Results of a monocentric field study: value of histology compared to sonication method and conventional tissue culture in the diagnosis of periprosthetic joint infection (PJI).

BACKGROUND: To confirm the diagnosis of periprosthetic joint infection (PJI), the Infectious Diseases Society of America (IDSA) and the International Consensus Meeting (ICM) have defined criteria that include histology as a minor criterion and the sonication method only as an additional criterion. The aim of this monocentric, retrospective study was to investigate the value of histology and whether sonication leads to a more accurate diagnosis. MATERIALS AND METHODS: All revision surgeries for knee and hip arthroplasty between 2017 and 2020 were included. With regard to microbiological diagnostic, conventional culture of periprosthetic biopsies and sonication of explant material were performed. In addition, histology and non-specific inflammatory markers (CRP, leukocytes) were recorded. RESULTS: A total of 78 patients with PJI and 62 aseptic controls were included. From both microbiological methods (conventional culture / sonication), Staphyloccus (S.) epidermidis and S. aureus were detected most frequently. However, compared to the conventional microbiology, a higher sensitivity was calculated for sonication, albeit with a lower specificity in relation to a PJI. In two logistic regression models for the significance of all diagnostic parameters in PJI, the AUC was 0.92 and 0.96 with histology in particular making the decisive contribution in both models (p < 0. 001, both models). CONCLUSION: Since histology showed the highest accuracy in the current study, its importance in the PJI criteria should be reevaluated. Sonication shows a high sensitivity for germ detection with a lower specificity and should only be used in combination with the conventional culture for microbiolgical diagnostics.

Parenting and Gender as Impact Factors for Social Participation, Quality of Life, and Mental Health in Long COVID.

OBJECTIVES: This study aims to investigate the impact of gender and parental tasks on social participation, health-related quality of life (hrQoL), and mental health in persons with long COVID. METHODS: A mixed-methods approach was followed including a cross-sectional web-based survey and semi-structured interviews. Multivariable linear regressions were used to quantify the effect of gender and parenting tasks on social participation, hrQoL, and mental health. Qualitative data from interviews with participants experiencing long COVID symptoms was analyzed using content analysis. RESULTS: Data from 920 participants in the quantitative study and 25 participants in the qualitative study was analyzed. Parenting tasks were associated with increased impairments in family and domestic responsibilities in persons with long COVID compared to lower impairments in persons without long COVID (P = .02). The qualitative data indicate that coping with long COVID and pursuing parenting tasks limit participants' ability to perform leisure activities and attend social gatherings. In long COVID, men had higher anxiety symptoms than women, and in those without long COVID, the opposite was observed (P < .001). In the qualitative study, participants expressed feelings of dejection and pessimism about their future private, occupational, and health situations. No differences between the genders could be observed. CONCLUSIONS: Long COVID is associated with impairments in family and domestic responsibilities in individuals who have parenting tasks. Among participants with long COVID, anxiety symptoms are higher in men than women.

Evaluating the Feasibility, Acceptance, and Beneficial Effects of Online Occupational Therapy for Post-COVID-19 Condition: Protocol for a Randomized Controlled Trial (ErgoLoCo Study).

BACKGROUND: Post-COVID-19 syndrome (PCS; also known as "long COVID") is a relatively novel disease comprising physical, psychological, and cognitive complaints persisting several weeks to months after acute infection with SARS-CoV-2. Approximately 10% of patients with COVID-19 are affected by long-term symptoms. However, effective treatment strategies are lacking. The ErgoLoCo (Occupational Therapy [Ergotherapie] for Long COVID) study was designed to develop and evaluate a novel occupational therapy (OT) concept of online delivery of therapy for long COVID. OBJECTIVE: The primary study objective is to assess the feasibility of the online OT intervention in PCS. Secondary aims include the evaluation of online OT concerning cognitive problems, occupational performance, and social participation. METHODS: This randomized controlled interventional pilot study involves parallel mixed methods process analyses and a realist evaluation approach. A total of 80 clients with PCS aged at least 16 years will be recruited into two interventional groups. The control cohort (watch and wait) comprises 80 clients with long COVID. Treatment is provided through teletherapy (n=40) or delivery of prerecorded videos (n=40) using the same standardized OT concept twice weekly over 12 weeks. Analyses of quantitative questionnaires and qualitative interviews based on the theoretical framework of acceptability will be performed to assess feasibility. Focus group meetings will be used to assess how acceptable and helpful the intervention was to the participating occupational therapists. Standardized tests will be used to assess the initial efficacy of the intervention on neurocognitive performance; limitations in mobility, self-care, and everyday activities; pain; disabilities; quality of life (QoL); social participation; and anxiety and depression in PCS, and the possible effects of online OT on these complaints. RESULTS: The German Ministry of Education and Research provided funding for this research in March 2022. Data collection took place from October 2022 to August 31, 2023. Data analysis will be completed by the end of April 2024. We anticipate publishing the results in the fall of 2024. CONCLUSIONS: Despite the enormous clinical need, effective and scalable treatment options for OT clients who have PCS remain scarce. The ErgoLoCo study will assess whether online-delivered OT is a feasible treatment approach in PCS. Furthermore, this study will assess the effect of the intervention on cognitive symptoms, QoL, and occupational performance and participation in everyday life. Particular emphasis will be placed on the experiences of clients and occupational therapists with digitally delivered OT. This study will pave the way for novel and effective treatment strategies in PCS. TRIAL REGISTRATION: German Clinical Trial Registry DRKS00029990; https://drks.de/search/de/trial/DRKS00029990. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): PRR1-10.2196/50230.

