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AIM: To test the clinical performance of carbohydrate-deficient transferrin (%CDT), gamma-glutamyltransferase (gamma-GT) and mean corpuscular erythrocyte volume (MCV) as biomarkers for alcoholism with a special focus on patients suffering from liver diseases. DESIGN: Well-characterized collectives of alcohol-dependent patients with current consumption (ALC patients, n = 101), and relevant control groups (115 social drinkers, 46 patients with unspecifically increased gamma-GT, 51 hepatitis patients and 20/31 patients with non-alcohol/alcohol-dependent liver cirrhosis) were included into the study. The Positive Alcohol Use Disorders Test (AUDIT) score, International Classification of Diseases version 10 (ICD-10)/Diagnostic and Statistical Manual version IV (DSM-IV) criteria and blood drawn within 4 days of last drinking were inclusion criteria for subjects with regular heavy drinking. %CDT was determined using an automated assay which recently had been completely modified. FINDINGS: Median AUDIT scores of patients without/with regular heavy drinking were 1-3/27. The following medians/95th percentiles were obtained for %CDT: social drinkers 2.2/3.0, patients with unspecifically increased gamma-GT 2.1/3.0, hepatitis 2.0/4.4, non-alcohol-dependent liver cirrhosis 2.4/4.8, alcohol-dependent liver cirrhosis 3.0/5.9, ALC patients 3.9/14.9. Differences between patients without and with alcohol abuse were highly significant (P < 0.001). No differences in CDT values were found between males and females. There was no correlation between %CDT values, gamma-GT, MCV and the amount of alcohol consumed in ALC patients; 3.0%CDT (95th percentile social drinkers) is proposed as cut-off for the test used (Tina-quant %CDT 2nd-generation). At this cut-off, the sensitivity for ALC patients was 73.3%, whereas gamma-GT/MCV had a sensitivity of 71.3%/64.4%. Multivariate analysis performed at 95% specificity resulted in an improvement of the sensitivity by combining %CDT with gamma-GT (83.2%). A further enhancement of the sensitivity to 88.1% was obtained by combination of %CDT, gamma-GT and MCV. The diagnostic specificity of %CDT calculated at the cut-off of 3% was 93.5% in patients with unspecifically increased gamma-GT, 88.2% in hepatitis patients and 70.0% in patients with non-alcohol-dependent liver cirrhosis. %CDT was more specific in these patient collectives than MCV, and especially more than gamma-GT (specificity in hepatitis 52.9%, and 35.0% in non-alcohol-dependent liver cirrhosis). CONCLUSION: %CDT is of high diagnostic value to support diagnosis of alcohol-use disorders. The specificity of this marker in patient groups with liver disorders is superior to the biomarkers gamma-GT and MCV. [ABSTRACT FROM AUTHOR]

Gender‐ and sex‐specific differences in medicine were long‐time disregarded. Despite numerous indications of gender‐ and sex‐specific influences on the treatment of dermatological conditions, these have not yet been systematically investigated. To meet this unmet need, we conducted the present systematic review on the topic of gender and sex differences in the treatement outcome of skin diseases. Embase (via Ovid), PubMed Medline and Web of Science were searched, in between January 2001 and December 2022. English and german randomized controlled trials, prospective and retrospective cohorts and case–control studies that examined differences between men and women in treatment outcomes of skin diseases were included. Two authors independently screened the reports for eligibility, one extracted all data (the second double‐checked) and critically appraised the quality and risk of bias of the studies. Eighty‐three reports were included. The largest share of the identified publications focused on gender differences in psoriasis and psoriatic arthritis (n = 49), followed by melanoma (n = 8) and sporadic studies (n < 5) of inflammatory, infectious and autoimmune skin diseases. The main topics in which gender differences could be identified were choice of treatment, time to initiation of treatment, therapy response, adverse events, adherence and treatment satisfaction. For psoriasis, gender differences could be found in all aspects, while for the other skin diseases specific publications on gender differences are still missing. This systematic review shows numerous gender differences but also reveals major gaps in gender‐specific care in dermatology which should be narrowed in the upcoming years to optimize a patient‐centred, individualized, gender‐equal healthcare. PROSPERO Registration: CRD42022306626. [ABSTRACT FROM AUTHOR]

