From the idea to the research question and hypothesis

Does Early Repair of Congenital Heart Disease Increase the Rate of ADHD Symptoms? Additional Information Is Necessary to Provide an Answer

We compared the short-term maternal and neonatal outcomes of women who deliver by cesarean without labor compared with women who deliver by cesarean after labor or by vaginal birth. This was a retrospective cohort study of women delivering a first baby from 1998 to 2002. Hospital discharge diagnostic coding identified unlabored cesarean deliveries (UCDs), labored cesarean deliveries (LCDs), and vaginal births (VBs). Medical records were abstracted and mode of delivery confirmed. The three outcomes of interest were maternal bleeding complications, maternal febrile morbidity, and neonatal respiratory complications. Using logistic regression for each outcome, we investigated whether mode of delivery was associated with the outcome, independent of other factors. The study groups included 513 UCDs, 261 LCDs, and 251 VBs. Compared with the UCD group, the adjusted odds of bleeding complications was higher in the LCD comparison group (odds ratio [OR] 2.3; 95% confidence interval [CI] 1.21, 4.53) and the VB comparison group (OR 1.96; 95% CI 0.95, 4.02). The incidence of febrile morbidity was similar for both cesarean groups but lower in the VB group. Both comparison groups had lower odds of neonatal complications than the UCD group (OR for LCD comparison group 0.52; 95% CI 0.27, 0.95 and OR for VB comparison group 0.26; 95% CI 0.098, 0.59). Scheduled cesarean is associated with increased odds of neonatal respiratory complications but decreased odds of maternal bleeding complications.

This study evaluated the effect on infant sleep of a novel intervention (Play2Sleep) that combined infant sleep information with self-modeled video feedback on parent-infant interactions. An explanatory sequential mixed-methods design consisting of a randomized controlled trial with 63 mother-father-infant triads randomized to Play2Sleep or comparison home visit interventions was used. We used repeated measures analysis of covariance to detect changes in infant night wakings, nocturnal wakefulness, and sleep durations and Wilcoxon signed rank test to evaluate changes in perception of infant sleep problems. Family interviews (n = 20) were used to explain the quantitative findings and analyzed qualitatively using thematic analysis. Play2Sleep was effective in reducing maternal-reported infant wakefulness, F(1,55) = 5.33, P = .03, partial η2 = .09, and the number of paternal-reported naps, F(1,58) = 4.90, P = .03, partial η2 = .08. Parents in the Play2Sleep group reported significant improvements in problematic infant sleep that were not observed in the comparison group; however, Play2Sleep was not effective in reducing the number of parent-reported night wakings. Information overwhelm, learning infant cues, and working together with a subtheme of father involvement were key qualitative themes developed to explain the quantitative results. Unplanned exploratory analyses revealed a significant improvement in maternal depression symptoms in the Play2Sleep group. This study suggests Play2Sleep could improve infant sleep by promoting parental awareness of infant cues and father involvement and improving maternal depression. Additional research is needed to determine the optimal number and timing of sessions. Registry: ClinicalTrials.gov; Name: Play2Sleep: Using Play to Improve Sleep; URL: https://clinicaltrials.gov/ct2/show/NCT02742155; Identifier: NCT02742155. Keys EM, Benzies KM, Kirk VG, Duffett-Leger L. Effect of Play2Sleep on mother-reported and father-reported infant sleep: a sequential explanatory mixed-methods study of a randomized controlled trial. J Clin Sleep Med. 2022;18(2):439-452.

BackgroundThis research prioritization aimed to identify major research gaps in maternal, newborn, child and adolescent health (MNCAH) to help mitigate the direct and indirect effects of the COVID-19 pandemic.MethodsWe adapted the Child Health and Nutrition Research Initiative methodology. We defined scope, domains, themes and scoring criteria. We approached diverse global experts via email to submit their research ideas in MNCAH and MNCAH-related cross-cutting/health systems area. We curated the research ideas as research questions (RQs) and sent them to the consenting experts for scoring via the online link. For each RQ, the research priority score (RPS) was calculated as an average of individual criterion scores and ranked based on RPS in each area.ResultsWe identified top-ranked 10 RQs in each maternal, newborn, and child and adolescent health and 5 in the cross-cutting/health systems area. In maternal health, indirect effects on care, measures to improve care, health risks and outcomes, and preventing and managing SARS-CoV-2 infection/COVID-19 disease were priority RQs. In newborn health, clinical characterization and managing SARS-CoV-2 infection/COVID-19 disease, mode of transmission and interventions to prevent transmission were the focus. For child and adolescent health, top-ranked RQs were indirect effects on care, clinical status and outcomes, interventions to protect against SARS-CoV-2 infection/COVID-19 disease, and educational institute-related RQs. The cross-cutting RQs were the effects of the pandemic on availability, access, care-seeking and utilization of MNCAH services and potential solutions.ConclusionsWe call on partners, including governments, non-governmental organizations, research institutes, and donors, to address this urgent research agenda.

