Exercise for knee osteoarthritis pain: Association or causation?

Exercise is universally recommended as a primary strategy for the management of knee osteoarthritis (OA) pain. The recommendations are based on results from more than 100 randomized controlled trials (RCTs) that compare exercise to no-attention control groups. However, due to the inherent difficulties with adequate placebo control, participant blinding and the use of patient-reported outcomes, the existing RCT evidence is imperfect. To better understand the evidence used to support a causal relationship between exercise and knee OA pain relief, we examined the existing evidence through the Bradford Hill considerations for causation. The Bradford Hill considerations, first proposed in 1965 by Sir Austin Bradford Hill, provide a framework for assessment of possible causal relationships. There are 9 considerations by which the evidence is reviewed: Strength of association, Consistency, Specificity, Temporality, Biological Gradient (Dose-Response), Plausibility, Coherence, Experiment, and Analogy. Viewing the evidence from these 9 viewpoints did neither bring forward indisputable evidence for nor against the causal relationship between exercise and improved knee OA pain. Rather, we conclude that the current evidence is not sufficient to support claims about (lack of) causality. With our review, we hope to advance the continued global conversation about how to improve the evidence-based management of patients with knee OA.

Improvement of bioanalytical parameters through automation: suitability of a hand-like robotic system.

Commercial automation systems for small- and medium-sized laboratories, including research environments, are often complex to use. For liquid handling systems (LHS), development is required not only for the robot's movements but also for adapting the bioanalytical method to the automated system. This study investigates whether a more human-like automation strategy-using a robotic system (RS)-is more suitable for research laboratories than a professional automation approach utilizing a commercial automated LHS. We conducted a series of measurements for protein determination using a Bradford assay manually, with a fully automated LHS, and with our human-like RS. Although the hand-like RS approach requires more than twice the time of the LHS, it achieved the best standard deviation in this setup (RS = 0.5, manual = 0.71, LHS = 0.86). Due to the low limit of detection (LOD) and limit of quantification (LOQ), most protein samples could be quantified with the RS (samples below LOQ = 9.7%, LOD = 0.23; LOQ = 0.25) compared to manual (samples below LOQ = 28.8%, LOD = 0.24; LOQ = 0.26) and the LHS (samples below LOQ = 36.1%, LOD = 0.27; LOQ = 0.31). In another time-dependent enzymatic assay test, the RS achieved results comparable to the manual method and the LHS, although the required time could be a constraint for short incubation times. Our results demonstrate that a more hand-like automation system closely models the manual process, leading easier to accurate bioanalytical results. We conclude that such a system could be more suitable for typical research environments than a complex LHS.

Pediatric acute kidney injury and adverse health outcomes: using a foundational framework to evaluate a causal link.

Acute kidney injury (AKI) is a major global health problem, expensive to manage, and its associations with negative pediatric health outcomes have been clearly demonstrated. One of the most fundamental questions to consider as we use previous epidemiological information to advance research and care paradigms is the strength of the causal link between pediatric AKI and health outcomes. In this review, we apply the foundational framework of the Bradford Hill criteria to evaluate the extent to which a causal link exists between AKI and the associated adverse outcomes in children. Available data in children support a causal link between AKI and short-term outcomes including mortality, length of stay, and ventilation time. Clarifying the causal nature of longer term associations requires further high-quality observational studies in children, careful consideration of what defines the most meaningful and measurable longer term outcomes after pediatric AKI, and integration of evolving biological data related to mechanisms of disease. Preventing or mitigating AKI should lead to improved outcomes. Demonstrating such reversibility will solidify confidence in the causal relationship, improve child health, and highlight an aspect which is highly relevant to clinicians, scientists, and policy makers.

New insights into the paradox between smoking and the risk of SARS-CoV-2 infection (COVID-19): Insufficient evidence for a causal association.