PATHFINDER-CHD: prospective registry on adults with congenital heart disease, abnormal ventricular function, and/or heart failure as a foundation for establishing rehabilitative, prehabilitative, preventive, and health-promoting measures: rationale, aims, design and methods.

BACKGROUND: Adults with congenital heart defects (ACHD) globally constitute a notably medically underserved patient population. Despite therapeutic advancements, these individuals often confront substantial physical and psychosocial residua or sequelae, requiring specialized, integrative cardiological care throughout their lifespan. Heart failure (HF) is a critical challenge in this population, markedly impacting morbidity and mortality. AIMS: The primary aim of this study is to establish a comprehensive, prospective registry to enhance understanding and management of HF in ACHD. Named PATHFINDER-CHD, this registry aims to establish foundational data for treatment strategies as well as the development of rehabilitative, prehabilitative, preventive, and health-promoting interventions, ultimately aiming to mitigate the elevated morbidity and mortality rates associated with congenital heart defects (CHD). METHODS: This multicenter survey will be conducted across various German university facilities with expertise in ACHD. Data collection will encompass real-world treatment scenarios and clinical trajectories in ACHD with manifest HF or at risk for its development, including those undergoing medical or interventional cardiac therapies, cardiac surgery, inclusive of pacemaker or ICD implantation, resynchronization therapy, assist devices, and those on solid organ transplantation. DESIGN: The study adopts an observational, exploratory design, prospectively gathering data from participating centers, with a focus on patient management and outcomes. The study is non-confirmatory, aiming to accumulate a broad spectrum of data to inform future hypotheses and studies. PROCESSES: Regular follow-ups will be conducted, systematically collecting data during routine clinical visits or hospital admissions, encompassing alterations in therapy or CHD-related complications, with visit schedules tailored to individual clinical needs. ASSESSMENTS: Baseline assessments and regular follow-ups will entail comprehensive assessments of medical history, ongoing treatments, and outcomes, with a focus on HF symptoms, cardiac function, and overall health status. DISCUSSION OF THE DESIGN: The design of the PATHFINDER-CHD Registry is tailored to capture a wide range of data, prioritizing real-world HF management in ACHD. Its prospective nature facilitates longitudinal data acquisition, pivotal for comprehending for disease progression and treatment impacts. CONCLUSION: The PATHFINDER-CHD Registry is poised to offer valuable insights into HF management in ACHD, bridging current knowledge gaps, enhancing patient care, and shaping future research endeavors in this domain.

Quantification of ventricular stress in univentricular hearts during early childhood using age-independent zlog-NT-proBNP.

BACKGROUND: Children with univentricular hearts (UVH) undergo up to three palliative surgical procedures to achieve complete circulatory separation (Fontan circulation). As a marker of cardiac wall stress, NT-proBNP is a promising tool to assess systemic ventricular load in these patients. However, different reference intervals (RI) apply to each stage, as NT-proBNP is highly age-dependent. METHODS: Children undergoing systemic-to-pulmonary (SP) shunt placement (stage 1), bidirectional cavopulmonary shunt (BCPS, stage 2) or total cavopulmonary connection (TCPC, stage 3) between 2011 and 2021 with NT-proBNP measurement within 7 days before surgery were included. Furthermore, outpatients after TCPC with NT-proBNP measurement were enrolled. Biomarker levels were evaluated using its age-adjusted z-score ("zlog-NT-proBNP"; age-independent RI, -1.96 to +1.96), allowing comparison between different stages and revealing changes in systemic ventricular load independent of the marked physiological decline in RI with age. RESULTS: Overall, 289 children (227 before, 62 after TCPC) met the eligibility criteria. Median time between blood sampling and surgery (SP shunt/BCPS/TCPC) was 2 [1-3] days and 3.2 [2.0-4.5] years after TCPC. Age-adjusted zlog-NT-proBNP levels were 3.47 [2.79-3.93] in children with native UVH (before SP shunt), 3.10 [1.89-3.58] at stage 1 (before BCPS), 1.08 [0.51-1.88] at stage 2 (before TCPC), and 1.09 [0.72-1.75] at stage 3 (after TCPC/Fontan completion). Consequently, BCPS revealed the strongest decrease (median - 2.02 logarithmized standard deviations, p < 0.001). CONCLUSIONS: In children with UVH undergoing staged Fontan palliation, zlog-NT-proBNP is a highly promising tool for course assessment of systemic ventricular load, independent of the age-related decline in physiological NT-proBNP concentration.