There is mounting evidence that antiretroviral drug combinations consisting of three nucleoside or nucleotide analogues are less effective in terms of viral suppression than two-class combinations. Despite the pleasing simplicity of these regimens, virus suppression as the uppermost goal of antiretroviral therapy should be kept in mind. [ABSTRACT FROM AUTHOR]

Background and Importance: Agitation of elderly patients in the emergency department (ED) often complicates workup and therapy., Objective: In this study, we investigated if agitation in the ED can be reduced by showing calming video sequences in elderly agitated patients., Designs: Prospective randomized intervention study., Settings and Participants: ED patients aged ≥65 years were screened for the risk of agitation/delirium using the 4-A's test (4-AT) test. In case of ≥4 4-AT points, patients were scored using the Richmond Agitation-Sedation Scale (RASS) and the Nursing Delirium Screening Scale (Nu-DESC). They were included in the study if RASS was ≥+2 and Nu-DESC ≥ 4 after informed consent of the legal representative. Patients were then randomized to the intervention or control group. A total of n = 57 patients were included in the study., Intervention: Patients in the intervention group were exposed to projections of calming video sequences for 60 min. Patients in the control group received standard care., Outcome Measures and Analysis: Changes in RASS and Nu-DESC were assessed 30 and 60 min after the intervention was started., Main Results: A total of 57 patients were included in the study, with 30 patients in the intervention group and 27 patients in the control group. Before the intervention, the median (interquartile range) RASS scores were comparable between the intervention group [3 (2-3)] and the control group [3 (2-3)]. After 30 min of exposure to calming video sequences, patients in the intervention group showed significantly lower RASS and Nu-DESC scores compared to the control group [RASS: 1 (0-1) vs. 2 (1.5-3), P < 0.001; Nu-DESC: 3 (2-4) vs. 5 (4-6), P < 0.001]. This difference persisted at 60 min [RASS: 0 (0-1) vs. 2 (1-2.5), P < 0.001; Nu-DESC: 2 (2-3) vs. 5 (4-6), P < 0.001]. Additionally, fewer patients in the intervention group required additional sedating or antipsychotic medication (1/30) compared to the control group (9/27), with this difference being statistically significant (P = 0.004)., Conclusion: In this randomized controlled trial, the use of calming video sequences in elderly patients with agitation in the ED resulted in significant reductions in agitation and the need for additional sedative or antipsychotic medication., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Objectives: To explore effectiveness and sustainability of guideline adherence and antibiotic consumption after establishing treatment guidelines and initiating antimicrobial stewardship (AMS) ward rounds in a university hospital emergency department (ED)., Methods: Data were gathered retrospectively from 2017 to 2021 in the LMU University Hospital in Munich, Germany. Four time periods were compared: P1 (pre-intervention period); P2 (distribution of guideline pocket cards); P3 (reassessment after 3 years); and P4 (refresher of guideline pocket cards and additional daily AMS ward rounds for different medical disciplines). Primary outcome was adherence to guideline pocket cards for community-acquired pneumonia, cystitis, pyelonephritis and COVID-19-associated bacterial pneumonia. Secondary outcomes were reduction in antibiotic consumption and adherence to AMS specialist recommendations., Results: The study included 1324 patients. Guideline adherence increased in P2 for each of the infectious diseases entities. After 3 years (P3), guideline adherence decreased again, but was mostly on a higher level than in P1. AMS ward rounds resulted in an additional increase in guideline adherence (P1/P2: 47% versus 58.6%, P  = 0.005; P2/P3: 58.6% versus 57.3%, P  = 0.750; P3/P4: 57.3% versus 72.5%, P  < 0.001). Adherence increased significantly, not only during workdays but also on weekends/nightshifts. Adherence to AMS specialist recommendations was excellent (91.3%). We observed an increase in use of narrow-spectrum antibiotics and a decrease in the application of fluoroquinolones and cephalosporins., Conclusions: Establishing treatment guidelines in the ED is effective. However, positive effects can be diminished over time. Daily AMS ward rounds are useful, not only to restore but to further increase guideline adherence significantly., (© The Author(s) 2024. Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy.)