AIMS: Previous studies have reported a 'smoker's paradox', where people who smoke appear to be protected against Severe Acute Respiratory Syndrome CoronaVirus-2 (SARS-CoV-2) infection (COVID-19). This conflicts with well-established evidence that people who smoke are generally more vulnerable to respiratory infections. In this study, we aimed to validate the association between smoking and SARS-CoV-2 infection in a general Dutch population, and to evaluate the evidence underlying the possible causal relationship between smoking and SARS-CoV-2 infection by applying a modern adaptation of the Bradford Hill criteria. METHODS: In total, 57,833 participants from the Lifelines Cohort Study were included in the analysis. Smoking status, including never smoker, current smoker, and former smoker, was derived from the Lifelines general assessment between 2014 and 2017, while SARS-CoV-2 infection status was derived from an additional COVID-19 questionnaire from 2021 to 2022. Logistic regressions were used for the association between smoking status and infection status. The adapted Bradford Hill's criteria, including the strength of association (including an analysis of plausible confounding), plausibility, temporality and study design suitability, were applied to evaluate the existing literature. RESULTS: We found, compared with never smokers, an increased risk of SARS-CoV-2 infection for former smokers (odds ratio (OR)=1.07, 95% confidence interval (CI)=1.01-1.13), but a reduced risk for current smokers (OR=0.85, 95% CI=0.79-0.92), after adjusting for several relevant covariates. However, we discerned a possible explanation of the smoker's paradox since we observed that current smokers were more likely to be non-responders to the COVID-19 questions and, more importantly, these non-responders were more likely to have other established risk factors for SARS-CoV-2 infection. CONCLUSIONS: There is insufficient evidence to suggest that smoking protects against SARS-CoV-2 infection. According to the adapted Bradford Hill's criteria, we observed a high inconsistency between study results, a high possibility for residual confounding and no clear evidence for biological plausibility. Future studies should include linkage with the confirmed testing results from national healthcare registries to mitigate avoidable bias.

Exploring attitudes and variation by sociodemographic factors in consent provided for financial data linkage in an experimental birth cohort study.

BACKGROUND: Improving our understanding of household incomes and what constitutes financial insecurity can help us to better understand how financial insecurity is experienced and how this can change over time within and between individuals and populations. However, financial circumstances are often perceived as sensitive and stigmatising, particularly within some ethnic minority groups. This research aims to explore attitudes and variation by sociodemographic factors in consent provided for financial data linkage in an experimental birth cohort study, in order to obtain validated income and benefits data and to better understand the impact of community interventions on the financial security of its participants and their families. METHODS: This research utilises an observational study design to explore consent rates, attitudes and variation in sociodemographic factors between participants of an experimental birth cohort in a deprived and ethnically diverse setting who consent and do not consent to financial data linkage. RESULTS: Overall, participants were equally likely to consent and decline consent for financial data linkage. Measures of socioeconomic insecurity were associated with being more likely to provide consent for financial data linkage. Participants who were not employed (OR 1.49 95% CI 0.93, 2.40) and were more financially insecure (OR 1.85 95% CI 1.14, 3.93) were more likely to provide consent for financial data linkage. Where the participant's first language was a language other than English, participants were also less likely to provide consent for data linkage (OR 0.65 95% CI 0.39, 0.98). The choice of consent for financial data linkage was not associated with: ethnicity; relationship factors; employment status of the participant's partner; person present at time of recruitment; and measures of health, such as general health, mental health, wellbeing and health-related quality of life. CONCLUSIONS: This research sets out an approach to obtaining validated income and benefits data, as a proxy measure for financial security, within an experimental birth cohort study in a deprived and ethnically diverse setting. It achieves good consent rates and demonstrates greater input from those who report greater potential need for financial support. Further research should be conducted to further understand the interplay of language spoken in this context.

Relationships Between Exposure to Gestational Diabetes Treatment and Neonatal Anthropometry: Evidence from the Born in Bradford (BiB) Cohort.

