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Natural history studies (NHS) can support regulatory decision-making at different stages of the drug product life cycle and are especially important in the context of rare diseases, which are associated with not only delayed or erroneous diagnoses but also a lack of approved treatments. Real-world evidence can fill knowledge gaps and support treatment decision-making, thereby benefiting affected patients. In this context, there are three important options for NHS design: retrospective, prospective, and cross-sectional. Each of these has been successfully used to support regulatory approval as external comparator arms (ECAs) for clinical studies, especially single-arm trials (SATs). While longitudinal data obtained from retrospective or prospective designs have been more commonly used and have been the focus of regulatory guidance documents, hybrid designs that combine retrospective and prospective data collection are particularly powerful for rare disease studies. This is due, in part, to the smaller number of patients impacted by each rare disease. In these settings, retrospective or prospective data collection alone may not be sufficient or fit-for-purpose for an external comparator. Rather, a strategic combination of all available data, regardless of timing, can deliver the right information of the desired quality and completeness to answer these important questions and support regulatory evidentiary needs. For instance, patients included in retrospective studies may differ from recently treated patients in terms of disease severity, disease variants, clinical management, or other important aspects of the disease that may impact patient outcomes. Further, retrospectively collected data may lack specific data elements required to achieve adequate comparison with the treated group in single-arm studies. In the context of prospective designs, the recruitment of sufficient new patients for prospective follow-up may not be feasible or may be prolonged due to the rarity of the disease. Further, the potential for premature truncation of patient follow-up may result in insufficient longitudinal data, or prospectively collected data alone may not provide insights into the disease course for specific groups of patients. In these situations, primary data collection in a prospective study may be supplemented with retrospectively collected data from chart reviews, registries, or electronic medical record databases, either for the same patients, in an ambispective design, or for a different set of patients. These hybrid designs allow for broader and more robust contextual information on the patient journey and the natural course of the disease to be obtained, which can improve the suitability of the data as an external comparator for SATs or studies that lack internal control in situations where a prospective design alone might not be sufficient. Because retrospective and prospective data, or any two data sources that are being combined, may differ in availability and quality, there are unique challenges alongside the strengths of these designs. In this paper, we discuss considerations for the design, analysis, and conduct of hybrid NHS intended as ECAs for single-arm studies in clinical development programs for rare diseases. [ABSTRACT FROM AUTHOR]

We examined the association between low‐calorie sweeteners (LCS) consumption during preconception, pregnancy, and breastfeeding and child health outcomes. A systematic search of electronic databases in PubMed, Embase, Cumulated Index to Nursing and Allied Health Literature, the Cochrane Library, Scopus, Web of Science, PsycINFO, ProQuest Health and Medical, ClinicalTrials.gov, and Google Scholar was conducted up to 21 September 2023. A random effects model with restricted maximum likelihood estimation was used for the meta‐analysis. Seventeen eligible studies were included. The standardised mean difference (SMD) and 95% confidence interval (CI) in birth weight between those who frequently consumed LCS (≥1 serve/day) during pregnancy and those who did not consume LCS was 0.04 (0.00, 0.08) (four cohort studies). Any LCS consumption during pregnancy compared with no consumption was not associated with birth weight [SMD (95% CI) = 0.03 (−0.03, 0.08)] (four cohort studies). Any LCS consumption during pregnancy was not associated with body mass index z‐scores. The weighted mean difference (95% CI) was 0.00 (−0.05, 0.06) at birth, 0.06 (−0.29, 0.40) at 6 months, −0.04 (−0.19, 0.10) at 1 year, 0.00 (−0.16, 0.17) at 3 years, and 0.10 (−0.15, 0.34) at 7 years of the child age, compared with no intake (five cohort studies). The odds of being overweight at 1 year among children exposed to LCS during pregnancy was 1.19 (OR [95% CI]: 1.19 [0.81, 1.58]) compared with unexposed children (two cohort studies). The effect sizes were not precise for all the outcomes as the 95% CI indicated the effect estimates could range from small protective to a higher risk. The effect of LCS consumption on child behaviour and cognition was inconsistent. There is not enough evidence to confirm LCS consumption during pregnancy affects birth weight and risk of overweight in children. However, frequent consumption increased birth weight and the risk of overweight at different ages, though the effects were imprecise. More robust research evidence is required as the quality of evidence is low. Key messages: Evidence regarding the effect of perinatal low‐calorie sweeteners (LCS) consumption and child health is limited and inconclusive.Our systematic review and meta‐analysis showed that any LCS consumption during pregnancy was not associated with birth weight and the risk of overweight in childhood. However, frequent LCS consumption during pregnancy was associated with a small but imprecise increase in birth weight and body mass index z‐score at different ages.Evidence regarding the effect of maternal LCS consumption on child behaviour, cognition, and the risk of other chronic disease is limited.The overall quality of the evidence remains low, warranting further high‐quality research. [ABSTRACT FROM AUTHOR]