Background: Severe mental illnesses are risk factors for SARS-CoV-2-related morbidity and mortality. Vaccination is an effective protection; therefore, high vaccination rates should be a major priority for people with mental illnesses., Objectives: (1) Identification of at-risk groups for non-vaccination and structures and interventions needed for widespread vaccination among people with mental illnesses from the perspective of outpatient psychiatrists and neurologists, (2) discussion of the results in the context of the international literature and (3) recommendations derived from them., Material and Methods: Qualitative content analysis of COVID-19 vaccination-related questions from the COVID Ψ online survey of n = 85 psychiatrists and neurologists in Germany., Results: In the survey, people with schizophrenia, severe lack of drive, low socioeconomic status and homelessness were seen as risk groups for non-vaccination. Increased and targeted information, education, addressing and motivation and easily accessible vaccination offers by general practitioners, psychiatrists, and neurologists as well as complementary institutions were considered as important interventions., Discussion: COVID-19 vaccinations as well as information, motivation and access support should be systematically offered by as many institutions of the psychiatric, psychotherapeutic and complementary care systems in Germany as possible., (© 2023. The Author(s), under exclusive licence to Springer Medizin Verlag GmbH, ein Teil von Springer Nature.)

Background: the organisation of a COVID-19 vaccination campaign for healthcare workers (HCWs) within a university hospital presents a challenge of a particularly large scale and urgency. Here, we evaluate the in-hospital vaccination process and centre for HCWs at LMU University Hospital in Munich, Germany., Methods: We executed a mixed-method process evaluation of the vaccination centre at LMU University Hospital during the first COVID-19 vaccination campaign. In a programme monitoring, we continuously assessed the implementation of the centre's operational management including personnel resources. In evaluating the outreach to and satisfaction of the target group with the centre and process, we executed two anonymous surveys aimed at the HCWs vaccinated at the in-hospital centre (1) as well as centre staff members (2)., Results: staff numbers and process time per person were reduced several times during the first vaccination campaign. Lessons concerning appointment scheduling were learned. HCWs vaccinated at the in-hospital centre were satisfied with the process. A longer waiting time between admission and inoculation, perceived dissatisfying accessibility as well as an increased frequency of observed adverse events were linked to a reduced satisfaction. Comparatively subpar willingness to adhere to non-pharmaceutical measures was observed. Centre staff reported high satisfaction and a workload relatively equal to that of their regular jobs. Our outcomes provide references for the implementation of an in-hospital vaccination centre in similar settings.

Considering the role of healthcare workers (HCW) in promoting vaccine uptake and previously recorded hesitancy among HCW, we aim to examine the COVID-19 vaccination intent and status of HCW through a cross-sectional anonymous online survey at LMU University Hospital in Munich. Data collection was informed by the Health Belief Model (HBM) and focused on vaccination intent, status and on potential factors affecting the decision-making process. In total, 2555 employees completed the questionnaire. Our data showed that an approving attitude towards recommended vaccines and having received an influenza vaccine in the previous winter were strongly associated with COVID-19 vaccination intent. Further, a positive COVID-19 vaccination status was associated with a higher likelihood of approving the extension of the validity of non-pharmaceutical interventions at the workplace. Our HBM-analysis demonstrated strong associations between the perceived benefits and barriers and COVID-19 vaccination intent. Unchanged or low perceived susceptibility and severity were associated with refusal or indecisiveness. Our findings highlight the factors associated with the decision regarding a COVID-19 vaccine and indicate a pattern-like behavior in the acceptance of novel vaccines by HCW. These insights can help inform the communication aims of vaccination campaigns among HCW within similar organizational contexts or in future outbreaks.