OBJECTIVES: To examine the relationships between gestational diabetes mellitus (GDM) treatment and neonatal anthropometry. METHODS: Covariate-adjusted multivariable linear regression analyses were used in 9907 offspring of the Born in Bradford cohort. GDM treatment type (lifestyle changes advice only, lifestyle changes and insulin or lifestyle changes and metformin) was the exposure, offspring born to mothers without GDM the control, and birth weight, head, mid-arm and abdominal circumference, and subscapular and triceps skinfold thickness the outcomes. RESULTS: Lower birth weight in offspring exposed to insulin (- 117.2 g (95% CI - 173.8, - 60.7)) and metformin (- 200.3 g (- 328.5, - 72.1)) compared to offspring not exposed to GDM was partly attributed to lower gestational age at birth and greater proportion of Pakistani mothers in the treatment groups. Higher subscapular skinfolds in offspring exposed to treatment compared to those not exposed to GDM was partly attributed to higher maternal glucose concentrations at diagnosis. In fully adjusted analyses, offspring exposed to GDM treatment had lower weight, smaller abdominal circumference and skinfolds at birth than those not exposed to GDM. Metformin exposure was associated with smaller offspring mid-arm circumference (- 0.3 cm (- 0.6, - 0.07)) than insulin exposure in fully adjusted models with no other differences found. CONCLUSIONS FOR PRACTICE: Offspring exposed to GDM treatment were lighter and smaller at birth than those not exposed to GDM. Metformin-exposed offspring had largely comparable birth anthropometric characteristics to those exposed to insulin.

Maternal metabolic syndrome in pregnancy and child development at age 5: exploring mediating mechanisms using cord blood markers.

BACKGROUND: There is limited evidence on how the classification of maternal metabolic syndrome during pregnancy affects children's developmental outcomes and the possible mediators of this association. This study uses a cohort sample of 12,644 to 13,832 mother-child pairs from the UK Born in Bradford Study to examine the associations between maternal metabolic syndrome classification (MetS) and child development outcomes at age 5, using cord blood markers as candidate mediators. METHODS: Maternal cardiometabolic markers included diabetes, obesity, triglycerides, high-density lipoprotein cholesterol, blood pressure, hypertension, and fasting glucose during pregnancy. Cord blood markers of high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, triglycerides, leptin, and adiponectin were used as child mediators. Child outcomes included two starting school variables: British Picture Vocabulary Scale (BPVS) and the Letter Identification Assessment (LID), and five developmental milestone domains from a national UK framework: (1) communication and language (COM); (2) personal, social, and emotional (PSE); (3) physical development (PHY); (4) literacy (LIT); and (5) mathematics (MAT). Mediation models were used to examine the associations between the classification of maternal metabolic syndrome and child developmental milestones. Models were adjusted for potential maternal, socioeconomic, and child confounders such as maternal education, deprivation, and gestational age. RESULTS: In mediation models, significant total effects were found for MetS associations with children's development in the LIT domain at age 5. MetS predicted individual cord blood mediators of lower HDL and increased leptin levels in both adjusted and unadjusted models. Total indirect effects (effects of all mediators combined) for MetS on a child's COM and PSE domain were significant, through all child cord blood mediators of LDL, HDL, triglycerides, adiponectin, and leptin for adjusted models. CONCLUSIONS: The results support the hypothesis that maternal metabolic syndrome classification during pregnancy is associated with some child developmental outcomes at age 5. After adjusting for maternal, child, and environmental covariates, maternal metabolic syndrome classification during pregnancy was associated with children's LIT domain through direct effects of maternal metabolic health and indirect effects of cord blood markers (total effects), and COM and PSE domains via changes only in a child's cord blood markers (total indirect effects).

Associations between maternal gestational diabetes metformin or insulin treatment and offspring growth trajectories from birth to 60 months of age: Findings from the Born in Bradford (BiB) study.

AIM: To investigate the associations between gestational diabetes mellitus (GDM) metformin or insulin treatment and offspring growth trajectories from 0 to 60 months. METHODS: Participants were from the Born in Bradford birth cohort study. Using covariate-adjusted multilevel linear spline models (4 splines: 0-1.6, 1.6-6, 6-17 and 17-60 months), we compared weight, height and body mass index (BMI) z-score trajectories of: (1) 76 offspring exposed to metformin (OGDM-Metformin) and 420 offspring exposed to insulin (OGDM-Insulin); (2) OGDM-Metformin and 9171 offspring not exposed to GDM (No-GDM); (3) OGDM-Insulin and No-GDM. RESULTS: (1) OGDM-Metformin had comparable growth trajectories to OGDM-Insulin from 0 to 60 months. (2) OGDM-Metformin had a lower mean birthweight z-score than No-GDM. OGDM-Metformin had faster changes in height z-score (0.13 [95% CI 0.026, 0.24]) from 17 to 60 months and by 60 months, had comparable mean BMI z-score to No-GDM. (3) OGDM-insulin had lower mean birthweight and height z-scores than No-GDM. OGDM-Insulin had faster changes in weight (0.32 [0.021, 0.62]) and height (0.50 [0.087, 0.91]) from 1.6 to 6 months and by 60 months, had comparable mean BMI z-score to No-GDM. CONCLUSIONS: GDM metformin treatment was not associated with differences in offspring growth trajectories compared to insulin treatment. Both metformin and insulin-exposed offspring had comparable BMI z-score to No-GDM by 60 months.

