Peter Martus

A false-negative diagnosis of cancer can lead to a delay in effective treatment and a poorer prognosis. Here, we use the example of cutaneous melanoma to examine how many years of life are lost after a false-negative diagnosis compared to a primarily correct diagnosis. From 1996 to 2015, 9,063 patients are prospectively registered in the German Central Malignant Melanoma Registry and followed up until December 2023. A false-negative diagnosis is found in 206 (2.3%) patients. The median time to correct diagnosis is 24.0 months. The 10-year recurrence-free survival probabilities are 32.9% for false-negative diagnoses and 76.2% for correct diagnoses (p < 0.001). The 10-year melanoma-specific survival probabilities are 62.1% versus 85.0% (p < 0.001). On average, each person with an initial false-negative diagnosis loses 8.2 years of life compared to people with a correct diagnosis. This high number of years of life lost raises the question of whether similar results also apply to other types of cancer.

Background: Acute respiratory distress syndrome (ARDS) is characterized by severe inflammatory lung injury leading to life-threatening hypoxemia. Standard treatment includes lung-protective mechanical ventilation and adjunctive measures, while veno-venous extracorporeal membrane oxygenation (vvECMO) is used as a rescue therapy in refractory cases. However, the optimal timing for initiation of vvECMO remains uncertain, with official recommendations identifying it as a rescue therapy, while emerging evidence suggests that earlier implementation of vvECMO during the disease course might provide benefits. Objective: The ELIEO (Early vs Late Initiation of vvECMO) trial aims to determine whether early initiation of vvECMO improves survival and clinical outcomes compared with a conventional strategy in patients with severe ARDS. Methods: ELIEO is a prospective, randomized, multicenter clinical trial enrolling 508 adult patients with severe ARDS. Participants will be randomized to one of two groups: (1) early vvECMO initiation within 24 hours after admission to the intensive care unit of an extracorporeal membrane oxygenation center or (2) conventional management according to ARDS Network guidelines, with vvECMO used only as rescue therapy. All-cause mortality at day 90 will serve as the primary outcome and will be analyzed using a 2-sided log-rank test within an O’Brien-Fleming group-sequential design. Secondary end points include Sequential Organ Failure Assessment scores, functional status at days 28 and 90, bleeding events, and intensive care unit–related complications, which will be analyzed using appropriate regression and nonparametric methods, with adjusted Cox models for sensitivity analyses. Results: Patient recruitment started on March 1, 2025, and is ongoing; study completion is expected in August 2028. An interim analysis is planned after the 94th patient has been enrolled. The trial is designed to evaluate whether early initiation of vvECMO reduces 90-day mortality and improves organ function and functional recovery compared with a conventional rescue strategy. Results will be reported after completion of enrollment and follow-up. As of May 2026, a total of 9 patients have been recruited. Conclusions: The ELIEO trial will provide robust evidence regarding the optimal timing of vvECMO initiation in patients with severe ARDS. The findings may influence clinical decision-making, resource allocation, and organizational strategies for the management of ARDS in specialized intensive care settings. Trial Registration: ClinicalTrials.gov NCT04208126; https://clinicaltrials.gov/study/NCT04208126 International Registered Report Identifier (IRRID): DERR1-10.2196/86652

Leptomeningeal metastatic disease (LMD) of solid tumors represents a cancer stage with high unmet therapeutic need. Here we report results from the dose escalation part of a multicenter phase 1 trial investigating intraventricular nivolumab, now continuing in the expansion part. Eligible participants had LMD from tumors with an approval for intraveneous PD1/PDL1 therapy or high tumor mutational burden. The primary endpoint was safety across four dose levels (20, 30, 40 and 50 mg) with each cohort reviewed by an independent data safety monitoring board before escalation. The secondary endpoint was overall survival. Exploratory endpoints included participant-reported outcome measures. Of 30 enrolled participants, 24 received at least one dose (intention-to-treat population) and 18 completed predefined safety evaluations (per-protocol population). One dose-limiting toxicity occurred at 40 mg. The primary endpoint was met and the recommended fixed dose for the ongoing expansion part is 50 mg. Median overall survival (OS) was 6.6 months. The 6-month, 12-month and 18-month OS rates were 55.0% (95% confidence interval (CI): 37.5–80.6%), 33.3% (95% CI: 17.8–62.4%) and 16.7% (95% CI 6.03–46.1%), respectively. Participant-reported quality of life remained stable. Intraventricular nivolumab has demonstrated safety and feasibility (ClinicalTrials.gov: NCT05112549 ).

