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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]

Background: The MHC class I chain-related protein A (MICA) and protein B (MICB) participate in tumor immunosurveillance and may be important in colorectal cancer, but have not been examined in colorectal cancer development. Methods: sMICA and sMICB blood levels were measured by SomaScan in Visit 2 (1990-92, baseline) and Visit 3 (1993-95) samples in cancer-free participants in the Atherosclerosis Risk in Communities Study. We selected rs1051792, rs1063635, rs2516448, rs3763288, rs1131896, rs2596542, and rs2395029 that were located in or in the vicinity of MICA or MICB and were associated with cancer or autoimmune diseases in published studies. SNPs were genotyped by the Affymetrix Genome-Wide Human SNP Array. We applied linear and Cox proportional hazards regressions to examine the associations of preselected SNPs with sMICA and sMICB levels and colorectal cancer risk (236 colorectal cancers, 8,609 participants) and of sMICA and sMICB levels with colorectal cancer risk (312 colorectal cancers, 10,834 participants). In genetic analyses, estimates adjusted for ancestry markers were meta-analyzed. Results: Rs1051792-A, rs1063635-A, rs2516448-C, rs3763288-A, rs2596542-T, and rs2395029-G were significantly associated with decreased sMICA levels. Rs2395029-G, in the vicinity of MICA and MICB, was also associated with increased sMICB levels. Rs2596542-T was significantly associated with decreased colorectal cancer risk. Lower sMICA levels were associated with lower colorectal cancer risk in males (HR = 0.68; 95% confidence interval, 0.49-0.96) but not in females (Pinteraction = 0.08). Conclusions: Rs2596542-T associated with lower sMICA levels was associated with decreased colorectal cancer risk. Lower sMICA levels were associated with lower colorectal cancer risk in males. Impact: These findings support an importance of immunosurveillance in colorectal cancer. [ABSTRACT FROM AUTHOR]

The last ten years have witnessed a significant scale-up and access to antiretroviral therapy in Africa, which has improved patient quality of life and survival. One major challenge associated with increased access to antiretroviral therapy is the development of antiretroviral resistance due to inconsistent drug supply and/or poor patient adherence. We review the current state of both acquired and transmitted drug resistance in Africa over the past ten years (2001-2011) to identify drug resistance associated with the different drug regimens used on the continent and to help guide affordable strategies for drug resistance surveillance. A total of 161 references (153 articles, six reports and two conference abstracts) were reviewed. Antiretroviral resistance data was available for 40 of 53 African countries. A total of 5,541 adult patients from 99 studies in Africa were included in this analysis. The pooled prevalence of drug resistance mutations in Africa was 10.6%, and Central Africa had the highest prevalence of 54.9%. The highest prevalence of nucleoside reverse transcriptase inhibitor mutations was in the west (55.3%) and central (54.8%) areas; nonnucleoside reverse transcriptase inhibitor mutations were highest in East Africa (57.0%) and protease inhibitors mutations highest in Southern Africa (16.3%). The major nucleoside reverse transcriptase inhibitor mutation in all four African regions was M184V. Major nonnucleoside reverse transcriptase inhibitor as well as protease inhibitor mutations varied by region. The prevalence of drug resistance has remained low in several African countries although the emergence of drug resistance mutations varied across countries. Continued surveillance of antiretroviral therapy resistance remains crucial in gauging the effectiveness of country antiretroviral therapy programs and strategizing on effective and affordable strategies for successful treatment. [ABSTRACT FROM AUTHOR]

Background: Inflammation contributes to the onset of chronic kidney disease (CKD). Diet is a modifiable risk factor for CKD; however, it remains unknown if the inflammatory potential of the diet is prospectively associated with CKD risk in healthy individuals., Methods: In 9,814 participants (mean age: 60 years) free of CKD in the Atherosclerosis Risk in Communities (ARIC) Study at visit 3 (1993-1995), we developed a novel empirically-derived, food-based, dietary inflammatory score (Comprehensive Dietary Inflammation Index, CDII) from a random two-thirds sample (N=6,542, discovery) and validated in the remaining one-third sample (N=3,272, validation). Reduced rank regression with 13 inflammatory biomarkers as the response variables and 31 food groups as the independent variables was used to develop the CDII. Cox proportional hazards models were used to calculate hazard ratios (HRs) and 95% confidence intervals (CI%) and test the association between the CDII and incident CKD, adjusting for important confounders., Results: The CDII included eight food groups (four pro-inflammatory and four anti-inflammatory), with a higher score representing a more pro-inflammatory diet. In the validation sample, the CDII was positively correlated with most pro-inflammatory proteins (C-reactive protein, interferon-γ, interleukin-8, interleukin-6, and monocyte chemoattractant protein-1) and negatively correlated with adiponectin. However, the CDII was positively associated with one anti-inflammatory protein (transforming growth factor-β). Over a median-follow-up of 19 years (mean follow-up of 18 years), 3,293 participants developed CKD. A diet that was the most vs. least concordant with the CDII (quartile 4 vs. quartile 1) had 28% greater risk of incident CKD (HR: 1.28, 95% CI: 1.15, 1.43, P trend<0.001)., Conclusions: A novel diet score, representing its inflammatory potential, was associated with a higher risk of developing CKD. Reducing consumption of pro-inflammatory diet may be a strategy to prevent CKD., (Copyright © 2025 by the American Society of Nephrology.)