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This white paper documents the consensus opinion of the Artificial Intelligence Surgery (AIS) task force on Artificial Intelligence (AI) Ethics and the AIS Editorial Board Study Group on Ethics on the ethical considerations and current trustworthiness of artificial intelligence and autonomous actions in surgery. The ethics were divided into 6 topics defined by the Task Force: Reliability of robotic and AI systems; Respect for privacy and sensitive data; Use of complete and representative (i.e., unbiased) data; Transparencies and uncertainties in AI; Fairness: are we exacerbating inequalities in access to healthcare?; Technology as an equalizer in surgical education. Task Force members were asked to research a topic, draft a section, and come up with several potential consensus statements. These were voted on by members of the Task Force and the Study Group, and all proposals that received > 75 % agreement were adopted and included in the White Paper.

In "Joint EANM/SNMMI/ESTRO Practice Recommendations for the Use of 2-[18F]FDG-PET/CT External Beam Radiation Treatment Planning in Lung Cancer V1.0" clinical indications for PET-CT in (non-)small cell lung cancer are highlighted and selective nodal irradiation is discussed. Additionally, concepts about target definition, target delineation and treatment evaluation are reviewed. (C) 2022 Published by Elsevier B.V.

Background Brucellosis, as a serious zoonotic infectious disease, has been recognized as a re-emerging disease in the developing countries worldwide. In china, the incidence of brucellosis is increasing each year, seriously threatening the health of humans as well as animal populations. Despite a quite number of diagnostic methods currently being used for brucellosis, innovative technologies are still needed for its rapid and accurate diagnosis, especially in area where traditional diagnostic is unavailable. Methodology/Principal findings In this study, a total of 22 B cell linear epitopes were predicted from five Brucella outer membrane proteins (OMPs) using an immunoinformatic approach. These epitopes were then chemically synthesized, and with the method of indirect ELISA (iELISA), each of them displayed a certain degree of capability in identifying human brucellosis positive sera. Subsequently, a fusion protein consisting of the 22 predicted epitopes was prokaryotically expressed and used as diagnostic antigen in a newly established brucellosis testing method, nano-ZnO modified paper-based ELISA (nano-p-ELISA). According to the verifying test using a collection of sera collected from brucellosis and non-brucellosis patients, the sensitivity and specificity of multiepitope based nano-p-ELISA were 92.38% and 98.35% respectively. The positive predictive value was 98.26% and the negative predictive value was 91.67%. The multiepitope based fusion protein also displayed significantly higher specificity than Brucella lipopolysaccharide (LPS) antigen. Conclusions B cell epitopes are important candidates for serologically testing brucellosis. Multiepitope fusion protein based nano-p-ELISA displayed significantly sensitivity and specificity compared to Brucella LPS antigen. The strategy applied in this study will be helpful to develop rapid and accurate diagnostic method for brucellosis in human as well as animal populations., Author summary Brucellosis is one of the most important zoonosis in the world and has caused tremendous economic losses in agriculture and animal husbandry in many countries. Developing rapid, sensitive and specific diagnostic methods is very important for early detection and treatment of brucellosis patients. In this study, a novel diagnostic technique, nano-ZnO modified paper ELISA, was established. The antigen used in this technique was a fusion protein containing multiple B cell epitopes, which were predicted from Brucella major outer membrane proteins such as Bp26, Omp31, Omp16, Omp2b and Omp25. Comparing to traditional LPS antigen, this multiepitope based antigen displayed considerably higher sensitivity and higher specificity in laboratory. With the strategy described in this paper, more efficient epitopes and protein antigen can be identified in the future. Currently, LPS antigen is only prepared from live Brucella, while protein antigen can be produced in large quantities in prokaryotic expression system. In addition to nano-p-ELISA, this protein antigen can also be used for development other methods such as fluorescent polarization assay (FPA) and immunochromatographic assay (ICA) to meet the varied demand for brucellosis testing.

Although regression models play a central role in the analysis of medical research projects, there still exist many misconceptions on various aspects of modeling leading to faulty analyses. Indeed, the rapidly developing statistical methodology and its recent advances in regression modeling do not seem to be adequately reflected in many medical publications. This problem of knowledge transfer from statistical research to application was identified by some medical journals, which have published series of statistical tutorials and (shorter) papers mainly addressing medical researchers. The aim of this review was to assess the current level of knowledge with regard to regression modeling contained in such statistical papers. We searched for target series by a request to international statistical experts. We identified 23 series including 57 topic-relevant articles. Within each article, two independent raters analyzed the content by investigating 44 predefined aspects on regression modeling. We assessed to what extent the aspects were explained and if examples, software advices, and recommendations for or against specific methods were given. Most series (21/23) included at least one article on multivariable regression. Logistic regression was the most frequently described regression type (19/23), followed by linear regression (18/23), Cox regression and survival models (12/23) and Poisson regression (3/23). Most general aspects on regression modeling, e.g. model assumptions, reporting and interpretation of regression results, were covered. We did not find many misconceptions or misleading recommendations, but we identified relevant gaps, in particular with respect to addressing nonlinear effects of continuous predictors, model specification and variable selection. Specific recommendations on software were rarely given. Statistical guidance should be developed for nonlinear effects, model specification and variable selection to better support medical researchers who perform or interpret regression analyses.

Recognizing the increase in cancer incidence globally and the need for effective cancer control interventions, several organizations, professional bodies, and international institutions have proposed strategies to improve treatment options and reduce mortality along with minimizing overall incidence. Despite these efforts, an estimated 9.6 million deaths in 2018 was attributed to this noncommunicable disease, making it the second leading cause of death worldwide. Left unchecked, this will further increase in scale, with an estimated 29.5 million new cases and 16.3 million deaths occurring worldwide in 2040. Although it is known and generally accepted that cancer services must include radiotherapy, such access is still very limited in many parts of the world, especially in low- and middle-income countries. After thorough review of the current status of radiotherapy including programs worldwide, as well as achievements and challenges at the global level, the International Atomic Energy Agency convened an international group of experts representing various radiation oncology societies to take a closer look into the current status of radiotherapy and provide a road map for future directions in this field. It was concluded that the plethora of global and regional initiatives would benefit further from the existence of a central framework, including an easily accessible repository through which better coordination can be done. Supporting this framework, a practical inventory of competencies needs to be made available on a global level emphasizing the knowledge, skills, and behavior required for a safe, sustainable, and professional practice for various settings. This white paper presents the current status of global radiotherapy and future directions for the community. It forms the basis for an action plan to be developed with professional societies worldwide.

Summary The IOF Epidemiology and Quality of Life Working Group has reviewed the potential role of population screening for high hip fracture risk against well-established criteria. The report concludes that such an approach should strongly be considered in many health care systems to reduce the burden of hip fractures. Introduction The burden of long-term osteoporosis management falls on primary care in most healthcare systems. However, a wide and stable treatment gap exists in many such settings; most of which appears to be secondary to a lack of awareness of fracture risk. Screening is a public health measure for the purpose of identifying individuals who are likely to benefit from further investigations and/or treatment to reduce the risk of a disease or its complications. The purpose of this report was to review the evidence for a potential screening programme to identify postmenopausal women at increased risk of hip fracture. Methods The approach took well-established criteria for the development of a screening program, adapted by the UK National Screening Committee, and sought the opinion of 20 members of the International Osteoporosis Foundation’s Working Group on Epidemiology and Quality of Life as to whether each criterion was met (yes, partial or no). For each criterion, the evidence base was then reviewed and summarized. Results and Conclusion The report concludes that evidence supports the proposal that screening for high fracture risk in primary care should strongly be considered for incorporation into many health care systems to reduce the burden of fractures, particularly hip fractures. The key remaining hurdles to overcome are engagement with primary care healthcare professionals, and the implementation of systems that facilitate and maintain the screening program.

ispartof: ASIA-PACIFIC JOURNAL OF OPHTHALMOLOGY vol:11 issue:1 pages:89-90 ispartof: location:China status: published

Non-invasive diagnosis on biological liquid samples, such as urine, sweat, saliva, and tears, may allow patients to evaluate their health by themselves. To obtain accurate diagnostic results, target liquid must be precisely sampled. Conventionally, urine sampling using filter paper can be given as an example sampling, but differences in the paper structure can cause variations in sampling volume. This paper describes precise liquid sampling using synthetic microfluidic papers, which are composed of obliquely combined micropillars. Sampling volume accuracy was investigated using different designs and collection methods to determine the optimal design and sample collecting method. The optimized protocol was followed to accurately measure potassium concentration using synthetic microfluidic paper and a commercially available densitometer, which verified the usefulness of the synthetic microfluidic papers for precision sampling.