Association of long COVID with health-related Quality of Life and Social Participation in Germany: Finding from an online-based cross-sectional survey.

Purpose: This study aims to examine the health-related Quality of Life (hrQoL) and social participation in participants with Long COVID compared to participants without symptoms after COVID-19 and participants with no prior SARS-CoV-2 infection. Methods: A cross-sectional online survey was conducted in Germany. The non-random sample consists of participants 18 years or older. Participants were divided in three groups: Lg COVID with a prior SARS-CoV-2 infection and new or persistent symptoms 28 days after infection, ExCOVID with a prior SARS-CoV-2 infection and without new or persistent symptoms after 28 days, and NoCOVID when participants had no prior SARS-CoV-2 infection. EQ-5D-3L was used as hrQoL measure and the Index for the Assessment of Health Impairments (IMET) to reflect social participation. Descriptive and inferential statistics were performed. Results: A total of 3188 participants were included in the analysis (1421 Lg COVID, 260 ExCOVID, 1507 NoCOVID). Lg COVID was associated with the lowest EQ-5D-3L index values (p < 0.001), Visual Analogue Scale (VAS) scores (p < 0.001), and IMET (p < 0.001) scores followed by NoCOVID and ExCOVID. After adjusting for sociodemographic and medical conditions in a multivariable model Long COVID was still associated with lower hrQoL compared to NoCOVID (p < 0.001). About 10% of Lg COVID participants showed no health impairments in all EQ-5D dimensions while 51.1% of NoCOVID and 60% of ExCOVID participants showed no health impairments. Conclusion: This study highlights the impairments of persons with Long COVID on hrQoL and social participation compared to individuals without Long COVID in Germany. Trial registration: German Clinical Trial Registry, DRKS00026007.

Longitudinal analysis of systemic ventricular function and atrioventricular valve function after the Norwood procedure.

OBJECTIVES: To evaluate longitudinal systemic ventricular function and atrioventricular valve regurgitation in patients after the neonatal Norwood procedure. METHODS: Serial postoperative echocardiographic images before Fontan completion were assessed in neonates who underwent the Norwood procedure between 2001 and 2020. Ventricular function and atrioventricular valve regurgitation were compared between patients with modified Blalock-Taussig shunt and right ventricle to pulmonary artery conduit. RESULTS: A total of 335 patients were identified including 273 hypoplastic left heart syndrome and 62 of its variants. Median age at Norwood was 8 (7-12) days. Modified Blalock-Taussig shunt was performed in 171 patients and the right ventricle to pulmonary artery conduit in 164 patients. Longitudinal ventricular function and atrioventricular valve regurgitation were evaluated using a total of 4352 echocardiograms. After the Norwood procedure, ventricular function was initially worse (1-30 days) but thereafter better (30 days to stage II) in the right ventricle to pulmonary artery conduit group (P < 0.001). After stage II, the ventricular function was inferior in the right ventricle to the pulmonary artery conduit group (P < 0.001). Atrioventricular valve regurgitation between the Norwood procedure and stage II was more frequent in the modified Blalock-Taussig shunt group (P < 0.001). After stage II, there was no significant difference in atrioventricular valve regurgitation between the groups (P = 0.171). CONCLUSIONS: The effect of shunt type on haemodynamics after the Norwood procedure seems to vary according to the stage of palliation. After the Norwood, the modified Blalock-Taussig shunt is associated with poorer ventricular function and worse atrioventricular valve regurgitation compared to right ventricle to pulmonary artery conduit. Whereas, after stage II, modified Blalock-Taussig shunt is associated with better ventricular function and comparable atrioventricular valve regurgitation, compared to the right ventricle to pulmonary artery conduit.

Optimal Selection of Sampling Points within Sewer Networks for Wastewater-Based Epidemiology Applications.

