Introduction: Cost-effectiveness (CEA) and cost–utility analyses (CUA) have become popular types of economic evaluations (EE) used for evidence-based decision-making in healthcare resource allocation. Newborn screening programs (NBS) can have significant clinical benefits for society, and cost-effectiveness analysis may help to select the optimal strategy among different screening programs, including the no-screening option, on different conditions. These economic analyses of NBS, however, are hindered by several methodological challenges. This study explored the methodological quality in recent NBS economic evaluations and analyzed the main challenges and strategies adopted by researchers to deal with them. Methods: A scoping review was conducted according to PRISMA methodology to identify CEAs and CUAs of NBS. The methodological quality of the retrieved studies was assessed quantitatively using a specific guideline for the quality assessment of NBS economic evaluations, by calculating a general score for each EE. Challenges in the studies were then explored using thematic analysis as a qualitative synthesis approach. Results: Thirty-five studies met the inclusion criteria. The quantitative analysis showed that the methodological quality of NBS economic evaluations was heterogeneous. Lack of clear description of items related to results, discussion, and discounting were the most frequent flaws. Methodological challenges in performing EEs of neonatal screenings include the adoption of a long time horizon, the use of quality-adjusted life years as health outcome measure, and the assessment of costs beyond the screening interventions. Conclusions: The results of this review can support future economic evaluation research, aiding researchers to develop a methodological guidance to perform EEs aimed at producing solid results to inform decisions for resource allocation in neonatal screening. Since the first broad-based test for phenylketonuria in the 1960s, newborn screening tests (NBS) have become a popular practice to detect potential, treatable diseases during the first days of neonatal life . NeonataAs the number of conditions assessable by NBS is increasing, resulting in additional costs for the healthcare systems, it is necessary to identify solid criteria which can inform health decision-making. Economic evaluations (EEs) represent an increasingly popular tool for policy-makers to make informed and effective choices in healthcare resource allocation and guarantee the financial sustainability of healthcare systems . By compEconomic appraisal of healthcare technologies is a tool to maximize health gains and secure health outcomes in healthcare policy-making. In fact, some national governments have implemented strategies to use the evidence coming from EEs, mainly in reimbursement decisions . DecidinDespite the similarity in screened conditions of many governments , to dateThe current state of the art of NBS EEs is unclear, as well as the most common methodological approaches used. Literature reviews on NBS have been conducted to synthesize evidence on cost-effectiveness of screening interventions for one or more conditions and to discuss specific methodological aspects in conducting economic evaluations of these screening programs ,15,16,17A scoping review was chosen as a research synthesis tool to identify relevant published EEs of NBS program. Scoping reviews can be used to examine how research is conducted on a certain topic or field, which is in line with our aim of studying the methodological quality of the economic evaluations and identifying the main challenges in performing economic evaluations . The revThe quality of the studies identified after full-text screening was assessed using the guideline developed by Langer and colleagues in the form of a checklist . This guThe literature search identified 1203 records in five databases. After duplicate removals, 716 articles were considered eligible for screening by title and abstract. After full-text screening, 35 articles were included for the final assessment (see n = 5 for each country), followed by France, Iran, the Netherlands, Spain, and the United Kingdom (n = 3 for each country), and various other countries (n = 12). The main assessed disease areas for NBS were congenital heart defects and metabolic disorders (n = 7 studies for each area), followed by severe combined immunodeficiency disorder and hearing loss (n = 5 for each of these diseases), cystic fibrosis and sickle cell disease (n = 4 for each of these), and others (n = 3).Most EEs came from the United States and Canada , and “Target population” . The most frequent primary outcome measure was the Incremental Cost-Effectiveness Ratio (ICER) , with two EEs not using a comparator and presenting the (Average) Cost-Effectiveness Ratio. Cost-effectiveness analysis (CEA) was the main type of EE , while only five studies (13%) were presented as cost–utility analyses (CUA), using health outcomes adjusted by utility weights and time [n = 32, 91%). Many of the studies  were conducted from a healthcare perspective, while societal and third-payer perspective were, respectively, considered only in eight and three studies. The time horizon of the EEs, when relevant, ranged from 1 month to 100 years, and 10 (29%) of the included studies adopted a lifetime horizon. In terms of comparators, the majority of the retrieved studies explored the cost-effectiveness of a newborn screening introduced in a naïve setting .The main overlooked items in the category “Study questions and design” were “Setting” , “Time horizon” . None of the EEs was a piggyback analysis .“Model validation” was reported in five EEs (14%), and this was mainly done by discussion with experts or comparison with previous studies ,33,52,56n = 22, 63%) and quality-adjusted/daily-adjusted life years (QALYs/DALYs) . A few EEs also considered health outcomes in monetary units , in addition to natural units or QALYs/DALYs. One EE specifically reported health outcomes defined as intermediate  [The analysis of the retrieved EEs of NBS showed that the choice of outcomes was not consistent and uniform, as the measures were fairly distributed between natural units (ndition) .No EE in this scoping review considered all the relevant categories of costs recommended by Langer et al. , namely Discounting refers to the conversion of future costs and effects to their present value . A discon = 10, 29%) and only one EE differentiated these outputs by payer [Most of the studies clearly presented absolute or incremental health outcomes and costs per newborn in their results. However, a small minority of the studies also presented values and trends of costs and health outcomes at the population level . In their EE on a panel of screening for metabolic disorders, Thiboonboon et al. included a budget impact analysis to estimate resource impact over a 10-year interval [Sensitivity analysis is a technique that allows to quantify the sensitivity of the EE outcome due to the uncertainty of the information included in the EE . It was interval . An expeinterval , who calOverall, the assessed EEs lacked a clear and detailed descriptions of the generalizability of their results and the extent to which they were applicable to other settings. Ethical and transferability issues were also constantly overlooked: less than one-third of the EEs (29%) considered the issues concerning the dissemination of the assessed screening intervention.n = 31, 89%) presented conclusions which resulted directly from the results of the EE. Only four papers lack a clear answer to the research question presented as the objective of the study [Nearly all studies .All authors including sensitivity analyses in their studies specifically stated that this was to account for the uncertainties of the parameters included in the model. In addition to this reason, Tobe et al. used sensitivity analysis to accommodate for the geographical and socioeconomic diversity within a target country . SeveralThe authors of the few studies presenting generalizability and transferability issues considered different elements to address these items. While most of the researchers considered the difference in population and health care systems as the main obstacle to generalizability ,28,52,56The goal of this scoping review was to analyze the methodological quality of NBS EEs and collect evidence on the main challenges of conducting this category of studies. The analysis of 38 EEs through the framework of a specific NBS guideline showed that the methodological quality of these NBS papers was heterogenous. Some items of the guideline were constantly underreported in the studies . In addition, the qualitative information contained in the identified EEs highlighted the most common challenges in this field and the resulting decisions or approaches taken by the authors around common themes of EEs, including health outcomes, costs and modeling decisions.As for the choice of the outcome measure, the review revealed a high level of heterogeneity among EEs. Health benefits, expressed as natural units , may be easy to quantify, but they may limit the comparability with other interventions/screening. For this reason, the use of QALY has become a recognized way to allow for comparability between interventions for various disorders, by standardizing mortality, morbidity and health status in a single measure . SeveralA review by Grange et al. in 2007 identified 16 generic health-related quality of life (HRQoL) measures for children less than five years of age, but none of them was conceptually and psychometrically robust  At the pBecause of their ability to intercept presymptomatic diseases, screening programmes can lead to savings, and this is particularly true when a treatable condition is identified early at the beginning of life . This reIn terms of comparators, the cost-effectiveness of an assessed screening is intrinsically influenced by the choice of the comparator screening program. In EEs, the gold standard comparator should reflect the most relevant options as used in clinical practice. In newborn screening, this can often be represented by the “no screening” option. Nevertheless, the routine clinical practice for screening can consist of already existent screening programs or technologies. Increasing the number of comparators can increase the informativity of the EE, but it requires data on the available interventions and can further complicate the analysis. The qualitative analysis of the identified studies proved this point: the authors often limited the number of comparators and prioritized their choice based on the amount of available information on alternative routine interventions (including the “no screening” option). A high-quality and transparent model should include a proper presentation of the assessed comparators and a justification of their choice , as indeed remarked by the European Network for Health Technology Assessment in its methodological guidance . In addiOne of the main challenges in EEs is setting an appropriate time horizon for the analysis. The choice of a time horizon affects the final measure  in a cost-effectiveness or cost–utility analysis . The selThis review confirmed the importance of decision models also in NBS EEs. Decision modeling uses mathematical relationships between parameters to describe a series of outcomes coming from possible scenarios involving healthcare interventions . BuildinFinally, the data used to develop decision-analytic models for EEs of NBS can often lead to uncertainty. This may be related to many reasons, including the rarity of the conditions assessed by the screening and the long-time horizons used in the model. By looking at the EEs in this review, it was clear that researchers usually handled these challenges by the employment of assumptions or proxy measures . However, this comes at a cost for the accuracy/precision of the results and conclusions of the EE. Sensitivity analysis has a potential to comprehensively address uncertainty  and guidThis study presents some limitations. First, only cost-effectiveness and cost–utility analyses developed in the last ten years were selected, for feasibility purposes. The temporal limit of the search and the exclusion of cost–benefit and cost-minimization analyses may have influenced the results of this review, as well as the inclusion of economic evaluations only written in Dutch, English, or Italian. Second, we used the only available appraisal tool for NBS EEs in the literature, which is not validated. This influenced the study results, as other generic available tools may provide different ways to assess the quality of NBS EEs . FurtherThis study aimed at closing the existing gap on methodological quality of EEs and the challenges associated with them. It identified items which are frequently overlooked by researchers; described the challenges around common themes such as the choice of outcomes, costs, and comparators in NBS EEs; and considered the methodological choices made to address them. More research is needed to systematically investigate the main strategies by HTA researchers and intercept the common trends in this field of EEs. The results of this scoping review can lay the groundwork for future projects investigating, among others, the development of a generic HRQoL instrument designed for newborns, appropriate outcomes measures when the condition is not treatable, a new framework for a clear definition of cost inputs, and a transparent model for prioritization of EE comparators. In addition, this review can possibly aid researchers to develop a methodological guidance to harmonize the process in performing NBS EEs, improve their transparency, and increase their transferability, so that policy-makers can rely on high-quality research to inform policy decision on neonatal screening interventions.