Objective: A two-part meta-analysis of studies examining the relationship of vitamin A supplementation and child mortality.Data Sources: We identified studies by searching the MEDLARS database from 1966 through 1992 and by scanning Current Contents and bibliographies of pertinent articles.Study Selection: All 12 vitamin A controlled trials with data on mortality identified in the search were used in the analysis.Data Extraction: Data were independently extracted by two investigators who also assessed the quality of each study using a previously described method.Data Synthesis: We formally tested for heterogeneity across studies. We pooled studies using the Mantel-Haenszel and the DerSimonian and Laird methods and adjusted for the effect of cluster assignment of treatment groups in community-based studies. Vitamin A supplementation to hospitalized measles patients was highly protective against mortality (DerSimonian and Laird odds ratio, 0.39; 95% confidence interval, 0.22 to 0.66; P = .0004) (part 1 of the meta-analysis). Supplementation was also protective against overall mortality in community-based studies (DerSimonian and Laird odds ratio, 0.70; clustering-adjusted 95% confidence interval, 0.56 to 0.87; P = .001) (part 2 of the meta-analysis).Conclusions: Vitamin A supplements are associated with a significant reduction in mortality when given periodically to children at the community level. Factors that affect the bioavailability of large doses of Vitamin A need to be studied further. Vitamin A supplements should be given to all measles patients in developing countries whether or not they have symptoms of vitamin A deficiency. [ABSTRACT FROM AUTHOR]

We performed a meta-analysis of 25 randomized control trials that compared endoscopic hemostasis with standard therapy for bleeding peptic ulcer. For recurrent or continued bleeding, the mean rate in control patients was 0.39, and the pooled rate difference, or reduction due to therapy, was 0.27 +/- 0.15 (95% confidence interval) (69% relative reduction). For emergency surgery, the mean rate in control patients was 0.26, and the pooled rate difference was 0.16 +/- 0.05 (62% relative reduction). Most important, for overall mortality, the mean rate in control patients was 0.10, and the pooled rate difference was 0.03 +/- 0.02 (30% relative reduction). The effects were greatest in patients with spurting or visible blood vessels and equivocal when the ulcer showed only signs of recent bleeding. We conclude that endoscopic hemostasis is clearly effective but that data were insufficient for direct comparisons between modalities. Randomized control trials to compare the different modes of endoscopic therapy should continue. [ABSTRACT FROM AUTHOR]