“Future randomized controlled studies are needed” is a conclusion all too familiar to readers of scientific articles. This statement, distributed liberally in the literature, has come to signify little more than an obligatory admission of a study’s deficiencies. It simultaneously seeks to absolve the authors of any fault from potentially exaggerating the importance of their statistical findings while leaving it to the reader to decide how to apply and disseminate the novel information. The statement also implies that higher quality studies could and should be devised and points to salvation by way of the randomized controlled trial (RCT), the pinnacle of evidence-based medicine.1 Despite this, historical and present-day data show that RCTs are undertaken less frequently in surgery than in other areas of medicine.2–4 This raises concerns about the quality of surgical research, but what can surgeons do about it? Surveys have demonstrated a preponderance of cohort studies and case series in surgical journals, with RCTs accounting for fewer than 10% of publications.5,6 Reasons for lack of quality surgical research have been attributed to unique methodologic, practical, and ethical considerations in evaluating surgical procedures, and surgeon reluctance and lack of experience with surgical trials.3,7,8 Although high-quality RCTs are something to strive for, it is also clear that not all problems in surgery can be evaluated in an RCT. Solomon and McLeod studied 250 research questions in gastrointestinal surgery and concluded that, under ideal conditions, only 38.8% could have been answered with an RCT.9 Rather than attempting to answer every question with an RCT, surgeons should focus on using the best research design for their clinical questions. A variety of study designs can shed important insights if they are applied to the correct problem and conducted with methodologic rigor. The idea, development, exploration, assessment, and long-term study (IDEAL) model is a five-stage framework developed to guide best research practices throughout progressive stages of surgical innovation (Table 1).10,11 Early stages focus on refining the technique and its safety profile, whereas later stages are generally amenable to higher levels of scientific inquiry. With consideration for the stage of development of the surgical technique being investigated, a simple stepwise approach can be applied using the highest feasible level of evidence when choosing a study design. In this article, we outline important concepts and discuss various study designs—RCTs, observational studies with control groups, and case series—with a focus on minimizing biases. We consider various practical and methodologic issues specific to surgical research throughout. Table 1. - IDEAL Stages of Surgical Innovationa Stage Objectives Study Methods 1. Idea Initial technical description of new surgical procedure or technology Case reports, case series 2a. Development Description of early experience with new procedure or technology, including technical modifications and short-term/safety-related outcomes Prospective case series, observational studies 2b. Exploration Larger exploratory study to better define the relevant comparator groups and outcomes, and evaluate feasibility of a future RCT Prospective observational studies, RCTsb 3. Assessment Definitive comparative evaluation against the standard of care RCTs, large prospective observational studiesc 4. Long-term study Collect data for surveillance in real-world practice, identify new complications, and revise indications as needed Registry-based prospective cohort studies or case-control studies, rare case reports aDeveloped from initial description of IDEAL framework by McCulloch P, Altman DG, Campbell WB, et al. No surgical innovation without evaluation: the IDEAL recommendations. Lancet 2009;374:1105–1112.bPerformed when feasible at this stage.cAppropriate when ethical or practical factors preclude performing an RCT. DESIGNING A SURGICAL RESEARCH STUDY A 1994 commentary entitled “The Scandal of Poor Medical Research” was a heated outcry for higher quality research to be performed for a purpose greater than expanding the researcher’s curriculum vitae.12 It pointed to a variety of factors plaguing medical research, including flawed designs, inadequate samples, inappropriate statistical analyses, and misleading interpretation of results. At the heart of the problem was the combination of the “publish or perish” research climate together with a “general failure to appreciate the basic principles underlying scientific research.” Although it is not the goal of this article to review these principles in detail, the concepts of validity, bias, and statistics warrant consideration for our subsequent discussion. Once a question and hypothesis have been established, choosing the study design is the next step. The process should consider ways to maximize validity and minimize bias. Internal validity refers to the accuracy with which the findings reflect true variation in the outcomes measured in the study sample, whereas external validity refers to the extent to which the findings are generalizable to clinical populations encountered in practice.13 The interplay between these concepts is complex. By way of selective inclusion and exclusion criteria, RCTs ensure that groups of patients compared are equivalent in almost all aspects, other than the treatment administered, in striving to achieve a high level of internal validity. This can come at the expense of external validity. For instance, surgeons in real-world practice encounter patients who would not meet the strict inclusion and exclusion criteria of such studies. Biases refer to factors outside of the surgical intervention that systematically influence the results of a study.14 They detract directly from the validity of the study and can occur during study design and preparation, data collection, analysis, and interpretation of results.13,14 Biases are categorized conceptually in terms of their overarching similarities.15 Important conceptual categories are selection biases, observation biases, and confounders (Table 2). Selection biases occur during design of a study and result in unintended differences between comparison groups. They are attributable to systematic flaws in the methodology used to select patients. For instance, in a nonrandomized study investigating a novel surgical procedure compared with nonoperative treatment, patients selected to undergo surgery would likely be healthier, more compliant, and have better access to care than patients treated nonoperatively. These baseline factors stack the odds in favor of surgical outcomes. Observation biases occur during data collection and can be attributed to flaws in the measurement tools used, effects of the study environment on patient behavior, or deferential attitudes of surgeons toward one of the groups. For example, surgeons may be more invested in obtaining favorable outcomes and minimizing complications of surgically treated patients, unintentionally providing better follow-up care. A confounder is any unaccounted for “third variable” responsible for the causal relationship observed in the study. This could be a patient factor, such as smoking, in a study comparing infection rates after different wound care regimens, or a treatment-related factor, such as asymmetry in the duration of postoperative immobilization, in a study comparing different interventions for fractures. Such factors could be more pertinent than the treatments themselves to the outcomes being investigated. Table 2. - Examples of Biases in Surgical Research Bias Description Means of Minimization Selection biases Nonrespondent bias Patients declining to participate in the study differ systematically from those who take part Optimizing communication of objectives, limiting burden of participating Referral bias Patients referred to clinician and recruited to study have more severe disease Predefined and evidence-based inclusion criteria Channeling bias Patients assigned to interventions based on prognostic factors Randomized studies with allocation concealment, stratification in nonrandomized studies Chronology bias Intervention group compared with historical cohort Using concurrent comparison groups Observation biases Recall bias Inaccurate reporting of treatment response by patients Using prospective design and objective outcome measurements Hawthorne effect Change in behavior as a result of participation in a study Randomization, blinding Performance bias Results influenced by variability in surgical technique or expertise Standardized protocols, different surgeons for different procedures, stratification by surgeon level of expertise Transfer bias Patients lost to follow-up differ from those who completed study By maintaining up-to-date contact information, limiting study burden, issuing reminders Detection bias Outcomes not measured uniformly in comparison groups Concurrent comparison groups, blinding, predefined objective outcomes Conflict of interest Competing interests or secondary gain influence outcomes Mandatory disclosure, randomized blinded designs Misuse of statistics and inappropriate interpretation of statistical findings are other common culprits of poor surgical research. The majority of these issues are attributable to unintentional oversights, but a small proportion are caused by deliberate fraud.16,17 Common statistical errors include inadequate power, selection of inappropriate statistical tests, and inappropriate subgroup analysis.18–20 Complex statistical techniques are often relied on to make up for deficiencies in the study design, such as lack of randomization. Studies also tend to focus on statistical differences without considering clinically important thresholds, leading to exaggeration of the findings. Like strategies to minimize bias, the use of statistics should be planned when designing the study, with primary and secondary outcome variables and the statistical plan specified a priori. A well-designed study can also simplify the statistical methods needed. A thorough understanding of validity, bias, and statistical methods is critical when selecting any of the specific study designs discussed below. RANDOMIZED CONTROLLED TRIALS Now suppose that you have formulated a novel and structurally sound research question and have the resources at your institution to conduct the ideal study. A logical approach would be to start atop the pyramid of evidence and determine whether an RCT could be devised before considering other study types at lower levels of evidence.21 RCTs are generally most appropriate in the exploration or assessment stage of surgical innovation, once the technical aspects and safety profile of the procedure are established. Conducting an RCT requires intensive devotion of resources and time. The Wrist and Radius Injury Surgical Trial, led by the senior author (K.C.C.) to evaluate outcomes of treatments for distal radius fractures, took 10 years to complete and required funding from two National Institutes of Health grants.22 Compared with other types of studies, the same factors that make the RCT a coveted entity can also make it unwieldy in surgical research. Ethical and Practical Considerations A variety of ethical and practical considerations pose challenges for surgical RCTs. Like other comparative studies, RCTs are designed to evaluate a null hypothesis, which requires a control group. Unlike pharmaceutical trials, a methodologically equivalent control in surgery, such as a placebo, is rarely possible. One might be tempted to consider nonoperative treatment to be analogous to the placebo. This common view has been the basis of many surgical trials but is often misguided. In reality, nonoperative treatments are highly variable and difficult to control. They can be interventions such as activity modification, immobilization, physical