Our aim was to assess both the credibility and strength of evidence arising from systematic reviews with meta-analyses of observational studies and physical health outcomes associated with human immunodeficiency virus (HIV) but not acquired immunodeficiency syndrome.We performed an umbrella review of observational studies. Evidence was graded as convincing, highly suggestive, suggestive, weak, or nonsignificant.P < .05). Only 5 outcomes  showed suggestive evidence, with P values < 10–3; only 3  outcomes showed stronger evidence using a stringent P value (<10–6). None of the unique outcomes presented convincing evidence (Class I), yet 3 outcomes presented highly suggestive evidence, 5 outcomes presented suggestive evidence, and 37 outcomes presented weak evidence.From 3413 studies returned, 20 were included, covering 55 health outcomes. Median number of participants was 18 743 (range 403–225 000 000). Overall, 45 (81.8%) of the 55 unique outcomes reported nominally significant summary results  had strong evidence. The incidence rates of human immunodeficiency virus (HIV) infection have shown a slow but steady decline over the past 2 decades. Despite this decline, 1.8 million people globally are newly infected with HIV every year, which maintains HIV’s status as a top global health issue [Globally, the most common cause of death in people living with HIV (PLWHIV) is tuberculosis . HoweverReasons for the rise in non–AIDS related morbidity is a question of some debate. In general, the availability of ART led to a substantial rise in the life expectancy of PLWHIV, which is now almost comparable to that of the general, seronegative population and may be accompanied by more non–AIDS related morbidity . StudiesGiven the incidence, morbidity, and mortality rates associated with HIV, numerous systematic reviews and meta-analyses have attempted to quantify this disparate literature. To date, most systematic reviews have focused on a single disease end point and there has not been a systematic evaluation of the relationships between HIV and diverse physical health outcomes. Moreover, the strength and reliability of the literature is unclear.In order to address the breadth of the literature of complex health behaviors and outcomes, an increasing emphasis has been placed on “umbrella reviews”  .An umbrella review was carried out following standardized procedures , 12. EleThe primary screening was carried out by 2 authors (I. G. and L. Y.) and any disagreements were resolved via screening of the disputed title/abstract by a third author (N. V.). Full texts were sourced for all potential eligible articles and were screened by 2 investigators (I. G. and L. Y.), who determined the final references to be included.We included systematic reviews with meta-analyses of observational studies  that investigated the relationship between HIV and any physical health outcomes. Specific inclusion criteria included: (1) systematic reviews with meta-analyses reporting data on HIV (diagnosed through self-reports or laboratory confirmation); and (2) meta-analyses of cross-sectional or cohort studies that investigated the association of HIV with any health outcome . Studies had to report these outcomes as odds ratios, relative risks (RRs), hazard ratios, or continuous data . Studies could have been published in any language. Studies were excluded if they were related to immunosuppression or related to correlates of HIV infection.The following information was extracted from each article by 2 independent investigators: (1) first author name; (2) year of publication; (3) journal; (4) number of included studies and total number of people included in the review; (5) inclusion criteria for the studied population; (6) effect size(s) used in the review; (7) subgrouping used in the meta-analysis (with or without ART); (8) study design ; and (9) number of cases  and controls  for each study. We then extracted the study-specific, estimated RR for the health outcome , along with the 95% confidence interval (CI). If 2 meta-analyses were available for the same association, we included the largest in terms of the number of studies.Independently, 2 authors rated the methodological quality of the included meta-analyses using the AMSTAR 2 tool  . The between-study association was estimated with the I2 metric; values > 50% were indicative of high heterogeneity, while values above 75% suggest very high heterogeneity [For each meta-analysis, we estimated the summary effect size and 95% CI through random-effects models . In caseogeneity , 20.P value < .10, with more conservative effects in larger studies than in random-effects meta-analyses, was considered as indicative of small-study effects [In addition, we calculated the evidence of small-study effects . To this end, we used the regression asymmetry test developed by Egger and coworkers . A P val effects .P < .05) among those included in a meta-analysis is too large, based on the power that these data sets have to detect effects at α = .05. For this analysis, the power estimate for each data set was calculated. The sum of the power estimates of each study provided the expected number of data sets with nominal statistical significance. As described elsewhere, the number of expected “positive”  studies can be compared with the observed number of statistically significant studies through a χ 2-based test [t distribution. The excess significance for a single meta-analysis was considered whenever the P value was < .10.Finally, we applied the excess significance test , which esed test . The larP value in random effect model <.05) in 4 classes . Full details are given in We used credibility assessment criteria  andAs shown in As reported in P < .05); among these, 5 outcomes (9.0%) showed suggestive evidence, with P values < 10–3, and 3 (5.5%) outcomes showed stronger evidence using a stringent P value (<10–6).Overall, for 45 (81.8%) of the 55 unique outcomes, there were nominally significant summary results (2 consistent with large heterogeneity (>50%), with 26 showing very large heterogeneity (>75%). There were 5 outcomes that presented 95% prediction intervals, excluding the null value. The evidence for excess statistical significance  was present in 17 outcomes (30.9%), and small-study effects were also seen in 16 of the outcomes (29.1%). Studies with the largest sample size for each outcome maintained their statistical significance in 38/55 outcomes (69.1%). Further, for 15/55 outcomes (27.3%), the largest study had a more conservative effect, compared to the random-effects model.Heterogeneity among studies was generally high: 39/55 outcomes (70.9%) had an estimated IBased on the above criteria, no outcome presented convincing evidence (Class I). There were 3 outcomes that presented highly suggestive evidence , 5 outcomes that presented suggestive evidence  on AMSTAR 2, and 4 scored low  but no convincing evidence was evident: highly suggestive evidence was observed for only 3 outcomes.In this study, which included 20 meta-analyses and 55 different outcomes that are associated with HIV infection, we found highly suggestive evidence that HIV infection is associated with a higher presence of coughing in cross-sectional studies and higher risks of pregnancy-related mortality and ischemic heart disease in cohort studies. Suggestive evidence was found for a higher likelihood of the presence of breathlessness, a higher COPD prevalence, maternal sepsis, a higher risk of anemia, and a higher risk of all fractures among PLWHIV. These conclusions are based on the evaluation of epidemiological evidence credibility, which is a common approach used in a variety of research. Such critical appraisals of literature are necessary, as the nominal significance level of We found highly suggestive evidence that HIV infection is associated with the presence of coughing and suggestive evidence for an association with the presence of breathlessness and the prevalence of COPD. These results indicate that, even with the high availability of ART, PLWHIV experience disproportionally more chronic respiratory illness in comparison to seronegative populations . This maOur analysis also showed highly suggestive evidence of the association between HIV infection and ischemic heart disease. Reasons for this include the aforementioned high prevalences of smoking and illicit drug use within this population, but may also be related to underlying, chronic inflammation and immune activation, combined with coagulation abnormalities and atherosclerosis . OverallWe report on highly suggestive and suggestive levels of evidence concerning the association of HIV with pregnancy-related mortality and sepsis, respectively. The pathological interactions between HIV infection and pregnancy-related outcomes are poorly understood , 43; howThe final 2 outcomes showing suggestive levels of evidence in our analysis were the risk of anemia in children and the risk of bone fractures. For both outcomes, the mechanisms remain unclear. While anemia has been reported to be among the most common hematological complications to follow HIV infection, bone fractures have not been as commonly reported. The literature suggests effects of HIV on erythrocyte production in cases of anemia , while t2 <50% as 1 of the criteria for Class I evidence (convincing), in order to assign the best evidence grade only to robust associations. Second, many studies in our umbrella review determined individuals’ HIV statuses using self-reported information, but the agreement between self-reported and bio-humoral diagnoses is often poor [Umbrella reviews provide top-tier evidence and important insights, but there are a number of limitations that need to be considered. The meta-analyses contained studies that differed in their designs, populations, and other characteristics. However, we applied an Iten poor . Finallyten poor : their fOur results show highly suggestive and suggestive evidence for links between HIV and the presence of coughs, prevalence of COPD, incidence of ischemic heart disease, incidence of pregnancy-related mortality, incidence of maternal sepsis, and risk of bone fractures. Public health policies should reflect and accommodate these changes, especially in light of the increases in both life expectancy and incidences of comorbidities in this population. The elevated risks of the reported outcomes requires more research to improve both the prevention and early detection of these comorbidities in PLWHIV.Clinical Infectious Diseases online. Consisting of data provided by the authors to benefit the reader, the posted materials are not copyedited and are the sole responsibility of the authors, so questions or comments should be addressed to the corresponding author.Supplementary materials are available at ciz539_suppl_Supplementary_Table-1Click here for additional data file.ciz539_suppl_Supplementary_Table-2Click here for additional data file.