Wastewater-based epidemiology (WBE) has great potential to monitor community public health, especially during pandemics. However, it faces substantial hurdles in pathogen surveillance through WBE, encompassing data representativeness, spatiotemporal variability, population estimates, pathogen decay, and environmental factors. This paper aims to enhance the reliability of WBE data, especially for early outbreak detection and improved sampling strategies within sewer networks. The tool implemented in this paper combines a monitoring model and an optimization model to facilitate the optimal selection of sampling points within sewer networks. The monitoring model utilizes parameters such as feces density and average water consumption to define the detectability of the virus that needs to be monitored. This allows for standardization and simplicity in the process of moving from the analysis of wastewater samples to the identification of infection in the source area. The entropy-based model can select optimal sampling points in a sewer network to obtain the most specific information at a minimum cost. The practicality of our tool is validated using data from Hildesheim, Germany, employing SARS-CoV-2 as a pilot pathogen. It is important to note that the tool's versatility empowers its extension to monitor other pathogens in the future.

Improvement of differential diagnosis of lung cancer by use of multiple protein tumor marker combinations.

BACKGROUND: Differential diagnosis of non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC) in hospitalized patients is crucial for appropriate treatment choice. OBJECTIVE: To investigate the relevance of serum tumor markers (STMs) and their combinations for the differentiation of NSCLC and SCLC subtypes. METHODS: Between 2000 and 2003, 10 established STMs were assessed retrospectively in 311 patients with NSCLC, 128 with SCLC prior systemic first-line therapy and 51 controls with benign lung diseases (BLD), by automatized electrochemiluminescence immunoassay technology. Receiver operating characteristic (ROC) curves and logistic regression analyses were used to evaluate the diagnostic efficacy of both individual and multiple STMs with corresponding sensitivities at 90% specificity. Standards for Reporting of Diagnostic Accuracy (STARD guidelines) were followed. RESULTS: CYFRA 21-1 (cytokeratin-19 fragment), CEA (carcinoembryonic antigen) and NSE (neuron specific enolase) were significantly higher in all lung cancers vs BLD, reaching AUCs of 0.81 (95% CI 0.76-0.87), 0.78 (0.73-0.84), and 0.88 (0.84-0.93), respectively. By the three marker combination, the discrimination between benign and all malignant cases was improved resulting in an AUC of 0.93 (95% CI 0.90-0.96). In NSCLC vs. BLD, CYFRA 21-1, CEA and NSE were best discriminative STMs, with AUCs of 0.86 (95% CI 0.81-0.91), 0.80 (0.74-0.85), and 0.85 (0.79-0.91). The three marker combination also improved the AUC: 0.92; 95% CI 0.89-0.96). In SCLC vs. BLD, ProGRP (pro-gastrin-releasing peptide) and NSE were best discriminative STMs, with AUCs of 0.89 (95% CI 0.84-0.94) and 0.96 (0.93-0.98), respectively, and slightly improved AUC of 0.97 (95% CI 0.95-0.99) when in combination. Finally, discrimination between SCLC and NSCLC was possible by ProGRP (AUC 0.86; 95% CI 0.81-0.91), NSE (AUC 0.83; 0.78-0.88) and CYFRA 21-1 (AUC 0.69; 0.64-0.75) and by the combination of the 3 STMs (AUC 0.93; 0.91-0.96), with a sensitivity of 88% at 90% specificity. CONCLUSIONS: The results confirm the power of STM combinations for the differential diagnosis of lung cancer from benign lesions and between histological lung cancer subtypes.

Elevated phospholipids and acylcarnitines C4 and C5 in cerebrospinal fluid distinguish viral CNS infections from autoimmune neuroinflammation.

