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ABSTRACTObjective:Recent studies have tried to find a reliable way of predicting the development of Alzheimer´s Disease (AD) among patients with mild cognitive impairment (MCI), often focusing on olfactory dysfunction or semantic memory. Our study aimed to validate these findings while also comparing the predictive accuracy of olfactory and semantic assessments for this purpose.Method: Six hundred fifty patients (median age 68, 58% females) including controls, SCD (subjective cognitive decline), non-amnestic MCI (naMCI), amnestic MCI (aMCI), and AD patients were tested for olfactory dysfunction by means of odor identification testing and semantic memory. Of those 650 patients, 120 participants with SCD, naMCI, or aMCI at baseline underwent a follow-up examination after two years on average. Of these 120 patients, 12% had developed AD at follow-up (converters), while 88% did not develop AD at follow-up (non-converters).Results: Analysis showed a significant difference only for initial olfactory identification between converters and non-converters. Sensitivity of impairment of olfactory identification for AD prediction was low at 46.2%, although specificity was high at 81.9%. Semantic memory impairment at baseline was not significantly related to AD conversion, although, when naming objects, significant differences were found between AD patients and all other groups and between naMCI and aMCI patients compared to controls and SCD patients.Conclusions: Objective olfactory assessments are promising instruments for predicting the conversion to AD among MCI patients. However, due to their low sensitivity and high specificity, a combination with other neuropsychological tests might lead to an improved predictive accuracy. Further longitudinal studies with more participants are required to investigate the usefulness of semantic memory tests in this case. [ABSTRACT FROM AUTHOR]

Measuring disease progression in clinical trials for testing novel treatments for multifaceted diseases as progressive supranuclear palsy (PSP), remains challenging. In this study we assess a range of statistical approaches to compare outcomes as measured by the items of the progressive supranuclear palsy rating scale (PSPRS). We consider several statistical approaches, including sum scores, a modified PSPRS rating scale that had been recommended by FDA in a pre-IND meeting, multivariate tests, and analysis approaches based on multiple comparisons of the individual items. In addition, we propose two novel approaches which measure disease status based on Item Response Theory models. We assess the performance of these tests under various scenarios in an extensive simulation study and illustrate their use with a re-analysis of the ABBV-8E12 clinical trial. Furthermore, we discuss the impact of the FDA-recommended scoring of item scores on the power of the statistical tests. We find that classical approaches as the PSPRS sum score demonstrate moderate to high power when treatment effects are consistent across the individual items. The tests based on Item Response Theory (IRT) models yield the highest power when the simulated data are generated from an IRT model. The multiple testing based approaches have a higher power in settings where the treatment effect is limited to certain domains or items. The study demonstrates that there is no one-size-fits-all testing procedure for evaluating treatment effects using PSPRS items; the optimal method varies based on the specific effect size patterns. The efficiency of the PSPRS sum score, while generally robust and straightforward to apply, varies depending on the specific patterns of effect sizes encountered and more powerful alternatives are available in specific settings. These findings can have important implications for the design of future clinical trials in PSP and similar multifaceted diseases., (© 2024. The Author(s).)

The closure principle is a powerful approach to constructing efficient testing procedures controlling the familywise error rate in the strong sense. For small numbers of hypotheses and the setting of independent elementary p -values we consider closed tests where each intersection hypothesis is tested with a p -value combination test. Examples of such combination tests are the Fisher combination test, the Stouffer test, the Omnibus test, the truncated test, or the Wilson test. Some of these tests, such as the Fisher combination, the Stouffer, or the Omnibus test, are not consonant and rejection of the global null hypothesis does not always lead to rejection of at least one elementary null hypothesis. We develop a general principle to uniformly improve closed tests based on p -value combination tests by modifying the rejection regions such that the new procedure becomes consonant. For the Fisher combination test and the Stouffer test, we show by simulations that this improvement can lead to a substantial increase in power., Competing Interests: Declaration of conflicting interestsThe authors declared no potential conflicts of interest with respect to the research, authorship and/or publication of this article.

RN Braun observed that frequencies of health disorders in general practice are so consistent that he called his discovery "Case Distribution Law". Our study compares morbidity data from methodologically similar surveys in primary care practices over a period of fifty years. Frequency ranks were determined for each observation period and the first 150 ranks were compared with Spearman's correlation coefficients. All correlations were consistently positive. Frequency ranks were strikingly similar for surveys carried out at approximately the same time, especially when nomenclatural matching had been carried out before data collection. Ranks were also very similar where clear disease classifications were possible, but less so for non-specific symptoms.The consistency of the distribution of health disorders helps develop diagnostic strategies (diagnostic protocols) and appropriate labeling for non-specific, diagnostically open symptom classifications. According to Braun's considerations, the regularity of case distribution plays an important role in the professionalization of primary care., (© 2024. The Author(s).)