Perceived memory problems may cause older adults to limit functional activities such as driving. For those individuals living in non-metropolitan communities, greater distances between activities, lack of public transportation, and fewer support systems may make reducing driving frequency less feasible. We hypothesized that older adults in non-metropolitan communities would be more likely to continue frequent driving even if they also perceived memory problems. We used the National Health and Aging Trends Study to examine the association between reported memory difficulty and the frequency of driving. These data were then stratified by metropolitan versus non-metropolitan classification using both ordinal logistic regression and Chi-Squared testing. In both metropolitan and non-metropolitan communities, respondents were more likely to report reductions in driving frequency if they also reported memory problems. However, in both metropolitan and non-metropolitan communities, the majority of respondents reporting fair or poor memory continued to report frequent driving; and, there were no statistical differences in frequency of reported driving between metropolitan and non-metropolitan respondents. These analyses suggest that strategies are necessary in both metropolitan and non-metropolitan areas to help older drivers with perceived memory difficulties to recognize when they need to limit driving. Further research is necessary to determine which strategies are likely to be effective in metropolitan and/or non-metropolitan communities.


Opioid overdose risk is particularly high in immigrant communities partly due to limited English proficiency . Previous studies reported that social determinants of health (SDH) have been associated with risk for opioid overdose . The current study examines the association between SDH and literacy of opioid overdose risk among the immigrant population living in a rural area. Specifically, we examine the association in various age groups including young adults (aged 20 to 34), middle-aged (aged 35 to 49), and older adults (ages 50 to 75). Data were drawn from a sample of Korean American immigrants residing in rural Alabama (N=225). The participants administered the Brief Opioid Knowledge (BOOK) Questionnaire . Multiple regression analyses were conducted for three age groups to identify predictors of opioid literacy. Overall, older adults had lower levels of opioid literacy relative to their younger counterparts. Among young adults, low English proficiency, more chronic conditions, and greater depressive symptoms were significant predictors of limited opioid literacy. For the middle-aged adults, lower levels of health literacy and more pain symptoms were associated with limited opioid literacy. Among older adults, women, those with higher English proficiency, and lower health literacy had lower levels of opioid literacy. The findings demonstrated a greater vulnerability of older immigrants to limited opioid literacy. Different predictors based on SDH of limited opioid literacy across age groups have implications for tailored health promotion strategies to reduce opioid overdose risk.


The COVID-19 pandemic presents unprecedented challenges to public health decision-making. Specifically, the lack of evidence and the urgency with which a response is called for, raise the ethical challenge of assessing how much (and what kind of) evidence is required for the justification of interventions in response to the various threats we face. Here we discuss the intervention of introducing technology that aims to trace and alert contacts of infected persons—contact tracing (CT) technology. Determining whether such an intervention is proportional is complicated by complex trade-offs and feedback loops. We suggest that the resulting uncertainties necessitate a precautionary approach. On the one hand, precautionary reasons support CT technology as a means to contribute to the prevention of harms caused by alternative interventions, or COVID-19 itself. On the other hand, however, both the extent to which such technology itself present risks of serious harm, as well as its effectiveness, remain unclear. We therefore argue that a precautionary approach should put reversibility of CT technology at the forefront. We outline several practical implications. It has been suggested that it could be morally justified, or even morally obligatory, to implement contact tracing technology (CT technology) in the response to the current COVID-19 pandemic  evidence is required for the justification of interventions in response to the various threats we face. This is a familiar challenge in discussions on the precautionary principle Steel .proportionality. If PP is to be of any use as a practical guidance to responsible policy decision-making, it needs to be fleshed out in a way that is non-arbitrary and consistent. A non-arbitrary version of PP allows principled comparison between different precautions. It demands that when one precaution is preferred over another, this is done on the basis of generalizable reasons, for example those relating to costs, expected side effects or expected effectiveness. Consistency, moreover, demands that a version of PP that recommends a certain precaution does not at the same time recommend against that precaution. In a presently apt metaphor, the cure should not be worse than the disease (Singer and Plant The precautionary principle (PP) is based on the tenet that uncertainty is not a sufficient reason to abstain from taking precautions to prevent some adverse outcome. Usually, responsible applications of PP will set lower standards of evidence to the extent that the potential damage that the precaution aims to prevent is serious and/or irreversible . Although this formulation does not offer a clear cut-off point, reversibility could be interpreted as a threshold criterion: when, in a complex and urgent situation, the reversal of a precaution is impossible, likely to be very costly, or disruptive, this offers a weighty, principled reason against this precaution. As the available evidence accumulates, a situation may arise in which one may more confidently choose an option that is less easily reversed. However, our discussion suggests that the prospect of even retrospectively determining a single best course of action is not great, which means that it is important not to be overconfident in implementing precautions.Our suggestion in this situation of epistemic uncertainty is not to abandon hope for a reasoned approach but to aim to keep one’s options open as much as possible. Since the current pandemic poses a multifaceted problem, there will be no “golden bullet” solution, rather some interventions may work well in some contexts or only in combination with specific other interventions. Note that, even though some of the trade-offs we described are specific to CT technology, uncertainty applies to many other interventions as well, including other types of contact tracing. These interventions pose risks of their own, which makes it even more difficult to give a balanced assessment of what the right course of action is likely to be. Given the lack of evidence, the need to act quickly and a precautionary requirement to prevent serious and irreversible harm, the importance of the Public policy should have sunset provisions and should clearly describe how the temporary character of the surveillance is to be guaranteed.Any responsible implementation of CT technology should give special weight to systemic risks, for example creating or exacerbating power asymmetries or the risk of creating or reinforcing monopolies.Reversibility provides an argument not to integrate CT technology into existing infrastructures: a keychain or card is prima facie preferable to an app that is installed on a smartphone. Specifically designated hardware may be easily discarded and plausibly has a relatively small impact on existing power distributions.Evidence should be acquired in local experiments, rather than nationally or even internationally rolling out possible solutions.The focus on reversibility also gives strong reasons not to presume effectiveness of CT apps in general. Different governments and private institutions have currently committed to digital CT, mostly without detailing the specific properties that would determine effectiveness, and without describing how effectiveness would be enhanced by other measures. This approach runs the risk of excluding considerations, which hinders a proper balancing of contextual factors.The focus on reversibility has several practical implications:Note that the fluidity of the current situation suggests that none of these implications is etched in stone and that they could themselves be subject to revision. Any plausible approach to the complex and urgent problems that we now face will, however, need to take reversibility into account.


