self-report their engagement, whereas others omitted reporting engagement altogether and solely related findings on app efficacy. One possible explanation for this gap might be that researchers are unfamiliar with how to derive analytic insights from their app. From our experience, the process of tagging interaction data to enable analytic insights requires deliberate foresight. A shared understanding between a researcher and a software developer of the research questions being answered is critical to determine how analytics data should be modeled. law of attrition [Our final recommendation concerns the reporting of attrition in data-driven mHealth evaluations. In 2005, Eysenbach published landmark work on the ttrition , which wttrition . Our finSome methodological limitations of our scoping review warrant discussion, the most significant being that we only reviewed articles published over a 2-year period. This sampling frame may not have captured a representative sample of mHealth literature. As such, we may have missed relevant studies published before November 2015 and after November 2017 that would have met our eligibility criteria. While we acknowledge that our sampling frame is limited in scoping the entire field of mHealth, we believe it captures the application of analytics within the field of mHealth. From our review of the literature before conducting our search, we identified a paucity of papers that focused on mHealth log data analyses. The systematic review on usage-based adherence to eHealth interventions conducted by Sieverink et al reviewed 62 papers, of which 7 were on smartphone-based interventions . They redigital exceptionalism given the iterative nature of their design and the prohibitive cost of trials compared with their perceived level of risk [To date, the potential for mHealth apps to positively impact chronic health outcomes has not yet been realized . This is of risk . We propOur proposed library of analytic indicators to evaluate effective engagement with consumer mHealth apps for chronic conditions may be of value to researchers as a resource to support their evaluative practice. Researchers can systematically incorporate these analytic indicators into their study measures by adding analytic tags to their app’s source code, allowing them to measure engagement without creating user burden or reactivity. Once generated, these data can be used in inferential analyses to delineate relationships with observed health outcomes. Researchers can further interrogate these data by conducting rapid cycles of research and development to validate hypothesized models of effective engagement. On the basis of these insights, researchers can (1) build a cumulative body of evidence for how users should engage with their app to achieve intended outcomes, (2) incrementally improve their app to optimize effective engagement, and (3) determine the optimal digital dose of effective engagement with their app for validation in a definitive trial to meet required levels of evidence for procurement and distribution . SuccessRaising the standard of mHealth app efficacy through measuring analytic indicators of engagement may enable greater confidence in the causal impact of apps on improved chronic health and well-being. It is this opportunity afforded by data-driven research to close the gap between promised and realized health benefits that is most meaningful.