Objectives: Early patient disposition is crucial to prevent crowding in emergency departments (EDs). Our study aimed to characterise the need of in-house resources for patients treated in the ED according to the Emergency Severity Index (ESI) and the presenting complaint at the timepoint of triage., Design: A retrospective single-centre study was conducted., Setting: Data of all patients who presented to the interdisciplinary ED of a tertiary care hospital in Munich, Germany, from 2014 to 2017 were analysed., Participants: n=113 694 patients were included., Measures: ESI Score, medical speciality according to the chief complaint, mode of arrival, admission rates and discharge destination from the ED were evaluated., Results: Patient disposition varied according to ESI scores in combination with the chief complaint. Patients with low ESI scores were more likely to be admitted after treatment in the ED than patients with high ESI scores. Highly prioritised patients (ESI 1) mainly required admission to an intensive care unit (ICU, 27%), intermediate care unit (IMC, 37%) or immediate intervention (11%). In this critical patient group, 30% of patients with neurological or medical symptoms required immediate intensive care, whereas only 17% of patients with surgical problems were admitted to an ICU. A significant number of patients (particularly with neurological or medical problems) required hospital (and in some cases even ICU or IMC) admission despite high ESI scores., Conclusions: Overall, ESI seems to be a useful tool to anticipate the need for specialised in-hospital resources on arrival. Patients with symptoms pointing at neurological or medical problems need particular attention as ESI may fail to sufficiently predict the care facility level for this patient group., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Adults with congenital heart disease and ventricular dysfunction are prone to liver congestion, leading to fibrosis or cirrhosis but little is known about the prevalence of liver disease in atrial switch patients. Liver impairment may develop due to increased systemic venous pressures. This prospective study aimed to assess non-invasively hepatic abnormalities in adults who underwent Senning or Mustard procedures., Methods: Hepatic involvement was assessed non-invasively clinically by laboratory analysis, hepatic fibrotic markers, sonography, and liver stiffness measurements [transient elastography (TE) and acoustic radiation force impulse imaging (ARFI)]., Results: Overall, 24 adults who had undergone atrial switch operation (13 Senning, 11 Mustard; four female; median age 27.8 years; range 24-45 years) were enrolled. In liver stiffness measurements, only three patients had values within the normal reference. All other patients showed mild, moderate or severe liver fibrosis or cirrhosis, respectively. Using imaging and laboratory analysis, 71% of the subjects had signs of liver fibrosis (46%) or cirrhosis (25%)., Conclusions: Non-invasive screening for liver congestion, fibrosis or cirrhosis could be meaningful in targeted screening for hepatic impairment in patients with TGA-ASO. As expert knowledge is essential, patients should be regularly controlled in highly specialised centres with cooperations between congenital cardiologists and hepatologists., Competing Interests: Conflicts of Interest: The authors have no conflicts of interest to declare., (2019 Cardiovascular Diagnosis and Therapy. All rights reserved.)