BUB1B, CEP57, or TRIP13. We describe the prenatal diagnosis, molecular characterization, and clinical management of a long‐lived patient with BUB1B‐related MVA.Mosaic variegated aneuploidy (MVA) is a rare genetic disorder caused by mutations in  BUB1B, CEP57, or TRIP13. We describe the prenatal diagnosis, molecular characterization, and clinical management of a long‐lived patient with BUB1B‐related MVA.Mosaic variegated aneuploidy (MVA) is a rare genetic disorder caused by mutations in  The clinical features of MVA syndrome include severe pre/postnatal growth retardation, microcephaly, central nervous system anomalies, intellectual disability, minor congenital malformation, and predisposition to malignancy. There is some genotype‐phenotype correlation  is a congenital autosomal recessive disorder characterized by mosaic aneuploidies, predominantly trisomies, and monosomies, involving multiple chromosomes and tissues.Several cases of MVA were diagnosed in prenatal period,2A 29‐year‐old multipara Chinese woman with two previous normal deliveries was referred for invasive prenatal diagnosis at 19 weeks of gestation in 1996. On antenatal screening, she was noted to have raised maternal serum alpha fetoprotein level of 3.08 MoM, abnormal fetal scan with early onset growth retardation, pericardial effusion and ascites, congenital heart disease, and duplication cyst of gut. Chromosome study of cultured amniotic fluid cells showed multiple cell line with a composite karyotype of 45~51,XX,+X[1],+2[3],+3[2],+5[6],‐5[1],+6[4],−6[2],+7[6],+8[3],+10[3],+12[1],+14[1],+15[1],+16[1],+17[7],+18[1],+20[1],+21[2][cp150] Figure . After cBUB1B gene were found  on physical examination Figure . At 15 y3Premature chromatid separation (PCS) and asynchrony of mitotic stages is described to be the pathogenic mechanism for mosaic variegated aneuploidies (MVA). PCS/MVA manifests cytogenetically as a variety of mosaic aneuploidies, especially trisomies, double trisomies, and monosomies. The proportion of aneuploid cells varies but is usually >25% and is substantially greater than in normal individuals. Conventional cytogenetic analysis with at least two independent amniocyte cultures should always be performed to diagnose prenatal MVA. In our case, amniocyte, placenta, and cord blood lymphocytes culture demonstrated that the proportion of aneuploidy cells was more than 25%, which confirmed the prenatal diagnosis of MVA.The phenotype is highly variable across individuals of MVA. Common abnormalities of MVA include intrauterine growth retardation, microcephaly, dysmorphic features, and mental retardation. There is also a high risk of early‐onset childhood cancer like Wilms tumor, rhabdomyosarcoma, or leukemia. Facial dysmorphic features in MVA syndrome include micrognathia, frontal bossing, triangular face, epicanthic folds, hypertelorism, low‐set ears, and broad nasal bridge. Cardiovascular, neurological, skeletal anomalies like rhizomelic shortening of the upper limbs, gastrointestinal, and dermatological anomalies, immunodeficiency, and endocrine problem like hypothyroidism have also been described.BUB1B involved in the mitotic spindle checkpoint might underlie MVA. The compound heterozygous variants NM_001211.5(BUB1B):c.[1402‐5A>G];[2387‐11A>G] found in this patient are located at the RNA splicing acceptor site of exons 11 and 19 of BUB1B, and reported in the literature.BUB1B expression on the spindle checkpoint is dose‐dependent. An analogous mutation (in mice) to the human MVA BUB1B (encodes protein BUBR1) has a reduced lifespan and develop several age‐related phenotypes at an accelerated rate. Sustained high expression of BUBR1 preserves genomic integrity and reduces tumorigenesis by correcting mitotic checkpoint impairment and microtubule‐kinetochore attachment defects.Genetic defect of chromosome segregation in cell mitosis might be associated with MVA, and mutations of UB1B):c.102‐5A>G;[BUB1B subtype. Early molecular diagnosis might enable risk stratification for tumor surveillance. Common tumors reported in BUB1B‐associated MVA syndrome are Wilms tumor, rhabdomyosarcoma, leukemia and granulosa cell tumor of the ovary. In this case, patient suffered from infantile neuroblastoma and Sertoli‐Leydig cell tumor. It is recommended that patients with MVA syndrome have regular abdominal ultrasound surveillance, to particularly look for Wilms tumor. However, as the incidence rate of other rare tumor in MVA is unknown, there is still no evidence to indicate that routine screening is beneficial. But high index of suspicion is necessary. In case there are any clinical symptoms of malignancy, further investigation should be carried out.Clinical management of patients with MVA syndrome includes symptomatic support and tumor surveillance, particularly for BUB1B‐related MVA syndrome in the literature, its clinical course, and management.We have reported the longest Chinese survivor of There is no any conflict of interest in relation to the work.Sheng Mou Lin and Ho Ming Luk: involved in conceptualization, methodology, drafting, and writing manuscript. Ivan Fai Man Lo: involved in data collection and curation. Wai‐Keung Tam and Kelvin Yuen Kwong Chan: carried out investigation. Hei‐Yee Tse, Wing Cheong Leung, and Mary Hoi Yin Tang: involved in data curation and validation. Anita Sik Yau Kan: involved in conceptualization, reviewing, and editing.Written informed consent was obtained from the patient.


Self-management (SM) includes activities that patients initiate and perform in the interest of controlling their disease and maintaining good health and well-being. This review examines the health literacy and patient activation elements of self-management interventions for Chronic Obstructive Pulmonary Diseases (COPD) patients. We investigated the effects of the intervention on health-related quality of life, self-efficacy, depression, and anxiety among people with COPD. We conducted a systematic review of studies evaluating the efficacy of self-management interventions among COPD patients that also included health literacy or patient activation as keywords. Four electronic databases Medline, EMBASE, PsycINFO, and Google Scholar, were searched to identify eligible studies. These studies were screened against predetermined inclusion criteria. Data were extracted according to the review questions. Twenty-seven studies met the criteria for inclusion. All of the included studies incorporated health literacy components and focused on COPD and self-management skills. Three studies measured health literacy; two showed improvements in disease knowledge, and one reported a significant change in health-related behaviors. Seventeen studies aimed to build and measured self-efficacy, but none measured patient activation. Eleven studies with multicomponent interventions showed an improvement in quality of life. Six studies that focused on specific behavioral changes with frequent counseling and monitoring demonstrated improvement in self-efficacy. Two interventions that used psychosocial counseling and patient empowerment methods showed improvement in anxiety and depression. Most self-management interventions did not measure health literacy or patient activation as an outcome. Successful interventions were multicomponent and comprehensive in addressing self-management. There is a need to evaluate the impact of comprehensive self-management interventions that address and measure both health literacy and patient activation on health outcomes for COPD patients. Chronic Obstructive Pulmonary Disease (COPD) is a common, preventable, and treatable disease that is characterized by persistent respiratory symptoms and airflow limitation . The treHealth literacy (HL) and patient activation (PA) play key roles in self-management interventions. HL helps patients to develop a “skillset” to better manage their health, while PA develops a “mindset” that helps them “to change the lifestyle behavior” . InterveAddressing health literacy in self-management interventions has been shown to improve individual decisions and actions ,13 in thHave COPD self-management interventions included health literacy and patient activation components, and have they measured improvements in health literacy and patient activation?What are the effects of the intervention on health-related quality of life, self-efficacy, depression, and anxiety among people with COPD in self-management interventions (SMIs)?The methodology was guided by the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) .Medline, EMBASE, PsycINFO, and Google Scholar, were searched to find eligible RCTs published between 1 January 2008 and 9 December 2019. Combinations of Medical Subject Headings (MeSH) terms, using “OR” and “AND”, were used to operate the electronic databases. To be selected, papers had to have self-management and either health literacy or patient activation search terms, as outlined in the Four well-known electronic databases, Box 1Self-management: The search terms included any of the following: “Self-management”, “Self-care”, “Self-treat”, “Personalised”, “Self-management Intervention”, “Supporting”, “Engaging” “Pulmonary disease”, “Chronic Obstructive Pulmonary Disease”, and “COPD”.ANDEITHERHealth literacy: The search terms included any of the following: “Health Literacy”, “Functional health literacy”, “Interactive health literacy”, “Knowledge on health”, “Reading and writing”, “Literacy level”, “Comprehensive health knowledge”, “health information” and “health promotion”, “Chronic Obstructive Pulmonary Disease”, and “COPD”.ORPatient activation: The search terms included any of the following: “Patient activation”, “Patient Activation Measure”, “Personalized support”, “Motivation”, Knowledge”, “Skills”, “Confidence”, “Empowerment”, “Chronic Obstructive Pulmonary Disease”, and “COPD”.The definition of COPD self-management put forward by Effing et al.  was usedPapers should be RCTs or comparative studies in the English language, available in full text, and aimed at the self-management of COPD. Participants had to be diagnosed with COPD. The intervention had to include elements which addressed either HL or PA. Primary outcome measures had to include quality of life (QOL), anxiety and depression, self-efficacy, or the measurement of health literacy and patient activation.Conferences abstracts, posters, studies with an intervention period of less than six months, published protocols, studies with patients with cancer as co-morbidity, telehealth interventions, drug trials, and studies reported in other than English language were excluded from this study.Initially, one author (U.N.Y.) screened all titles and excluded articles that were irrelevant under the supervision of MFH. After that, five authors  used a standardized form based on eligibility criteria to independently review full-text articles in line with the Preferred Reporting Items for Systematic reviews. Finally, MFH separately examined the full-text articles meeting eligibility and exclusion criteria. There were few discrepancies between U.N.Y. and M.F.H. in the excluded data that were resolved in consensus discussion between the two reviewers. A vote of the majority was used to address disagreements during the review of full texts.Initially, 481 potentially relevant articles were identified. Twenty-seven studies met the inclusion criteria. Our screening process is depicted in All twenty-seven studies included in our review had interventions that address health literacy. This was provided through educational materials  and improving clinical communication between health providers and patients. Three ,21,22 stEighteen studies ,36,37,38Health-related quality of life was assessed by twenty-five studies ,41,42,43The effects on self-efficacy were measured in fifteen studies ,39,40,41Eleven studies ,36,39,42Despite a wealth of evidence showing beneficial outcomes of COPD self-management programs, substantial gaps remained in the evidence base. To the best of our knowledge, this is the first review to analyze the inclusion of health literacy and patient activation elements in COPD self-management interventions. All the included studies  evaluateIn more than a third of the included studies, self-management interventions improved the quality of life of COPD patients. More importantly, QOL improvements were seen majorly in those interventions that addressed both HL and PA (10 out of 11 interventions that improved QOL) to some degree and offered a comprehensive package of self-management components . In line with our findings, other reviews have suggested that multicomponent self-management interventions (SMIs) are significantly effective in improving HRQOL ,6,45. HoOf fifteen studies that addressed self-efficacy, only six showed a positive effect on self-efficacy for behavior changes, such as quitting smoking, performing a daily exercise, or taking medicine according to guidelines. Available literature  suggestsSelf-management programs need to be guided by learning and behavior-change theories that can be tailored to a population’s needs, taking into account literacy, confidence level, ethnic, cultural, and cognitive factors . InterveAn inherent limitation of this review was the lack of meta-analysis because the intervention and outcome measurements were too heterogeneous. Although multiple databases were searched, using MeSH terms, the search may not have yielded all published relevant studies, given the variation in terminology for “self-management”, “health literacy”, and “patient activation”.This review provided insights into how frequently SMI includes features that address health literacy and patient activation. HL interventions were not comprehensive  and PA interventions with improving self-efficacy. This suggests the need to further evaluate the impact of comprehensive self-management interventions, which include elements which address both health literacy and patient activation on health outcomes for COPD patients.