therapy, injections, or a combination thereof. Patients may also implement their own individualized lifestyle changes, such as specialized diets and fitness regimens. Even if the nonoperative treatment is tightly and reliably controlled, the natural history of the patient’s condition may confound outcomes. In surgical trials, the true equivalent of a placebo would be sham surgery, a notion that transgresses ethical boundaries except in the most selective circumstances.23 In most cases, the use of an RCT to evaluate a surgical procedure mandates clinical equipoise between the surgical treatment being investigated and some other treatment.8 Nevertheless, even the existence of true clinical equipoise does not guarantee the feasibility of an RCT. Randomization and allocation concealment can be difficult to execute.7,8 These attributes strip the patient and physician of the opportunity for shared decision-making. Patients may be uncomfortable with randomized treatment selection without input from the surgeon, or with the notion of being part of an experiment. Patients often arrive at the surgeon’s office with a preference for a particular treatment.24 Even when all of these factors are accounted for, patients who agree to participate in an RCT may differ from patients who do not consent, introducing selection bias.3 Ethical considerations are not limited to the patient. Surgeons conducting the study must strive to treat participants equally to avoid unduly influencing the results of the treatment groups. However, surgeons often have their own preferences for one procedure over another.25 If the same surgeon is performing multiple procedures in the study, he or she may also be more facile in one of the procedures, creating potential for performance bias. This brings forth the issue of blinding, which is generally easier to accomplish in medical trials than in surgical trials. Clearly, the surgeon performing the operation cannot be blinded, but it is also difficult to ensure that patients are blinded to the treatment that they received. Patients may become aware of the surgery that was performed based on the shape of a scar, length of time spent in the operating room, or some other discernible feature. The ethics of withholding information about the surgery from the patient and examiners at follow-up visits are controversial, particularly if difficulties with recovery or complications arise. Cost and challenges recruiting patients and ensuring they return to follow-up are other factors that can make the RCT unfeasible.26 Given some of the ethical and practical factors associated with RCTs, other study designs discussed below may be better options. Minimizing Bias in RCTs Good design is crucial for maximizing validity and minimizing bias. Alarmingly, analyses of all RCTs published in The Journal of Bone and Joint Surgery between 1998 and 2013 showed that trials evaluating surgical procedures (as opposed to nonoperative or medical interventions) and with surgeons as first authors scored significantly lower in quality.27,28 To illustrate features of a well-designed surgical RCT, consider a landmark trial investigating open reduction and internal fixation versus casting for minimally displaced scaphoid waist fractures (the Scaphoid Waist Internal Fixation for Fractures Trial).29 This study sought to answer a timely question that has been a longstanding area of clinical equipoise. Allocation concealment and randomization were used with a remote randomization service that stratified patients based on their pattern of fracture displacement, further minimizing confounders. Sample size was determined based on a priori power analysis, and statistical analyses were performed by a blinded statistician following a strict prespecified plan. Primary and secondary outcomes were stated from the outset, and potentially subjective radiologic tests were evaluated independently by two musculoskeletal radiologists and a surgeon. Instead of blinding patients and surgeons, the surgical technique and postoperative protocols were left to the discretion of the surgeons, allowing patient-centered care and accounting for differences in surgeons’ technical preference and skill. This practical approach sought to minimize bias while also maximizing external validity, which was important for a trial aiming to inform clinical practice on an international scale. Empiric data support the importance of sound study design on the results of an RCT. Colditz et al. found that the likelihood of an improved outcome from an experimental treatment increased significantly in the absence of randomization.30,31 In a study analyzing 250 controlled trials, treatment effects were increased by 41% when allocation concealment was inadequate and 30% when the extent of concealment was unclear.32 Trials that were not double-blinded yielded treatment effects 17% greater than double-blinded trials. Methodologic problems like these can lead to inaccurate interpretation of findings and distort knowledge found in the published literature. They can be avoided with use of validated quality checklists such as the Consolidated Standards of Reporting Clinical Trials guidelines when planning a study.33 Such frameworks serve as an important quality safeguard and should be familiar to surgeons undertaking RCTs. Grading systems specific to plastic surgery have also been developed.34 OBSERVATIONAL STUDIES WITH A CONTROL GROUP Many questions in surgery cannot be addressed with an RCT but are amenable to other study designs. A nonrandomized study with a control group should be considered when one of the ethical or practical factors discussed above precludes an RCT. Commonly used designs are cohort studies and case-control studies (Fig. 1).15 Although cohort studies are in a higher tier of evidence, both designs have specific indications, methodologic considerations, and biases.Fig. 1.: Observational study designs.Like RCTs, cohort studies can be highly influential in their scope. Because of fewer upfront demands on participants and less stringent inclusion criteria, these studies lend themselves to broader investigations when more knowledge is needed before performing an RCT. For instance, a prospective cohort study was devised to evaluate the effectiveness and safety of immediate implant-based breast reconstruction with or without mesh following mastectomy (Implant Breast Reconstruction Evaluation study).35 This is a current topic of interest for many plastic surgeons, with recent trends toward immediate reconstruction following mastectomy.36 Although previous RCTs evaluating immediate breast reconstruction had been performed, their validity was questioned because of performance biases and low sample size.37–39 The Implant Breast Reconstruction Evaluation study addressed this gap in knowledge with an exploratory design that included more than 2000 patients from 81 participating centers. Patients underwent different variations of breast reconstruction at the discretion of the treating surgeon, eliminating concerns for patient preference that are a major hindrance to RCTs in breast surgery.40 Multiple predefined primary outcomes were evaluated and multivariable logistic regression was used to control for confounders. In addition to eliminating practical hurdles of RCTs, advantages of cohort studies illustrated in this example include obtaining larger samples, evaluating multiple exposures and outcomes at once, and generating new hypotheses for future studies through an exploratory approach. Surgeons must also be aware of the pitfalls of nonrandomized studies. Without randomization, cohort studies have limited ability to account for confounders. A causal relationship is inferred from the chronologic sequence of exposures and outcomes, which is most convincing in prospective studies. Without blinding or allocation concealment, cohort studies are also susceptible to selection biases. Recall bias is a limitation for retrospective cohort studies because of factors such as inaccurate patient recall and reliance on information from patient charts.41 Variability in documentation practices makes the fidelity of large databases particularly concerning. In case-control studies, the inference of causation is especially problematic because comparison groups are selected based on their outcomes and analyzed retrospectively for exposures. Designing an observational study with a control group requires paying special attention to these inherent limitations and must be individualized to the research question. Exposures, outcomes, inclusion criteria, and statistical methods should all be planned in advance, even for studies meant to be “exploratory” or hypothesis-generating. Observational studies should be evaluated using standardized guidelines such as the Strengthening the Reporting of Observational Studies in Epidemiology framework.42,43 Retrospective cohort studies lend themselves to studying rare conditions and procedures, particularly with the availability of large national databases. Vast amounts of data can be extracted and analyzed rapidly. Meanwhile, case-control studies are useful for investigating factors underlying rare outcomes or complications. When using a registry or database, its purpose, completeness, and accuracy should be carefully evaluated.44 If the question would be better suited for an RCT and there are no major practical or ethical barriers, a higher level of evidence design should be pursued. CASE SERIES An appraisal of articles published in the general surgery literature in 1996 compared the preponderance of case series, 46% of all studies, to “comic opera,” pointing to a necessary shift toward higher quality research.6 A similar survey conducted 10 years later found the proportion of case series had decreased to 34%, with 51% of publications being cohort studies.5 Case series, which typically involve a retrospective account of outcomes from a single procedure, often from a single institution and surgeon, remain a common avenue for publishing novel information. The absence of a control group is their primary flaw, as a hypothesis cannot be tested.44 Retrospective case series are also culprits of publication bias, as new procedures with poor outcomes are unlikely to be published.45–47 Furthermore, failure to favorable results of new techniques are unlikely to be concerns about the validity of a case series from a single Case series are for providing for subsequent hypothesis They should be undertaken with specific such as the safety of a novel procedure or rare or complications. The IDEAL model the use of a case series to be appropriate in the or development first with a new procedure are a and are to the surgical To some of the pitfalls discussed prospective series should be performed with protocols for the new procedure and in of conducting the study. studies should also be to publication The use of retrospective series should be but at a involve patients without and a standardized reporting in the case of RCTs and observational studies, validated checklists can be used to minimize bias when reporting novel surgical interventions in a case A simple approach can be used to the best research design for a surgical question. with consideration for the IDEAL stage of the surgery being investigated, the highest level of appropriate for that stage should be evaluated for feasibility before considering designs at lower levels of the evidence RCTs the highest level of but are not suited for many questions. such as observation studies and case series, to be when practical and ethical considerations preclude the use of an RCT. of the study surgical research should quality design and minimize bias. funding from the National Institutes of from and and a research from to study outcomes. has no interest to in to the of this The authors would like to for and to the development of this They appreciate the review and from of at the of