Background: Eisenmenger syndrome as a severe form of cyanotic congenital heart disease results in a complex multisystemic disorder. Due to increased systemic venous pressure and the inability to ensure systemic perfusion and metabolic requirements, the liver may develop congestion, fibrosis or cirrhosis. This study aimed to assess hepatic abnormalities in Eisenmenger patients non-invasively., Methods and Results: 10 adults with Eisenmenger syndrome (six female; median age 44.2years; range 23-62years) were enrolled and hepatic involvement was assessed - using clinical assessment, laboratory analysis, hepatic fibrotic markers, abdominal sonography and liver stiffness measurements (transient elastography (TE) and acoustic radiation force impulse imaging (ARFI)). Using imaging and laboratory analysis, 60% (6/10) of the Eisenmenger patients had signs of liver fibrosis (5/10) or cirrhosis (1/10). While TE, however, showed no relevant liver abnormalities in any Eisenmenger patient, ARFI detected liver fibrosis in 5/10 and cirrhosis and 1/10 patients., Conclusions: Adult Eisenmenger patients are at increased risk of hepatic impairment. Non-invasive screening could be helpful in detecting liver alterations. In our small series, however, TE could not detect fibrosis or cirrhosis in any affected patient, while ARFI was very reliable. Patients should be transferred to centres, where a multidisciplinary expert knowledge is available and a close collaboration between cardiologists and hepatologists exists., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Background: Anthracyclines are agents with a well known documented anti-tumoral activity. Cardiac side effects are the principal toxicity. Here we evaluate and monitor the onset of late anthracycline-induced cardiotoxicity with real-time CW-Doppler ultrasound cardiac output monitoring (USCOM®) and echocardiography in combination with serum biomarkers., Methods: Fifty-two patients without cardiac disease who had received an anthracycline-based regimen for various cancer types were included in this study. Patients' hemodynamic parameters as stroke volume (SV USCOM (mL)) and ejection fraction (EF ECHOCARDIOGRAPHY (%)) were measured with USCOM and echocardiography and correlated to serum biomarkers (NT-pro-BNP and cTnT)., Results: Eighteen patients (34.6%) developed cardiac disease (NYHA I-III). An increasing cumulative anthracycline dose was associated with a decrease of the EF determined by echocardiography as well the SV by USCOM and with a higher NYHA class. Those patients who experienced cardiac disease showed a reduction of the EF and SV and increased serum biomarkers., Conclusions: Real-time CW-Doppler USCOM, is a fast and reliable method to monitor late hemodynamic changes as a symptom of anthracycline-induced cardiotoxicity comparable to the findings by echocardiography and serum biomarkers., Competing Interests: The authors declare no conflict of interest.

Objectives: Gender differences between donors and recipients might have an effect on outcome after heart transplantation. Literature and registries reveal controversial results. We reviewed 1000 heart transplantations at our center focusing on the influence of gender differences on short- and long-term outcome after heart transplantation., Materials and Methods: We performed a retrospective analysis of 1000 (960 primary and 40 redo-heart transplantations) between August 1981 and July 2008. In contrast to other studies, the data for gender differences (donor gender and recipient gender) were evaluated for recipient survival and survival conditional to early mortality., Results: Female donors are significantly older than male donors (females, 36.5 ± 14.5 years; males, 31.2 ± 13.8 years). One-year survival was significantly inferior in male recipients receiving female donor hearts (mR/fD: 73.7%) compared to females receiving male donor organs (fR/mD: 90.9%) (P = .045). Univariate analysis revealed that, for recipients who survived > 1 year, survival at 10 years was significantly greater for female donors and female recipients (90%) than it was for male donors and male recipients (72%; P = .034). Multivariate analysis showed that the gender combination with female donors and female recipients was an independent indicator for greater long-term survival (P = .04)., Conclusions: The gender combination of female donors and male recipients had a greater risk for early mortality after heart transplantation, and the combination of male donors and female recipients resulted in favorable short-term outcomes. In long-term follow-up, recipients of hearts from female donors had better survival, especially female recipients.

History: A 70-year-old woman had been under oncological supervision for several years because of breast cancer with bone and lymph node metastases. For several weeks she had been treated for increasing vocal cord paresis of uncertain cause, requiring a tracheostomy, a speech cannula being inserted after eight days. Several days later the patient began to complain of dyspnea, but repeated inspection and cleaning of the cannula failed to reveal its cause. The increasingly anxious patient was given a benzodiazepine preparation to calm her. She was then transferred to the intensive care unit because of worsening respiratory insufficiency and impaired consciousness., Diagnosis and Course: A fiberoptic bronchoscopy was performed immediately, which revealed a black foreign body immediately distal to the tip of the tracheal cannula. The cannula was removed and the slightly sedated patient at once coughed up a large amount of bronchial secretion and a long, curved and fairly firm blood clot. Control bronchoscopy now revealed a flat, slightly hemorrhagic ulcer on the dorsal tracheal wall at the point where the cannula tip had made contact with the tracheal wall., Conclusion: Even trained personnel may have difficulty in recognizing intratracheal thrombi in patients with a tracheostomy. It is thus essential that an endoscopy is performed in patients with obstructive symptoms after a tracheostomy., (© Georg Thieme Verlag KG Stuttgart · New York.)