Background: Dietary protein has long been thought to play a role in the progression of chronic renal disease, but clinical trials to date have not consistently shown that dietary protein restriction is beneficial.Purpose: To use meta-analysis to assess the efficacy of dietary protein restriction in previously published studies of diabetic and nondiabetic renal diseases, including the recently completed Modification of Diet in Renal Disease Study.Data Sources: The English-language medical literature published from January 1966 through December 1994 was searched for studies examining the effect of low-protein diets in humans with chronic renal disease. A total of 1413 patients in five studies on nondiabetic renal disease (mean length of follow-up, 18 to 36 months) and 108 patients in five studies of type I diabetes mellitus (mean length of follow-up, 9 to 35 months) were included.Study Selection: Randomized, controlled studies were selected for nondiabetic renal disease; randomized, controlled studies or time-controlled studies with nonrandomized crossover design were selected for diabetic nephropathy.Data Extraction: Data in tables, figures, or text were independently extracted by two of the authors.Data Synthesis: The relative risk for progression of renal disease in patients receiving a low-protein diet compared with patients receiving a usual-protein diet was calculated by using a random-effects model. In five studies of nondiabetic renal disease, a low-protein diet significantly reduced the risk for renal failure or death (relative risk, 0.67 [95% Cl, 0.50 to 0.89]). In five studies of insulin-dependent diabetes mellitus, a low-protein diet significantly slowed the increase in urinary albumin level or the decline in glomerular filtration rate or creatinine clearance (relative risk, 0.56 [Cl, 0.40 to 0.77]). Tests for heterogeneity showed no significant differences in relative risk among studies of either diabetic or nondiabetic renal disease. No significant differences were seen between diet groups in pooled mean arterial blood pressure (diabetic and nondiabetic patients) or glycosylated hemoglobin level (diabetic patients only).Conclusion: Dietary protein restriction effectively slows the progression of both diabetic and nondiabetic renal diseases. [ABSTRACT FROM AUTHOR]

Purpose: A meta-analysis of the effect of antihypertensive drug treatment on mortality and morbidity in elderly patients.Data Sources: A literature search of published articles from January 1980 to February 1992.Study Selection: Randomized controlled trials of drug treatment of hypertension with end points for elderly patients reported separately.Data Extraction: Mortality or morbidity end points or both in patients older than 59 years were pooled by determination of typical odds ratio. A meta-regression was used to study heterogeneity.Results: Nine major trials with 15,559 patients older than 59 years were identified. Death rates in the control group varied between 2.7% and 77.2%; stroke and coronary mortality increased with the severity-of-illness rank (P < 0.001). Overall, treated patients had an approximately 12% reduction in all-cause mortality (odds ratio, 0.88; 95% CI, 0.80 to 0.97; 953 events compared with 1069 events, P = 0.009). There was a 36% reduction in stroke mortality (odds ratio, 0.64; CI, 0.49 to 0.82; 94 events compared with 149 events, P < 0.001) and a 25% reduction in coronary heart disease mortality (odds ratio, 0.75; CI, 0.64 to 0.88; 263 events compared with 350 events, P < 0.001). Coronary morbidity was reduced 15% (odds ratio, 0.85; CI, 0.73 to 0.99; 325 events compared with 379 events, P = 0.036), and stroke morbidity was reduced 35% (odds ratio, 0.65; CI, 0.55 to 0.76; 247 events compared with 382 events, P < 0.001).Conclusion: Overall, treatment of hypertension in elderly patients produces a significant benefit in total mortality and cardiovascular morbidity and mortality. However, this benefit may be reduced in the oldest age groups. [ABSTRACT FROM AUTHOR]

Objectives: To introduce guidelines for the conduct, reporting, and critical appraisal of meta-analyses evaluating diagnostic tests and to apply these guidelines to recently published meta-analyses of diagnostic tests.Data Sources: Based on current concepts of how to assess diagnostic tests and conduct meta-analyses. They are applied to all meta-analyses evaluating diagnostic tests published in English-language journals from January 1990 through December 1991, identified through MEDLINE searching and by experts in the field.Study Selection: Meta-analyses were included if at least two of three independent readers regarded their main purpose as the evaluation of diagnostic tests against a concurrent reference standard.Data Extraction: By three independent readers on the extent to which meta-analyses fulfilled each guideline, with consensus defined as agreement by at least two readers.Data Synthesis: The guidelines are concerned with determining the objective of the meta-analysis, identifying the relevant literature and extracting the data, estimating diagnostic accuracy, and identifying the extent to which variability is explained by study design characteristics and characteristics of the patients and diagnostic test. In general, the guidelines were only partially fulfilled.Conclusion: Meta-analysis is potentially important in the assessment of diagnostic tests. Those reading meta-analyses evaluating diagnostic tests should critically appraise them; those doing meta-analyses should apply recently developed methods. The conduct and reporting of primary studies on which meta-analyses are based require improvement. [ABSTRACT FROM AUTHOR]

