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Colorectal cancer (CRC) is the second most common cause of all cancer deaths in Europe and the Western world with a lifetime risk of approximately 5%. Despite several improvements in the treatment of patients with unresectable CRC prognosis is poor and there is the need of developing new treatment strategies for patients with metastatic chemorefractory disease. The S100 calcium binding protein A4 (S100A4) predicts metastasis formation and reduced CRC patient survival. S100A4 was previously identified as transcriptional target of the Wnt/β-catenin signaling pathway. The Food and Drug Administration (FDA)-approved anti-helminthic drug niclosamide is known to intervene in the Wnt/β-catenin pathway signaling, leading to reduced expression of S100A4 linked to restricted in vivo metastasis formation. Thus, we aim at translation of our findings on restricting S100A4-driven metastasis into clinical practice for treating metastasized CRC patients progressing after standard therapy.BACKGROUNDColorectal cancer (CRC) is the second most common cause of all cancer deaths in Europe and the Western world with a lifetime risk of approximately 5%. Despite several improvements in the treatment of patients with unresectable CRC prognosis is poor and there is the need of developing new treatment strategies for patients with metastatic chemorefractory disease. The S100 calcium binding protein A4 (S100A4) predicts metastasis formation and reduced CRC patient survival. S100A4 was previously identified as transcriptional target of the Wnt/β-catenin signaling pathway. The Food and Drug Administration (FDA)-approved anti-helminthic drug niclosamide is known to intervene in the Wnt/β-catenin pathway signaling, leading to reduced expression of S100A4 linked to restricted in vivo metastasis formation. Thus, we aim at translation of our findings on restricting S100A4-driven metastasis into clinical practice for treating metastasized CRC patients progressing after standard therapy.NIKOLO is a phase II, single center, one-arm open-label clinical trial to investigate the safety and efficacy of niclosamide tablets in patients with metastasized CRC progressing under standard therapy. Eligible patients will receive 2 g of orally applied niclosamide once a day and will continue with the treatment once daily till disease progression or toxicity. Toxicities will be graded according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v4.03. The primary objective of this trial is to assess the progression free survival after 4 months, secondary objectives are overall survival, time to progression, disease control rate (remission + partial remission + stable disease), and safety. Furthermore, pharmacokinetic analysis will be conducted to evaluate niclosamide plasma concentration.METHODS/DESIGNNIKOLO is a phase II, single center, one-arm open-label clinical trial to investigate the safety and efficacy of niclosamide tablets in patients with metastasized CRC progressing under standard therapy. Eligible patients will receive 2 g of orally applied niclosamide once a day and will continue with the treatment once daily till disease progression or toxicity. Toxicities will be graded according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v4.03. The primary objective of this trial is to assess the progression free survival after 4 months, secondary objectives are overall survival, time to progression, disease control rate (remission + partial remission + stable disease), and safety. Furthermore, pharmacokinetic analysis will be conducted to evaluate niclosamide plasma concentration.This study is expected to provide evidence of the feasibility, toxicity and efficacy of niclosamide in the treatment of patients with metastasized CRC and could help to establish a new treatment option.DISCUSSIONThis study is expected to provide evidence of the feasibility, toxicity and efficacy of niclosamide in the treatment of patients with metastasized CRC and could help to establish a new treatment option.The study is registered with ClinicalTrials.gov (NCT02519582) and the European Clinical Trials Database (EudraCT 2014-005151-20).TRIAL REGISTRATIONThe study is registered with ClinicalTrials.gov (NCT02519582) and the European Clinical Trials Database (EudraCT 2014-005151-20).