To conduct a successful research study, several criteria must be satisfied: the research question must be important (not only to the investigators but to clinicians and managers in other institutions); the research question must be answerable with the available resources; the investigators must be motivated and capable; and the research setting must be appropriate for the study (the institution must have a supportive culture and analytical resources, and the local institutional review board must approve the proposed study). Quality-assurance (QA) research poses some special challenges and requirements. First, although QA studies should be hypothesis-driven, they are usually before-and-after studies, rather than randomized controlled trials. Second, in before-and-after studies the investigators must address and minimize several possible sources of bias that could confound the results. For example, the compared groups must be similar in important features that could affect development of the outcome(s) of interest, and clinical practices other than the practice change that is being tested during the study must be shown not to independently affect the outcome(s) of interest. We discuss several examples of QA studies, and we offer a checklist for the process of considering, designing, executing, presenting, and publishing a QA study.

BACKGROUND: This article is part of a special series designed to help health professionals in the process of developing a research project and writing a manuscript. The research question is the keystone in this process, and represents the first step of every research project. However, its importance is frequently neglected. OBJECTIVE: To highlight important considerations in the development and formulation of a research idea, with the purpose of identifying main guiding elements, in order to prevent errors in one of the most important stages of an experiment. METHODS: The authors performed a non-systematic literature review (PubMed.gov - U.S. National Library of Medicine/National Institute of Health) to retrieve papers that addressed the main steps to build a research question. RESULTS: The construction process includes the conception of the research idea, seeking an appropriate environment and resources, performing a literature review, then crafting and refining the research question, while being aware of potential challenges and pitfalls that may be encountered. The FINER and PICOT criteria can be useful tools in this process. CONCLUSION: It is essential to invest time, energy, and resources in the construction of the research question prior to detailing the study design, thus supporting the further development of the research project on a solid initial foundation.