People powered research: what do communities identify as important for happy and healthy children and young people? A multi-disciplinary community research priority setting exercise in the City of Bradford, United Kingdom (UK).

BACKGROUND: Involving communities in research priority setting can increase the relevance and efficiency of research, leading to better health outcomes. However these exercises often lack clarity in how communities are involved and the extent to which priorities are acted upon is unclear. Seldom-heard groups, for example ethnic minorities may experience barriers to participation. We report methods and outcomes of an inclusive co-produced community research priority setting exercise within the multicultural and deprived city of Bradford, UK. The aim was to identify priorities for keeping children happy and healthy and was undertaken by the Born in Bradford (BiB) research programme to inform future research agendas. METHODS: A 12 member multi-disciplinary, multi-ethnic community steering group led the process using a modified James Lind Alliance approach between December 2018-March 2020. Research priorities were collected through a widely distributed paper and online survey. Respondents were asked to list three important things to keep children i) happy, ii) healthy and what needs to change to improve either health or happiness. Free text data were coded iteratively by community researchers, and shared priorities were co-produced in a series of workshops and meetings with the community steering group and community members. RESULTS: Five hundred eighty-eight respondents to the survey identified 5748 priorities, which were coded into 22 themes. These covered a range of individual, social and wider socioeconomic, environmental and cultural priorities. Diet/nutrition and exercise were most commonly identified as important for health, including what needs to change to improve health. For happiness, home life and family relationships, listening to children, and education/activities were the most commonly identified. Community assets were identified as important to change for both health and happiness. From the survey response the steering group developed 27 research questions. There were mapped onto existing and planned research agendas within BiB. CONCLUSIONS: Communities identified both structural and individual factors as important priorities for health and happiness. We demonstrate how communities can be involved in priority setting using a co-productive approach in the hope this can be used as a model for others. The resulting shared research agenda will shape future research to improve the health of families living in Bradford.

Evidential requirements for the regulatory hazard and risk assessment of respiratory sensitisers: methyl methacrylate as an example.

This review addresses the need for a framework to increase the consistency, objectivity and transparency in the regulatory assessment of respiratory sensitisers and associated uncertainties. Principal issues are considered and illustrated through a case study (with methyl methacrylate). In the absence of test methods validated for regulatory use, formal documentation of the weight-of-evidence for hazard classification both at the level of integration of individual studies within lines of evidence and across a broad range of data streams was agreed to be critical for such a framework. An integrated approach is proposed to include not only occupational studies and clinical evidence for the regulatory assessment of respiratory sensitisers, but also information on structure and physical and chemical factors, predictive approaches such as structure activity analysis and in vitro and in vivo mechanistic and toxicokinetic findings. A weight-of-evidence protocol, incorporating integration of these sources of data based on predefined considerations, would contribute to transparency and consistency in the outcome of the assessment. In those cases where a decision may need to be taken on the basis of occupational findings alone, conclusions should be based on transparent weighting of relevant data on the observed prevalence of occupational asthma in various studies taking into account all relevant information including the range and nature of workplace exposures to the substance of interest, co-exposure to other chemicals and study quality.

Compliant citizens, defiant rebels or neither? Exploring change and complexity in COVID-19 vaccine attitudes and decisions in Bradford, UK: Findings from a follow-up qualitative study.