Background Patients who survive critical illness suffer from a significant physical disability. The impact of rehabilitation strategies on health-related quality of life is inconsistent, with population heterogeneity cited as one potential confounder. This secondary analysis aimed to (1) examine trajectories of functional recovery in critically ill patients to delineate sub-phenotypes and (2) to assess differences between these cohorts in both clinical characteristics and clinimetric properties of physical function assessment tools. Methods Two hundred ninety-one adult sepsis survivors were followed-up for 24 months by telephone interviews. Physical function was assessed using the Physical Component Score (PCS) of the Short Form-36 Questionnaire (SF-36) and Activities of Daily Living and the Extra Short Musculoskeletal Function Assessment (XSFMA-F/B). Longitudinal trajectories were clustered by factor analysis. Logistical regression analyses were applied to patient characteristics potentially determining cluster allocation. Responsiveness, floor and ceiling effects and concurrent validity were assessed within clusters. Results One hundred fifty-nine patients completed 24 months of follow-up, presenting overall low PCS scores. Two distinct sub-cohorts were identified, exhibiting complete recovery or persistent impairment. A third sub-cohort could not be classified into either trajectory. Age, education level and number of co-morbidities were independent determinants of poor recovery (AUROC 0.743 ((95%CI 0.659–0.826), p  < 0.001). Those with complete recovery trajectories demonstrated high levels of ceiling effects in physical function (PF) (15%), role physical (RP) (45%) and body pain (BP) (57%) domains of the SF-36. Those with persistent impairment demonstrated high levels of floor effects in the same domains: PF (21%), RP (71%) and BP (12%). The PF domain demonstrated high responsiveness between ICU discharge and at 6 months and was predictive of a persistent impairment trajectory (AUROC 0.859 (95%CI 0.804–0.914), p  < 0.001). Conclusions Within sepsis survivors, two distinct recovery trajectories of physical recovery were demonstrated. Older patients with more co-morbidities and lower educational achievements were more likely to have a persistent physical impairment trajectory. In regard to trajectory prediction, the PF score of the SF-36 was more responsive than the PCS and could be considered for primary outcomes. Future trials should consider adaptive trial designs that can deal with non-responders or sub-cohort specific outcome measures more effectively.

Lymph node metastases are common in malignant neoplasms of head and neck. Since cervical lymph nodes (cLN) are localized superficially, ultrasound (US) represents the primary imaging modality. The aim of the study is to report the value of US and contrast-enhanced ultrasound (CEUS) and their diagnostic confidence in the characterization of inconclusive cLN. A systematic review was performed using the literature data base PubMed. Results were filtered (published in a peer-reviewed journal, full-text available, published within the last ten years, species human, English or German full-text) and inclusion criteria were clearly defined (cohort with lymphadenopathy or malignancy in head and neck ≥ 50 patients, histological confirmation of malignant imaging findings, performance of CEUS as outcome variable). The results were quantified in a meta-analysis using a random-effects model. Overall, five studies were included in qualitative and quantitative analysis. The combination of non-enhanced US and CEUS enlarges the diagnostic confidence in the characterization of lymph nodes of unclear dignity. The pooled values for sensitivity and specificity in the characterization of a malignant cervical lymph node using US are 76% (95%-CI 66–83%, I 2  = 63%, p  < 0.01) and 80% (95%-CI 45–95%, I 2  = 92%, p  < 0.01), compared to 92% (95%-CI 89–95%, I 2  = 0%, p  = 0.65) and 91% (95%-CI 87–94%, I 2  = 0%, p  = 0.40) for the combination of US and CEUS, respectively. Consistent results of the included studies show improved diagnostic performance by additional CEUS. Nevertheless, more prospective studies are needed to implement CEUS in the diagnostic pathway of cLN.