Objective: To examine the temporal relationship between accumulating data from randomized control trials of treatments for myocardial infarction and the recommendations of clinical experts writing review articles and textbook chapters.Data Sources: (1) MEDLINE search from 1966 to present; search terms used were myocardial infarction, clinical trials, multicenter studies, double-blind method, meta-analysis, and the text word "random:"; (2) references from pertinent articles and books; and (3) all editions of English-language general medical texts and manuals and review articles on treatment of myocardial infarction.Study Selection: Randomized control trials of therapies for reducing the risk of total mortality in myocardial infarction (acute and secondary prevention). Review articles and textbook chapters dealing with the general clinical management of patients with myocardial infarction.Data Extraction: Two authors read the material and recorded the results; disagreements were resolved by conference.Data Synthesis: We used the technique of cumulative meta-analysis (performing a new meta-analysis when the results of a new clinical trial are published) and compared the results with the recommendations of the experts for various treatments for myocardial infarction. Discrepancies were detected between the meta-analytic patterns of effectiveness in the randomized trials and the recommendations of reviewers. Review articles often failed to mention important advances or exhibited delays in recommending effective preventive measures. In some cases, treatments that have no effect on mortality or are potentially harmful continued to be recommended by several clinical experts.Conclusions: Finding and analyzing all therapeutic trials in a given field has become such a difficult and specialized task that the clinical experts called on to summarize the evidence in a timely fashion need access to better databases and new statistical techniques to assist them in this important task. [ABSTRACT FROM AUTHOR]

Substantial numbers of clinical trials continue to be reported only in summary reports that present insufficient methodological details to permit informed judgments about the likely validity of the conclusions. Using a cohort of 176 controlled trials reported in summary form, we tested the hypotheses that they would be more likely to be followed by full reports if, on the basis of the information provided in the summary report, (1) the trial was judged to be methodologically sound, (2) the results favored the test treatment, and (3) the sample size was relatively large. The results of univariate and multivariate analyses provided support for only the third of these hypotheses. Investigators, as well as those who fund and sanction the conduct of clinical research, should make greater efforts to ensure that clinical trials are reported properly. [ABSTRACT FROM AUTHOR]

Objective: To evaluate the results of large clinical trials vs the pooled results of smaller trials.Data Identification: Meta-analyses with at least 1 "large" study were identified from the Cochrane Pregnancy and Childbirth Database and from MEDLINE (1966-1995).Study Selection: We used a sample size approach to select 79 meta-analyses with at least 1 large study of 1000 or more patients. We used a statistical power approach to select 61 meta-analyses with at least 1 large study based on statistical power considerations.Data Extraction: The outcome of interest for each meta-analysis was the primary one stated in the original publication or, when not clearly specified, was decided on clinically.Data Synthesis: By random effects calculations, we found agreement between large and smaller trials in 90% of the meta-analyses selected by the sample size approach and in 82% of the meta-analyses selected by the statistical power approach. Twice as many disagreements appeared when the variability among large studies and among smaller studies was not considered (ie, fixed effects calculations). Of the 15 disagreements between results of large and smaller trials using the random effects model, plausible explanations were identified in 10 meta-analyses: 5 with differences in the control rate of events between large and smaller trials, 4 with specific protocol or study differences, and 1 with potential publication bias. Two other disagreements were not clinically important, and tentative reasons could be identified for 2 of the remaining 3 disagreements.Conclusions: Results of smaller studies are usually compatible with the results of large studies, but discrepancies do occur even when the diversity among both large studies and smaller studies is considered. Clinically important differences without a potential explanation are extremely uncommon. Future research should further examine sources of heterogeneity between the results of large and smaller trials. [ABSTRACT FROM AUTHOR]