BACKGROUND: Viral and autoimmune encephalitis may present with similar symptoms, but require different treatments. Thus, there is a need for biomarkers to improve diagnosis and understanding of pathogenesis. We hypothesized that virus-host cell interactions lead to different changes in central nervous system (CNS) metabolism than autoimmune processes and searched for metabolite biomarkers in cerebrospinal fluid (CSF) to distinguish between the two conditions. METHODS: We applied a targeted metabolomic/lipidomic analysis to CSF samples from patients with viral CNS infections (n = 34; due to herpes simplex virus [n = 9], varicella zoster virus [n = 15], enteroviruses [n = 10]), autoimmune neuroinflammation (n = 25; autoimmune anti-NMDA-receptor encephalitis [n = 8], multiple sclerosis [n = 17), and non-inflamed controls (n = 31; Gilles de la Tourette syndrome [n = 20], Bell's palsy with normal CSF cell count [n = 11]). 85 metabolites passed quality screening and were evaluated as biomarkers. Standard diagnostic CSF parameters were assessed for comparison. RESULTS: Of the standard CSF parameters, the best biomarkers were: CSF cell count for viral infections vs. controls (area under the ROC curve, AUC = 0.93), Q-albumin for viral infections vs. autoimmune neuroinflammation (AUC = 0.86), and IgG index for autoimmune neuroinflammation vs. controls (AUC = 0.90). Concentrations of 2 metabolites differed significantly (p < 0.05) between autoimmune neuroinflammation and controls, with proline being the best biomarker (AUC = 0.77). In contrast, concentrations of 67 metabolites were significantly higher in viral infections than controls, with SM.C16.0 being the best biomarker (AUC = 0.94). Concentrations of 68 metabolites were significantly higher in viral infections than in autoimmune neuroinflammation, and the 10 most accurate metabolite biomarkers (AUC = 0.89-0.93) were substantially better than Q-albumin (AUC = 0.86). These biomarkers comprised six phosphatidylcholines (AUC = 0.89-0.92), two sphingomyelins (AUC = 0.89, 0.91), and acylcarnitines isobutyrylcarnitine (C4, AUC = 0.92) and isovalerylcarnitine (C5, AUC = 0.93). Elevated C4 and C5 concentrations suggested dysfunctional mitochondrial ß-oxidation and correlated only moderately with CSF cell count (Spearman ρ = 0.41 and 0.44), indicating that their increase is not primarily driven by inflammation. CONCLUSIONS: Changes in CNS metabolism differ substantially between viral CNS infections and autoimmune neuroinflammation and reveal CSF metabolites as pathophysiologically relevant diagnostic biomarkers for the differentiation between the two conditions. In viral CNS infections, the observed higher concentrations of free phospholipids are consistent with disruption of host cell membranes, whereas the elevated short-chain acylcarnitines likely reflect compromised mitochondrial homeostasis and energy generation.

Method Comparison and Clinical Performance of Breast Cancer Tumor Markers on Novel Multiplex Immunoassay and Automatized LOCI Technology Platforms.

Tumor marker determinations are valuable tools for the guidance of breast cancer patients during the course of disease. They are assessed on diverse analytical platforms that may be associated with differences according to the methods applied and the clinical performance. To investigate the method dependency and clinical significance of breast cancer protein tumor markers, CEA, CA 15-3, CA 125, CA 19-9 and AFP were measured in a total of 154 biobanked samples from 77 patients with breast cancer, 10 with DCIS, 31 with benign breast diseases and 36 healthy controls using a Millipore multiplex biomarker panel (MP) and an automized version of the routinely used Vista LOCI technology. The markers were compared between methods and investigated for diagnostic performance. CEA, CA 15-3 and AFP showed good correlations between both platforms with correlation coefficients of R = 0.85, 0.85 and 0.92, respectively, in all samples, but similarly also in the various subgroups. CA 125 and CA 19-9 showed only moderate correlations (R = 0.71 and 0.56, respectively). Absolute values were significantly higher for CEA, CA 15-3, CA 125 and AFP in the Vista LOCI as compared with the MP method and vice versa for CA 19-9. The diagnostic performance for discrimination of breast cancer from healthy controls was similar for both methods with AUCs in ROC curves for CEA (MP 0.81, 95% CI 0.72-0.91; LOCI 0.81; 95% CI 0.72-0.91) and CA-15-3 (MP 0.75, 95% CI 0.65-0.86; LOCI 0.67, 95% CI 0.54-0.79). Similar results were obtained for the comparison of breast cancer with benign breast diseases regarding CEA (AUC MP 0.62, 95% CI 0.51-0.73; LOCI 0.64, 95% CI 0.53-0.74) and CA-15-3 (MP 0.70, 95% CI 0.6-0.81; LOCI 0.66, 95% CI 0.54-0.77). Both platforms show moderate to good method comparability for tumor markers with similar clinical performance. However, absolute levels in individual patients should be interpreted with care.

Sex-specific differences in pain localization in female patients with endometriosis: A comparison of sexless and female human body outlines.

BACKGROUND: This study explores sex-specific differences in pain localization using pain drawings in female patients with endometriosis. Traditional human body outlines (HBOs) used for pain drawings are often viewed as male, making accurate pain assessment difficult. The study aims to compare pain localization and extent between patients presented with sexless and female HBOs. METHODS: A total of 49 female patients with endometriosis completed questionnaires and pain drawings (n = 24 and n = 26 with individually designed sexless and female HBOs, respectively). The Ruzika similarity index was used to investigate potential differences in pain drawings between sexless and female HBOs. Hypothesis testing was applied to compare the number of pixels marked in the pain extents and to investigate the suitability of the presented body outline. RESULTS: Sex of HBOs used in pain drawings had no effect on pain area, and no statistically significant differences were found in pain localization or area between female and sexless outlines. Most, but not all participants found the body outlines suitable. CONCLUSIONS: The findings suggest that differences in the resulting areas marked in the pain drawings were negligible and the preferences for sexless pain drawings were not significant, so that a sexless body outline for pain drawings could be a good choice, especially when a study does not focus on one specific sex.