Increasing data suggest that subclinical hypothyroidism (SCH) and thyroid autoimmunity (TAI) are associated with adverse pregnancy outcomes, but there are limited data on the association of these conditions in early pregnancy with subsequent miscarriage. In this prospective cohort study, we screened 3315 women at low risk for thyroid dysfunction at four to eight weeks' gestation from iodine-sufficient areas of China between January 2012 and September 2012. Thyrotropin (TSH), free thyroxine (fT4), and the autoantibodies thyroid-peroxidase antibody (TPOAb) and thyroglobulin antibody (TgAb) were measured. Based on these results, women were divided into four groups for comparison: euthyroidism (ET), isolated SCH, isolated TAI (positive TPOAb or/and TgAb), and SCH with TAI (SCH+TAI). The SCH group was stratified into two subgroups (SCH 1 and SCH 2) on the basis of the level of TSH (2.5 ≤ TSH < 5.22 or 5.22 ≤ TSH < 10 respectively). Accordingly, the SCH+TAI group was also stratified into two subgroups (SCH+TAI 1 and SCH+TAI 2). The outcome of interest was miscarriage, defined as spontaneous pregnancy loss prior to 20 weeks. Compared to women with ET, the risk of miscarriage was significantly higher among women with SCH 2 (7.1% vs. 2.2%, aOR 3.40 [CI 1.62-7.15]; p = 0.002), isolated TAI (5.7% vs. 2.2%, aOR 2.71 [CI 1.43-5.12]; p = 0.003), SCH+TAI 1 (10.0% vs. 2.2%, aOR 4.96 [CI 2.76-8.90]; p = 0.000), and SCH+TAI 2 (15.2% vs. 2.2%, aOR 9.56 [CI 3.76-24.28]; p = 0.000). The gestational ages of 110 women at miscarriage were lower among women with subclinical thyroid abnormalities compared to ET (11.13 ± 3.21 weeks with subclinical thyroid abnormalities vs. 9.33 ± 1.71 weeks with ET; p = 0.024). In parallel with the higher TSH levels, there were earlier gestation ages at miscarriage between subgroups of SCH and SCH+TAI (SCH 1 vs. SCH 2: 10.79 ± 1.77 vs. 9.70 ± 1.47 weeks, p = 0.039; SCH+TAI 1 vs. SCH+TAI 2: 9.59 ± 1.97 vs. 8.88 ± 1.24 weeks, p = 0.031). Women with SCH and TAI are at an increased risk of miscarriage between four and eight gestational weeks. Women with a combination of SCH and TAI were found to have the highest risk and earlier gestational ages of miscarriage.

This primer introduces the domains into which the aims of quantitative health research generally fall and provides tools to improve the methodological quality of observational clinical and population-based research articles-with a special focus on the field of neurology. Generally, research questions can be categorized into one of the following 3 data science domains: description, prediction, and causal inference. A descriptive question aims to quantify and describe the frequency and distribution of a given health condition in a certain population at or during a specific time. A predictive question aims to estimate either the probability of the presence of a given disease or health condition in an individual (diagnostic prediction) or the probability of an individual developing a disease of interest over a specified period (prognostic prediction). A causal question aims to estimate the causal effect of interest (estimand) of an exposure or intervention on an outcome in a given population. Depending on the research question, estimands could be the total causal effect, a mediated indirect effect, or effect (measure) modification by third variables, among others. Each of these domains comes with its own set of research methods, study designs, reporting guidelines, scientific language, strengths, and limitations, whereby the correct attribution of a research domain will have an impact in 3 ways: i) help authors to formulate appropriate research questions and choose and implement suitable study designs and methods; ii) allow reviewers and editors to assess studies with an increased focus on their clinical relevance, methodological advances, and novelty and quality of clinical evidence; and iii) facilitate clear communication of findings and clinical implications to the broader research community in neurology and related fields.

Formulating a proper research question is a precondition to robust clinical research. A properly developed research question helps to ensure that the research to be performed is focused and has clinical relevance. The research question must satisfy the following criteria: it is Feasible, Interesting, Novel, Ethical, and Relevant; to be remembered by the acronym FINER. The final research question should be formulated in such a way as to identify the Population (Patients) studied, the novel Intervention explored, the Comparative intervention, the Outcome to be measured, and the Time horizon (when the outcome is to be measured). This formulation can be remembered by the acronym PICOT. When a clinical question is asked in the PICOT format, it will help the reader search the literature to find the evidence efficiently. For the surgeon-investigator, it will set the foundation for proper research to solve a clinical problem.