BACKGROUND: COVID-19 vaccines have been the central pillar of the public health response to the pandemic, intended to enable us to 'live with Covid'. It is important to understand change and complexity of COVID-19 vaccines attitudes and decisions to maximize uptake through an empathetic lens. OBJECTIVE: To explore the factors that influenced people's COVID-19 vaccines decisions and how their complex attitudes towards the vaccines had changed in an eventful year. DESIGN AND PARTICIPANTS: This is a follow-up study that took place in Bradford, UK between October 2021 and January 2022, 1 year after the original study. In-depth phone interviews were conducted with 12 (of the 20 originally interviewed) people from different ethnic groups and areas of Bradford. Reflexive thematic analysis was conducted. RESULTS: Eleven of the 12 participants interviewed had received both doses of the COVID-19 vaccine and most intended to have a booster dose. Participants described a variety of reasons why they had decided to have the vaccines, including the following: feeling at increased risk at work; protecting family and others in their communities; unrestricted travel and being influenced by the vaccine decisions of family, friends and colleagues. All participants discussed ongoing interaction with COVID-19 misinformation and for some, this meant they were uneasy about their decision to have the vaccine. They described feeling overloaded by and disengaged from COVID-19 information, which they often found contradictory and some felt mistrustful of the UK Government's motives and decisions during the pandemic. CONCLUSIONS: The majority of participants had managed to navigate an overwhelming amount of circulating COVID-19 misinformation and chosen to have two or more COVID-19 vaccines, even if they had been previously said they were unsure. However, these decisions were complicated, demonstrating the continuum of vaccine hesitancy and acceptance. This follow-up study underlines that vaccine attitudes are changeable and contextual. PATIENT OR PUBLIC CONTRIBUTION: The original study was developed through a rapid community and stakeholder engagement process in 2020. Discussion with the Bradford Council Public Health team and the public through the Bradford COVID-19 Community Insights Group was undertaken in 2021 to identify important priorities for this follow-up study.

[A common dilemma in medicine : fortuitous association or causal relationship ?] / Vignette diagnostique de l'étudiant. Un dilemme fréquent en médecine : association fortuite ou relation causale ?

Making the differential diagnosis between a simple fortuitous association and a true causal relationship is a challenge commonly encountered not only in epidemiology, but also in clinical practice. The nine criteria supporting a causal relationship published by Bradford-Hill in 1965 remain relevant, even if some amendments were proposed in recent years. The present clinical scenario illustrates this problem by analyzing the controversies concerning the relationships between hypercholesterolemia (LDL) and coronary heart disease on the one hand and between statin therapy and myalgia on the other hand.

Faire le diagnostic différentiel entre une simple association fortuite et une réelle relation de causalité est un défi fréquemment rencontré, non seulement en épidémiologie mais aussi dans la pratique médicale. Les neuf critères plaidant pour une relation causale publiés par Bradford-Hill en 1965 restent toujours d'actualité, même si certains amendements ont été proposés dans les dernières années. Cette vignette clinique illustre cette problématique en analysant les controverses à propos, d'une part, de la relation entre hypercholestérolémie (LDL) et maladie coronarienne, et d'autre part, de la relation entre traitement par statines et myalgie.

Causation and causal inference in obstetrics-gynecology.

Causation and causal inference are of utmost importance in obstetrics and gynecology. In many clinical situations, causal reasoning is involved in etiological explanations, diagnostic considerations, and conversations about prognosis. In this paper, we offer an overview of the philosophical accounts of causation that may not be familiar to, but still be appreciated by, the busy clinician. In our discussion, we do not try to simplify what is a rather complex range of ideas. We begin with an introduction to some important basic ideas, followed by 2 sections on the metaphysical and epistemological aspects of causality, which offer a more detailed discussion of some of its specific philosophical facets, using examples from obstetrical and gynecologic research and practice along the way. We hope our discussion will help deepen the thinking and discourse about causation and causal inference in gynecology and obstetrics.

Exploring the obesity concerns of British Pakistani women living in deprived inner-city areas: A qualitative study.