Contains fulltext : 225338.pdf (Publisher’s version ) (Open Access) OBJECTIVES: The number of older people dying in long-term care facilities (LTCFs) is increasing globally, but care quality may be variable. A framework was developed drawing on empirical research findings from the Palliative Care for Older People (PACE) study and a scoping review of literature on the implementation of palliative care interventions in LTCFs. The PACE study mapped palliative care in LTCFs in Europe, evaluated quality of end-of-life care and quality of dying in a cross-sectional study of deceased residents of LTCFs in 6 countries, and undertook a cluster-randomized control trial that evaluated the impact of the PACE Steps to Success intervention in 7 countries. Working with the European Association for Palliative Care, a white paper was written that outlined recommendations for the implementation of interventions to improve palliative and end-of-life care for all older adults with serious illness, regardless of diagnosis, living in LTCFs. The goal of the article is to present these key domains and recommendations. DESIGN: Transparent expert consultation. SETTING: International experts in LTCFs. PARTICIPANTS: Eighteen (of 20 invited) international experts from 15 countries participated in a 1-day face-to-face Transparent Expert Consultation (TEC) workshop in Bern, Switzerland, and 21 (of 28 invited) completed a follow-up online survey. METHODS: The TEC study used (1) a face-to-face workshop to discuss a scoping review and initial recommendations and (2) an online survey. RESULTS: Thirty recommendations about implementing palliative care for older people in LTCFs were refined during the TEC workshop and, of these, 20 were selected following the survey. These 20 recommendations cover domains at micro (within organizations), meso (across organizations), and macro (at national or regional) levels addressed in 3 phases: establishing conditions for action, embedding in everyday practice, and sustaining ongoing change. CONCLUSIONS AND IMPLICATIONS: We developed a framework of 20 recommendations to guide implementation of improvements in palliative care in LTCFs.

Rabies is a lethal zoonotic encephalomyelitis that causes an estimated 59,000 human deaths yearly worldwide. Although developing countries of Asia and Africa bear the heaviest burden, surveillance and disease detection in these countries is often hampered by the absence of local laboratories able to diagnose rabies and/or the difficulties of sample shipment from low-access areas to national reference laboratories. Filter papers offer a convenient cost-effective alternative for the sampling, shipment, and storage of biological materials for the diagnosis of many pathogens including rabies virus, yet the properties of diagnostic tests using this support have not been evaluated thoroughly. Sensitivity and specificity of molecular diagnosis of rabies infection using a reverse transcription followed by a hemi-nested polymerase chain reaction (RT-hn-PCR) either directly on brain tissue or using brain tissue dried on filter paper were assessed on 113 suspected field animal samples in comparison to the direct fluorescent antibody test (FAT) recommended by the World Health Organization as one of the reference tests for rabies diagnosis. Impact of the duration of the storage was also evaluated. The sensitivity and the specificity of RT-hn-PCR i) on brain tissue were 96.6% (95% CI: [88.1–99.6]) and 92.7% (95% CI: [82.4–98.0]) respectively and ii) on brain tissue dried on filter paper 100% (95% CI: [93.8–100.0]) and 90.9% (95% CI: [80.0–97.0]) respectively. No loss of sensitivity of RT-hn-PCR on samples of brain tissue dried on filter paper left 7 days at ambient temperature was detected indicating that this method would enable analyzing impregnated filter papers sent to the national reference laboratory at ambient temperature within a 1-week shipment time. It could therefore be an effective alternative to facilitate storage and shipment of samples from low-access areas to enhance and expand rabies surveillance., Author summary Dogs are responsible for 99% of human rabies deaths. Facilitating diagnostic of rabid dogs can help further identify i) people who were exposed to rabies in order to encourage them to seek post exposure prophylaxis and ii) other exposed animals to break the transmission chain (i.e. prevent them from further transmitting the virus to other people and animals). Yet, the reference diagnostic method for animal rabies requires brain samples to be collected post-mortem and shipped under temperature-controlled conditions. The shipping of such samples is complex in low-access areas, especially in low income countries, which are often those that bear the heaviest rabies burden. Filter papers offer a convenient alternative for biological sample shipment and storage. Here the efficiency of a molecular diagnostic method applied to brain tissue dried on filter paper is compared to one of the reference methods, the direct fluorescent antibody test. Our results show it has an excellent sensitivity (it does not miss any positive samples), even when filter papers are left 7 days at ambient temperature. These results let us foresee a cost-effective alternative facilitating shipment, storage and testing of samples from rabies suspected animals from low-access areas. This could considerably enhance and expand rabies surveillance in low-income countries, allowing a more comprehensive evaluation of rabies burden, and thus reinforcing arguments for allocating funds to rabies control policies.

BACKGROUND: The partograph has been endorsed by World Health Organization (WHO) since 1994 which presents an algorithm for assessing maternal and foetal conditions and labor progression. Monitoring labour with a partograph can reduce adverse pregnancy outcomes such as prolonged labor, emergency C-sections, birth asphyxia and stillbirths. However, partograph use is still very low, particularly in low and middle income countries (LMICs). In Bangladesh the reported partograph user rate varies from 1.4% to 33.0%. Recently, an electronic version of the partograph, with the provision of online data entry and user aid for emergency clinical support, has been tested successfully in different settings. With this proven evidence, we conducted and operations research to test the feasibility and effectiveness of implementing an e-partograph, for the first time, in 2 public hospitals in Bangladesh.METHODS: We followed a prospective crossover design. Two secondary level referral hospitals, Jessore and Kushtia District Hospital (DH) were the study sites. All pregnant women who delivered in the study hospitals were the study participants. All nurse-midwives working in the labor ward of study hospitals were trained on appropriate use of both types of partograph along with standard labour management guidelines. Collected quantitative data was analyzed using SPSS 23 statistical software. Discrete variables were expressed as percentages and presented as frequency distribution and cross tabulations. Chi square tests were employed to test the association between exposure and outcome variables. Potential confounding factors were adjusted using multivariate binary logistic regression methods. Ethical approval was obtained from the institutional review board of the International Centre for Diarrheal Disease Research, Bangladesh (icddr,b).FINDINGS: In total 2918 deliveries were conducted at Jessore DH and 2312 at Kushtia DH during one-year study period. Of them, 1012 (506 in each facility) deliveries were monitored using partograph (paper or electronic). The trends of facility based C-section rates was downwards in both the hospitals; 43% to 37% in Jessore and from 36% to 25% in Kushtia Hospital. There was a significant reduction of prolonged labour with e-partograph use. In Kushtia DH, the prolonged labour rate was 42% during phase 1 with the paper version which came down to 29% during phase-2 with the e-partograph use. The similar result was observed in Jessore DH where the prolonged labour rate reduced to 7% with paper partograph from the reported 30% prolonged labour with e-partograph. The e-partograph user rate was higher than the paper partograph during both phases (phase 1: 3.31, CI: 2.04-5.38, p < .001 and in phase 2: 15.20 CI: 6.36-36.33, p < .001) after adjusting for maternal age, parity, gestational age, religion, mother's education, husband's education, and fetal sex.CONCLUSION: The partograph user rate has significantly improved with the e- partograph and was associated with an overall reduction in cesarean births. Use of the e-partograph was also associated with reduced rates of prolonged labour. This study has added to the growing body of evidence on the positive impact of e-partograph use. We recommend implementing e-partograph intervention at scale in both public and private hospitals in Bangladesh.TRIAL REGISTRATION: ClinicalTrials.gov NCT03509103.

Various data sharing platforms are being developed to enhance the sharing of cohort data by addressing the fragmented state of data storage and access systems. However, policy challenges in several domains remain unresolved. The euCanSHare workshop was organized to identify and discuss these challenges and to set the future research agenda. Concerns over the multiplicity and long-term sustainability of platforms, lack of resources, access of commercial parties to medical data, credit and recognition mechanisms in academia and the organization of data access committees are outlined. Within these areas, solutions need to be devised to ensure an optimal functioning of platforms.

Background Global estimates for cholera annually approximate 4 million cases worldwide with 95,000 deaths. Recent outbreaks, including Haiti and Yemen, are reminders that cholera is still a global health concern. Cholera outbreaks can rapidly induce high death tolls by overwhelming the capacity of health facilities, especially in remote areas or areas of civil unrest. Recent studies demonstrated that stool specimens preserved on filter paper facilitate molecular analysis of Vibrio cholerae in resource limited settings. Specimens preserved in a rapid, low-cost, safe and sustainable manner for sequencing provides previously unavailable data about circulating cholera strains. This may ultimately contribute new information to shape public policy response on cholera control and elimination. Methodology/Principal findings Whole genome sequencing (WGS) recovered close to a complete sequence of the V. cholerae O1 genome with satisfactory genome coverage from stool specimens enriched in alkaline peptone water (APW) and V. cholerae culture isolates, both spotted on filter paper. The minimum concentration of V. cholerae DNA sufficient to produce quality genomic information was 0.02 ng/μL. The genomic data confirmed the presence or absence of genes of epidemiological interest, including cholera toxin and pilus loci. WGS identified a variety of diarrheal pathogens from APW-enriched specimen spotted filter paper, highlighting the potential for this technique to explore the gut microbiome, potentially identifying co-infections, which may impact the severity of disease. WGS demonstrated that these specimens fit within the current global cholera phylogenetic tree, identifying the strains as the 7th pandemic El Tor. Conclusions WGS results allowed for mapping of short reads from APW-enriched specimen and culture isolate spotted filter papers. This provided valuable molecular epidemiological sequence information on V. cholerae strains from remote, low-resource settings. These results identified the presence of co-infecting pathogens while providing rare insight into the specific V. cholerae strains causing outbreaks in cholera-endemic areas., Author summary Cholera affects more than 4 million people globally every year; people predominantly living in poverty or in resource-constrained conditions including political crises or natural disasters. Cholera’s typical presentation is characterized by rapid onset of acute watery diarrhea and vomiting which can progress from watery stool to shock in as little as four hours. Laboratory conditions needed for culture confirmation and strain preservation are rarely to never present in these affected areas. In fact, many cholera endemic areas in Sub-Saharan African are so remote that even treatment response alone is often challenging. Here we present the genomic analysis of DNA extracted from dried filter paper, which is a low-cost, low-tech and sustainable method. Previously this method has facilitated cholera confirmation by PCR, but we demonstrate that this method is also suitable for whole genome sequencing and subsequent strain characterization by presenting the analysis of samples from an outbreak in a remote area of Cameroon. This method will facilitate the understanding of the molecular epidemiology in cholera-prone areas, which were previously too challenging to attempt. It also introduces a method that can be used on a broader scale for diarrheal disease surveillance, including providing a window into co-infection and microbiome analyses.

