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Interleukin-17A Drives IL-19 and IL-24 Expression in Skin Stromal Cells Regulating Keratinocyte Proliferation
No full textIL-17A has been shown to be up-regulated in psoriasis lesions and is central to psoriasis pathogenesis. IL-19, along with other IL-20 subfamily cytokines such as IL-20 and IL-24, is induced by IL-17A and contributes especially to epidermal hyperplasia in psoriasis. However, the regulation, cellular sources of IL-19 and whether targeting of IL-17A by biologics influence IL-19 expression is not completely understood. To investigate the regulation of IL-19 by IL-17A in psoriasis, the imiquimod-induced psoriasis mouse (IMQ) model was used. Enhanced expression of IL-17A in the IMQ model was achieved by anti-IL-10 antibody treatment. Assessments of skin inflammation macroscopically, by histology and flow cytometry, all confirmed increased psoriatic symptoms. Interestingly, depletion of IL-10 markedly upregulated IL-23/IL-17 pathway related cytokines followed by a significant increase in IL-19 and IL-24. The up-regulation of IL-19 and IL-24, but not IL-17A, coincided with increased keratinocyte proliferation. To investigate the cellular source and effects of biologics on IL-19, human skin fibroblasts from healthy controls and psoriasis patients were cultured alone or co-cultured with activated memory CD4+ T cells. Besides IL-1β, IL-17A induced direct expression of IL-19 and IL-24 in skin fibroblasts and keratinocytes. Importantly, intrinsic higher expression of IL-19 in psoriatic skin fibroblasts was observed in comparison to healthy skin fibroblasts. Neutralization of IL-17A in the human skin fibroblast-T cell co-culture system significantly suppressed IL-19 and IL-24 expression. Together, our data show that IL-17A-induced IL-19 and IL-24 expression in skin stromal cells contribute to keratinocyte proliferation.</p
Three-year clinical outcomes of the absorb bioresorbable vascular scaffold compared to Xience everolimus-eluting stent in routine PCI in patients with diabetes mellitus—AIDA sub-study
No full textBackground: In this prespecified AIDA-trial sub-study we investigate the clinical performance of absorb bioresorbable vascular scaffold (BVS) compared to Xience everolimus-eluting stent (EES) in routine percutaneous coronary intervention (PCI) in patients with diabetes mellitus (DM) at complete 3-year follow-up. Methods and results: All 1,845 randomized patients were subdivided by medical history with DM or without DM. Of the 924 Absorb BVS patients, 171 (18.5%) patients had DM, of which 65 (38.0%) were treated with insulin (iTDM). Of the 921 Xience EES patients, 153 (16.6%) patients had DM, of which 45 (29.4%) were insulin-treated diabetes mellitus (iTDM). Target vessel failure (TVF), composite of cardiac death, target vessel myocardial infarction, and target vessel revascularization, occurred in 18.7% of diabetic patients treated with Absorb patients versus in 18.0% patients treated with Xience EES (p =.840). In nondiabetics the rates of TVF were 12.3% in Absorb BVS versus 11.0% in Xience EES (p =.391). Definite/probable device thrombosis occurred more frequently in Absorb BVS compared to Xience EES in both diabetic and nondiabetic patients (4.8% versus 0.7%; p =.028 and 3.2% vs. 0.5%; p <.001, respectively). Conclusions: In routine PCI practice, both Absorb BVS and Xience EES have worse clinical outcomes in diabetic patients as compared to nondiabetic patients. Throughout all clinical presentations, Absorb BVS was associated with higher rates of device thrombosis at 3-year follow-up.</p
Management of Soft Tissue Sarcomas in Extremities
No full textBackground: This study aimed to provide an insight into clinical decision-making and surveillance strategy of sarcoma specialists for patients with primary soft tissue sarcoma of the extremities (eSTS). The secondary aim was to quantify the role of patient- and tumor-specific factors in the perioperative management. Methods: Members of sarcoma societies were sent a Web-based 21-item survey about eSTS management. The survey concerned only primary resectable high-grade eSTS in adults. Results: The study enrolled 396 respondents. The majority of the surgical specialists thought the evidence for perioperative chemotherapy (CTX) for high-grade eSTS was insufficient. Radiotherapy (RTX) was less frequently offered in Asia than in North America and Europe. The specialties and continents also differed regarding the importance of patient and tumor characteristics influencing RTX and CTX recommendation. For surveillance after initial treatment outpatient visits, chest computed tomography (CT) scans, and magnetic resonance images of the extremity were the methods primarily used. The specialists in North America preferred chest CT scan over chest x-ray, whereas those in Asia and Europe had no clear preference. Discussion: Specialty and continent are important factors contributing to the variation in clinical practice, treatment recommendations, and surveillance of patients with primary resectable high-grade eSTS.</p