INTRODUCTION: British South Asians have a higher prevalence of overweight and obesity than the wider population. Bradford (UK), with its high Pakistani presence and levels of economic deprivation, has exceptionally high instances, especially in deprived areas where many Pakistanis reside. British Pakistani women in Bradford are more likely to be overweight and obese. There is uncertainty on how these women can be aided to manage their weight. Therefore, the objective of this study was to explore the obesity concerns of Pakistani women living in deprived inner-city areas of Bradford. METHODS: Three focus groups interviews were carried out with 23 Pakistani women living in deprived areas of Bradford. Data were analysed thematically. RESULTS: This exploratory study identified a wide range of concerns that women had around managing their weight. Participants disclosed distrust in information given around medication, conflicting dietary information and reported low levels of trust in women-only organized physical activities. Cultural barriers were identified, which included the gender role of the woman, the lack of culturally appropriate dietary advice, cultural misunderstandings of what constitutes a healthy diet and healthy weight, the lack of culturally suitable exercise facilities and conforming to family and community expectations. Other concerns were language barriers around a lack of understanding, the inability to read Urdu and reliance on others to translate information. CONCLUSION: These findings have implications for researchers, local authorities, policy makers and others with an interest in reducing the rates of obesity in this population. Recommendations include training health practitioners to be culturally aware of the diet and eating practices of this community, exploring different ways to support socially isolated women to be more physically active at home, addressing physical activity and diet misconceptions and designing obesity management information materials appropriate for a range of literacy levels. PATIENT OR PUBLIC CONTRIBUTION: Public contributors were involved in the development of the interview guide and design of the research. A pilot focus group with participants not included in the present paper was used to help test and refine the focus group questions. Interview transcripts were member checked by participants, and participants assisted with data analysis.

Developing an obesity research agenda with British Pakistani women living in deprived areas with involvement from multisectoral stakeholders: Research priority setting with a seldom heard group.

INTRODUCTION: British Pakistani women have exceptionally high rates of obesity and yet are seldom heard in a research priority setting concerning weight management. The objectives of this study were (i) to ascertain what multisectoral professionals perceive to be the most pressing unmet obesity needs or topic areas that need more research in relation to Pakistani women living in deprived areas of Bradford and (ii) to determine the top 10 obesity health priorities for this group to develop an obesity research agenda. METHODS: A two-step process was adopted using the following: (i) a survey of a wide range of multisectoral professional stakeholders (n = 159) and (ii) a ranking exercise involving Pakistani women living in deprived areas of Bradford (n = 32) to select and prioritize their top 10 obesity health concerns and unmet needs from a list of 31 statements identified in the survey and previous research. Survey data were analysed using inductive content analysis and themes were identified. Themes were translated into statements to be ranked by Pakistani women. The ranking exercise was conducted by telephone either via voice or video call. Data were analysed using a reverse scoring system. RESULTS: Survey responses were grouped into statements reflecting the following three categories: education needs; healthy behaviour barriers and mental well-being. The highest rankings were given by Pakistani women to statements on mental health and the need for education. The top 10 prioritized statements were developed with members of the public into an obesity research agenda that reflected the target population. CONCLUSION: Actively engaging British Pakistani women in setting research priorities provided a unique opportunity to understand the key areas they think are important for future research. The culminating research agenda can be used by researchers to advance the field of obesity research in Pakistani communities, thus producing research outputs that are relevant to and have impact in this population. PATIENT OR PUBLIC CONTRIBUTION: Participants in the ranking exercise collected data. Public contributors were involved in developing the prioritized statements into a research agenda.

Metabolic proteins at birth predict early childhood mental health symptoms.

Child mental health disorders are the leading cause of disability in children and adolescents worldwide. Biological correlates predict psychosocial outcomes throughout human development; however, less is known about metabolic proteins. Drawing from a longitudinal birth cohort study, Born in Bradford (BiB), we examined the role of infant metabolic proteins at birth in predicting early childhood mental health symptoms at 3 and 5 years. We found that higher leptin predicted more prosocial behavior at age 3. Additionally, a higher leptin-to-adiponectin ratio predicted increased total symptom difficulties. At age 5, we found that higher adiponectin predicted a decreased likelihood of being rated by teachers as meeting or exceeding expectations in the domain of "managing feelings and behaviors" and marginally predicted lower competency in "making relationships" on national developmental milestone evaluations. To our knowledge, this is among the first few studies to prospectively predict mental health symptoms from cord blood metabolic proteins, and the first examining this association with a leptin-to-adiponectin ratio. Our results provide support for the possibility that metabolic proteins at birth forecast risk for mental health symptoms in early childhood.

Opto-Microfluidic Integration of the Bradford Protein Assay in Lithium Niobate Lab-on-a-Chip.