314 Treatment With Intravenous Fluid Therapy Was Not Associated With Improved Survival Among Patients With Ebola Virus Disease: An International Multisite Cohort Study

BackgroundGabapentin and pregabalin are commonly prescribed medications to treat pain in patients with diabetic neuropathy. Gabapentin and pregabalin can cause fluid retention, which is hypothesized to be associated with cardiovascular diseases. However, whether long-term use of gabapentin and pregabalin is associated with adverse cardiovascular diseases remains unknown. This study aims to examine the association between gabapentin use, pregabalin use and several adverse cardiovascular events.MethodsThis retrospective cohort study used propensity score matching within patient electronic health records (EHRs) from a multicenter database with 106 million patients from 69 health care organizations in the US. The study population comprised 210,064 patients who had a diagnosis of diabetic neuropathy and were prescribed diabetic neuropathy medications in their EHRs. The exposure cohort comprised patients who were prescribed gabapentin or pregabalin to treat diabetic neuropathy. The comparison cohort comprised patients who were not prescribed either gabapentin or pregabalin but were prescribed other drugs to treat diabetic neuropathy. The outcomes of interest were myocardial infarcts, strokes, heart failure, peripheral vascular disease, and venous thromboembolic events. We calculated hazard ratios (HRs) and 95% confidence intervals (CIs) for 3-month and 5-year risk for adverse cardiovascular events between the propensity score-matched cohorts.ResultsBoth gabapentin and pregabalin were associated with increased risk of 5-year adverse cardiovascular events compared with the comparison group. In patients prescribed gabapentin, the highest risk was observed for deep venous thrombosis (HR: 1.58, 95% CI 1.37–1.82), followed by pulmonary embolism (HR: 1.5, 95% CI 1.27–1.76), peripheral vascular disease (HR: 1.37, 95% CI 1.27–1.47), stroke (HR: 1.31, 95% CI 1.2–1.43), myocardial infarction (HR: 1.25, 95% CI 1.14–1.38) and heart failure (HR: 1.14, 95% CI 1.07–1.21). In patients prescribed pregabalin, the highest risk was observed for deep venous thrombosis (HR: 1.57, 95% CI 1.31–1.88), followed by peripheral vascular disease (HR: 1.35, 95% CI 1.22–1.49), myocardial infarction (HR: 1.29, 95% CI 1.13–1.47), pulmonary embolism (HR: 1.28, 95% CI 1.04–1.59), stroke (HR: 1.26, 95% CI 1.12–1.42), and heart failure (HR: 1.2, 95% CI 1.11–1.3). There were significant associations between short-term (3 month) gabapentin use and heart failure, myocardial infarction, peripheral vascular disease, deep venous thrombosis, and pulmonary embolism. Short-term (3 month) pregabalin use was associated with deep venous thrombosis, peripheral vascular disease.ConclusionIn patients with diabetic neuropathy who were prescribed gabapentin and pregabalin, there is an increased risk for heart failure, myocardial infarction, peripheral vascular disease, stroke, deep venous thrombosis, and pulmonary embolism with long-term use. Our findings suggest that increased risk for adverse cardiovascular events, along with other side effects, the efficacy of pain control and the degree of tolerance of the patient, should be considered when prescribing gabapentin and pregabalin long-term in patients with diabetic neuropathy.

The Role of Multiparametric Magnetic Resonance Imaging/Ultrasound Fusion Biopsy in Active Surveillance

To test the feasibility and acceptability of a dementia literacy intervention for Korean American (KA) elders with dementia and their caregivers: K-PLAN (Preparing successful aging through dementia Literacy education And Navigation). Twenty cognitively impaired Korean elders (Clinical Dementia Rating 1+) and their caregivers participated in a pilot trial to receive the K-PLAN intervention, which consisted of 1-h dementia literacy education followed by monthly phone counseling sessions and navigation assistance for 3 months by a trained bilingual community health worker. Outcomes of interest were linkage to medical services for dementia evaluation (KA elders) and dementia literacy, social support, self-efficacy in dementia care, depression, and quality of life (caregivers). Using a one-group pre-and post-test design, all ten dyads were followed up at 12 weeks. The K-PLAN intervention was highly feasible and acceptable. We were able to retain all twenty participants over the study period (100% retention rate). In addition, 100% of the caregivers would recommend the program with an overall satisfaction rating of 9.7 on a 1-10-point scale. Three of the elders (30%) were linked to medical services for dementia by medical record review. The effect sizes for caregiver outcomes ranged from 0.4 to 0.7 in absolute value. Dementia literacy intervention has the potential to promote linkage to medical services for dementia evaluation and early diagnosis among linguistically isolated KA elders while improving caregiver psychological outcomes. Studies with larger sample sizes, comparison groups, and cost-effective analyses are needed to inform the application of K-PLAN in diverse community settings. Early diagnosis of dementia can help preserve functional status. Promoting dementia literacy and linkage to health services through community-based programs such as K-PLAN may enable underserved racial/ethnic minority communities to make timely follow-up for dementia evaluation and care planning.