The breakthrough potentials of research papers can be explained by their boundary-spanning qualities. Here, for the first time, we apply the structural variation analysis (SVA) model and its affiliated metrics to investigate the extent to which such qualities characterize a group of Nobel Prize winning papers. We find that these papers share remarkable boundary-spanning traits, marked by exceptional abilities to connect disparate and topically-diverse clusters of research papers. Further, their publications exert structural variations on the scale that significantly alters the betweenness centrality distributions of existing intellectual space. Overall, SVA not only provides a set of leading indicators for describing future Nobel Prize winning papers, but also broadens our understanding of the similar prize-winning properties that may have been overlooked among other regular publications., 27 pages, 8 figures, 9 tables. Submitted to Frontiers in Research Metrics and Analytics

ObjectiveTo evaluate the consistency of causal statements in observational studies published in The BMJ.DesignReview of observational studies published in a general medical journal.Data sourceCohort and other longitudinal studies describing an exposure-outcome relationship published in The BMJ in 2018. We also had access to the submitted papers and reviewer reports.Main outcome measuresProportion of published research papers with ‘inconsistent’ use of causal language. Papers where language was consistently causal or non-causal were classified as ‘consistently causal’ or ‘consistently not causal’, respectively. For the ‘inconsistent’ papers, we then compared the published and submitted version.ResultsOf 151 published research papers, 60 described eligible studies. Of these 60, we classified the causal language used as ‘consistently causal’ (48%), ‘inconsistent’ (20%) and ‘consistently not causal’(32%). Eleven out of 12 (92%) of the ‘inconsistent’ papers were already inconsistent on submission. The inconsistencies found in both submitted and published versions were mainly due to mismatches between objectives and conclusions. One section might be carefully phrased in terms of association while the other presented causal language. When identifying only an association, some authors jumped to recommending acting on the findings as if motivated by the evidence presented.ConclusionFurther guidance is necessary for authors on what constitutes a causal statement and how to justify or discuss assumptions involved. Based on screening these papers, we provide a list of expressions beyond the obvious ‘cause’ word which may inspire a useful more comprehensive compendium on causal language.

International audience; The differential diagnosis of differences or disorders of sex development (DSD) belongs to the most complex fields in medicine. It requires a multidisciplinary team conducting a synoptic and complementary approach consisting of thorough clinical, hormonal and genetic workups. This position paper of EU COST (European Cooperation in Science and Technology) Action BM1303 'DSDnet' was written by leading experts in the field and focuses on current best practice in genetic diagnosis in DSD patients. Ascertainment of the karyotpye defines one of the three major diagnostic DSD subclasses and is therefore the mandatory initial step. Subsequently, further analyses comprise molecular studies of monogenic DSD causes or analysis of copy number variations (CNV) or both. Panels of candidate genes provide rapid and reliable results. Whole exome and genome sequencing (WES and WGS) represent valuable methodological developments that are currently in the transition from basic science to clinical routine service in the field of DSD. However, in addition to covering known DSD candidate genes, WES and WGS help to identify novel genetic causes for DSD. Diagnostic interpretation must be performed with utmost caution and needs careful scientific validation in each DSD case.

ObjectivesRecently, the results of two economic evaluations were published both of which seemingly demonstrate the cost-effectiveness of sofosbuvir-based regimens for the treatment of chronic hepatitis C genotype 1 infection in Germany. Both analyses were sponsored by the manufacturer of sofosbuvir and use a different methodology: Whereas one evaluation is based on a conventional cost-utility analysis, the other rests upon the efficiency-frontier method used by the German Institute for Quality and Efficiency in Health Care (IQWiG). The purpose of this study is to reanalysis the results of both economic evaluations in combination.DesignReanalysis of published decision modelling results.SettingPrimary care in Germany.ParticipantsPatients with chronic hepatitis C genotype 1 infection (treatment-naïve and -experienced, cirrhotic and non-cirrhotic).InterventionsSofosbuvir, other anti-hepatitis C virus drugs, and no treatment.Primary and secondary outcome measuresCost per unit of health benefit and cost per quality-adjusted life year.ResultsReanalysis of the results of both economic evaluations in combination reveals an unclear rationale for choosing the selected cost-effectiveness methods as well as a potential publication bias, favoring the product of the manufacturer. Based on the reanalysis, sofosbuvir is not cost-effective in treatment-experienced non-cirrhotic patients, potentially lacks cost-effectiveness in treatment-experienced cirrhotic patients, and is only partially cost-effective in treatment-naïve non-cirrhotic patients. Taken together, these results indicate a lack of cost-effectiveness in three quarters of the German patient population.ConclusionsTwo economic evaluations on sofosbuvir suggest, in combination, that sofosbuvir cannot be considered a cost-effective treatment in three quarters of the German patient population.

Background Digitally enabled rehabilitation may lead to better outcomes but has not been tested in large pragmatic trials. We aimed to evaluate a tailored prescription of affordable digital devices in addition to usual care for people with mobility limitations admitted to aged care and neurological rehabilitation. Methods and findings We conducted a pragmatic, outcome-assessor-blinded, parallel-group randomised trial in 3 Australian hospitals in Sydney and Adelaide recruiting adults 18 to 101 years old with mobility limitations undertaking aged care and neurological inpatient rehabilitation. Both the intervention and control groups received usual multidisciplinary inpatient and post-hospital rehabilitation care as determined by the treating rehabilitation clinicians. In addition to usual care, the intervention group used devices to target mobility and physical activity problems, individually prescribed by a physiotherapist according to an intervention protocol, including virtual reality video games, activity monitors, and handheld computer devices for 6 months in hospital and at home. Co-primary outcomes were mobility (performance-based Short Physical Performance Battery [SPPB]; continuous version; range 0 to 3; higher score indicates better mobility) and upright time as a proxy measure of physical activity (proportion of the day upright measured with activPAL) at 6 months. The dataset was analysed using intention-to-treat principles. The trial was prospectively registered with the Australian New Zealand Clinical Trials Registry (ACTRN12614000936628). Between 22 September 2014 and 10 November 2016, 300 patients (mean age 74 years, SD 14; 50% female; 54% neurological condition causing activity limitation) were randomly assigned to intervention (n = 149) or control (n = 151) using a secure online database (REDCap) to achieve allocation concealment. Six-month assessments were completed by 258 participants (129 intervention, 129 control). Intervention participants received on average 12 (SD 11) supervised inpatient sessions using 4 (SD 1) different devices and 15 (SD 5) physiotherapy contacts supporting device use after hospital discharge. Changes in mobility scores were higher in the intervention group compared to the control group from baseline (SPPB [continuous, 0–3] mean [SD]: intervention group, 1.5 [0.7]; control group, 1.5 [0.8]) to 6 months (SPPB [continuous, 0–3] mean [SD]: intervention group, 2.3 [0.6]; control group, 2.1 [0.8]; mean between-group difference 0.2 points, 95% CI 0.1 to 0.3; p = 0.006). However, there was no evidence of a difference between groups for upright time at 6 months (mean [SD] proportion of the day spent upright at 6 months: intervention group, 18.2 [9.8]; control group, 18.4 [10.2]; mean between-group difference −0.2, 95% CI −2.7 to 2.3; p = 0.87). Scores were higher in the intervention group compared to the control group across most secondary mobility outcomes, but there was no evidence of a difference between groups for most other secondary outcomes including self-reported balance confidence and quality of life. No adverse events were reported in the intervention group. Thirteen participants died while in the trial (intervention group: 9; control group: 4) due to unrelated causes, and there was no evidence of a difference between groups in fall rates (unadjusted incidence rate ratio 1.19, 95% CI 0.78 to 1.83; p = 0.43). Study limitations include 15%–19% loss to follow-up at 6 months on the co-primary outcomes, as anticipated; the number of secondary outcome measures in our trial, which may increase the risk of a type I error; and potential low statistical power to demonstrate significant between-group differences on important secondary patient-reported outcomes. Conclusions In this study, we observed improved mobility in people with a wide range of health conditions making use of digitally enabled rehabilitation, whereas time spent upright was not impacted. Trial registration The trial was prospectively registered with the Australian New Zealand Clinical Trials Register; ACTRN12614000936628, In a randomised controlled trial, Leanne Hassett and colleagues investigate the impact of digitally-enabled aged care and neurological rehabilitation on activity and mobility outcomes in Australia., Author summary Why was this study done? A higher dose of therapy in physical rehabilitation is associated with better outcomes; however, current rehabilitation models deliver low therapy doses. Use of digital devices such as virtual reality video games, activity monitors, and handheld computer devices can be enjoyable, provide feedback on performance, and may enable a greater dose of task-specific therapy to improve outcomes. Current evidence is yet to confidently confirm the effects of rehabilitation using digital devices in addition to usual rehabilitation care on mobility tasks such as walking and other important outcomes such as quality of life. What did the researchers do and find? In a pragmatic, outcome-assessor-blinded randomised controlled trial, 300 people with walking difficulties (age 72 ± 16 years, 50% female) received usual multidisciplinary inpatient and post-hospital aged care and neurological rehabilitation alone, or in addition used a range of affordable devices such as virtual reality video games, activity monitors, and handheld devices to target mobility and physical activity, as individually prescribed by a physiotherapist for 6 months. On average participants in the intervention group used 4 ± 1 devices in the inpatient setting and 2 ± 1 devices in the post-hospital setting. This approach was feasible and enjoyed, and demonstrated it could be provided across care settings including the post-hospital setting with mostly remote support. Clinically important improvement was seen in mobility at 3 weeks and 6 months after baseline, but this was not accompanied by greater time spent upright. No adverse events were reported by participants whilst undertaking rehabilitation using digital devices, and there was no difference in the rate of falls between groups. What do these findings mean? Digitally enabled rehabilitation using a range of devices prescribed by a physiotherapist to target a range of mobility limitations across care settings for adults with mixed health conditions can improve mobility but not time spent upright. These results need to be interpreted in light of study limitations including a 15%–19% loss to follow-up at 6 months on the co-primary outcomes. Future models of rehabilitation should investigate incorporating digital devices to enhance inpatient and post-hospital rehabilitation, but prescription should ensure quality and quantity of practice.