USCOM is an ultrasound-based method which has been accepted for noninvasive hemodynamic monitoring in various clinical conditions (USCOM, Ultrasonic cardiac output monitoring). The present study aimed at comparing the accuracy of the USCOM device with that of the thermodilution technique in patients with septicemia. We conducted a prospective observational study in a medical but noncardiological ICU of a university hospital. Septic adult patients (median age 55 years, median SAPS-II-Score 43 points) on mechanical ventilation and catecholamine support were monitored with USCOM and PiCCO (n = 70). Seventy paired left-sided CO measurements (transaortic access = CO(US-A)) were obtained. The mean CO(US-A) were 6.55 l/min (±2.19) versus CO(PiCCO) 6.5 l/min (±2.18). The correlation coefficient was r = 0.89. Comparison by Bland-Altman analysis revealed a bias of -0.36 l/min (±0.99 l/min) leading to a mean percentage error of 29%. USCOM is a feasible and rapid method to evaluate CO in septic patients. USCOM does reliably represent CO values as compared to the reference technique based on thermodilution (PiCCO). It seems to be appropriate in situations where CO measurements are most pertinent to patient management.

Background: Anthracyclines are agents with a wellknown cardiotoxicity. The study sought to evaluate the hemodynamic response to an anthracycline using realtime continuous-wave (CW)-Doppler ultrasound cardiac output monitoring (USCOM) and echocardiography in combination with serum biomarkers., Methods: 50 patients (26 male, 24 female, median age 59 years) suffering from various types of cancer received an anthracycline-based regimen. Patients' responses were measured at different time points (T0 prior to infusion, T1 6 h post infusion, T2 after 1 day, T3 after 7 days, and T4 after 3 months) with CW-Doppler ultrasound (T0-T4) and echocardiography (T1, T4) for hemodynamic parameters such as stroke volume (SV; SVUSCOM ml) and ejection fraction (EF; EFechocardiography%) and with NT-pro-BNP and hs-Troponin T (T0-T4)., Results: During the 3-month observation period, the relative decrease in the EF determined by echocardiography was -2.1% (▵T0-T4, T0 71 ± 7.8%, T4 69.5 ± 7%, p = 0.04), whereas the decrease in SV observed using CW-Doppler was -6.5% (▵T0-T4, T0 54 ± 19.2 ml, T4 50.5 ± 20.6 ml, p = 0.14). The kinetics for serum biomarkers were inversely correlated., Conclusions: Combining real-time CW-Doppler USCOM and serum biomarkers is feasible for monitoring the immediate and chronic hemodynamic changes during an anthracycline-based regimen; the results obtained were comparable to those from echocardiography., (Copyright © 2012 S. Karger AG, Basel.)