Both morbidity and mortality data (MMD) and learning curves (LCs) do not provide information on the nature of intraoperative errors and their mechanisms when these adversely impact on patient outcome. OCHRA was developed specifically to address the unmet surgical need for an objective assessment technique of the quality of technical execution of operations at individual operator level. The aim of this systematic review was to review of OCHRA as a method of objective assessment of surgical operative performance.Systematic review based on searching 4 databases for articles published from January 1998 to January 2019. The review complies with Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines and includes original publications on surgical task performance based on technical errors during operations across several surgical specialties.Only 26 published studies met the search criteria, indicating that the uptake of OCHRA during the study period has been low. In 31% of reported studies, the operations were performed by fully qualified consultant/attending surgeons and by surgical trainees in 69% in approved training programs. OCHRA identified 7869 consequential errors (CE) during the conduct of 719 clinical operations (mean = 11 CEs). It also identified ‘hazard zones’ of operations and proficiency–gain curves (P-GCs) that confirm attainment of persistent competent execution of specific operations by individual trainee surgeons. P-GCs are both surgeon and operation specific.Increased OCHRA use has the potential to improve patient outcome after surgery, but this is a contingent progress towards automatic assessment of unedited videos of operations. The low uptake of OCHRA is attributed to its labor-intensive nature involving human factors (cognitive engineering) expertise. Aside from faster and more objective peer-based assessment, this development should accelerate increased clinical uptake and use of the technique in both routine surgical practice and surgical training. Learning curves (LC) are often used by surgeons who are ‘learning’  in the execution of an operation, as performance improves with increasing experience . On. On43]. Since this study was a systematic review and there were no human subjects involved, thus, the institutional review board (IRB) approval and written consent were not required.An initial search was carried out on PubMed, EMBASE, Web of Science and the Cochrane Library for English language articles published from January 1998 to January 2019. Search strategy and terms used included ‘human reliability analysis (HRA),’ ‘observational clinical human reliability analysis (OCHRA),’ ‘human error in surgery,’ ‘adverse events,’ ‘human error identification,’ ‘technical error in surgery,’ ‘surgical performance,’ ‘task analysis in surgery,’ and ‘competency assessment.’ A further search used terms such ‘patient safety,’ ‘hazard zones in surgery,’ ‘human factors in surgery,’ ‘proficiency–gain curves in surgery,’ ‘surgical skills training.’ All the key search terms were combined subsequently.The culled publications were retrieved in full text for further assessment for eligibility. Following review, relevant references cited in the included articles were also retrieved and scrutinized.Studies describing use of HRA or OCHRA for direct assessment of surgical operations were grouped together. Other publications in which HRA or OCHRA were used as one of the methods to assess surgical task performance for research projects were grouped separately. Microsoft Excel 2016  was used to manage the extracted data. Risk of bias within individual or across studies was not specifically assessed.The Medical Education Research Study Quality Instrument (MERSQI)  was applA total of 2341 publications were screened, of which 297 were read in full text. Of these, 82 studies were excluded as not relevant. After the eligibility criteria of inclusion and exclusion were applied, a total of 26 studies were selected in the final data set for analysis  , 4534, 4OCHRA assesses the quality of execution by a surgeon (performance level) by detection and characterisation of technical errors  and  enacted by the operator during the operation , 21-34. The reported significant correlation between OCHRA error rates and quality of total mesorectal excision also confirms the clinical relevance of the technique in quality assessment of surgical performance , 28. It In the OCHRA paradigm, technical errors are classified as consequential  and inconsequential , 21, 22.Technical errors associated with inability of the surgeon to execute the component steps in the correct order are categorized as ‘procedural error modes,’ while ‘execution error modes’ reflect ineffective/traumatic manipulations , 16, 22.Underling mechanisms which provide a deeper understanding of the likelihood of occurrence of technical errors were reported in some studies, e.g., applying excessive force, incorrect order of steps, concentration lapses, misjudgements, poor instrument selection etc., have been identified as factors. Several hazard zones have also been described Table  15, 16,, 25-30 aThe study by Miskovic et al. which evaluated the performance of specialists executing live operations in the operating room, confirmed the validity of OCHRA in adjudicating surgical performance at a specialist level and suggested that this method could be implemented for competency assessment within a clinical training program . PotentiEqually important, the review highlights the current limitations of OCHRA including its labor-intensive nature involving human factors scientists using established criteria to identify and categorize errors from unedited videos of operations , 21-42. The resulting increased uptake and use of OCHRA would enhance patient outcome after surgery in routine hospital surgical practice and surgical training, aside from being a useful tool for privileging, accreditation and re-validation. The low uptake of OCHRA despite its ability to assess execution quality of operations is attributed to its labor-intensive nature involving human factors (cognitive engineering) expertise. This issue can only be resolved by development of smart video recorders equipped with AI and ML based on incorporated and/or WIFI-accessible huge data sets of unedited recorded operations.


Meaning in Life (MiL) is considered protective against suicidal behavior (SB). However, few studies specifically addressed the role of the constructs, “presence of MiL” and “search for MiL,” and their dynamic interplay. In this cross-sectional study of patients with SB (N = 199) visiting a psychiatric Emergency Department for either suicidal ideation (SI) or suicide attempt (SA), we pursued the following objectives: 1) to explore the relationship between the two constructs; 2) to verify the protective value of presence of MiL on SB; and 3) to assess the influence of search for MiL on the relationship between presence of MiL and SI. The two constructs were found to be independent of one another. Higher presence of MiL was globally associated with lower SB levels, particularly SI. Search for MiL was not related to SB and did not moderate the relationship between presence of MiL and SI. In conclusion, formal support for the role of presence of MiL against SB in a psychiatric sample was demonstrated. These findings, with a view toward refinement of SB risk assessment and new psychotherapeutic approaches, may lead to an enrichment of the dialogue with suicidal patients to help alleviate their unbearable suffering. Our conclusions must be replicated in psychiatric clinical populations in settings other than a psychiatric ED and by using a longitudinal prospective and case-control study design. The presence of Meaning in Life (MiL) has long been associated with protection against suicide, as initially observed in prisoners of Nazi concentration camps , 2. MoreTo our knowledge, only four studies have investigated the roles of both constructs of MiL in the development of suicidal behavior (SB)  = 15.711, p < 0.001) and accounted for 22.9% of the total variance. The presence of MiL construct was the only single variable that had a significant effect on SI .A two-step multiple linear regression equation was built using the SSI score as the dependent variable. In the first step, we used the sociodemographic parameters that showed positive correlations with the presence of MiL construct, namely age, having children, and relationship status. As summarized in 2R = 0.014, Nagelkerke 2R = 0.019), and the odds ratio (OR) of each sociodemographic variable did not predict the dependent variable at our significance threshold. Thereafter, we added the presence of MiL construct as predictor in a second model, and it accounted for a larger proportion of the variance in the dependent variable . In addition, the presence of MiL construct predicted the probability to be included in the study with an SA rather than with SI only .We then built a logistic regression model using a criterion variable that dichotomized participants incorporated in the study for SI only (coded 0) from those included in the study for an SA (coded 1). As before, we first used the sociodemographic variables that showed positive correlations with the presence of MiL construct and in this case found that the model accounted for a small proportion of the variance in the study inclusion criterion , and explained 23.3% of its total variance (adjusted 2R). Although the presence of the MiL construct had a protective effect on SI , neither search construct nor the interaction variable between presence of MiL construct and search construct had a significant effect on the dependent variable.As shown in This study investigated the role of the two MiL constructs in a clinical population of patients attending a psychiatric ED for SB, namely SI and SA.via a greater theoretical flexibility. For instance, it can allow the identification and distinction of individuals who feel great meaningfulness yet are still engaged in seeking life’s meaning and contrast them with those who feel the same meaningfulness but are not engaged in further search for meaning  by providing a research path that reinforces the proven independence of the two MiL constructs. It follows that a more nuanced and dynamic description of the individual’s personal attitude toward MiL can be generated through investigation of the constructs in the following combinations: 1) high presence of MiL-high search for MiL ; 2) high presence of MiL-low search for MiL ; 3) moderate presence of MiL-moderate search for MiL ; 4) low presence of MiL-low search for MiL ; and 5) low presence of MiL-high search for MiL  , 21. TheWith regard to our second hypothesis, that is that the presence of MiL construct has a protective impact on both SI and SA, we found that higher presence of MiL was associated with lower SI. No significant correlation was found between the search for MiL construct and SI/SA. Previous studies that have addressed this issue –18 reporr = −0.485), we can hypothesize that this MiL construct was influenced by the latter psychological process on SI and, consequently, possibly more so before rather than after an SA. Unfortunately, the data providing information on the attitudes and reactions of individuals following an SA are limited, but one study found that a process of awareness of life responsibilities occurred at an initial stage (Somewhat counterintuitively, the presence of MiL construct predicted the probability of being included in the study with an SA rather than with SI only. To our knowledge, this is the first study to report this finding. In our sample population, participants with an SA had lower SI than those included with SI only, possibly implying that the psychological process that unfolds after an SA can have mitigating effects on SI . Becauseal stage . In addial stage . Though As for our explored third point, i.e., to assess the influence of the search for MiL construct on the relationship between the presence of MiL construct and SI, we did not find that the search for MiL construct moderated the relationship as hypothesized. This novel finding reinforced, along with our first hypothesis, that the two constructs are independent of one another.In summary, this study provided formal support for the role of the presence of MiL construct against SB in a general psychiatric study group. In contrast, the search for MiL construct was not related to SB and did not moderate the relationship between the presence of MiL construct and SI, suggesting, along with other findings, that the two constructs are independent of one another. This is the first study to examine the direct impacts of both constructs on SB in a clinical psychiatric population. To confirm these findings, our conclusions must be replicated in psychiatric clinical populations in settings other than a psychiatric ED and by using a longitudinal prospective and case-control study design.This study had several limitations to consider. First, the use of regression analyses on cross-sectional data limited the interpretation of causality. Thus, this aspect should be interpreted with caution and replicated in longitudinal research. Second, we lacked a control group which limited the validity of our conclusions. Third, the MLQ questionnaire has not been formally validated in French. Fourth, the sample of patients we tested attended the psychiatric ED for SI and SA, and our results should be confirmed in suicidal patients belonging to more specialized psychiatric settings in order to be more generalizable. Finally, we did not test the impact of the two constructs using a typological methodology: the identification of different MiL profiles deriving from combinations of the two constructs can represent an opportunity to further refine individual diagnostic profiles with the goal of improving clinical outcomes by providing a more personalized approach.The datasets generated for this study are available on request to the corresponding author.The protocol was approved by the Research Ethics Committee of Geneva under the registration number 14-168. All subjects gave written informed consent in accordance with the Declaration of Helsinki.ACo drafted the primary manuscript, contributed to the conceptualization of the study, and participated to data collection and data interpretation. MB contributed to the conceptualization of the study, participated to data collection and data interpretation, and made statistical analysis. HR-L contributed to the conceptualization of the study and participated to study data collection. KW contributed to the conceptualization of the study and participated to data collection and data interpretation. MP and ACa contributed to the conceptualization of the study, corrected the manuscript, supervised all the steps of the work, and provided the intellectual impetus. All authors approved the final manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Clinical practice guidelines have become increasingly widely used to guide quality improvement of clinical practice. Qualitative research may be a useful way to improve the quality and implementation of guidelines. The methodology for qualitative evidence used in guidelines development is worthy of further research.A comprehensive search was made of WHO, NICE, SIGN, NGC, RNAO, PubMed, Embase, Web of Science, CNKI, Wanfang, CBM, and VIP from January 1, 2011 to February 25, 2020. Guidelines which met IOM criteria and were focused on clinical questions using qualitative research or qualitative evidence, were included. Four authors extracted significant information and entered this onto data extraction forms. The Appraisal of Guidelines for Research and Evaluation (AGREE II) tool was used to evaluate the guidelines’ quality. The data were analyzed using SPSS version 17.0 and R version 3.3.2.Sixty four guidelines were identified. The overall quality of the guidelines was high . Domain 1 (Scope and Purpose) was ranked the highest with a median score of 83% (IQ 78–83). Domain 2 (Stakeholder involvement) and Domain 5 (Applicability) were ranked the lowest with median scores of 67% (IQ 67–78) and 67% (IQ 63–73) respectively. 