Paper wasps (Polistes dominula), parasitized by the strepsipteran Xenos vesparum, are castrated and desert the colony to gather on plants where the parasite mates and releases primary larvae, thus completing its lifecycle. One of these plants is the trumpet creeper Campsis radicans: in a previous study the majority of all wasps collected from this plant were parasitized and focused their foraging activity on C. radicans buds. The unexpected prevalence and unusual feeding strategy prompted us to investigate the influence of this plant on wasp behavior and physiology through a multidisciplinary approach. First, in a series of laboratory bioassays, we observed that parasitized wasps spent more time than non-parasitized ones on fresh C. radicans buds, rich of extra-floral nectaries (EFNs), while the same wasps ignored treated buds that lacked nectar drops. Then, we described the structure and ultra-structure of EFNs secreting cells, compatible with the synthesis of phenolic compounds. Subsequently, we analysed extracts from different bud tissues by HPLC-DAD-MS and found that verbascoside was the most abundant bioactive molecule in those tissues rich in EFNs. Finally, we tested the immune-stimulant properties of verbascoside, as the biochemical nature of this compound indicates it might function as an antibacterial and antioxidant. We measured bacterial clearance in wasps, as a proxy for overall immune competence, and observed that it was enhanced after administration of verbascoside—even more so if the wasp was parasitized. We hypothesize that the parasite manipulates wasp behavior to preferentially feed on C. radicans EFNs, since the bioactive properties of verbascoside likely increase host survival and thus the parasite own fitness.

Amphimeriasis, a fish-borne zoonotic disease caused by the liver fluke Amphimerus spp., has recently been reported as an emerging disease affecting an indigenous Ameridian group, the Chachi, living in Ecuador. The only method for diagnosing amphimeriasis was the microscopic detection of eggs from the parasite in patients' stool samples with very low sensitivity. Our group developed an ELISA technique for detection of anti-Amphimerus IgG in human sera and a molecular method based on LAMP technology (named LAMPhimerus) for specific and sensitive parasite DNA detection. The LAMPhimerus method showed to be much more sensitive than classical parasitological methods for amphimeriasis diagnosis using human stool samples for analysis. The objective of this work is to demonstrate the feasibility of using dried stool samples on filter paper as source of DNA in combination with the effectiveness of our previously designed LAMPhimerus assay for successfully Amphimerus sp. detection in clinical stool samples. A total of 102 untreated and undiluted stool samples collected from Chachi population were spread as thin layer onto common filter paper for easily transportation to our laboratory and stored at room temperature for one year until DNA extraction. When LAMPhimerus method was applied for Amphimerus sp. DNA detection, a higher number of positive results was detected (61/102; 59.80%) in comparison to parasitological methods (38/102; 37.25%), including 28/61 (45.90%) microscopy-confirmed Amphimerus sp. infections. The diagnostic parameters for the sensitivity and specificity werecalculated for our LAMPhimerus assay, which were 79.17% and 65.98%, respectively. We demonstrate, for the first time, that common filter paper is useful for easy collection and long-term storage of human stool samples for later DNA extraction and molecular analysis of human-parasitic trematode eggs. This simple, economic and easily handling method combined with the specific and sensible LAMPhimerus assay has the potential to beused as an effective molecular large-scale screening test for amphimeriasis-endemic areas.

The present work was focused to design a cheap, rapid, portable and easy to use filter paper based assay for the qualitative and quantitate analysis of acetone. Sodium alginate gel was loaded with the acetone specific optical signal probe, and subsequently coated onto filter paper surface to design portable colorimetric assays for acetone monitoring. The color of the paper sensor strip was observed to change from dark yellow to light yellowish in the presence of varying concentrations of acetone. Three different color analyzing models including RGB, HSV, and LAB were employed to probe the output optical signal, and their performance was compared in terms of better interpretation of the generated signal. The LAB model was found to provide better analytical figures of merit with a linear response for the acetone concentration ranging from 2.5 to 1500 ppm, and a limit of detection of 0.5 ppm. Furthermore, the specificity of the designed filter paper based sensor was demonstrated against different common interfering compounds. The results demonstrated the potential of our proposed filter paper based sensor as a novel tool for the analysis of acetone.

Introduction \ud Data collection using paper-based questionnaires can be time consuming and return errors affect data accuracy, completeness, and information quality in health surveys. We compared smartphone and paper-based data collection systems in the Burden of Obstructive Lung Disease (BOLD) study in rural Sudan. \ud Methods \ud This exploratory pilot study was designed to run in parallel with the cross-sectional household survey. The Open Data Kit was used to programme questionnaires in Arabic into smartphones. We included 100 study participants (83% women; median age = 41.5 ± 16.4 years) from the BOLD study from 3 rural villages in East-Gezira and Kamleen localities of Gezira state, Sudan. Questionnaire data were collected using smartphone and paper-based technologies simultaneously. We used Kappa statistics and inter-rater class coefficient to test agreement between the two methods. Results Symptoms reported included cough (24%), phlegm (15%), wheezing (17%), and shortness of breath (18%). One in five were or had been cigarette smokers. The two data collection methods varied between perfect to slight agreement across the 204 variables evaluated (Kappa varied between 1.00 and 0.02 and inter-rater coefficient between 1.00 and -0.12). Errors were most commonly seen with paper questionnaires (83% of errors seen) vs smartphones (17% of errors seen) administered questionnaires with questions with complex skip-patterns being a major source of errors in paper questionnaires. Automated checks and validations in smartphone-administered questionnaires avoided skip-pattern related errors. Incomplete and inconsistent records were more likely seen on paper questionnaires. \ud Conclusion \ud Compared to paper-based data collection, smartphone technology worked well for data collection in the study, which was conducted in a challenging rural environment in Sudan. This approach provided timely, quality data with fewer errors and inconsistencies compared to paper-based data collection. We recommend this method for future BOLD studies and other population-based studies in similar settings.

BackgroundMost research manuscripts are not accepted for publication on first submission. A major part of the resubmission process is reformatting to another journal's specific requirements, a process separate from revising the scientific content. There has been little research to understand the magnitude of the burden imposed by the current resubmission process.MethodsWe analyzed original research article submission requirements from twelve randomly selected journals in each of eight scientific and clinical focus areas from the InCites Journal Citation Reports database. From the 96 journals selected, we randomly identified three recently published manuscripts and sent surveys to those first and/or corresponding authors (288 total) to solicit information on time spent reformatting resubmissions and opinions on the process.FindingsThere was significant variation in manuscript submission requirements for journals within the same scientific focus and only 4% of journals offered a fully format-free initial submission. Of 203 authors responding (71.5% response rate), only 11.8% expressed satisfaction with the resubmission process and 91% desired reforming the current system. Time spent on reformatting delays most publications by at least two weeks and by over three months in about 20% of manuscripts. The effort to comply with submission requirements has significant global economic burden, estimated at over $1.1 billion dollars annually when accounting for a research team's time.InterpretationWe demonstrate that there is significant resource utilization associated with resubmitting manuscripts, heretofore not properly quantified. The vast majority of authors are not satisfied with the current process. Addressing these issues by reconciling reformatting requirements among journals or adopting a universal format-free initial submission policy would help resolve a major subject for the scientific research community and provide more efficient dissemination of findings.