BACKGROUND Acute respiratory distress syndrome (ARDS) is characterized by severe inflammatory lung injury leading to life-threatening hypoxemia. Standard treatment includes lung-protective mechanical ventilation and adjunctive measures, while veno-venous extracorporeal membrane oxygenation (vvECMO) is used as a rescue therapy in refractory cases. However, the optimal timing for initiation of vvECMO remains uncertain, with official recommendations identifying it as a rescue therapy, while emerging evidence suggests that earlier implementation of vvECMO during the disease course might provide benefits. OBJECTIVE The ELIEO (Early vs Late Initiation of vvECMO) trial aims to determine whether early initiation of vvECMO improves survival and clinical outcomes compared with a conventional strategy in patients with severe ARDS. METHODS ELIEO is a prospective, randomized, multicenter clinical trial enrolling 508 adult patients with severe ARDS. Participants will be randomized to one of two groups: (1) early vvECMO initiation within 24 hours after admission to the intensive care unit of an extracorporeal membrane oxygenation center or (2) conventional management according to ARDS Network guidelines, with vvECMO used only as rescue therapy. All-cause mortality at day 90 will serve as the primary outcome and will be analyzed using a 2-sided log-rank test within an O’Brien-Fleming group-sequential design. Secondary end points include Sequential Organ Failure Assessment scores, functional status at days 28 and 90, bleeding events, and intensive care unit–related complications, which will be analyzed using appropriate regression and nonparametric methods, with adjusted Cox models for sensitivity analyses. RESULTS Patient recruitment started on March 1, 2025, and is ongoing; study completion is expected in August 2028. An interim analysis is planned after the 94th patient has been enrolled. The trial is designed to evaluate whether early initiation of vvECMO reduces 90-day mortality and improves organ function and functional recovery compared with a conventional rescue strategy. Results will be reported after completion of enrollment and follow-up. As of May 2026, a total of 9 patients have been recruited. CONCLUSIONS The ELIEO trial will provide robust evidence regarding the optimal timing of vvECMO initiation in patients with severe ARDS. The findings may influence clinical decision-making, resource allocation, and organizational strategies for the management of ARDS in specialized intensive care settings. CLINICALTRIAL ClinicalTrials.gov NCT04208126; https://clinicaltrials.gov/study/NCT04208126 INTERNATIONAL REGISTERED REPORT DERR1-10.2196/86652

Background: About 1 in 2 patients with knee osteoarthritis (OA) receives a referral or recommendation for exercise. Digital health applications could counteract this undersupply. Objective: We aimed to investigate the effectiveness of a 12-week self-directed mobile health exercise intervention (re.flex) when used in addition to usual care compared to a control group receiving usual care only on pain reduction and improvement in physical function in patients with knee OA. Methods: This monocentric, 2-arm, randomized controlled parallel-group trial included patients from Germany with moderate to severe knee OA. Participants were mainly recruited via newspapers. Randomization was 1:1 into an intervention group (re.flex+usual care) and a control group (usual care) using computer-generated blocks. Participants were unmasked to group assignment. The re.flex group conducted a 12-week self-directed app-based and sensor-assisted exercise program with 3 sessions per week in addition to usual care. Primary outcomes were OA-specific knee pain and physical function (using the subscales pain and activities in daily living of the Knee Osteoarthritis Outcome Score, 0‐100) at 3 months. Secondary outcomes included adherence and safety. Multiple imputation was used to account for missing data. Intervention effects were calculated using a baseline-adjusted analyses of covariance (ANCOVA). Bonferroni correction with an alpha level of .025 was applied. Results: Between January 25, 2023, and August 11, 2023, a total of 195 participants were enrolled. Of them, 98 participants were allocated to re.flex, and 97 participants to usual care. The primary analysis included 194 participants. The mean age was 61.9 (SD 7.7) years, and the majority were female (132/194, 68%). Pain reduction was significantly larger in re.flex than in usual care, with an adjusted mean difference between study groups of 4.8 (95% CI 0.7-8.9; P=.02; Cohen d=0.35) points. Improvement in physical function was not statistically significant (beta coefficient [β]=3.9 points, 95% CI 0.0-7.9, P=.049). A total of 12 adverse events were linked to re.flex, none of which were serious. Participants adhered to 77% (2705/3528) of all scheduled exercise sessions. Conclusions: The self-directed sensor-based mobile health exercise intervention re.flex demonstrates superiority over usual care for pain reduction and justifies this kind of intervention as an alternative exercise delivery mode for patients with knee OA.