20% guidelines used qualitative research to identify clinical questions. 86% guidelines used qualitative evidence to support recommendations . 19% guidelines applied qualitative evidence when considering facilitators and barriers to recommendations’ implementation. 52% guideline developers evaluated the quality of the primary qualitative research study using the CASP tool or NICE checklist for qualitative studies. No guidelines evaluated the quality of qualitative evidence synthesis to formulate recommendations. 17% guidelines presented the level of qualitative research using the grade criteria of evidence and recommendation in different forms such as I, III, IV, very low. 28% guidelines described the grades of the recommendations supported by qualitative and quantitative evidence. No guidelines described the grade of recommendations only supported by qualitative evidence.The majority of the included guidelines were high-quality. Qualitative evidence was mainly used to identify clinical questions, support recommendations, and consider facilitators and barriers to implementation of recommendations’. However, more attention needs to be paid to the methodology. For example, no experts proficient in qualitative research were involved in guideline development groups, no assessment of the quality of qualitative evidence synthesis was included and there was lack of details reported on the level of qualitative evidence or grade of recommendations. Qualitative research can be defined as research that involves “the collection, analysis and interpretation of data that are not easily reduced to numbers; these data relate to the social world and the concepts and behaviors of people within it” . Data frTaking the merits of qualitative research into account, it has attracted the attention of guideline developers and is gradually becoming accepted to inform guideline recommendations, for example WHO  has affirmed in its handbook for guideline development that qualitative evidence should be considered and used in the process of guideline development and the WHO Guidelines Review Committee (GRC) internet site also provides additional guidance on when and how to use qualitative research data to inform WHO guidelines . Many prAs Lewin & Glenton said, qualitative research may be entering a new era of being used in the process of guideline development, and it is beneficial for decision making . Our aimThe systematic review was performed according to the PRISMA  guidelines .We included guidelines focused on improving healthcare that met the following criteria: 1) the guidelines were primarily published in Chinese or English from January 1, 2011 to February 25, 2020. In 2011, IOM (Institute of Medicine) claimed that for a CPG to be trustworthy it needs to “be developed via a transparent process by a group of multidisciplinary experts (including patient representatives), screened for minimal potential bias and conflicts of interest, and supported by a systematic review of the evidence” . This, wRelevant representative guidelines repositories, such as WHO, NICE , SIGN (Scottish Intercollegiate Guidelines Network), NGC , RNAO (Registered Nurses’ Association of Ontario), and other databases, including three English databases , four Chinese databases , were systematically searched from January 1, 2011 to February 25, 2020. The search strategy used MeSH terms, Title/Abstract and text words. Taking PubMed as an example, the retrieval strategy is shown in Fig. Three  authors experienced in literature retrieval independently selected eligible guidelines. Three reviewers  extracted significant information from the guidelines and completed data extraction forms by means of reading the text content of the guideline, references and the online relevant attachments. The detailed process of data extraction is presented in Additional file We hypothesized that the development of guidelines using qualitative research or evidence would be relevant to these items in the forms. The hypothesis was based on related methodological literature, COnsolidated criteria for REporting Qualitative research (COREQ) checklists  and discTwo researchers (Y.YW and D.H) independently evaluated the quality of the guidelines by using the Appraisal of Guidelines for Research and Evaluation (AGREE II) tool, which consists of 23 items under 6 domains involving scope and purpose, stakeholder involvement, rigor of development, clarity of presentation, applicability, and editorial independence . Each itDescriptive statistics were computed for the scores for each AGREE domain. Data for each AGREE II domain were provided as medians and interquartile ranges (IQRs). Intraclass correlation coefficients (ICCs) were calculated to evaluate the agreement between two reviewers for each domain , 19. WheThe searches identified 10,245 discrete records, of which 449 were selected for a full-text review. Sixty-four guidelines were eventually included –84. The As Table The ICC values for all six domains were over 0.75, which indicated high consistency in the assessment results between the two raters.As Table As Fig. As Table Our review shows that the majority of the included guidelines were high-quality. Qualitative evidence was mainly used to identify clinical questions, support recommendations, and consider facilitators and barriers to recommendations’ implementation. However, the methodology still needs more attention, as there were, no experts proficient in qualitative research involved in guideline development group, no assessment of the quality of qualitative evidence synthesis and a lack of detailed reporting the level of qualitative evidence and its grade of recommendations’.The majority of the included guidelines introduced the overall aim of the guideline, the specific health questions, and the target population in tabulated form, bold, or using separate paragraphs. They described the gathering and synthesis of the evidence, gave details of updating and dealt with the language, structure, and format of the guideline recommendations.. However, the guidelines still had some noticeable shortcomings. For instance, a few guidelines did not describe the methods of formulating recommendations , 76, 82;The methodological quality of qualitative evidence affects interpretation of its results. Unfortunately, while the majority of guidelines developers used qualitative evidence synthesis to formulate recommendations, they did not appraise confidence in each individual review, which resulted in some difficulties in explaining relevant themes or theories formulated in different articles. In addition, only three of the grade systems used, referred to single qualitative studies or synthesis of qualitative research as a level of the grade criteria of evidence and recommendation , 85–87. When comparing our findings with similar relevant articles, lack of statements about conflict of interest, details on how to gain patients, doctors or other stakeholders’ views, consideration of facilitators and barriers to guidelines’ implementation are also common issues e.g. oncology CPGs , inflammIn Addition, qualitative research is increasingly being recognised as having an important role to play in addressing questions relating to interventions or system complexity, and guideline development processes. As with our topic, other researchers have also focused on the methodology of involving qualitative research in the development process of guidelines. Flemming et al. provided guidance for the choice of qualitative evidence synthesis methods in the context of guideline development for complex interventions by using a best fit framework synthesis to address interactions between components of complex interventions; interactions of interventions with context and multiple  outcomes; using meta-ethnography to deal with sociocultural acceptability of an intervention . In addiThe development of guidelines is a complex undertaking which needs a significant focus on its methodology. Based on our findings, we put forward some proposals for guideline developers, which may be helpful to improve their guideline’s quality. Firstly, guidelines developers can record and report details about how they reach agreement on recommendations and how they deal with possible disagreement when formulating recommendations and present different options for the same CQs with information on population characteristics or clinical situations for each option. Secondly, they can also develop a series of methods to avoid potential COI before the initiation of the guideline development project. Guideline developers may also obtain the target population’ views by interviewing stakeholders or extracting some relevant themes from existing qualitative data on the topic of interest. Finally, guideline developers should formally consider how to evaluate and grade single qualitative studies or synthesis of qualitative research into the grade system for guideline development prior to start-up of the guideline development project, and identify which factors influence the grade classification with the help of experts proficient in qualitative research. They should also select appropriate tools to appraise the quality of qualitative evidence such as CASP tool, NICE checklist for primary studies, GRADE-CERQual  for qualitative evidence synthesis, which is an approach for assessing how much confidence to place in findings from qualitative evidence syntheses in terms of four components  , 96.Our study has some potential limitations. Firstly, although we selected eligible guidelines by means of reading their text content, references and the online relevant attachments, we used a quick search strategy on the guideline development. We also used the filter capability when using Endnote to manage literature from databases. But because of the size of the task there may be selection bias because of unavailable guidelines published in government documents, books or other guideline publication platforms. Additionally, we did not specify how many guidelines were recommended, recommended with modifications, and not recommended, because AGREE II protocol states that no overall score is calculated to determine if a CPG is recommended or not recommended and the main focus of this article was the methodology for qualitative research or qualitative evidence used in guidelines development . NonetheQualitative research or qualitative evidence will be extensively used in the guideline development process in the future. There are three interesting topics needing further research. Firstly, when available data exists, this can be explored to provide more reliable conclusions related to the potential association between AGREE appraisal and the identification, incorporation and reporting of qualitative research by means of statistical methods such as non-parametric tests. Secondly, it will be interesting to compare the use of qualitative and quantitative data when formulating recommendations in guidelines, perhaps by matching guidelines on similar topics or key questions, and comparing those which did and didn’t use use qualitative evidence. Thirdly, exploring how qualitative research may be used to obtain the information related to conflict of interest will also be useful to inform guideline transparency. These topics are worthy of future exploration.The majority of the included guidelines were high-quality. Qualitative evidence was mainly used to identify clinical questions, support recommendations, and consider facilitators and barriers to recommendations’ implementation. However, more attention needs to be given to the methodology, for instance, no experts proficient in qualitative research have been involved in guideline development group, there has been no assessment of the quality of qualitative evidence synthesis, and there is a lack of detail when reporting on the level of qualitative evidence and its grade recommendations’.Additional file 1. The process of data extraction.