Background: The admission of patients with malignancies to an intensive care unit (ICU) still remains a matter of substantial controversy. The identification of factors that potentially influence the patient outcome can help ICU professionals make appropriate decisions., Patients and Methods: 90 adult patients with hematological malignancy (leukemia 47.8%, high-grade lymphoma 50%) admitted to the ICU were analyzed retrospectively in this single-center study considering numerous variables with regard to their influence on ICU and day-100 mortality., Results: The median simplified acute physiology score (SAPS) II at ICU admission was 55 (ICU survivors 47 vs. 60.5 for non-survivors). The overall ICU mortality rate was 45.6%. With multivariate regression analysis, patients admitted with sepsis and acute respiratory failure had a significantly increased ICU mortality (sepsis odds ratio (OR) 9.12, 95% confidence interval (CI) 1.1- 99.7, p = 0.04; respiratory failure OR 13.72, 95% CI 1.39-136.15, p = 0.025). Additional factors associated with an increased mortality were: high doses of catecholamines (ICU: OR 7.37, p = 0.005; day 100: hazard ratio (HR) 2.96, p < 0.0001), renal replacement therapy (day 100: HR 1.93, p = 0.026), and high SAPS II (ICU: HR 1.05, p = 0.038; day 100: HR 1.2, p = 0.027)., Conclusion: The decision for or against ICU admission of patients with hematological diseases should become increasingly independent of the underlying malignant disease., (Copyright © 2012 S. Karger AG, Basel.)

Recent epidemiological studies suggest that chemotherapy for metastatic breast cancer (MBC) has not contributed to a marked improvement in the patient outcome during the last decades. Randomized trials that investigated the efficacy of a first-line schedule for MBC, observed a median survival of 18-24 months. This study aimed to analyze patients with MBC who have been treated in a single university outpatient clinic for survival. Patients with MBC who had received their complete anticancer treatment in our outpatient clinic between 2000 and 2005 were analyzed for treatment schedules and survival. A total of 232 patients [median age, 53 years; range, 27-87 years; estrogen receptor and/or progesterone-positive hormone receptor, n=174 (75%); human epidermal growth factor receptor 2 overexpression (human epidermal growth factor receptor 2 positive), n=79 (34%)] were included in this analysis, of which 43.7% of hormone receptor-positive patients received 1-2, 28.3% received 3-4, and 1.7% received more than four hormonal regimens. In addition, 53.4% of all patients received up to three chemotherapeutic agents in palliative intent, whereas four to six regimens were applied in 22.1, and 12.9% received more than six subsequent regimens. An increased number of regimens were associated with an improvement in survival. The median overall survival was 44 months (95% confidence interval: 39-49). HR positivity, bone only, or single-site metastases were associated with an improved survival. An improved survival was also shown in patients who underwent locoregional procedures for oligometastatic disease (n=31; median overall survival >50 months), whereas triple-negative breast cancer was related to worse outcome (16 months; 95% confidence interval: 7-25). These data collected from a selective patient population of a single center support the hypothesis that the sequential use of all treatment modalities for MBC to its full potential may result in an increased survival. Whether innovative medicine, a step-by-step escalation of all treatment modalities according to standard guidelines and individualized clinical requirements, and a multidisciplinary treatment approach contribute to these good outcomes is debatable.