Social participation during the COVID-19 pandemic in persons with a high risk for a severe course of COVID-19 - results of a longitudinal, multi-center observational study in Germany.

Objective: The COVID-19 pandemic has affected how people go about their daily lives, often in various and substantial ways. This study aims to prospectively evaluate the changes in social participation during the COVID-19 pandemic in persons with a high risk for a severe COVID-19 course in Germany. Methods: A paper-pencil-based survey was conducted starting at March 2021. Participants filled out questionnaires at four time points based on their COVID-19 vaccination status: before COVID-19 vaccination, one month, six months and twelve months after COVID-19 vaccination. Social participation measures included the Pandemic Social Participation Questionnaire (PSP-Q) and the Index for measuring participation restrictions (IMET). Repeated measures ANOVA and paired t-test were used to test for changes between time-points. Repeated measures correlation was used to assess the relationship between social participation and local COVID-19 incidences. Results: Data from 245 participants was analyzed before and one month after COVID-19 vaccination. In addition, data from 156 participants was analyzed at time points one, six and twelve months after COVID-19. PSP-Q and IMET scores changed significantly after participants received a COVID-19 vaccination. Between one month and twelve months after vaccination, social participation improved significantly measured by PSP-Q. Social participation was negatively correlated with regional COVID-19 incidences before and after COVID-19 vaccination. Social participation was positively correlated with COVID-19 incidences between one month and twelve months after COVID-19 vaccination. Conclusions: Social participation improved in persons with a high risk for a severe COVID-19 course during the pandemic. The local COVID-19 incidence showed a negative association with social participation only until the fall of 2021 when it was used as the sole metric to regulate COVID-19 protective measures. Although our data describes the trends in social participation, further studies are needed to identify the influencing factors for the observed increase in social participation.

Proteomics reveals a global phenotypic shift of NK cells in HCV patients treated with direct-acting antivirals.

Chronic hepatitis C virus (HCV) infections compromise natural killer (NK)-cell immunity. Direct-acting antivirals (DAA) effectively eliminate HCV, but the long-term effects on NK cells in cured patients are debated. We conducted a proteomic study on CD56+ NK cells of chronic HCV-infected patients before and 1 year after DAA therapy. Donor-variation was observed in NK-cell proteomes of HCV-infected patients, with 46 dysregulated proteins restored after DAA therapy. However, 30% of the CD56+ NK-cell proteome remained altered 1 year post-therapy, indicating a phenotypic shift with low donor-variation. NK cells from virus-negative cured patients exhibited global regulation of RNA-processing and pathways related to "stimuli response", "chemokine signaling", and "cytotoxicity regulation". Proteomics identified downregulation of vesicle transport components (CD107a, COPI/II complexes) and altered receptor expression profiles, indicating an inhibited NK-cell phenotype. Yet, activated NK cells from HCV patients before and after therapy effectively upregulated IFN-γ and recruited CD107a. Conversely, reduced surface expression levels of Tim-3 and 2B4 were observed before and after therapy. In conclusion, this study reveals long-term effects on the CD56+ NK-cell compartment in convalescent HCV patients 1 year after therapy, with limited abundance of vesicle transport complexes and surface receptors, associated with a responsive NK-cell phenotype.

Amino acids, post-translational modifications, nitric oxide, and oxidative stress in serum and urine of long COVID and ex COVID human subjects.

In this study, we investigated the status of amino acids, their post-translational modifications (PTM), major nitric oxide (NO) metabolites and of malondialdehyde (MDA) as a biomarker of oxidative stress in serum and urine samples of long COVID (LoCo, n = 124) and ex COVID (ExCo, n = 24) human subjects collected in 2022. Amino acids and metabolites were measured by gas chromatography-mass spectrometry (GC-MS) methods using stable-isotope labelled analogs as internal standards. There were no differences with respect to circulating and excretory arginine and asymmetric dimethylarginine (ADMA). LoCo participants excreted higher amounts of guanidino acetate than ExCo participants (17.8 ± 10.4 µM/mM vs. 12.6 ± 8.86 µM/mM, P = 0.005). By contrast, LoCo participants excreted lower amounts of the advanced glycation end-product (AGE) NG-carboxyethylarginine (CEA) than ExCo participants did (0.675 ± 0.781 µM/mM vs. 1.16 ± 2.04 µM/mM, P = 0.0326). The serum concentrations of MDA did not differ between the groups, indicating no elevated oxidative stress in LoCo or ExCo. The serum concentration of nitrite was lower in LoCo compared to ExCo (1.96 ± 0.92 µM vs. 2.56 ± 1.08 µM; AUC, 0.718), suggesting altered NO synthesis in the endothelium. The serum concentration of nitrite correlated inversely with the symptom anxiety (r = - 0.293, P = 0.0003). The creatinine-corrected urinary excretion of Lys and its metabolite L-5-hydroxy-Lys correlated positively with COVID toes (r = 0.306, P = 0.00027) and sore throat (r = 0.302, P = 0.0003). Our results suggest that amino acid metabolism, PTM and oxidative stress are not severely affected in long COVID. LoCo participants may have a lower circulating NO reservoir than ExCo.