This paper deals with the quantification of proteins by implementing the Bradford protein assay method in a portable opto-microfluidic platform for protein concentrations lower than 1.4 mg/mL. Absorbance is measured by way of optical waveguides integrated to a cross-junction microfluidic circuit on a single lithium niobate substrate. A new protocol is proposed to perform the protein quantification based on the high correlation of the light absorbance at 595 nm, as commonly used in the Bradford method, with the one achieved at 633 nm with a cheap commercially available diode laser. This protocol demonstrates the possibility to quantify proteins by using nL volumes, 1000 times less than the standard technique such as paper-analytical devices. Moreover, it shows a limit of quantification of at least 0.12 mg/mL, which is four times lower than the last literature, as well as a better accuracy (98%). The protein quantification is obtained either by using one single microfluidic droplet as well by performing statistical analysis over ensembles of several thousands of droplets in less than 1 min. The proposed methodology presents the further advantage that the protein solutions can be reused for other investigations and the same pertains to the opto-microfluidic platform.

Edward Hickling Bradford (1848-1926): The Founder of Pediatric Orthopedics in America.

Edward Hickling Bradford (1848-1926) is considered as 1 of the most important figures in American and world orthopedics during 19th and early 20th century. His teaching ability, his gifted surgical skills and his innovations in orthopedics attracted the interest of the world orthopedic's community and gave him a long lasting reputation. But most of all he is considered as the founder of pediatric orthopedics in America.

Research in eating disorders: the misunderstanding of supposing serious mental illnesses as a niche specialty.

PURPOSE: Eating disorders (EDs) are mental illnesses with severe consequences and high mortality rates. Notwithstanding, EDs are considered a niche specialty making it often difficult for researchers to publish in high-impact journals. Subsequently, research on EDs receives less funding than other fields of psychiatry potentially slowing treatment progress. This study aimed to compare research vitality between EDs and schizophrenia focusing on: number and type of publications; top-cited articles; geographical distribution of top-ten publishing countries; journal distribution of scientific production as measured by bibliometric analysis; funded research and collaborations. METHODS: We used the Scopus database, then we adopted the Bibliometrix R-package software with the web interface app Biblioshiny. We included in the analyses 1,916 papers on EDs and 6491 on schizophrenia. RESULTS: The ED field published three times less than schizophrenia in top-ranking journals - with letters and notes particularly lacking-notwithstanding a comparable number of papers published per author. Only 50% of top-cited articles focused on EDs and a smaller pool of journals available for ED research (i.e., Zones 1 and 2 according to Bradford's law) emerged; journals publishing on EDs showed an overall lower rank compared to the schizophrenia field. Schizophrenia research was more geographically distributed and more funded; in contrast, a comparable collaboration index was found between the fields. CONCLUSION: These data show that research on EDs is currently marginalized and top-rank journals are seldom achievable by researchers in EDs. Such difficulties in research dissemination entail potentially serious repercussions on clinical advancements. LEVEL OF EVIDENCE: Level V: opinions of respected authorities, based on descriptive studies, narrative reviews, clinical experience, or reports of expert committees.

Combining Longitudinal Data From Different Cohorts to Examine the Life-Course Trajectory.

Longitudinal data are necessary to reveal changes within an individual as he or she ages. However, rarely will a single cohort study capture data throughout a person's entire life span. Here we describe in detail the steps needed to develop life-course trajectories from cohort studies that cover different and overlapping periods of life. Such independent studies are probably from heterogenous populations, which raises several challenges, including: 1) data harmonization (deriving new harmonized variables from differently measured variables by identifying common elements across all studies); 2) systematically missing data (variables not measured are missing for all participants in a cohort); and 3) model selection with differing age ranges and measurement schedules. We illustrate how to overcome these challenges using an example which examines the associations of parental education, sex, and race/ethnicity with children's weight trajectories. Data were obtained from 5 prospective cohort studies (carried out in Belarus and 4 regions of the United Kingdom) spanning data collected from birth to early adulthood during differing calendar periods (1936-1964, 1972-1979, 1990-2012, 1996-2016, and 2007-2015). Key strengths of our approach include modeling of trajectories over wide age ranges, sharing of information across studies, and direct comparison of the same parts of the life course in different geographical regions and time periods. We also introduce a novel approach of imputing individual-level covariates of a multilevel model with a nonlinear growth trajectory and interactions.