Dysphagia patients are at increased risk of stroke-associated pneumonia (SAP). This bicenter study evaluated whether dietary restrictions, specifically nil per os (NPO) and texture-modified food (TMF), reduce SAP incidence in post-stroke dysphagia (PSD). Data from 160 consecutive acute PSD patients treated in two university stroke units were retrospectively analyzed. The primary outcome was SAP incidence; secondary outcomes included length of hospitalization, mortality, and nasogastric tube placement. Stroke severity, male sex, and age emerged as significant SAP risk factors. On admission, 63% of SAP patients were already on NPO, 33.3% received TMF, and only 3.7% had unrestricted oral intake. Notably, NPO patients were 2.5 times more likely to develop SAP than those without dietary restrictions ( p  = 0.008). Most SAP cases were diagnosed before any oral intake, with the majority occurring by day three. These findings align with emerging evidence highlighting the role of oral hygiene factors and immune alterations in pulmonary bacterial defense. This study provides no support for NPO or TMF as effective pneumonia prophylaxis in PSD. Instead, early intervention and comprehensive care strategies are essential to mitigate SAP risk. Appropriate dysphagia diets enhancing residual swallowing capacity could positively impact both SAP rates and dysphagia rehabilitation.

Emerging evidence suggests a role of neuronal autoantibodies (nAbs) for long-term stroke outcomes. However, data remain limited and many domains unexamined. We present a comprehensive analysis of nAbs and their association with a broad range of outcome measures at multiple timepoints in the six months following moderate stroke. In this explorative analysis of the multicenter, randomized-controlled trial, serum samples from stroke patients were tested for 40 nAbs at baseline (5-45 days post-stroke), post-intervention (4 weeks after baseline), and at three and six months after stroke. Generalized estimating equation (GEE)-models were used to evaluate the dynamics of nAbs over time. Multiple linear regression models were applied to investigate the prognostic role of nAbs on various outcomes at three and six months. Two hundred stroke patients (41% female; mean age: 69 ± 12 years, median acute National Institutes of Health Stroke Scale: 8) were enrolled. Cell-based seroreactivity decreased from baseline to six months (39 of 183 patients [21%] 18 of 137 patients [13%]). while tissue-based reactivity increased (4 of 183 patients [2%] 9 of 137 patients [7%]). The GEE applied to the imputed dataset indicated a statistically significant decreased likelihood of seroreactive nAbs in cell-based assays from baseline to six months ( = 0.36 to 0.98; = 0.041), while tissue-based analyses showed an inverse effect for the same time period ( = 1.11 to 8.51; = 0.032). The most frequently detected antibody was anti-N-Methyl-D-Aspartate receptor GluN1 (NMDAR (IgM, IgA, IgG), 30 patients [15.1%]). Baseline nAB seropositivity was associated with worse depression scores ( = 0.03 to 7.82; = 0.048) and poorer subjective mobility ( 0.04 to 0.99; = 0.033) at six months post-stroke. NMDAR-antibodies at baseline were linked to a lower subjective overall health rating ( = -17.96 to -0.16; = 0.046) and lower maximum walking speed ( = -0.57 to -0.03; = 0.027) at six months. No associations were found with outcomes at three months. Antibody seropositivity was associated with poorer outcomes in certain neuropsychological and motor outcome measures at six but not three months post-stroke. These findings require confirmation in larger cohorts and emphasize the need for future studies with longer follow-up periods in this patient population. clinicaltrials.gov NCT01953549.

Background Budding is a complementary prognostic factor for colorectal cancer. In this study, we aimed to clarify the role of tumor budding in rectal cancer patients after preoperative chemoradiotherapy. Methods A total of 124 patients with rectal cancer treated with neoadjuvant chemoradiotherapy and consecutive surgery were included. Surgical specimens were evaluated for budding and routine clinicopathological features. Budding was evaluated on hematoxylin and eosin (H&E)-stained slides and by cytokeratin immunohistochemical (IHC) staining. Results A budding rate of 36.9% ( n  = 38) by H&E and 55.6% ( n  = 55) by IHC was observed. Budding was significantly associated with a high ypT and ypN status, poor differentiation, and low degrees of tumor regression. Moreover, budding was strongly predictive of a worse patient outcome, as measured by tumor recurrence or death. In multivariate analyses, budding remained the only significant parameter for overall survival and was even superior to the ypT and ypN status (budding in H&E: hazard ratio (HR) 2.72, 95% confidence interval (95% CI) 1.15–6.44, p  = 0.023; budding in IHC: HR 5.19, 95% CI 1.62–16.61, p  = 0.006). Conclusion Budding is a strong prognostic predictor of survival in rectal cancer patients after neoadjuvant therapy. A standardized evaluation of tumor budding after neoadjuvant therapy may thus aid in risk stratification and guide the clinical management of patients with rectal cancer. Immunostaining can help to enhance the diagnostic accuracy and prognostic significance.