Background: Asthma is increasingly recognized as heterogeneous, characterized by different endotypes, with obesity not only a distinct phenotype but a risk factor for severe asthma., Objective: We sought to understand the associations of obesity with relevant parameters of severe asthma, including asthma control, disease burden, and lung function., Methods: The German Asthma Net registry is a multicenter international real-life registry capturing long-term follow-up data. This analysis included 2213 patients (52 ± 16 years, 58% female, 29% with obesity [body mass index ≥30 kg/m 2 ], 4.2 ± 4.3 exacerbations/year). The primary analysis assessed relationships between BMI and variables through univariate tests, followed by a multiple regression model. Secondary outcomes regarded clinically relevant variables in relation to weight groups., Results: Patients with obesity were more frequently female, more likely to have depression and gastroesophageal reflux, and suffered from worse asthma control, lower quality of life, reduced static lung volumes, more pronounced hypoxemia, and higher blood neutrophil counts, all statistically significant. Blood eosinophils, exhaled nitric oxide, and total IgE were independent of obesity. In the multiple regression analysis, obesity was significantly associated with more frequent reflux and depression, reduced static lung function values, older age, poor asthma control, and long-acting muscarinic antagonist therapy, and inversely associated with bronchiectasis and nonsmoking status., Conclusion: In this large, well-characterized cohort, we identified the association of obesity with a significantly higher disease burden and a similar portfolio of inflammation type 2 markers in patients with and without obesity; therefore, patients with obesity seem similarly eligible for the treatment with biologics targeting these disease endotypes., (Copyright © 2023 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Purpose: To determine the diagnostic accuracy of preinterventional imaging modalities in patients being evaluated for iliocaval venous recanalization and stent placement., Methods: Consecutive patients with iliocaval postthrombotic obstructions or nonthrombotic iliac vein lesions (NIVL), who were scheduled for recanalization, underwent duplex ultrasound (DUS), magnetic resonance venography (MRV), multiplanar venography (MPV), and intravascular ultrasound (IVUS). The diagnostic accuracies of DUS, MRV, and MPV were analyzed using IVUS as reference., Results: A total of 216 limbs in 108 patients (80 patients with postthrombotic obstructions, 28 patients with NIVL) were examined. In patients with postthrombotic obstructions, the diagnostic sensitivities for the detection of lesions of the common femoral vein were 81% (95% CI 71-89%) for DUS, 76% (95% CI 65-85%) for MRV, and 86% (95% CI 76-93%) for MPV. The sensitivities for detecting lesions of the iliac veins were 96% (95% CI 89-99%) for DUS, 99% (95% CI 92-100%) for MRV, and 100% (95% CI 94-100%) for MPV. Regarding the inferior vena cava, the sensitivities were 44% (95% CI 24-65%) for DUS, 52% (95% CI 31-73%) for MRV, and 70% (95% CI 47-86%) for MPV. The sensitivities for detecting NIVL were 58% (95% CI 34-79%) for DUS, 90% (95% CI 68-97%) for MRV, and 95% (95% CI 73-99%) for MPV., Conclusion: In patients scheduled for recanalization of iliocaval postthrombotic obstructions, the sensitivities of DUS, MRV, and MPV were similar. In patients with suspected inferior vena cava involvement and in patients with NIVL, additional imaging with MR or conventional venography is required.

Background: Dynamic MELD deterioration (Delta MELD) during waiting time was shown to have significant impact on post-transplant survival. The aim of this study was to analyze the impact of MELD-Na score alterations on waiting list outcomes in liver transplant candidates., Method: 36,806 patients listed at UNOS for liver transplantation in 2011-2015 were analyzed according to their delisting reasons. Several different MELD-Na alterations during waiting time were analyzed (e.g., maximal change, last change before delisting/transplantation). Outcome estimates were calculated according to MELD-Na scores at listing and Delta MELD., Results: Patients who died while on the waiting list showed a significantly higher deterioration in MELD-Na during the waiting time (6.8 ± 8.4 points) than stable patients who remained actively listed (-0.1 ± 5.2 points; p < 0.01). Patients who were considered too healthy for transplantation improved by more than 3 points on average during the waiting time. The mean peak MELD-Na alteration during the waiting time was 10.0 ± 7.6 for patients who died on the waiting list, compared to 6.6 ± 6.1 in the group of patients who finally underwent transplantation., Conclusions: Deterioration of MELD-Na during waiting time and maximal MELD-Na deterioration have a significant negative impact on the liver transplant waiting list outcome.

Background and Objectives: Gender inequality in medicine remains an issue. Despite the increasing proportion of female physicians, women still appear underrepresented in interventional pulmonology (IP) careers. To date, no data are available on the gender distribution in IP., Method: An online survey was sent to pulmonary physicians internationally between July and December 2022. The survey included questions on gender diversity in the pulmonology departments, such as the proportion of male, female, and gender diverse physicians performing bronchoscopy, career progression, and social life., Results: Responses from 92 physicians (mean age 45 ± 10 years) from 47 hospitals across 17 countries were analysed, of whom 52% were women. Overall, 79% of the respondents were pulmonologists and 83% perform bronchoscopy. Although men continue to dominate bronchoscopy (65 vs. 43%) and are more likely to be involved in research (89 vs. 77%), the observed difference is statistically not significant (p = 0.135 and p = 0.281). Leading positions are held by 60% of male respondents and 23% of female respondents (p = 0.002). Men are also more often reported to have academic awards. Discrimination based on gender was reported by 5.3% of all men and 26.8% of all women (p = 0.023)., Conclusions: Men and women are almost equally involved in IP, especially in female-led bronchoscopy units. However, leading positions and academic awards are still predominantly held by men., (© 2023 S. Karger AG, Basel.)

When testing multiple hypotheses, a suitable error rate should be controlled even in exploratory trials. Conventional methods to control the False Discovery Rate assume that all p -values are available at the time point of test decision. In platform trials, however, treatment arms enter and leave the trial at different times during its conduct. Therefore, the actual number of treatments and hypothesis tests is not fixed in advance and hypotheses are not tested at once, but sequentially. Recently, for such a setting the concept of online control of the False Discovery Rate was introduced. We propose several heuristic variations of the LOND procedure (significance Levels based On Number of Discoveries) that incorporate interim analyses for platform trials, and study their online False Discovery Rate via simulations. To adjust for the interim looks spending functions are applied with O'Brien-Fleming or Pocock type group-sequential boundaries. The power depends on the prior distribution of effect sizes, for example, whether true alternatives are uniformly distributed over time or not. We consider the choice of design parameters for the LOND procedure to maximize the overall power and investigate the impact on the False Discovery Rate by including both concurrent and non-concurrent control data.