Background: The increasing prevalence of dermatological diseases will pose a growing challenge to the health care system and, in particular, to general practitioners (GPs) as the first point of contact for these patients. In many countries, primary care physicians are supported by teledermatology services. Objective: The aim of this study was to detect learning effects and gains among GPs through teledermatology consultations (TCs) in daily practice. Methods: As part of a mixed methods study embedded in a cluster-randomized controlled trial (TeleDerm), a full survey and semiguided face-to-face interviews were conducted among GPs of participating intervention practices using the telemedicine approach. A TC assessment tool (TC-AT) was developed to evaluate the quality of clinical data and images of TCs conducted during the run-in and intervention phases, with a score ranging from 0 (lowest quality) to 10 (highest quality). Mixed methods analysis triangulated qualitative content analysis, survey data with a growth curve model calculated from TC-AT data, comparing subjective experiences of GPs with objective process data. Results: A total of 487 TCs of 33 practices were analyzed. Questionnaires from n=46 GPs (practice-level response rate: 69.9%) were included in the quantitative analysis. Two-thirds of the GPs (n=31; 67.4%) in the written survey rated the TCs as helpful for differential diagnosis and treatment management. Improved self-reported confidence in diagnosing skin diseases due to the timely clinical feedback from dermatologists was reported by more than half of the responding GPs (n=25; 54.3%). In the interviews (n=13), teleconsultations were mainly seen as a learning opportunity by the GPs. Regarding the quality of TCs, a mean TC-AT score of 7.4 (SD 1.7, range 0‐10) was observed. In the growth curve model, a simple linear time trend provided the best fit to the TC-AT score trajectory across the observed study period. A significant time * TC-AT start score interaction was found (F₄₅₂=30.66, P<.001). While regardless of the initial TC-AT score, repeated TCs lead to process quality improvements over time, post hoc probing of the TC-AT start score as a moderator of the learning effect over time revealed the highest improvements among GP practices with a lower initial TC-AT score (−1 SD: standardized slope=0.59, P<.001; mean: standardized slope=0.38, P<.001; +1 SD: standardized slope=0.18, P<.001). Conclusions: TCs have been shown to be an effective method of education for GPs in terms of “learning on the job” in daily practice. The telemedicine approach seems to be an easily implementable and effective tool to support continuing medical education in the field of dermatology. Strategies could be developed to train GPs and medical students in the use of TC to adequately prepare them for the increasing technological demands of their future profession in primary care.

Febrile seizures are the most common seizure disorder in children. Fever-induced hyperventilation and subsequent hypocapnia may precipitate febrile seizures. In preclinical studies and in individual children, increasing CO ₂ partial pressure has shown potential to terminate febrile seizures. We hypothesized that the use of carbogen (5 % CO ₂ plus 95 % oxygen) in the home environment would be an effective and safe treatment for recurrent febrile seizures. The CARDIF (CARbon DIoxide against Febrile seizures) trial is a randomized, monocentric, prospective, double-blind, placebo-controlled, crossover study to determine whether short-term inhalation of carbogen in the home environment can stop febrile seizures. 100 % oxygen was used as a placebo control. We included children aged 0.5 to 5.0 years who presented after a first febrile seizure in the absence of severe organ or neurological disease, pathological EEG, or afebrile seizures. We recorded parent-reported seizure duration, benzodiazepine use, and any serious adverse events. We enrolled n = 93 patients. In n = 20 children, at least one recurrent febrile seizure was treated with either carbogen or oxygen . Six of these children received both carbogen and oxygen in a planned crossover design. The febrile seizure was terminated in 5/15 children on carbogen and in 8/11 children on oxygen (chi-squared, p = 0.112). Children with ≥2 recurrent febrile seizures completed the cross-over arm. In these children, febrile seizures stopped during carbogen administration in 3/6 cases and during oxygen administration in 5/6 cases (chi-squared, p = 0.221). In conclusion, Carbogen did not interrupt acute febrile seizures significantly more often than placebo. Home caregivers had difficulty determining when a seizure had stopped. Clinical Trial Registration: ClinicalTrials.gov identifier NCT01370044 , EudraCT 2011-001403-12