International audience; Background: Identification of the source of mosquito blood meals is an important component for disease control and surveillance. Recently, matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) profiling has emerged as an effective tool for mosquito blood meal identification, using the abdomens of freshly engorged mosquitoes. In the field, mosquito abdomens are crushed on Whatman filter papers to determine the host feeding patterns by identifying the origin of their blood meals. The aim of this study was to test whether crushing engorged mosquito abdomens on Whatman filter papers was compatible with MALDI-TOF MS for mosquito blood meal identification. Both laboratory reared and field collected mosquitoes were tested.Material and methods: Sixty Anopheles gambiae Giles were experimentally engorged on the blood of six distinct vertebrate hosts (human, sheep, rabbit, dog, chicken and rat). The engorged mosquito abdomens were crushed on Whatman filter papers for MALDI-TOF MS analysis. 150 Whatman filter papers, with mosquitoes engorged on cow and goat blood, were preserved. A total of 77 engorged mosquito abdomens collected in the Comoros Islands and crushed on Whatman filter papers were tested with MALDI-TOF MS. Results The MS profiles generated from mosquito engorged abdomens crushed on Whatman filter papers exhibited high reproducibility according to the original host blood. The blood meal host was correctly identified from mosquito abdomens crushed on Whatman filter papers by MALDI-TOF MS. The MS spectra obtained after storage were stable regardless of the room temperature and whether or not they were frozen. The MS profiles were reproducible for up to three months. For the Comoros samples, 70/77 quality MS spectra were obtained and matched with human blood spectra. This was confirmed by molecular tools.Conclusion: The results demonstrated that MALDI-TOF MS could identify mosquito blood meals from Whatman filter papers collected in the field during entomological surveys. The application of MALDI-TOF MS has proved to be rapid and successful, making it a new and efficient tool for mosquito-borne disease surveillance.

Bisphenol A (BPA) is an endocrine disrupting chemical used in a wide range of consumer products including photoactive dyes used in thermal paper. Recent studies have shown that dermal absorption of BPA can occur when handling these papers. Yet, regulatory agencies have largely dismissed thermal paper as a major source of BPA exposure. Exposure estimates provided by agencies such as the European Food Safety Authority (EFSA) are based on assumptions about how humans interact with this material, stating that ‘typical’ exposures for adults involve only one handling per day for short periods of time (30% of individuals hold thermal paper with more than three fingertips, and >60% allow the paper to touch their palm. Only 11% of the participants we observed were consistent with the EFSA model for time of contact and dermal surface area. Mathematical modeling based on handling times we measured and previously published transfer coefficients, concentrations of BPA in paper, and absorption factors indicate the most conservative estimated intake from handling thermal paper in this population is 51.1 ng/kg/day, similar to EFSA’s estimates of 59 ng/kg/day from dermal exposures. Less conservative estimates, using published data on concentrations in thermal paper and transfer rates to skin, indicate that exposures are likely significantly higher. Based on our observational data, we propose that the current models for estimating dermal BPA exposures are not consistent with normal human behavior and should be reevaluated.

PurposeThe aim of this experimental study was to investigate whether paper-and-pencil and computerized surveys administered in the school setting yield equivalent data quality indicators and risk behavior prevalence estimates.MethodsData were drawn from the European School Survey Project on Alcohol and Other Drugs (ESPAD®) carried out in Italy to monitor drug, alcohol, tobacco use and other risk-behaviors among Italian high school students aged 15-19 years. A sub-sample of schools was recruited for the study (1673 pupils). For each school, two entire randomly selected courses (from the first to the fifth grade) participated and were assigned randomly to the self-administered paper-and-pencil (N = 811) or computerized survey (N = 862). Differences in data quality were assessed using the following indicators: questionnaire completeness (missing gender and/or 50% of missing answers) and internal consistency (repetitive extreme response patterns). Separate logistic regression models were used to estimate the mode effect on the reporting of each risk behavior, controlling for gender and age. Finally, the prevalence estimates of the experimental study were compared to the results of the national ESPAD® study.ResultsThe computerized administration mode produced a higher proportion of invalid questionnaires, but the prevalence estimates generated from responses to the paper-and-pencil and computerized surveys were generally equivalent. Nevertheless, comparing these results with those of the national ESPAD® study, some differences in the prevalence rates were found.ConclusionsThe findings suggest that in a proctored school setting, the computerized survey mode yields almost the same results as the paper-and-pencil mode. However, because of the reliance on existing informatics facilities until when all schools in the country will be sufficiently equipped for the computerized data collection, they should be given the opportunity to choose between paper-and-pencil and computerized survey modes, in order to avoid a possible selection bias.

The UK is one of the largest funders of health research in the world, but little is known about how health funding is spent. Our study explores whether major UK public and charitable health research funders support the research of UK-based scientists producing the most highly-cited research. To address this question, we searched for UK-based authors of peer-reviewed papers that were published between January 2006 and February 2018 and received over 1000 citations in Scopus. We explored whether these authors have held a grant from the National Institute for Health Research (NIHR), the Medical Research Council (MRC) and the Wellcome Trust and compared the results with UK-based researchers who serve currently on the boards of these bodies. From the 1,370 papers relevant to medical, biomedical, life and health sciences with more than 1000 citations in the period examined, we identified 223 individuals from a UK institution at the time of publication who were either first/last or single authors. Of those, 164 are still in UK academic institutions, while 59 are not currently in UK academia (have left the country, are retired, or work in other sectors). Of the 164 individuals, only 59 (36%; 95% CI: 29-43%) currently hold an active grant from one of the three funders. Only 79 (48%; 95% CI: 41-56%) have held an active grant from any of the three funders between 2006-2017. Conversely, 457 of the 664 board members of MRC, Wellcome Trust, and NIHR (69%; 95% CI: 65-72%) have held an active grant in the same period by any of these funders. Only 7 out of 655 board members (1.1%) were first, last or single authors of an extremely highly-cited paper.\ud \ud There are many reasons why the majority of the most influential UK authors do not hold a grant from the country’s major public and charitable funding bodies. Nevertheless, the results are worrisome and subscribe to similar patterns shown in the US. We discuss possible implications and suggest ways forward.

BACKGROUND The lack of information regarding the burden of acute bacterial meningitis in Latin America leads to a reduction in the estimated incidence rates of the disease, and impairs public health decisions on the use and follow-up of preventive interventions, particularly, the evaluation of existing vaccination policies. The use of the real-time PCR in diagnostic routine procedures has resulted in a substantial increase in confirmed bacterial meningitis cases. However, in resource-poor countries, these assays are only available in reference laboratories. Sample transportation to these laboratories is a critical constraint, as it requires specialized, high cost courier services. To overcome this barrier we evaluated the use of FTATM Elute filter paper cards for the conservation and processing of samples under normal environmental conditions, as they would be when transported from remote and under-equipped healthcare facilities to the reference centers. A total of 401 samples received in 2015 as part of Sao Paulo's national surveillance for routine diagnosis were selected for this study. METHODS The sensitivity and specificity of real-time PCR were evaluated using fresh serum and cerebrospinal fluid (CSF) samples processed using our laboratory's standard DNA extraction, and processing the same samples after being dried and stored on FTATM card, and DNA extracted following the manufacturer's instructions. RESULTS The sensitivities for detection of Neisseria meningitidis, Streptococcus pneumoniae, and Haemophilus influenzae from CSF dried and stored on FTATM cards were 98%, 92%, and 100%, respectively, and with serum samples were 73%, 88%, and 100%, respectively. When compared to our laboratory's standard methodology, results showed high concordance, with Kappa index ranges of 0.9877-1.00 for CSF, and 0.8004-1.00 for serum samples. CONCLUSION The use of FTATM cards for CSF and serum conservation and transport represents a rapid, reliable, and cost-effective alternative that will allow obtaining valuable epidemiological information that would otherwise be lost.