Cell-Free Methylated PTGER4 and SHOX2 Plasma DNA as a Biomarker for Therapy Monitoring and Prognosis in Advanced Stage NSCLC Patients.

Notwithstanding some improvement in the earlier detection of patients with lung cancer, most of them still present with a late-stage disease at the time of diagnosis. Next to the most frequently utilized factors affecting the prognosis of lung cancer patients (stage, performance, and age), the recent application of biomarkers obtained by liquid profiling has gained more acceptance. In our study, we aimed to answer these questions: (i) Is the quantification of free-circulating methylated PTGER4 and SHOX2 plasma DNA a useful method for therapy monitoring, and is this also possible for patients treated with different therapy regimens? (ii) Is this approach possible when blood-drawing tubes, which allow for a delayed processing of blood samples, are utilized? Baseline values for mPTGER4 and mSHOX2 do not allow for clear discrimination between different response groups. In contrast, the combination of the methylation values for both genes shows a clear difference between responders vs. non-responders at the time of re-staging. Furthermore, blood drawing into tubes stabilizing the sample allows researchers more flexibility.

Feasibility of self-organized blood sample collection in adults for study purposes in a primary care setting.

BACKGROUND/AIMS: The COVID-19 pandemic situation poses new challenges for research. Ethical issues might arise if especially vulnerable individuals for severe COVID-19 course expose themselves because of participation in studies to a higher risk of infection for study purposes. How is the feasibility and acceptance of self-organized blood sample collections to measure anti-SARS-CoV-2 Spike IgG antibodies in persons with a high risk for a severe COVID-19 disease progression? METHODS: Persons with a high risk for a severe COVID-19 disease progression (immunocompromised, oncology patients or over 80 years old) were recruited between January and September 2021 to send in blood samples (at least 500 µl) 1 month and 6 months after second COVID-19 vaccination. Participants were given the choice of drawing capillary or venous blood themselves or having blood drawn by health professionals belonging to either the study's own research team or the personnel found in local practices or clinics. Participants were surveyed via a telephone interview in December 2021 and January 2022 about their choice of blood sampling methods and influence of blood collection choice upon study participation. RESULTS: Data from 360 participants was collected via telephone follow-up. First blood samples were collected by the participants themselves (35.8%), local practices or clinics (31.9%) and the research team (22.5%). Second blood samples were mostly collected in local practices or clinics (35.6%) followed by participants themselves (25.9%) and the research team (11.5%). Blood samples were not collected in 2.5% and 19.1% of persons during first and second blood draw, respectively. Only 2% of blood samples did not reach the laboratory or were not analyzable. About one-fourth (26%) of participants stated that they would not have participated in the study if it would have been required to travel to the university hospital to give their blood sample. CONCLUSIONS: Participants were able to self-organize blood collection, making use of several different blood sample methods. Nearly all blood samples were analyzable when self-collected and sent in by post. One-fourth of the participants would not have participated in the study if required to give their blood sample in the study location. TRIAL REGISTRATION: German Clinical Trial Registry, DRKS00021152.

Cluster-Analytic Identification of Clinically Meaningful Subtypes in MCAS: The Relevance of Heat and Cold.

BACKGROUND: Mast cell activation syndrome (MCAS) is a clinically heterogeneous disease with allergy-like symptoms and abdominal complaints. Its etiology is only partially understood and it is often overlooked. AIMS: The aim of this study was to identify subgroups of MCAS patients to facilitate diagnosis and allow a personalized therapy. METHODS: Based on data from 250 MCAS patients, hierarchical and two-step cluster analyses as well as association analyses were performed. The data used included data from a MCAS checklist asking about symptoms and triggers and a set of diagnostically relevant laboratory parameters. RESULTS: Using a two-step cluster analysis, MCAS patients could be divided into three clusters. Physical trigger factors were particularly decisive for the classification as they showed remarkable differences between the three clusters. Cluster 1, labeled high responders, showed high values for the triggers heat and cold, whereas cluster 2, labeled intermediate responders, presented with high values for the trigger heat and low values for cold. The third cluster, labeled low responders, did not react to thermal triggers. The first two clusters showed more divers clinical symptoms especially with regard to dermatological and cardiological complaints. Subsequent association analyses revealed relationships between triggers and clinical complaints: Abdominal discomfort is mainly triggered by histamine consumption, dermatological discomfort by exercise, and neurological symptoms are related to physical exertion and periods of starvation. The reasons for the occurrence of cardiological complaints are manifold and triggers for respiratory complaints still need better identification. CONCLUSION: Our study identified three distinct clusters on the basis of physical triggers, which also differ significantly in their clinical symptoms. A trigger-related classification can be helpful in clinical practice for diagnosis and therapy. Longitudinal studies should be conducted to further understand the relationship between triggers and symptoms.