Fabricius. The important of spleen has been largely dismissed until recently. However, its importance in both innate and specific immunity is increasingly recognized. There is a major difference between birds and mammals is the female reproductive system as birds produce large yolk filled eggs. The precursors of the yolk are synthesized by the liver. Another difference is that there is a single ovary and oviduct in birds.There are marked differences between the physiology of birds and mammals. These reflect the evolutionary distance between the two classes with the last common ancestor estimated as existing 318 million years ago. There are analogous organ systems in birds and mammals. However, marked differences exist. For instance, in the avian gastro-intestinal tract, there is a crop at the lower end of the esophagus. This functions both to store feed and for microbial action. The avian immune system lacks lymph nodes and has a distinct organ producing B-lymphocytes, namely the bursa  Fabricius and spleen and female reproduction. Moreover, a series of questions are asked. It is noted that the physiology of birds reflects impacts of their evolutionary history, effects of domestication and the sequentia of flight.The physiology of birds has attracted significant attention. A caveat is that much of the research on the physiology birds has been with domesticated birds, particularly chickens and ducks. The present communication discusses examples from the following systems where birds differ from mammals: gastrointestinal tract and specifically the crop and ceca, immune system and specifically the bursa Synapsida  and Reptilia  diverged 318 million years ago (MYA)  . Common go (MYA) . Birds ego (MYA) . Based o•Palaeognathae  and the Neognathae  – 113 MYA during Cretaceous period.•Neoaves  and Galloanseres  88 MYA during Cretaceous period.•The ancestors of the major groups of birds including land birds and water birds diverged at about the time of the Cretaceous–Paleogene (K-Pg) boundary (66 MYA) with some diverging before and some immediately after .An identifiable fossil land bird has been described from ∼62.5 million-year-old rocks . An “expGallus genus beginning at least 8000 years ago  together with introgressions from the green jungle fowl (G. varius) (G. sonneratii) presumably after domestication. Prior to scientific selection, there were also shifts in the genetics and hence physiology of poultry. For instance, based on studies with native chickens from Africa and Europe, chickens from different regions are genetically equipped for different environmental temperatures (There is clear evidence that domestication and later selection has influenced the genetics and phenotype of poultry. Chickens were domesticated from members of the ears ago  with mulears ago . The gen varius)  and the eratures . Breeds White Leghorns are frequently used as a surrogate for all chickens or even all birds e.g.,  but the Gallus gallus) with depressed basal circulating concentrations of pregnenolone and dehydroepiandrosterone (DHEA) together with circulating concentrations of corticosterone following restraint in domesticated chickens  (a missense mutation from glycine to arginine) and wild-type allele (Shifts in supposedly “domestication related” genes have been reported for yellow skin color (β-carotene dioxygenase 2) and thyroid-stimulating hormone receptor . The gastrointestinal tract of birds shows close similarities to that of mammals with, for instance, an esophagus for the passage of ingesta from the mouth to the equivalent of the stomach and a small intestine made up of duodenum, jejunum and ileum where much enzymatic digestion and virtually all of absorption occurs and a colon (large intestine). Moreover, the liver and pancreas play similar roles supplying, respectively, bile with bile salts and pancreatic juice with digestive enzymes. There are also differences including the following, using chickens and ducks as exemplars:1.The absence of teeth and hence chewing.2.The presence of the crop as an outgrowth of the lower esophagus.3.The separation of the enzymatic and muscular aspects of the stomach into the proventriculus and gizzard.4.The presence of two large ceca.5.The small size of the colon.6.The presence of a common exit for urine and feces.7.The retrograde flow of ingesta with urine from the cloaca through the colon.Two avian features will be considered in more detail, namely the crop and ceca.Based on studies in chickens and turkeys, the crop can act as a storage organ for feed. While there is little feed in the crop during the day, ingesta are present in the crop throughout the scotophase e.g.,  when fee Question: What is the selective advantages if these?Both the crop developed and the stomach separated into two distinct anatomical features (the gizzard and proventriculus); occurring during avian evolution and with the arrangement has been retained in multiple taxonomic groups.Opisthocomus hoazin) to ferment plant materials is well established  4.1 μMoles gWhat is not clear is whether and, if so, the rate to which, VFAs are absorbed from the ceca? The concentrations of VFA in the ingesta have been reported to decrease in the colon and cloaca . This arQuestion 1: What are the rates of absorption of VFAs and other nutrients from the ceca? Question 2: Is this physiologically relevant and, if not, why are the ceca so large?There are similarities between the avian and mammalian immune system with the presence of both innate and both T and B cell mediated specific immune responses and the presence of the thymus. However, there are marked differences between the organization of the immune system in the two classes including the following in birds:1.The presence of the bursa Fabricius – the primary immune organ producing B cells in birds.2.The lack of lymph nodes in birds.Question 1: Are the structures that have yet to be described that are essentially “lymph nodes”? Question 2: What have birds to replace the functions of the lymph nodes?Until recently, the avian spleen was largely ignored. Indeed, The avian bursa Fabricius played an important role in the development of understanding of immune functioning. Antibody formation is greatly reduced in chickens bursectomized at 2 weeks old . Birds tThe avian spleen is smaller than the mammalian organ see  John, 1. In birdThe roles of the avian spleen are considered as the following:1.As a lymphoid organ2.Phagocytosis of senescent or damaged erythrocytes .Question 1: If the spleen does not act as a temporary storage site for erythrocytes, is there an alternate system?However, the avian spleen does not appear to be a temporary store of erythrocytes . QuestioMC2-R gene is expressed in the chicken spleen (1: E. coli lipopolysaccharide (see Spleen weights in birds are depressed by stress see . This isn spleen . Moreoven spleen . Similarn spleen . Spleen pleen 1:  (see Tabpleen 1: . In contride see  (Boa-Ampride see .There is evidence that the avian spleen has both positive and negative effects on immunity. Splenectomy decreased primary immune response (the titer of antisera) after intravenous challenge with sheep red blood cells . ParadoxSTING (stimulator of interferon genes) is expressed in the spleen  pyrin domain containing 3 (NLRP3) (Question 1: Is there redundancy such that the spleen is notnecessary in birds?The avian spleen plays important roles in both innate and specific immune responses. chicken: . Infectichicken: . Rous sachicken: . In pigee spleen . LPS chae spleen . There ie spleen . In the e spleen . Adminise spleen . Chickene spleen . Spread e spleen . Escheri (NLRP3) . QuestioThe avian egg is large with a yolk filled ovum, surrounded by egg white, membranes and a shell composed of calcium carbonate. Yolk is composed of the following:•Water – ∼50%•Solids – ∼50% composed of the following:○Low-density fraction (∼65% of yolk solids)○Granules (∼25% of yolk solids) composed of the following:∎Lipovitellin (a lipoprotein formed by the cleavage of vitellogenin in the oocyte)∎Phosvitin (a phosphoprotein formed by the cleavage of vitellogenin in the oocyte)○Water soluble or proteins in the aqueous fraction – the livetins (∼10% of yolk solids) composed of the following:∎α Livetins – Synonymous with blood serum albumen∎2-globulin presumably containing transport proteinsβ Livetins – Synonymous with blood serum α∎γ Livetins – Synonymous with blood serum γ -globulin specifically immunoglobulin Y (IgY) .Question 1: Are there alternate mechanisms for transport of yolk precursors into the oocyte?The yolk precursors, vitellogenin (VTG) and very low density lipoproteins (VLDL), are synthesized in the liver under the estrogen stimulus . They paQuestion 2: What is the mechanism for the transport of IgY into the oocyte? Question 3: What is the mechanism for selection of IgY versus IgM and IgA? Question 4: To what extent does this reflect limits on molecular size for proteins passing into the interstitial space? The concentrations of albumen and γ-globulin in the interstitial space of chickens were greater than those of α-globulin and β-globulin when expressed as a percentage of vascular concentrations  and lower than the plasma concentration  IgY . Questiota in –1 . This isntration . QuestioIn most birds, there is a single ovary (the left) and the left Müllerian duct develops into an organ called the oviduct. However, in a few species such as kiwis, there are paired ovaries and oviducts . The ovi–1 and shell gland 10.1 ± (6) 2.42 ml min–1 than the infundibulum 1.01 ± (5) 0.10 ml min–1, isthmus 2.47 ± (6) 0.40 ml min–1 and vagina 0.96 ± (2) 0.20 ml min–1  forming the egg. tamin D3 , there atamin D3 . There wtamin D3 . Moreovetamin D3 .in vitro  . Uterinein vitro . QuestioIn avian physiology, there are a series of assumptions employed that may or may not be valid. Examples of these assumptions include the following:•Domesticated birds provide little or no information about wild birds as the former have been subjected to intensive anthropomorphic selection.