India has the highest burden of Tuberculosis (TB) and multidrug-resistant TB (MDR-TB) worldwide. Innovative technology is the need of the hour to identify these cases that remain either undiagnosed or inadequately diagnosed due to the unavailability of appropriate tools at primary healthcare settings. We developed and evaluated 3 kits, namely ‘TB Detect’ (containing BioFM-Filter device), ‘TB Concentration and Transport’ (containing Trans-Filter device) and ‘TB DNA Extraction’ kits. These kits enable bio-safe equipment-free concentration of sputum on filters and improved fluorescence microscopy at primary healthcare centres, ambient temperature transport of dried inactivated sputum filters to central laboratories and molecular detection of drug resistance by PCR and DNA sequencing (Mol-DST). In a 2-site evaluation (n = 1190 sputum specimens) on presumptive TB patients, BioFM-Filter smear exhibited a significant increase in positivity of 7% and 4% over ZN smear and LED-FM smear (p

Levosimendan is an inodilator that promotes cardiac contractility primarily through calcium sensitization of cardiac troponin C and vasodilatation via opening of adenosine triphosphate-sensitive potassium (KATP) channels in vascular smooth muscle cells; the drug also exerts organ-protective effects through a similar effect on mitochondrial KATP channels. This pharmacological profile identifies levosimendan as a drug that may have applications in a wide range of critical illness situations encountered in intensive care unit medicine: hemodynamic support in cardiogenic or septic shock; weaning from mechanical ventilation or from extracorporeal membrane oxygenation; and in the context of cardiorenal syndrome. This review, authored by experts from 9 European countries (Austria, Belgium, Czech republic, Finland, France, Germany, Italy, Sweden, and Switzerland), examines the clinical and experimental data for levosimendan in these situations and concludes that, in most instances, the evidence is encouraging, which is not the case with other cardioactive and vasoactive drugs routinely used in the intensive care unit. The size of the available studies is, however, limited and the data are in need of verification in larger controlled trials. Some proposals are offered for the aims and designs of these additional studies., SCOPUS: ar.j, info:eu-repo/semantics/published

Background For the diagnosis of prosthetic joint infection, real evidence-based guidelines to aid clinicians in choosing the most accurate diagnostic strategy are lacking. Aim and Methods To address this need, we performed a multidisciplinary systematic review of relevant nuclear medicine, radiological, orthopaedic, infectious, and microbiological literature to define the diagnostic accuracy of each diagnostic technique and to address and provide evidence-based answers on uniform statements for each topic that was found to be important to develop a commonly agreed upon diagnostic flowchart. Results and Conclusion The approach used to prepare this set of multidisciplinary guidelines was to define statements of interest and follow the procedure indicated by the Oxford Centre for Evidence-based Medicine (OCEBM). Electronic supplementary material The online version of this article (10.1007/s00259-019-4263-9) contains supplementary material, which is available to authorized users.

Rapid advances in microarray and sequencing technologies are making genotyping and genome sequencing more affordable and readily available. There is an expectation that genomic sequencing technologies improve personalized diagnosis and personalized drug therapy. Concurrently, provision of direct-to-consumer genetic testing by commercial providers has enabled individuals’ direct access to their genomic data. The expanded availability of genomic data is perceived as influencing the relationship between the various parties involved including healthcare professionals, researchers, patients, individuals, families, industry, and government. This results in a need to revisit their roles and responsibilities. In a 1-day agenda-setting meeting organized by the COST Action IS1303 “Citizen’s Health through public-private Initiatives: Public health, Market and Ethical perspectives,” participants discussed the main challenges associated with the expanded availability of genomic information, with a specific focus on public-private partnerships, and provided an outline from which to discuss in detail the identified challenges. This paper summarizes the points raised at this meeting in five main parts and highlights the key cross-cutting themes. In light of the increasing availability of genomic information, it is expected that this paper will provide timely direction for future research and policy making in this area. Funding Deborah Mascalzoni is supported under Grant Agreement number 305444. Álvaro Mendes is supported by the FCT—The Portuguese Foundation for Science and Technology under postdoctoral grant SFRH/BPD/88647/2012. Isabelle Budin-Ljøsne receives support from the National Research and Innovation Platform for Personalized Cancer Medicine funded by The Research Council of Norway (NFR BIOTEK2021/ES495029) and Biobank Norway funded by The Research Council of Norway—grant number 245464. Heidi Carmen Howard is partly supported by supported by the Swedish Foundation for Humanities and Social Science under grant M13-0260:1), the Biobanking and Molecular Resource Infrastructure of Sweden (BBMRI.se) and the BBMRI-ERIC. Brígida Riso is supported by the Portuguese Foundation for Science and Technology (FCT) under the PhD grant SFRH/BD/100779/2014. Heidi Beate Bentzen receives support from the project Legal Regulation of Information Processing relating to Personalized Cancer Medicine funded by The Research Council of Norway BIOTEK2021/238999.

Background The use of filter paper as a simple, inexpensive tool for storage and transportation of blood, ‘Dried Blood Spots’ or Guthrie cards, for diagnostic assays is well-established. In contrast, there are a paucity of diagnostic evaluations of dried cerebrospinal fluid (CSF) spots. These have potential applications in low-resource settings, such as Laos, where laboratory facilities for central nervous system (CNS) diagnostics are only available in Vientiane. In Laos, a major cause of CNS infection is Japanese encephalitis virus (JEV). We aimed to develop a dried CSF spot protocol and to evaluate its diagnostic performance using the World Health Organisation recommended anti-JEV IgM antibody capture enzyme-linked immunosorbent assay (JEV MAC-ELISA). Methodology and Principal Findings Sample volumes, spotting techniques and filter paper type were evaluated using a CSF-substitute of anti-JEV IgM positive serum diluted in Phosphate Buffer Solution (PBS) to end-limits of detection by JEV MAC-ELISA. A conventional protocol, involving eluting one paper punch in 200μl PBS, did not detect the end-dilution, nor did multiple punches utilising diverse spotting techniques. However, pre-cut filter paper enabled saturation with five times the volume of CSF-substitute, sufficiently improving sensitivity to detect the end-dilution. The diagnostic accuracy of this optimised protocol was compared with routine, neat CSF in a pilot, retrospective study of JEV MAC-ELISA on consecutive CSF samples, collected 2009–15, from three Lao hospitals. In comparison to neat CSF, 132 CSF samples stored as dried CSF spots for one month at 25–30°C showed 81.6% (65.7–92.3 95%CI) positive agreement, 96.8% (91.0–99.3 95%CI) negative agreement, with a kappa coefficient of 0.81 (0.70–0.92 95%CI). Conclusions/Significance The novel design of pre-cut filter paper saturated with CSF could provide a useful tool for JEV diagnostics in settings with limited laboratory access. It has the potential to improve national JEV surveillance and inform vaccination policies. The saturation of filter paper has potential use in the wider context of pathogen detection, including dried spots for detecting other analytes in CSF, and other body fluids., Author Summary Japanese encephalitis virus infection is widespread in Asia, and primarily affects children in poor, rural areas. The virus spreads to the brain and spinal cord resulting in significant death and disability. Diagnosis requires testing for the immune response ‘antibody’ specific to Japanese encephalitis virus in the cerebrospinal fluid that surrounds the brain and spinal cord. However, in most areas where the infection occurs there are no laboratory facilities. In the absence of laboratory diagnosis, we have poor knowledge of the extent of the problem in these areas. Dried blood spots on filter paper have been used widely for many years as simple, cost-effective tools for transporting samples for testing. However, there have been few attempts at using dried cerebrospinal fluid spots. We developed a technique for using dried spots to store and test cerebrospinal fluid for antibodies to Japanese encephalitis virus. We compared the results of dried spots with routine neat cerebrospinal fluid in 132 patient samples, and demonstrated excellent agreement between the two tests. This novel method for saturating dried cerebrospinal fluid spots has the potential to enhance our knowledge of Japanese encephalitis virus epidemiology, and inform health policies where they are most needed. It could also be transferred for use in diagnosing other infectious diseases, including using other body fluid samples.

Poor research reporting is a major contributing factor to low study reproducibility, financial and animal waste. The ARRIVE (Animal Research: Reporting of In Vivo Experiments) guidelines were developed to improve reporting quality and many journals support these guidelines. The influence of this support is unknown. We hypothesized that papers published in journals supporting the ARRIVE guidelines would show improved reporting compared with those in non-supporting journals. In a retrospective, observational cohort study, papers from 5 ARRIVE supporting (SUPP) and 2 non-supporting (nonSUPP) journals, published before (2009) and 5 years after (2015) the ARRIVE guidelines, were selected. Adherence to the ARRIVE checklist of 20 items was independently evaluated by two reviewers and items assessed as fully, partially or not reported. Mean percentages of items reported were compared between journal types and years with an unequal variance t-test. Individual items and sub-items were compared with a chi-square test. From an initial cohort of 956, 236 papers were included: 120 from 2009 (SUPP; n = 52, nonSUPP; n = 68), 116 from 2015 (SUPP; n = 61, nonSUPP; n = 55). The percentage of fully reported items was similar between journal types in 2009 (SUPP: 55.3 ± 11.5% [SD]; nonSUPP: 51.8 ± 9.0%; p = 0.07, 95% CI of mean difference -0.3-7.3%) and 2015 (SUPP: 60.5 ± 11.2%; nonSUPP; 60.2 ± 10.0%; p = 0.89, 95%CI -3.6-4.2%). The small increase in fully reported items between years was similar for both journal types (p = 0.09, 95% CI -0.5-4.3%). No paper fully reported 100% of items on the ARRIVE checklist and measures associated with bias were poorly reported. These results suggest that journal support for the ARRIVE guidelines has not resulted in a meaningful improvement in reporting quality, contributing to ongoing waste in animal research.