Objectives: To determine the relationship between the quality of articles and whether they were published in a supplement or in the parent journal.Data Sources and Study Selection: All randomized control trials of drug therapies in adults published in the American Journal of Cardiology, the American Journal of Medicine and the American Heart Journal from January 1990 and obtained in November 1992 by means of a MEDLINE search. A total of 318 abstracts appeared to meet our inclusion criteria, and these articles were obtained and reviewed in further detail. An additional 76 were excluded.Data Extraction: Three reviewers who were "blinded" and thus unaware of supplement status independently assessed the quality of each of the remaining 242 articles according to a standard quality scoring system.Data Synthesis: Overall, 67 (27.7%) of the articles were published in journal supplements. Article quality scores ranged from 4.2% to 87.5%, with a mean (+/- SD) score of 37.2% +/- 13.1%. Quality scores were lower in articles published in journal supplements than in those published in the parent journal (t[240] = 2.61, P = .01). The mean quality score for articles published in journal supplements was 33.6% +/- 12.8% compared with a score of 38.5% +/- 13.1% for articles published in the parent journal. Supplement articles included in their final analysis a smaller proportion of the patients initially randomized (t[75] = 2.8, P = .007).Conclusion: Our findings suggest that randomized control trials published in journal supplements are generally of inferior quality compared with articles published in the parent journal. The review process surrounding the publication of journal supplements should be consistent with that of the parent journal. [ABSTRACT FROM AUTHOR]

The growing body of research on geotourism and geoheritage presents an opportunity to explore the applied strategies for achieving the sustainable development goals (SDGs). Geoheritage and geotourism have emerged as concepts that can contribute to these goals by promoting responsible tourism, conservation, and community development. This systematic review critically examines the interrelationships between "geoheritage" and "geotourism" approaches in relation to their integration with the SDGs and broader sustainability considerations within the scholarly domain. A total of 205 research articles, collected from the Scopus database over an 18-year period (2005 to October 2023) were initially identified. Following a comprehensive analysis, 40 articles were found to fully meet the objectives of the systematic literature review and were subsequently included in the main study. Utilizing a meticulous framework based on the PRISMA guidelines, this study scrutinizes and synthesizes these 40 peer-reviewed research articles. It explores the dynamics between geoheritage, geotourism, and their implications for advancing sustainability goals inherent in the SDGs across different landscapes. VOSviewer software was employed for various citation-related network analyses. The discussion features successful case studies in complex topographies such as volcanic regions, mining sites, and deserts that highlight practical strategies for promoting sustainability as suggested in the reviewed articles, while also revealing a notable gap in effective applied strategies. The findings showthat the prevailing trend favors inventory-centric investigations, primarily emphasizing quantitative analyses of the geosites. This focus limits the applied policies of geotourism and geoheritage for local communities and regions. The insights derived from this review serve as valuable guidance for both academic and non-academic stakeholders in formulating tactics that underscore the region's untapped geotouristic potential. Furthermore, the review's outcomes hold promise for contributing to the objectives of the Global Geopark Network, particularly in the area of sharing "geopark-related knowledge.". [ABSTRACT FROM AUTHOR]

In 1977, Michael Lipton introduced the Urban Bias Thesis as a framework for understanding how most economic policy initiatives have contributed to the overdevelopment of urban areas and the underdevelopment of rural areas. In Latin America, there has historically been a positive correlation between urbanization and mortality decline, as the region's health transition generally began in the main cities and tended to proceed more rapidly in countries with higher levels of urbanization. This paper seeks evidence of a residual urban bias in the region's mortality patterns. Using a sample of Latin American countries over the 2000–2010 period, I analyse the disparities in mortality patterns and avoidable causes of death by looking closely at urban and rural areas using continuum categories. The results indicate that the urban advantage does persist and that rural–urban mortality differentials have consistently favoured the largest cities. The metropolitan advantage in mortality is an outcome of lower mortality in causes of death that are avoidable through primary interventions. Even in scenarios of high mortality at younger adult ages (15–44), the metropolitan advantage remains, due primarily to unsuccessful efforts to reduce mortality in populations aged 45 years and over outside the main and large cities. [ABSTRACT FROM AUTHOR]