Longitudinal analysis of systemic ventricular function and atrioventricular valve function after the Fontan procedure.

OBJECTIVES: This study aimed to determine the longitudinal change of systemic ventricular function and atrioventricular valve (AVV) regurgitation after total cavopulmonary connection (TCPC). METHODS: In 620 patients who underwent TCPC between 1994 and 2021, 4219 longitudinal echocardiographic examinations of systemic ventricular function and AVV regurgitation were evaluated retrospectively. RESULTS: The most frequent primary diagnosis was hypoplastic left heart syndrome in 172, followed by single ventricle in 131, tricuspid atresia in 95 and double inlet left ventricle (LV) in 91 patients. Dominant right ventricle (RV) was observed in 329 (53%) and dominant LV in 291 (47%). The median age at TCPC was 2.3 (1.8-3.4) years. Transplant-free survival at 5, 10 and 15 years after TCPC was 96.3%, 94.7% and 93.6%, respectively, in patients with dominant RV and 97.3%, 94.6% and 94.6%, respectively, in those with dominant LV (P = 0.987). Longitudinal analysis of systemic ventricular function was similar in both groups during the first 10 years postoperatively. Thereafter, systemic ventricular function worsened significantly in patients with dominant RV, compared with those with dominant LV (15 years: P = 0.007, 20 years: P = 0.03). AVV regurgitation was more frequent after TCPC in patients with dominant RV compared with those with dominant LV (P < 0.001 at 3 months, 3 years, 5 years, 10 years and 15 years, P = 0.023 at 20 years). There was a significant correlation between postoperative systemic ventricular dysfunction and AVV regurgitation (P < 0.001). CONCLUSIONS: There were no transplant-free survival difference and no difference in ventricular function between dominant RV and dominant LV for the first 10 years after TCPC. Thereafter, ventricular function in dominant RV was inferior to that in dominant LV. The degree of AVV regurgitation was significantly higher in dominant RV, compared with dominant LV, and it was positively associated with ventricular dysfunction, especially in dominant RV.

Focusing on severe infections with the respiratory syncytial virus (RSV) in adults: Risk factors, symptomatology and clinical course compared to influenza A / B and the original SARS-CoV-2 strain.

BACKGROUND: The role and impact of RSV in the adult population is not well understood and comparative data of RSV infection, influenza A/B and SARS-CoV-2 in the elderly hospitalized for respiratory infections is limited. METHODS: In a retrospective, monocentric study we analyzed data of adult patients with respiratory infections tested positive by PCR for RSV, Influenza A/B and SARS-CoV-2 over a four-year period from 2017 to 2020. Symptoms on admission, laboratory results, and risk factors were assessed, and the clinical course and outcomes were studied. RESULTS: A total of 1541 patients hospitalized with respiratory disease and PCR positive for one of the 4 viruses were enrolled in the study. RSV was the second most prevalent virus before the COVID-19 pandemic and RSV patients represent the oldest group in this study with an average age of 75 years. Neither clinical nor laboratory characteristics differ clearly between RSV, Influenza A / B and SARS-CoV-2 infections. Up to 85% of patients had risk factors, with COPD and kidney disease found particularly frequently in RSV infections. Hospital stay was 12.66 days for RSV patients and thus significantly longer than for influenza A / B (10.88 and 8.86, respectively, p < 0.001), but shorter than for SARS-CoV-2 (17.87 days, p < 0.001). The risk for ICU admission and the rate of mechanical ventilation were also higher for RSV than for influenza A (OR 1.69 (p = 0.020) and 1.59 (p = 0.050)) and influenza B: (1.98 (p = 0.018) and 2.33 (p < 0.001)), but lower than for SARS-CoV-2 (0.65 (p < 0.001) and 0.59 (p = 0.035)). The risk of hospital mortality for RSV was increased compared with influenza A (1.55 (p = 0.050)) and influenza B (1.42 (p = 0.262)), but lower compared to SARs-CoV-2 (0.37 (p < 0.001). CONCLUSION: RSV infections in elderly are frequent and more severe than those with influenza A/B. While the impact of SARS-CoV-2 most likely decreased in the elderly population due to vaccination, RSV can be expected to continue to be problematic for elderly patients, especially those with comorbidities and thus, more awareness on the disastrous impact of RSV in this age group is urgently needed.