•The contrary view is that the physiology of one species of bird, domesticated or wild, are readily transferable to another.The debate between these views is accentuated by some rigidity of those with either an ornithological or poultry orientation. This situation is confounded by the lack of common meetings, departments and education. The differences in education include the following:•The lack of courses (particularly at the graduate level) experienced by poultry physiologists on wild birds and on the ungirding principle of biology, namely evolution.•There is a corollary with appreciation for poultry lacking in those studying wild birds.Another erroneous assumption is that birds are merely “feathered” mammals with a few specific differences related, for instance, to flight and production of large yolky eggs. Instead, the physiology of birds reflects their long evolutionary history.Those who fail to learn from or even read the literature including the older literature are doomed to repeat the studies and not advance science.”Finally, to adapt the quotation from both George Santayana and Winston Churchill, “This is solely the work of CS.The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Dirofilaria immitis, is a vector-borne infection, which can be transmitted to humans. The main hosts are both domestic and wild canids. This species mainly occurs in tropical and subtropical climates, and temperature and humidity are the main factors that favor the presence and proliferation of culicid mosquitoes as vectors of the disease. There are few reports of cardiopulmonary dirofilariosis in dogs and humans in Colombia, a region with favorable climatic conditions which favors the presence of mosquitoes that act as vectors of the disease. Therefore, this study aimed to examine its current prevalence in dogs and the risk of human exposure to the disease in Bucaramanga, one of the most populated areas in Colombia located at the center of the country. Furthermore, its demographic and environmental characteristics could be useful as a study model for other similar locations and neighboring countries. Serum samples from 351 dogs and 506 humans from the Bucaramanga Metropolitan area were analyzed. All dog samples were analyzed by Knott's technique and tested with a commercial immunochromatographic to detect the presence of circulating antigens of D. immitis. Human samples were analyzed using a non-commercial ELISA test kit to detect IgG against the somatic antigens of adult D. immitis and Wolbachia. Positive results were further confirmed using western blot analysis. Thirty-eight dogs tested positive with a overall prevalence of 10.82%. Of these dogs, 18 showed D. immitis microfilariae, being 5.12% of the total population. The overall seroprevalence in humans was 6.71%; seroprevalence was significantly higher in individuals aged 16–34 years-old and in women than in men. To our knowledge, this study describes seropositivity to D. immitis for the first time in a Colombian human population located in the same area as that of dogs infected with D. immitis, which represents a potential threat to public health. In humans, age and gender can be considered risk factors for exposure to D. immitis.The cardiopulmonary dirofilariosis caused by  Dirofilaria immitis, is a worldwide vector-borne disease in which the definitive hosts are both domestic and wild canines mainly  are inoculated into the definitive host during the next blood meal . In huma disease , 6.Dirofilaria immitis is primarily distributed in tropical and subtropical climates and depends mainly on environmental factors, including temperature and humidity, in addition to human behavior, such as installation of irrigation systems, taking pets on trips, and new urban developments, that favor the presence and proliferation of its transmission vectors. However, the number of reports in areas with cooler climates has increased, which indicates that the disease is expanding  according to the manufacturer's instructions. Human samples were analyzed for the presence of D. immitis and Wolbachia IgG antibodies using a non-commercial ELISA with some modifications  conjugated to horseradish peroxidase  was used at a 1:4,000 dilutions in both cases. Optical densities (OD) were measured at 492 nm. The cut-off point (OD = 0.8 for DiSA and OD = 0.5 for rWSP) was established by calculating the mean value + 3 standard deviations (3SD) of 30 serum samples obtained from dogs and clinically healthy humans (negative controls) who belonged to an area free of D. immitis. Human sera were considered positive when both non-commercial ELISAs were positive for the same serum sample. These results were additionally confirmed using western blot analysis performed according to a previously described methodology  based on the Monte Carlo statistical significance test. Further, we established clusters, which are areas with a relative risk of infection in dogs and humans, with a maximum size of 50% of the exposed population, based on population census and positive cases. Clusters were imported into the QGIS software version 3.8.0 to be visualized on the study area map.A geospatial analysis was performed on the population of dogs and humans from the metropolitan area of Bucaramanga through a spatial overlay of positive cases using the SatScan software v.9.6. and the Bernoulli's model with a 95% significance level . This is a descriptive study applying univariate analysis for the determination of frequencies and a bivariate analysis through Chi-square and odds ratio (OR) estimation, based on which a statistical analysis was performed for the determination of the association between variables. In all cases, the level of significance was established with a D. immitis in dogs was 10.82% (38/351). Of these positive dogs, 18 showed D. immitis microfilariae, being 5.12% of the total population. The prevalence of D. immitis and of microfilariae broken down by gender, age, municipality , socioeconomic status and place of permanence are provided in The overall prevalence of The overall seroprevalence in humans was 6.71% (34/506). The seroprevalence broken down by gender, age, municipality , socioeconomic status, water sources located at <200 m from the house and living with pets or not are described in D. immitis within the study area (P < 0.01).In the spatial exploration of dogs positive for udy area , 4 signiD. immitis in dogs and humans in the metropolitan area of Bucaramanga, Colombia, analyzing the presence of circulating antigens of D. immitis within the canine population, and the response of anti-D. immitis and anti-Wolbachia IgG antibodies in the human population as a study model for other areas in South America. This first study, to our knowledge of heartworm disease in Bucaramanga, Colombia, revealed an overall prevalence in dogs of 10.82%. Bucaramanga is surrounded by vegetation and is characterized by an average annual temperature of 24°C, high humidity levels, several gullies in its proximity or even in the central areas that accumulate water during the rainy season, and the presence of two rivers . In addition, there are vector species described in the both area, such as Aedes aegypti, and other species that could be involved in disease transmission  and Bucaramanga (6.87%), where the prevalences in dogs were 12.5 and 7.6%, respectively. We observed slightly lower seroprevalence values of 5.68% in Floridablanca and 3.12% in Girón, where the prevalence observed in dogs was 13.7 and 12.85%, respectively. The occurrence of dirofilariosis in humans depends mainly on the presence of infected dogs and vectors for transmission within a given area. At the same time, other factors, such as an increase in temperature and humidity owing to climate change; emergence of new disease-transmitting species; transportation of infected hosts; modification of the environment owing to human activities; agricultural practices and irrigation areas; deficiency and economic instability; and adverse meteorological events, such as hurricanes or tropical rains in the area, affect the development of the disease , Romania and Moldova (10.9%), and Russia (0.63–4.3%), where the risk of infection among humans has been studied (Data points related to the geographical location of the samples, and humans with positive serology have been reported in the same location as infected dogs. In addition, spatial clusters in these areas with a relative risk of <1 were detected for humans, suggesting a positive association between the variables studied and a higher frequency of contact with the parasite. These data may suggest a relationship between the presence of ussia 0.6–4.3%, wh studied , 26, 27.Regarding the variables evaluated, we observed that age can be a risk factor. In our study, the population with the highest seropositivity was that from the age group of 51–65 years-old. This result is similar to other studies that report that the risk of infection increases with age , 26, 27.D. immitis and Wolbachia Surface Protein in one of the most populated areas of Colombia with a high presence of dogs infected with D. immitis. The corresponding authorities should take measures to monitor and control this emerging zoonotic disease to reduce prevalence in canines, while including human pulmonary dirofilariosis in the differential diagnosis of pulmonary nodules. It is necessary to perform further studies in Colombia regarding vectors, reservoirs and humans to clarify the risk of this infection.In conclusion, this study describes, for the first time, seropositivity to All datasets generated for this study are included in the article/supplementary material.The sampling process complied with the Helsinki Code of Ethics and Animal Welfare and was approved under resolution no. 040-2019 by the ethics committee of Universidad Cooperativa de Colombia. The participants provided their written informed consent to participate in this study.ME-M, RM, and VA-Q designed the study, wrote the manuscript, participated in the discussion of the results, and corrected the manuscript. JA-N, IH, and MF-A performed the fieldwork and collected the data. All authors read and approved the final manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.