The purpose of this project is to cut a window in the opaque edifice of medical liability for young and aspiring OBGYNs to peer through. In addition to reviewing a wealth of literature on medical liability, I interviewed a diverse collection of OBGYNs at UCSD about their experiences with and views of medical malpractice. By integrating these narratives with the literature. This paper attempts to capture three perspectives that, I hope, offer greater texture and deeper understanding to young clinicians trying to make sense of medical liability: 1) What it feels like to be sued and the challenges associated with coping on the job; 2) What advice physicians have to avoid being sued (and a note on attorneys); 3) Where our system of medical liability falls short and how it might be improved.

Background There is widespread evidence that statistical methods play an important role in original research articles, especially in medical research. The evaluation of statistical methods and reporting in journals suffers from a lack of standardized methods for assessing the use of statistics. The objective of this study was to develop and evaluate an instrument to assess the statistical intensity in research articles in a standardized way. Methods A checklist-type measure scale was developed by selecting and refining items from previous reports about the statistical contents of medical journal articles and from published guidelines for statistical reporting. A total of 840 original medical research articles that were published between 2007–2015 in 16 journals were evaluated to test the scoring instrument. The total sum of all items was used to assess the intensity between sub-fields and journals. Inter-rater agreement was examined using a random sample of 40 articles. Four raters read and evaluated the selected articles using the developed instrument. Results The scale consisted of 66 items. The total summary score adequately discriminated between research articles according to their study design characteristics. The new instrument could also discriminate between journals according to their statistical intensity. The inter-observer agreement measured by the ICC was 0.88 between all four raters. Individual item analysis showed very high agreement between the rater pairs, the percentage agreement ranged from 91.7% to 95.2%. Conclusions A reliable and applicable instrument for evaluating the statistical intensity in research papers was developed. It is a helpful tool for comparing the statistical intensity between sub-fields and journals. The novel instrument may be applied in manuscript peer review to identify papers in need of additional statistical review.

As more HIV-infected people gain access to antiretroviral therapy (ART), monitoring HIV drug resistance (HIVDR) becomes essential to combat both acquired and transmitted HIVDR. Studies have demonstrated dried blood spots (DBS) are a suitable alternative in HIVDR monitoring using DBS collected on Whatman 903 (W-903). In this study, we sought to evaluate two other commercially available filter papers, Ahlstrom 226 (A-226) and Munktell TFN (M-TFN), for HIVDR genotyping following ambient temperature storage. DBS were prepared from remnant blood specimens collected from 334 ART patients and stored at ambient temperature for a median time of 30 days. HIV-1 viral load was determined using NucliSENS EasyQ® HIV-1 v2.0 RUO test kits prior to genotyping of the protease and reverse transcriptase regions of the HIV-1 pol gene using an in-house assay. Among the DBS tested, 26 specimens had a viral load ≥ 1000 copies/mL in all three types of filter paper and were included in the genotyping analysis. Genotyping efficiencies were similar between DBS collected on W-903 (92.3%), A-226 (88.5%), and M-TFN (92.3%) filter papers (P = 1.00). We identified 50 DR-associated mutations in DBS collected on W-903, 33 in DBS collected on A-226, and 48 in DBS collected on M-TFN, resulting in mutation detection sensitivities of 66.0% for A-226 and 88.0% for M-TFN when compared to W-903. Our data indicate that differences among filter papers may exist at this storage condition and warrant further studies evaluating filter paper type for HIVDR monitoring.

University scientific research ability is an important indicator to express the strength of universities. In this paper, the evaluation of university scientific research ability is investigated based on the output of sci-tech papers. Four university alliances from North America, UK, Australia, and China, are selected as the case study of the university scientific research evaluation. Data coming from Thomson Reuters InCites are collected to support the evaluation. The work has contributed new framework to the issue of university scientific research ability evaluation. At first, we have established a hierarchical structure to show the factors that impact the evaluation of university scientific research ability. Then, a new MCDM method called D-AHP model is used to implement the evaluation and ranking of different university alliances, in which a data-driven approach is proposed to automatically generate the D numbers preference relations. Next, a sensitivity analysis has been given to show the impact of weights of factors and sub-factors on the evaluation result. At last, the results obtained by using different methods are compared and discussed to verify the effectiveness and reasonability of this study, and some suggestions are given to promote China’s scientific research ability.

When young children do not receive adequate amounts of the micronutrient iodine in their diet, their growth and cognitive development can be impaired. Nearly every country in the world has programs in place to track iodine intake and provide supplemental iodine if needed, usually in the form of fortified salt. The iodine nutrition status of a population can be tracked by monitoring iodine levels in urine samples to see if the median value falls in the range of 100-300 micrograms of iodine per liter of urine (μg I/L), which indicates adequate or more than adequate iodine nutrition. Many low and middle-income countries (LMIC) do not have a laboratory capable of carrying out this challenging assay, so samples must be sent out for assay in external labs, which is expensive and time-consuming. In most LMIC, population iodine surveys are carried out every 5-10 years, which limits the utility of the data for program monitoring and evaluation. To solve this problem, we developed a field-friendly paper test card that uses the Sandell-Kolthoff reaction to measure urinary iodine levels. A blind internal validation study showed that 93% of samples (n = 60) of iodide in an artificial urine matrix were categorized correctly by visual analysis as deficient, adequate, or excessive for levels set forth by the World Health Organization. Quantitative measurements based on computer image analysis had an error of 40 ± 20 μg I/L (n = 35 for samples in the calibration range) and these results categorized 88% of the samples (n = 60) correctly. We employed lifecycle analysis principles to address the known toxicity of arsenic, which is an obligatory reagent in the Sandell-Kolthoff reaction. Disposal of the cards in a landfill (their most likely destination after use) could let arsenic leach into groundwater; toxicity characteristic leaching procedure (TCLP) tests showed that the level of arsenic leached from the cards was 28.78 ppm, which is above the United States Environmental Protection Agency's limit of 5 parts per million for solid waste. We integrated a remediation module into the card. This module contains oxone, to oxidize As(III) to As(V) oxyacids, and the iron oxide goethite. TCLP testing showed that the leachable amount of arsenic was reduced by at least 97.6%-from 28.8 ppm to lower than 0.7 ± 0.7 ppm (n = 20). This upstream intervention rendered the test card suitable for landfilling while retaining its functionality to perform a critical public health evaluation.

International audience; Bisphenol A (BPA) is an endocrine disrupting environmental contaminant used in a wide variety of products, and BPA metabolites are found in almost everyone's urine, suggesting widespread exposure from multiple sources. Regulatory agencies estimate that virtually all BPA exposure is from food and beverage packaging. However, free BPA is applied to the outer layer of thermal receipt paper present in very high (∼20 mg BPA/g paper) quantities as a print developer. Not taken into account when considering thermal paper as a source of BPA exposure is that some commonly used hand sanitizers, as well as other skin care products, contain mixtures of dermal penetration enhancing chemicals that can increase by up to 100 fold the dermal absorption of lipophilic compounds such as BPA. We found that when men and women held thermal receipt paper immediately after using a hand sanitizer with penetration enhancing chemicals, significant free BPA was transferred to their hands and then to French fries that were eaten, and the combination of dermal and oral BPA absorption led to a rapid and dramatic average maximum increase (Cmax) in unconjugated (bioactive) BPA of ∼7 ng/mL in serum and ∼20 µg total BPA/g creatinine in urine within 90 min. The default method used by regulatory agencies to test for hazards posed by chemicals is intra-gastric gavage. For BPA this approach results in less than 1% of the administered dose being bioavailable in blood. It also ignores dermal absorption as well as sublingual absorption in the mouth that both bypass first-pass liver metabolism. The elevated levels of BPA that we observed due to holding thermal paper after using a product containing dermal penetration enhancing chemicals have been related to an increased risk for a wide range of developmental abnormalities as well as diseases in adults.