The age at which children enter school represents a transitional period between early childhood and adolescence that involves increasing autonomy, interaction with peers, and exposure to environments outside the home. Although mortality is generally much lower in the 5 to 9 age group compared with infancy and early childhood, there are many preventable causes of mortality, morbidity, and disability that emerge in this age group, including injuries, noncommunicable diseases, and vaccine-preventable and highly treatable infections.1 Partly because of relatively low mortality rates and less frequent contacts with the health system, school-age children and younger adolescents ages 5 to 14 have been referred to as the “missing middle,” in that there is a dearth of robust data on key health indicators, morbidity burden, and cause-specific mortality in this group.2 Many health issues that have a high burden in early childhood can persist in older children, especially in low- and middle-income countries (LMIC), resource-constrained settings, and marginalized communities worldwide. Undernutrition and infections occurring in the context of poverty remain leading causes of morbidity and mortality in school-age children living in LMIC,3 whereas those children in higher-income settings are more likely to die due to injuries or noncommunicable disease (NCD). In addition, the prevalence of overweight and obesity in children and adolescents has increased steadily over the last few decades,4 though the rate of these increases varies widely among countries.5New risk factors relating to diet, lifestyle, mental health, injuries, and NCDs also become more prominent as children approach and enter adolescence, many of which can contribute to the development of chronic NCDs over the life course. Within this period, school-age children begin to establish healthy lifestyle habits (eg, diet, physical activity, avoidance of substance use), and are learning about sexual and reproductive health and rights, as well as the measures they can take to protect themselves and others. This represents a window of opportunity for educational interventions to support good health, optimal development, and well-being. A growing body of evidence suggests that school-based and digital platforms and delivery strategies are promising tools that aid in the delivery of health interventions to older children.The methodology and reviews described herein contributed to the portion of the upcoming 2022 Lancet Optimizing Child and Adolescent Health and Development Series6 related to school-age child and adolescent health interventions. This Lancet Series is the product of an ongoing academic collaboration involving global child health researchers worldwide, including many who are authors on articles within this supplement. The aim of the specific Lancet Series article citing this supplement is to provide a comprehensive overview of systematic reviews describing the most recent evidence for effective interventions to support maternal, newborn, child, and adolescent health and development from preconception through to 20 years of age.Figure 1 provides an overview of the key child health domains, and a breakdown of the intervention review topics addressing key risk factors covered by the articles included in this journal supplement. On the basis of work done in previous comprehensive overviews of interventions for child and adolescent health (eg, Disease Control Priorities, 3rd edition7; Lancet Adolescent Health Commission8), we identified a comprehensive set of key child health domains that represented priority areas for interventions to address modifiable risks for the major causes of child mortality and morbidity. The factors that informed which domains were covered in this supplement included: conditions with a high global burden of disease, conditions with disproportionate impacts on vulnerable and marginalized populations, potential to support improved human capital development across the life course, and pragmatic considerations including whether the topic had recently been covered elsewhere. In cases where the child health domain was deemed too broad in scope for a single review (eg, infectious diseases), the subtopics for individual reviews were also chosen on the basis of these factors. The age group of specific interest for these reviews was older school-age children (ages 5–9.9), though the period of early adolescence (ages 10–14.9) was also recognized as an important area of overlap and transition. The general outcomes of interest aligned with those chosen through consensus by the Lancet Series working group. These included, but were not limited to, mortality, severe morbidity, disability, growth and development, knowledge and behavior, and indicators of improved human capital development such as academic achievement.The methodological approaches taken, and child health domains covered in this supplement of reviews, was informed by a broad initial literature-scoping and evidence-mapping process to identify key health interventions and associated evidence for their effectiveness in the form of systematic reviews. This was done across all domains, from preconception and pregnancy to ages 0 to 20 to inform the 2022 Lancet Optimizing Child and Adolescent Health and Development Series.6 This involved leveraging existing large-scale intervention overviews (eg, Disease Control Priorities 3rd edition, Lancet Series) that had already highlighted existing effective interventions and the most recent systematic reviews detailing the evidence for their effectiveness. Additional targeted searches for newer interventions and systematic reviews in each domain were also conducted. Through this evidence-mapping process, we explored coverage and extent of LMIC-specific evidence across all child health domains to identify areas where school-age evidence was lacking and determined that there were significant gaps in existing evidence for intervention effectiveness in school-age children.We funneled the reviews identified during this initial scoping process that contained studies covering school-age children and adolescents into the individual reviews for each domain of child health covered in this supplement. We elected to conduct targeted overviews of systematic reviews if there was deemed to be a large body of existing evidence syntheses. In cases where there was a lack of evidence syntheses of intervention effectiveness for a given domain of school-age child health, conventional systematic reviews of primary literature (ie, experimental studies) were conducted. The general methodology for these 2 approaches are described below. See Table 1 and Fig 1 for a summary of the review methods used for each child health domain, and Fig 2 for a breakdown of the main methodology followed in each type of review.For those child health domains that encompassed a variety of intervention types addressing a wide range of risk factors and health conditions, and for which the initial scoping process identified a variety of existing systematic reviews of intervention effectiveness, an overview of systematic reviews was undertaken. This approach was taken to ensure comprehensiveness, reduce duplication of review efforts, and make the review process feasible.In addition to incorporating those relevant reviews previously identified in the initial literature-scoping and evidence-mapping exercise, tailored searches were executed in several databases (eg, Medline, Cochrane Database of Systematic Reviews, Campbell Library) to identify literature published up until the end of 2020. Evidence derived from Cochrane reviews and other high-quality systematic reviews that synthesized evidence from randomized controlled trials and quasi-experimental studies examining the effectiveness of interventions was prioritized for inclusion. A first pass of title and abstract screening for relevance was conducted, followed by a full text screening that was done by at least 2 reviewers against inclusion criteria. Two reviewers independently filled a standardized data abstraction form to capture review characteristics, the characteristics of included studies and interventions (eg, age coverage, country representation, delivery platform), and pooled-effect estimates (eg, risk ratios, odds ratios, mean differences, 95% confidence intervals) derived from meta-analyses where they were reported. The main outcomes of interest across the reviews included measures of child morbidity, mortality, development, academic achievement, and mental and physical well-being. The extracted data were then matched among reviewers to check for errors and ensure