Patients as team members
No full textBackground: Active patient involvement in treatment decisions is seen as a feature of patient-centred care that will ultimately lead to better healthcare services and patient outcomes. Although many factors have been identified that influence patient involvement in treatment decisions, little is known about the different views that patients have on which factors are most important. Objective: This study explores the views of patients with a chronic condition on factors influencing their involvement in treatment decisions. Design: Q-methodology was used to study the views of patients. Respondents were asked to rank a set of 42 statements from the least important to the most important for active patient involvement in treatment decision-making. The set of 42 statements was developed based on a literature search and a pilot in which two external researchers, 15 patients and four healthcare professionals participated. A total of 136 patients with one of three major chronic conditions were included: diabetes types 1 and 2, respiratory disease (i.e., chronic obstructive pulmonary disease and asthma) and cancer (i.e., breast cancer and prostate cancer). Data were collected in a face-to-face interview setting in the Netherlands. Results: Four distinct views on the factors influencing active patient involvement were identified among patients with a chronic condition. (1) Enabled involvement: the extent to which patients are facilitated and empowered to participate will lead to patient involvement. (2) Relationship-driven involvement: the relationship between patients and healthcare professionals drives patient involvement. (3) Disease impact-driven involvement: the severity of disease drives patient involvement. (4) Cognition-driven involvement: knowledge and information drive patient involvement. Discussion and Conclusion: From the patients' perspective, this study shows that there is no one-size-fits-all approach to involving patients more actively in their healthcare journey. Strategies aiming to enhance active patient involvement among patients with a chronic condition should consider this diversity in perspectives among these patients. Patient Contribution: Patients are the respondents as this study researches their perspective on factors influencing patient involvement. In addition, patients were involved in pilot-testing the statement set.</p
Knowledge, attitude and practice of antibiotics and their determinants in Eritrea
No full textObjective To measure knowledge, attitude and practice of antibiotics and antibiotic resistance (ABR) and their determinants in the Eritrean urban population. Design A population-based, nation-wide, cross-sectional study. Setting Urban settings of Eritrea. Participants Members of the general public aged ≥18 years and living in 13 urban places of Eritrea. Three-stage stratified cluster sampling was used to select the study participants. Data collection and analysis Date were collected from July 2019 to September 2019 in a face-to-face interview using a structured questionnaire. The collected data were double entered and analysed using Census and Survey Processing system (V.7.0) and SPSS (V.23), respectively. Descriptive statistics, χ 2 test, t-tests, analysis of variance, factorial analysis and multivariable logistic regression were performed. All analyses were weighted and p<0.05 was considered significant. Primary and secondary outcome measures Main outcome variables were knowledge, attitude and practice of antibiotics and ABR. Secondary outcome measure was the determinants of knowledge, attitude and practice. Results A total of 2477 adults were interviewed. The mean score of knowledge and attitude of antibiotics and ABR was 10.36/20 (SD=3.51, minimum=0 and maximum=20) and 22.34/30 (SD=3.59, minimum=6 and maximum=30), respectively. Of those who used antibiotics, the proportion of at least one inappropriate practice (use of antibiotics without prescription and/or discontinuation of prescribed antibiotics before completing the full course) was 23.8%. Young age <24 years (adjusted odds ratio (AOR)=1.61, 95% CI: 1.08 to 2.41), male sex (AOR=1.48, 95% CI: 1.14 to 1.91), higher level of education (AOR=1.76, 95% CI: 1.08 to 2.88), and negative attitude towards appropriate use of antibiotics (AOR=0.95, 95% CI: 0.92 to 0.97) were found to be the significant determinants of inappropriate practice of antibiotics. Conclusion The gap in knowledge and inappropriate practice of antibiotics in the Eritrean urban population was widespread; requiring immediate attention from policy-makers and healthcare professionals. </p