Background Little is known about how adverse events are summarised and reported in trials, as detailed information is usually considered confidential. We have acquired clinical study reports (CSRs) from the European Medicines Agency through the Freedom of Information Act. The CSRs describe the results of studies conducted as part of the application for marketing authorisation for the slimming pill orlistat. The purpose of this study was to study how adverse events were summarised and reported in study protocols, CSRs, and published papers of orlistat trials. Methods and Findings We received the CSRs from seven randomised placebo controlled orlistat trials (4,225 participants) submitted by Roche. The CSRs consisted of 8,716 pages and included protocols. Two researchers independently extracted data on adverse events from protocols and CSRs. Corresponding published papers were identified on PubMed and adverse event data were extracted from this source as well. All three sources were compared. Individual adverse events from one trial were summed and compared to the totals in the summary report. None of the protocols or CSRs contained instructions for investigators on how to question participants about adverse events. In CSRs, gastrointestinal adverse events were only coded if the participant reported that they were “bothersome,” a condition that was not specified in the protocol for two of the trials. Serious adverse events were assessed for relationship to the drug by the sponsor, and all adverse events were coded by the sponsor using a glossary that could be updated by the sponsor. The criteria for withdrawal due to adverse events were in one case related to efficacy (high fasting glucose led to withdrawal), which meant that one trial had more withdrawals due to adverse events in the placebo group. Finally, only between 3% and 33% of the total number of investigator-reported adverse events from the trials were reported in the publications because of post hoc filters, though six of seven papers stated that “all adverse events were recorded.” For one trial, we identified an additional 1,318 adverse events that were not listed or mentioned in the CSR itself but could be identified through manually counting individual adverse events reported in an appendix. We discovered that the majority of patients had multiple episodes of the same adverse event that were only counted once, though this was not described in the CSRs. We also discovered that participants treated with orlistat experienced twice as many days with adverse events as participants treated with placebo (22.7 d versus 14.9 d, p-value < 0.0001, Student’s t test). Furthermore, compared with the placebo group, adverse events in the orlistat group were more severe. None of this was stated in the CSR or in the published paper. Our analysis was restricted to one drug tested in the mid-1990s; our results might therefore not be applicable for newer drugs. Conclusions In the orlistat trials, we identified important disparities in the reporting of adverse events between protocols, clinical study reports, and published papers. Reports of these trials seemed to have systematically understated adverse events. Based on these findings, systematic reviews of drugs might be improved by including protocols and CSRs in addition to published articles., In a document analysis, Jeppe B. Schroll and colleagues seek insights into potential bias and underreporting in documentation of adverse events from the mid-1990s clinical trials of the anti-obesity drug orlistat., Author Summary Why Was This Study Done? Most drugs have adverse effects, or harms, that may become evident in clinical trials. Pharmaceutical companies seeking to market a new drug must report adverse effects observed in trial participants in the Clinical Study Reports (CSRs), which they provide to regulatory authorities. Additionally, investigators may report harms in published reports of their trials. We sought to understand the accuracy, and potential bias, in harms reporting for trials of orlistat, a slimming drug from Roche approved in Europe in 1998 and still marketed in Europe today. What Did The Researchers Do And Find? Using a Freedom of Information Act request to the European Medicines Agency (EMA), we obtained CSRs describing seven clinical trials of orlistat. We studied protocol instructions to investigators for reporting harms, the actual reporting of harms in individual CSR records versus summaries, and the final reporting of harms in published papers. We found that protocol instructions to trial investigators had the potential to dilute the appearance of drug-associated harms. Between 3% and 33% of the total adverse effects from CSR summaries were described in published papers. In one trial, we counted adverse events individually and found that both the number of adverse effects and the number of days with adverse effects in participants taking the drug were understated in the corresponding publication. What Do These Findings Mean? The reporting of trials of orlistat in the 1990s understated harms in the summarised results submitted to the EMA for drug approval and in the published papers. Based on the characteristics of harms observed and reported in these trials, we suggest that reports of harms include duration of adverse effects. We also suggest that systematic reviews of drugs might be improved by including protocols and CSRs in addition to published articles.

Do highly productive researchers have significantly higher probability to produce top cited papers? Or do high productive researchers mainly produce a sea of irrelevant papers—in other words do we find a diminishing marginal result from productivity? The answer on these questions is important, as it may help to answer the question of whether the increased competition and increased use of indicators for research evaluation and accountability focus has perverse effects or not. We use a Swedish author disambiguated dataset consisting of 48.000 researchers and their WoS-publications during the period of 2008–2011 with citations until 2014 to investigate the relation between productivity and production of highly cited papers. As the analysis shows, quantity does make a difference. QC 20161227

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PLOS Medicine editors and guest editors announce a call for papers for submissions for a special issue on diabetes prevention.

BACKGROUND: Sponsors that seek to commercialize new drugs apply to the Food and Drug Administration (FDA) which independently analyzes the raw data and reports the results on its website.OBJECTIVES: This study sought to determine if there are differences between the FDA assessments and journal reports on biologic agents developed for the treatment of rheumatoid arthritis.METHODS: Available data on FDA-approved drugs were extracted from the website, and a systematic literature search was conducted to identify matching studies in peer-reviewed medical journals. Outcome measures were the American College of Rheumatology response criteria ACR20 (efficacy) and withdrawal due to adverse events (safety). As effect size odds ratios were estimated for each active trial arm vs. control arm (i.e. for both sources: FDA and journal report), followed by calculation of the ratios of the FDA and journal report odds ratios. A ratio of odds ratios not equal to 1 was categorized as a discrepancy.RESULTS: FDA reports were available for 8 of 9 FDA-approved biologic agents for rheumatoid arthritis; all identified trials (34) except one were published in peer-reviewed journals. Overall, discrepancies were noted for 20 of the 33 evaluated trials. Differences in the apparent benefit reporting were found in 39% (24/61) pairwise comparisons and in 11 cases these were statistically significant; the FDA report showed greater benefit than the journal publication in 15 comparisons and lesser benefit in 9. Differences in the reported harms were found in 51% (28/55) pairwise comparisons and were statistically significant in 5. The "signal" in FDA reports showed a less harmful effect than the journal publication in 17 comparisons whereas a more harmful effect in 11. The differences were attributed to differences in analytic approach, patient inclusion, rounding effect, and counting discrepancies. However, no differences were categorized as critical.CONCLUSION: There was no empirical evidence to suggest biased estimates between the two sources. Increased and detailed transparency in publications would improve the understanding and credibility of published results. Further, the FDA report was found to be a useful source when data are missing in the published report (i.e. reporting bias).

We present key points from the updated Dutch-Flemish guideline on comprehensive diagnostics in disorders/differences of sex development (DSD) that have not been widely addressed in the current (inter)national literature. These points are of interest to physicians working in DSD (expert) centres and to professionals who come across persons with a DSD but have no (or limited) experience in this area. The Dutch-Flemish guideline is based on internationally accepted principles. Recent initiatives striving for uniform high-quality care across Europe, and beyond, such as the completed COST action 1303 and the European Reference Network for rare endocrine conditions (EndoERN), have generated several excellent papers covering nearly all aspects of DSD. The Dutch-Flemish guideline follows these international consensus papers and covers a number of other topics relevant to daily practice. For instance, although next-generation sequencing (NGS)-based molecular diagnostics are becoming the gold standard for genetic evaluation, it can be difficult to prove variant causality or relate the genotype to the clinical presentation. Network formation and centralisation are essential to promote functional studies that assess the effects of genetic variants and to the correct histological assessment of gonadal material from DSD patients, as well as allowing for maximisation of expertise and possible cost reductions. The Dutch-Flemish guidelines uniquely address three aspects of DSD. First, we propose an algorithm for counselling and diagnostic evaluation when a DSD is suspected prenatally, a clinical situation that is becoming more common. Referral to ultrasound sonographers and obstetricians who are part of a DSD team is increasingly important here. Second, we pay special attention to healthcare professionals not working within a DSD centre as they are often the first to diagnose or suspect a DSD, but are not regularly exposed to DSDs and may have limited experience. Their thoughtful communication to patients, carers and colleagues, and the accessibility of protocols for first-line management and efficient referral are essential. Careful communication in the prenatal to neonatal period and the adolescent to adult transition are equally important and relatively under-reported in the literature. Third, we discuss the timing of (NGS-based) molecular diagnostics in the initial workup of new patients and in people with a diagnosis made solely on clinical grounds or those who had earlier genetic testing that is not compatible with current state-of-the-art diagnostics.

Objectives To assess hypertension prevalence and the extent and associated factors of hypertension diagnosis, follow‐up, treatment and control gaps in low‐income urban Medellin, Colombia. Methods We randomly sampled 1873 adults aged 35 or older. Unaware hypertensive individuals were defined as those without previous diagnosis whose average blood pressure was equal to or above 140/90 mmHg. For aware hypertensive patients, control was delimited as average blood pressure below 140/90 if under 59 years old or diabetic, and as less than 150/90 otherwise. We used logistic regression to identify care gap‐associated factors. Results Hypertension prevalence was 43.5% (95% CI 41.2–45.7). We found 28.2% aware and 15.3% unaware hypertensive individuals, which corresponds to a 35.1% (95% CI 31.9–38.5) underdiagnosis. This gap was determined by age, sex, education and lifestyle factors. 14.4% (95% CI 11.6–17.6) of aware hypertensive patients presented a follow‐up gap, 93.4% (95% CI 90.9–95.2) were prescribed antihypertensive drugs, but 38.9% (95% CI 34.7–43.3) were not compliant. The latter was strongly associated with follow‐up. The hypertension control gap in aware hypertensive patients, 39.0% (95% CI: 34.9–43.2), was associated with being older, having diabetes, weakly adhering to pharmacological treatment and receiving poor non‐pharmacological advice. Overall, 60.4% (95% CI 57.0–63.8) of aware and unaware hypertensive participants had either diagnosed but uncontrolled or undiagnosed hypertension. Conclusions We found high hypertension prevalence coupled with, from an international perspective, encouraging awareness and control figures. Still, there remains ample room for improvement. Our findings can assist in designing integrated primary healthcare measures that further strengthen equitable and effective access to hypertension care and control.