Background & Aims: Inhibitory receptors such as programmed death 1 (PD-1) and cytotoxic T lymphocyte-associated antigen (CTLA)-4 mediate CD8+ T-cell exhaustion during chronic viral infection, but little is known about roles in dysfunction of CD4+ T cells., Methods: We investigated the functions of inhibitory molecules on hepatitis C virus (HCV)-, influenza-, and Epstein-Barr virus (EBV)-specific CD4+ T cells in patients with chronic infections compared with patients with resolved HCV infection and healthy donors. Expression of PD-1, CTLA-4, CD305, and CD200R were analyzed on HCV-specific CD4+ T cells, isolated from peripheral blood using major histocompatibility complex class II tetramers. We investigated the effects of in vitro inhibition of various inhibitory pathways on proliferation and cytokine production by CD4+ T cells, and we compared these effects with those from inhibition of interleukin (IL)-10 and transforming growth factor (TGF)-β1., Results: PD-1 and CTLA-4 were up-regulated on virus-specific CD4+ T cells from patients with chronic HCV infections. PD-1 expression was lower on influenza- than on HCV-specific CD4+ T cells from subjects with chronic HCV infection, whereas CTLA-4 was expressed at similar levels, independent of their specificity. CD305 and CD200R were up-regulated in HCV resolvers. Blockade of PD-L1/2, IL-10, and TGF-β1 increased expansion of CD4+ T cells in patients with chronic HCV, whereas inhibition of IL-10 and TGF-β1 was most effective in restoring HCV-specific production of interferon gamma, IL-2, and tumor necrosis factor α., Conclusions: We characterized expression of inhibitory molecules on HCV-, influenza-, and EBV-specific CD4+ T cells and the effects of in vitro blockade on CD4+ T-cell expansion and cytokine production. Inhibition of PD-1, IL-10, and TGF-β1 is most efficient in restoration of HCV-specific CD4+ T cells., (Copyright © 2011 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Background: The angiographic incidence of coronary dilatation (CD) in the nontransplant population is approximately 0.2% to 5%. The endothelial-dependent and -independent causes for CD are postulated. So far, the incidence and prognosis of CD after heart transplantation is unknown., Methods: We retrospectively analyzed the annual coronary angiographies of 688 heart transplant recipients regarding the incidence of CD (defined as ≥1.5-fold localized increased vessel diameter or diffuse dilatation involving more than 50% of the coronary artery). A subgroup analysis of coronary epicardial (quantitative angiography) and microvascular (doppler flow measurement) vasomotor function in response to acetylcholine (endothelial dependent) and adenosine (endothelial independent) as well as intravascular ultrasound was performed in 177 patients., Results: CD was detectable in 26 patients (3.8%) and was associated with stenosing coronary artery disease in 27% of the patients. Segments with CD tended to have less intimal hyperplasia compared with nondilated segments. A diffuse dilatation (type I-II) was present in 63% of the recipients. The right coronary artery was always involved. The patients with CD (5 of 177) showed a 31% reduced flow velocity in the dilated coronaries compared with the nondilated coronary arteries (P=0.03). Microvascular endothelial-independent function was impaired in CD by -29% (coronary flow reserve mean 1.9 vs. 2.7; P=0.04), whereas endothelial-dependent response was unchanged. Epicardial endothelial-dependent and -independent responses were not different between the groups. Incidence of CD was not associated with limited survival., Conclusion: The incidence of CD in the nontransplant population is similar to that in the transplanted population. However, the latter shows a more diffuse extent. Heart transplantation patients with CD had microvascular endothelial-independent functional limitations and flow deceleration, whereas survival was not affected.

Background & Aims: Down-regulation of hepatitis C virus (HCV)-specific CD4(+) T-cell responses is a hallmark of chronic viral persistence in acute hepatitis C. FOXP3(+)CD25(+)CD4(+) regulatory T cells can modulate HCV-specific immune responses in vitro, but the role of virus-specific regulatory T cells in the pathogenesis of chronic viral persistence is unknown., Methods: Two novel HLA-DR15 tetramers were synthesized to study the kinetics and phenotype of FOXP3(+)-expressing HCV-specific CD4(+) T cells from 10 patients with acute hepatitis C and 15 patients with chronic hepatitis C., Results: In acute hepatitis C, generally only a low percentage of HCV-specific CD4(+) T cells expressed FOXP3(+) (mean of 2.5% in patients with self-limited acute hepatitis C vs 2.4% in patients with evolving chronic hepatitis C). Although distinct but short-lived increases in virus-specific FOXP3(+)CD4(+) T cells occurred in 3 patients (30%, 26%, and 7% of tet(+) CD4(+) T cells, respectively), these did not correlate with the evolution of chronic hepatitis C. HCV-specific FOXP3(+)CD4(+) T cells displayed a distinct phenotype, with only 10% expressing CD25 and 40% being CD127low. Interestingly, this phenotype of FOXP3(+)CD4(+) T cells was already expanded in bulk CD4(+) T cells in patients with chronic hepatitis C., Conclusions: Although short-lived increases in HCV-specific FOXP3(+)CD4(+) T cells occur during the course of acute hepatitis C, we could not demonstrate an association of HCV-specific regulatory T cells and persistent viremia.