National protocol for model-based selection for proton therapy in head and neck cancer
No full textIn the Netherlands, the model-based approach is used to identify patients with head and neck cancer who may benefit most from proton therapy in terms of prevention of late radiation-induced side effects in comparison with photon therapy. To this purpose, a National Indication Protocol Proton therapy for Head and Neck Cancer patients (NIPPHNC) was developed, which has been approved by the health care authorities. When patients qualify according to the guidelines of the NIPP-HNC, proton therapy is fully reimbursed. This article describes the procedures that were followed to develop this NIPP-HNC and provides all necessary information to introduce model-based selection for patients with head and neck cancer into routine clinical practice. </p
Reflecting on 20 years of breast cancer modeling in CISNET
No full textSince 2000, the National Cancer Institute’s Cancer Intervention and Surveillance Modeling Network (CISNET) modeling teams have developed and applied microsimulation and statistical models of breast cancer. Here, we illustrate the use of collaborative breast cancer multilevel systems modeling in CISNET to demonstrate the flexibility of systems modeling to address important clinical and policy-relevant questions. Challenges and opportunities of future systems modeling are also summarized. The 6 CISNET breast cancer models embody the key features of systems modeling by incorporating numerous data sources and reflecting tumor, person, and health system factors that change over time and interact to affect the burden of breast cancer. Multidisciplinary modeling teams have explored alternative representations of breast cancer to reveal insights into breast cancer natural history, including the role of overdiagnosis and race differences in tumor characteristics. The models have been used to compare strategies for improving the balance of benefits and harms of breast cancer screening based on personal risk factors, including age, breast density, polygenic risk, and history of Down syndrome or a history of childhood cancer. The models have also provided evidence to support the delivery of care by simulating outcomes following clinical decisions about breast cancer treatment and estimating the relative impact of screening and treatment on the United States population. The insights provided by the CISNET breast cancer multilevel modeling efforts have informed policy and clinical guidelines. The 20 years of CISNET modeling experience has highlighted opportunities and challenges to expanding the impact of systems modeling. Moving forward, CISNET research will continue to use systems modeling to address cancer control issues, including modeling structural inequities affecting racial disparities in the burden of breast cancer. Future work will also leverage the lessons from team science, expand resource sharing, and foster the careers of early stage modeling scientists to ensure the sustainability of these efforts.</p
Aspergillus in critically ill covid‐19 patients
No full textSeveral reports have been published on Aspergillus findings in COVID‐19 patients leading to a proposition of new disease entity COVID‐19‐associated pulmonary aspergillosis. This scoping review is designed at clarifying the concepts on how the findings of Aspergillus spp. in COVID‐19 patients were interpreted. We searched Medline to identify the studies on Aspergillus spp. findings in COVID‐19 patients. Included were observational studies containing the following information: explicit mention of the total number of the study population, study period, reason for obtaining respiratory samples, case definition, and clinical outcomes. Excluded were case series, case reports and reviews. Identified were 123 publications, and 8 observational studies were included. From the included studies the following issues were identified. The proportion of immunocompromised patients considered as host factors varied from 0 to 17%. Most of