consistency, and then consolidated into a single table for inclusion in the article. The AMSTAR 2 tool12 was used for review quality assessment, and was also conducted in duplicate, with any disagreements in ratings resolved by consensus or the involvement of a third reviewer.If for a given domain the initial evidence-mapping exercise revealed that the existing evidence-synthesis literature was lacking for the school-age group, we proceeded with a conventional systematic review of primary literature. All systematic reviews were reported in accordance with the reporting guidance provided by the Preferred Reporting Items for Systematic Reviews and Meta-Analyses criteria.13Search strategies were developed using the population, intervention, control, and outcomes methodology, relevant medical subject headings terms, and keywords derived from the scoping search. The search terms were adapted for use in other bibliographic databases in combination with database-specific filters for controlled trials, where these were available. Searches for the individual, domain-specific reviews were conducted in a variety of databases, including but not limited to: PubMed, Embase, Medline, PsycINFO, Ovid SP, The Cochrane Library, Cochrane Central Register of Controlled Trials, Cochrane Methodology Register, and the World Health Organization regional databases. Evidence derived from LMIC was prioritized for synthesis, though evidence from high-income countries (HIC) settings was leveraged to highlight whether effective interventions exist in cases where LMIC evidence was sparse. Gray literature searches and additional hand searching were conducted in Google Scholar and reference lists of relevant articles, book chapters, and reviews.After removal of duplicate studies, a multistage screening process was performed to select studies that met the eligibility criteria. Each title and abstract was assessed by at least 1 reviewer, who excluded those that were deemed irrelevant. At the full-text review stage, at least 2 reviewers assessed all full texts. Any disagreements in inclusion decisions were resolved by discussion and, where necessary, by consulting a third reviewer. At this stage, reasons for exclusion were documented. The methods section of each individual review in this supplement describes their selection and eligibility criteria, which differed depending on the child health domain being assessed. Data from included studies were independently extracted and coded by 2 review authors using standardized, previously piloted data extraction forms, which sought general study characteristics, details of the population, intervention, comparison groups, and quantitative outcome data. Data extraction forms were matched and checked, and if necessary, a third review author was consulted in the event of any disagreements to establish consensus.Assessment of risk of bias for included studies was conducted according to criteria and tools outlined in the Cochrane Effective Practice and Organization of Care guidelines14 for randomized trials, nonrandomized trials, controlled before–after, interrupted time series, and the Cochrane Handbook for Systematic Reviews of Interventions.15 Assessments were conducted independently by 2 review authors; scores were compared, and a final risk of bias judgement was reported for the included studies of each systematic review. Randomized trials were assessed using the Cochrane Risk of Bias tool15 across the following domains: randomization process, deviations from the intended interventions (blinding of personnel, participants, and outcome assessment), missing outcome data, outcome measurement, the selection of the reported result, disclosure of funding, and conflicts of interest. Studies were assigned an overall risk of bias judgement accordingly (low risk, high risk, or some concerns/medium risk). Quasi-experimental study designs were assessed using the Risk of Bias Tool for Nonrandomized Studies of Interventions (ROBINS-I) tool.15,16 Studies were assessed according to the following domains: bias because of confounding, bias in selection of study participants, bias in classification of interventions, bias because of deviations from intended interventions, bias because of missing data, bias in measurement of outcomes, and bias in selection of the reported result. Each study was assigned an overall risk of bias judgement (low, moderate, serious, and critical risk).Meta-analyses were conducted where possible using Review Manager 5.4 software.17 Randomized controlled trials and cluster-randomized controlled trials were analyzed separately from quasi-experimental study designs. To mitigate heterogeneity within included studies, a random-effects meta-analysis was used for pooled outcomes. For those situations where meta-analysis was not possible, data on the effect of interventions from individual studies was tabulated and reported, and a narrative synthesis was conducted for each key intervention domain.Where there were a sufficient quantity of comparable studies (in both interventions and outcome), a summary of the intervention effect and a measure of quality for key outcomes were produced using the Grading of Recommendations Assessment, Development and Evaluation approach.18 The Grading of Recommendations Assessment, Development and Evaluation approach considers 5 domains (study limitations, consistency of effect, imprecision, indirectness, and publication bias) to assess the quality of the body of evidence for each outcome. The evidence was downgraded from “high quality” by 1 level for serious (or by 2 levels for very serious) limitations, depending on assessments for risk of bias, indirectness of evidence, serious inconsistency, imprecision of effect estimates, or potential publication bias.The aim of the authors of this supplement of reviews is to comprehensively assess the available evidence for the effectiveness of interventions to improve health and well-being in school-age children and adolescents. The initial literature-scoping and evidence-mapping process, followed by the different review approaches taken, has helped to maximize the scope covered across this set of reviews, and has allowed us to provide the most comprehensive assessment of the state of the published literature covering interventions for school-age children and adolescents. The individual reviews in this supplement have also highlighted child health domain-specific gaps in the evidence for both primary literature in the school-age group, and gaps in existing evidence syntheses.It is important to note that, for the reviews within this supplement, the descriptions of intervention effects are meant to provide an overview of what is currently known in terms of evidence for effectiveness, and do not imply that other interventions were ineffective simply because there was an evidence gap. Given the limited space and large scope, it was only possible to provide the highlights of specific comparisons and outcomes in each of the results sections. Comprehensive tables of study characteristics, outcomes, and effect estimates are provided in both the main articles and appendices.Although we were specifically interested in focusing on LMIC research, this was only feasible for a few review topics (eg, sexual and reproductive health and rights, neglected tropical diseases) because of a dearth of literature. Instead of being used to attempt to generalize their effectiveness to LMIC settings, evidence from intervention effectiveness in HIC settings are included and described to establish that effective interventions do indeed exist and may differ in their impact between settings. This approach has previously been used in the context of adolescent health interventions.19 This evidence from HIC could act as a starting point for future research and implementation in various LMIC settings, with program components tailored to local contexts.In the case of those reviews taking the overview of systematic reviews approach, we were limited to including only those primary studies already included in systematic reviews and could not cover each subdomain in depth. Thus, we were unable to identify and include those primary studies that may not have been included in systematic reviews because of studies not being identified in review authors’ database searches, not meeting their inclusion criteria, or falling out of the time frame of the review. Furthermore, some systematic reviews of primary literature were unable to perform meta-analyses because of high heterogeneity or a lack of high-quality evidence from randomized trials, which makes synthesizing the existing evidence more difficult.