The Job Content Questionnaire JCQ 2.0 (JCQ 2.0) thoroughly revises the well-known JCQ 1, based on an expanded Demand/Control theory-consistent platform with new scales, the Associationalist Demand Control (ADC) theory. This study tests the JCQ 2.0 in an urban population in Germany (N = 2326) for concurrent validity of each specific task and organizational-level scale and the relative importance of the task and organizational-level scales, using burnout and commitment as outcome measures. Cross-sectional regression analyses in the test and validation samples were run after multiple imputation. Five JCQ 2.0 task-level scales explain 44% of burnout variance; three JCQ 2.0 task-level scales explain 25% of commitment variance. Adding organizational-level scales, organizational disorder and rewards, increases the explained variance for burnout by five percentage points; consideration of workers’ interests and reward add four percentage points of variance for commitment. Organizational-level scales alone explain 33% and 28% of the variance in burnout and commitment, respectively, due to three and five organizational-level scales for both outcomes. Thus, the JCQ 2.0 task and organizational-level scales show substantial relations to work- and health-related outcomes, with task level more relevant for burnout and organizational level more relevant for commitment. The most strongly related JCQ 2.0 scales have evolved from new ADC theory, confirming its utility.

: Achieving universal access to affordable medicines and at the same time ensuring the quality of medicines presents a challenge, especially in low- and middle-income countries. Here, the relationship between medicine prices and medicine quality was investigated in three African countries. From different types of health facilities and medicine vendors, 711 samples of 18 different essential medicines were purchased and analyzed for quality (assay and dissolution) according to the United States Pharmacopeia. Without exception, all originator brand medicines and all SRA generics (generic medicines manufactured in countries with stringent regulatory authorities [SRAs]) complied with pharmacopeial specifications. In contrast, 21.1% of the non-SRA generics (manufactured in countries without SRAs) were substandard. The median prices of originator brands and SRA generics were three times and two times higher than those of non-SRA generics, respectively. Within the non-SRA generics, no positive correlation was observed between medicine quality and medicine price. Medicines manufactured in India, China, or African countries showed similar quality and similar prices. Only a single WHO-prequalified medicine sample was found among the 711 samples. Non-SRA generic medicines produced by manufacturers for which WHO had published Public Inspection Reports showed a significantly lower rate of substandard medicines (7.3%) and, at the same time, significantly lower prices (by 33%) than other non-SRA generics. Falsified medicines (total 2.0%) were found among all categories of medicines and had prices similar to those of non-SRA generics. Our findings indicate that adequate quality assurance does not necessarily imply an increase in medicine prices.

Before revascularization, moyamoya patients require hemodynamic evaluation. In this study, we evaluated the scoring system Prior Infarcts, Reactivity and Angiography in Moyamoya Disease (PIRAMID). We also devised a new scoring system, MRI-Based Assessment of Risk for Stroke in Moyamoya Angiopathy (MARS-MMA), and compared the scoring systems with respect to the capability to predict impaired [¹⁵O]water PET cerebral perfusion reserve capacity (CPR). We evaluated 69 MRI, 69 DSA and 38 [¹⁵O]water PET data sets. The PIRAMID system was validated by ROC curve analysis with neurological symptomatology as a dependent variable. The components of the MARS-MMA system and their weightings were determined by binary logistic regression analysis. The comparison of PIRAMID and MARS-MMA was performed by ROC curve analysis. The PIRAMID score correlated well with the symptomatology (AUC = 0.784). The MARS-MMA system, including impaired breath-hold-fMRI, the presence of the Ivy sign and arterial wall contrast enhancement, correlated slightly better with CPR impairment than the PIRAMID system (AUC = 0.859 vs. 0.827, Akaike information criterion 140 vs. 146). For simplified clinical use, we determined three MARS-MMA grades without loss of diagnostic performance (AUC = 0.855). The entirely MRI-based MARS-MMA scoring system might be a promising tool to predict the risk of stroke.