the studies did not mention radiographic findings explicitly. Respiratory samples were mostly obtained to investigate clinical deterioration. Aspergillus culture, antigen or PCR testing on bronchoalveolar lavage (BAL) fluid were performed in between 23.3% and 66.3% of the study population. Two studies performed periodic samples of BAL. Galactomannan index (GI) positivity in BAL was between 10% and 28%. GI in blood was found in 0.9% to 6.7% of the available samples. The prevalence of COVID‐19‐associated pulmonary aspergillosis ranged from 2.7% to 27.7%. Studies compared the mortality between defined cases and non‐cases, and all showed increased mortality in cases. No studies showed that antifungal treatment reduced mortality. Concluding, this review showed how studies defined the clinical entity COVID‐19‐associated pulmonary aspergillosis where positive Aspergillus test in the respiratory sample was the main driver for the diagnosis. There were many differences between studies in terms of test algorithm and Aspergillus test used that largely determined the prevalence. Whether antifungal therapy, either as prophylaxis, pre‐emptive or targeted therapy will lead to better outcomes of COVID‐19‐associated pulmonary aspergillosis patients is still need to be answered.</p
Pharmacokinetics of antibiotics in pediatric intensive care
No full textChildren show important developmental and maturational changes, which may contribute greatly to pharmacokinetic (PK) variability observed in pediatric patients. These PK alterations are further enhanced by disease-related, non-maturational factors. Specific to the intensive care setting, such factors include critical illness, inflammatory status, augmented renal clearance (ARC), as well as therapeutic interventions (e.g., extracorporeal organ support systems or whole-body hypothermia [WBH]). This narrative review illustrates the relevance of both maturational and non-maturational changes in absorption, distribution, metabolism, and excretion (ADME) applied to antibiotics. It hereby provides a focused assessment of the available literature on the impact of critical illness—in general, and in specific subpopulations (ARC, extracorporeal organ support systems, WBH)—on PK and potential underexposure in children and neonates. Overall, literature discussing antibiotic PK alterations in pediatric intensive care is scarce. Most studies describe antibiotics commonly monitored in clinical practice such as vancomycin and aminoglycosides. Because of the large PK variability, therapeutic drug monitoring, further extended to other antibiotics, and integration of model-informed precision dosing in clinical practice are suggested to optimise antibiotic dose and exposure in each newborn, infant, or child during intensive care.</p
AML/normal progenitor balance instead of total tumor load (MRD) accounts for prognostic impact of flowcytometric residual disease in AML
No full textMeasurable residual disease (MRD) in AML, assessed by multicolor flow cytometry, is an important prognostic factor. Progenitors are key populations in defining MRD, and cases of MRD involving these progenitors are calculated as percentage of WBC and referred to as white blood cell MRD (WBC-MRD). Two main compartments of WBC-MRD can be defined: (1) the AML part of the total primitive/progenitor (CD34+, CD117+, CD133+) compartment (referred to as primitive marker MRD; PM-MRD) and (2) the total progenitor compartment (% of WBC, referred to as PM%), which is the main quantitative determinant of WBC-MRD. Both are related as follows: WBC-MRD = PM-MRD × PM%. We explored the relative contribution of each parameter to the prognostic impact. In the HOVON/SAKK study H102 (300 patients), based on two objectively assessed cut-off points (2.34% and 10%), PM-MRD was found to offer an independent prognostic parameter that was able to identify three patient groups with different prognoses with larger discriminative power than WBC-MRD. In line with this, the PM% parameter itself showed no prognostic impact, implying that the prognostic impact of WBC-MRD results from the PM-MRD parameter it contains. Moreover, the presence of the PM% parameter in WBC-MRD may cause WBC-MRD false positivity and WBC-MRD false negativity. For the latter, at present, it is clinically relevant that PM-MRD ≥ 10% identifies a patient sub-group with a poor prognosis that is currently classified as good prognosis MRDnegative using the European LeukemiaNet 0.1% consensus MRD cut-off value. These observations suggest that residual disease analysis using PM-MRD should be conducted.</p