Background Algorithm-based patient navigation is a key feature of the emergency and acute care reform being discussed in Germany. The software Structured Initial Medical Evaluation in Germany (SmED) is designed to assist in determining the appropriate time for medical complaints to be treated, as well as their most appropriate level of care. SmED is available in three different configurations, each of which is currently used in the German acute care sector and can be utilized by either a provider (SmED-Contact, SmED-Contact +) or a self-applicant (SmED-Patient). SmED-Patient is offered as a web-based self-assessment application that provides recommendations on the medical urgency and appropriate level of care for acute symptoms. This is the first study to explore and evaluate the accuracy, safety, utility and feasibility of using the self-assessment application SmED-Patient for self-referring patients and medical staff in the emergency department (ED) setting in Germany. Methods The study uses a mixed methods approach, including a prospective, multicenter cohort study combined with retrospective expert review of SmED-Patient recommendations for all cases by an expert panel as well as focus groups and a microsimulation. Expert reviews assess SmED-Patient recommendations on patients’ treatment urgency and the appropriate level of care based on routine clinical data. Adult patients (≥ 18 years) who self-refer at two inner-city emergency departments in Berlin (Germany) and able to provide written informed consent will be invited to participate. Target number of patients is n  = 150. The primary endpoint is the accuracy of SmED-Patient’s recommended level of care, measured as the agreement with the expert review for all cases. Secondary endpoints include safety, utility and feasibility of use. Data sources include primary data, routine clinical data, and qualitative data from focus groups and a microsimulation. Discussion This study will provide insight into the accuracy, utility, safety and feasibility of using the self-assessment application SmED-Patient in the ED. By facilitating medical self-assessment for self-referring walk-in patients, SmED-Patient could contribute to re-directing patients to ambulatory care providers, improving the efficiency of ED operations and benefit providers’ as well as patients’ care experiences in the ED. Trial registration German Clinical Trials Register: DRKS00036266. 25/02/2025.

Objectives To investigate the effect of different pre-treatments on the long-term bond strength of fiberglass posts luted either with dual-curing self-etch adhesives and core build-up composites or with a self-adhesive resin (SAR) cement. Materials and methods In total, 180 human root-filled teeth received post-space preparations and three different dentin pre-treatments (PTs): PT1, ethanol (99%); PT2, ethanol-tertiary-butanol-water-solution (AH Plus Cleaner, Dentsply Sirona; York, USA); and PT3, distilled water (control). Five luting systems were used: FU, Futurabond U (Voco; Cuxhaven, Germany); CL, Clearfil DC Bond (Kuraray Noritake; Okayama, Japan); GR, Gradia Core SE Bond (GC Europe NV; Leuven, Belgium); LU, LuxaBond Universal (DMG; Hamburg, Germany); and RX, RelyX Unicem 2 (3M; Minnesota, USA). Roots were cut into six slices (1 mm thick). From each root canal region, three slices were submitted to immediate and three to post-storage push-out testing. The latter were subjected to thermocycling (5–55°C, 6.000 cycles) and stored for six months in saline solution (0.9%, 37°C). Data were analysed using repeated measures ANOVA and chi-square tests (MV±SD). Results Bond strength was significantly affected by material ( p <0.0005), pre-treatment ( p =0.016), and storage ( p <0.0005; repeated-measures ANOVA). LU (18.8±8.1MPa) revealed significantly higher bond strength than RX (16.08±6.4MPa), GR (15.1±4.6MPa), CL (13.95±5.2MPa), and FU (13.7±6.3MPa). PT1 (16.5±6.9MPa) revealed significantly higher bond strength than PT3 (14.5±5.7MPa). Conclusions A universal adhesive in self-etch mode combined with a core build-up material revealed higher bond strength than a SAR cement, both interacted positively with Ethanol pre-treatment. Clinical relevance statement Ethanol (99%) rinsing can be recommended as part of post and core pre-treatment for the investigated luting systems.

Many clinical studies reporting accelerometry data use sum score measures such as percentage of time spent in moderate to vigorous activity which do not provide insight into differences in activity patterns over 24 hours, and thus do not adequately depict circadian activity patterns. Here, we present an improved functional data analysis approach to model activity patterns and circadian rhythms from accelerometer data. As a use case, we demonstrated its application in patients with mild cognitive impairment (MCI) and age-matched healthy older volunteers (HOV). Data of two studies were pooled for this analysis. Following baseline cognitive assessment participants were provided with accelerometers for seven consecutive days. A function on scalar regression (FoSR) approach was used to analyze 24 hours accelerometer data. Information on 48 HOV (mean age 65 SD 6 years) and 18 patients with MCI (mean age 70, SD 8 years) were available for this analysis. MCI patients displayed slightly lower activity in the morning hours (minimum relative activity at 6:05 am: -41.3%, 95% CI -64.7 to -2.5%, p = 0.031) and in the evening (minimum relative activity at 21:40 am: -48.4%, 95% CI -68.5 to 15.4%, p = 0.001) as compared to HOV after adjusting for age and sex. Using a novel approach of FoSR, we found timeframes with lower activity levels in MCI patients compared to HOV which were not evident if sum scores of amount of activity were used, possibly indicating that changes in circadian rhythmicity in neurodegenerative disease are detectable using easy-to-administer accelerometry. Effects of Brain Stimulation During Nocturnal Sleep on Memory Consolidation in Patients With Mild Cognitive Impairments, ClinicalTrial.gov identifier: NCT01782391. Effects of Brain Stimulation During a Daytime Nap on Memory Consolidation in Patients With Mild Cognitive Impairment, ClinicalTrial.gov identifier: NCT01782365.

Background Flexible bronchoscopy is an indispensable tool in respiratory medicine. In the context of an aging society and increasing life expectancy, the number of elderly, often multimorbid patients is growing. This raises important questions regarding the safety of flexible bronchoscopy in this population. Methods In this retrospective study 1841 flexible bronchoscopies performed at two sites of Charité Universitätsmedizin Berlin in the years 2022 and 2023 were assessed and classified into two age groups: patients ≥ 70 years (elderly group) and patients < 70 years (non-elderly group). Safety was assessed by the occurrence of complications, and in a GEE-analysis potential risk factors of complications were identified. Results In total, 466 bronchoscopies in the elderly group and 1375 bronchoscopies in the non-elderly group were assessed. Bronchoscopies in the elderly group were performed more frequently under endotracheal intubation than in the non-elderly group (81.8% vs. 70.0%; p  < 0.001). The overall complication rate was 2.3% with no significant differences between bronchoscopies of the elderly (1.7%) and non-elderly group (2.5%; p  = 0.345). The most common complications were pneumothorax (0.9%) in the elderly group and hypoxia (0.8%) in the non-elderly group. Transbronchial forceps biopsy ( p  < 0.001; OR = 3.99) and endobronchial valve implantation ( p  = 0.002; OR = 6.44) were significantly associated with an increased risk of complications independent of age. Discussion In our study, flexible bronchoscopy proved to be a safe procedure with low complication rates in elderly and non-elderly patients. Age was also not associated with an increased risk of complications. Invasive interventions such as transbronchial forceps biopsies and endobronchial valve implantations were identified as risk factors independent of age. This underscores the importance of individualized risk minimizing strategies, in particular for complex and invasive procedures.