Protocol of a cluster randomized trial of an educational intervention to increase knowledge of living donor kidney transplant among potential transplant candidates

BackgroundThe best treatment option for end-stage renal disease is usually a transplant, preferably a live donor kidney transplant (LDKT). The most effective ways to educate kidney transplant candidates about the risks, benefits, and process of LDKT remain unknown.Methods/designWe report the protocol of the Enhancing Living Donor Kidney Transplant Education (ELITE) Study, a cluster randomized trial of an educational intervention to be implemented during initial transplant evaluation at a large, suburban U.S. transplant center. Five hundred potential transplant candidates are cluster randomized (by date of visit) to receive either: (1) standard-of-care ("usual") transplant education, or (2) intensive education that is based upon the Explore Transplant series of educational materials. Intensive transplant education includes viewing an educational video about LDKT, receiving print education, and meeting with a transplant educator. The primary outcome consists of knowledge of the benefits, risks, and process of LDKT, assessed one week after the transplant evaluation. As a secondary outcome, knowledge and understanding of LDKT are assessed 3 months after the evaluation. Additional secondary outcomes, assessed one week and 3 months after the evaluation, include readiness, self-efficacy, and decisional balance regarding transplant and LDKT, with differences assessed by race. Although the unit of randomization is the date of the transplant evaluation visit, the unit of analysis will be the individual potential transplant candidate.DiscussionThe ELITE Study will help to determine how education in a transplant center can best be designed to help Black and non-Black patients learn about the option of LDKT.Trial registrationClinicaltrials.gov number NCT01261910

Viability PCR shows that non-ocular surfaces could contribute to transmission of Chlamydia trachomatis infection in trachoma.

BACKGROUND: The presence of Chlamydia trachomatis (Ct) DNA at non-ocular sites suggests that these sites may represent plausible routes of Ct transmission in trachoma. However, qPCR cannot discriminate between DNA from viable and non-viable bacteria. Here we use a propodium monoazide based viability PCR to investigate how long Ct remains viable at non-ocular sites under laboratory-controlled conditions. METHODS: Cultured Ct stocks (strain A2497) were diluted to final concentrations of 1000, 100, 10 and 1 omcB copies/μL and applied to plastic, woven mat, cotton cloth and pig skin. Swabs were then systemically collected from each surface and tested for the presence Ct DNA using qPCR. If Ct DNA was recovered, Ct viability was assessed over time by spiking multiple areas of the same surface type with the same final concentrations. Swabs were collected from each surface at 0, 2, 4, 6, 8 and 24 hours after spiking. Viability PCR was used to determine Ct viability at each timepoint. RESULTS: We were able to detect Ct DNA on all surfaces except the woven mat. Total Ct DNA remained detectable and stable over 24 hours for all concentrations applied to plastic, pig skin and cotton cloth. The amount of viable Ct decreased over time. For plastic and skin surfaces, only those where concentrations of 100 or 1000 omcB copies/μL were applied still had viable loads detectable after 24 hours. Cotton cloth showed a more rapid decrease and only those where concentrations of 1000 omcB copies/μL were applied still had viable DNA detectable after 24 hours. CONCLUSION: Plastic, cotton cloth and skin may contribute to transmission of the Ct strains that cause trachoma, by acting as sites where reservoirs of bacteria are deposited and later collected and transferred mechanically into previously uninfected eyes

Defining Responses to Therapy and Study Outcomes in Clinical Trials of Invasive Fungal Diseases: Mycoses Study Group and European Organization for Research and Treatment of Cancer Consensus Criteria

Invasive fungal diseases (IFDs) have become major causes of morbidity and mortality among highly immunocompromised patients. Authoritative consensus criteria to diagnose IFD have been useful in establishing eligibility criteria for antifungal trials. There is an important need for generation of consensus definitions of outcomes of IFD that will form a standard for evaluating treatment success and failure in clinical trials. Therefore, an expert international panel consisting of the Mycoses Study Group and the European Organization for Research and Treatment of Cancer was convened to propose guidelines for assessing treatment responses in clinical trials of IFDs and for defining study outcomes. Major fungal diseases that are discussed include invasive disease due to Candida species, Aspergillus species and other molds, Cryptococcus neoformans, Histoplasma capsulatum, and Coccidioides immitis. We also discuss potential pitfalls in assessing outcome, such as conflicting clinical, radiological, and/or mycological data and gaps in knowledg

STAT1 Hyperphosphorylation and Defective IL12R/IL23R Signaling Underlie Defective Immunity in Autosomal Dominant Chronic Mucocutaneous Candidiasis

We recently reported the genetic cause of autosomal dominant chronic mucocutaneous candidiasis (AD-CMC) as a mutation in the STAT1 gene. In the present study we show that STAT1 Arg274Trp mutations in the coiled-coil (CC) domain is the genetic cause of AD-CMC in three families of patients. Cloning and transfection experiments demonstrate that mutated STAT1 inhibits IL12R/IL-23R signaling, with hyperphosphorylation of STAT1 as the likely underlying molecular mechanism. Inhibition of signaling through the receptors for IL-12 and IL-23 leads to strongly diminished Th1/Th17 responses and hence to increased susceptibility to fungal infections. The challenge for the future is to translate this knowledge into novel strategies for the treatment of this severe immunodeficiency

Distinct Cerebrospinal Fluid Proteomes Differentiate Post-Treatment Lyme Disease from Chronic Fatigue Syndrome

Neurologic Post Treatment Lyme disease (nPTLS) and Chronic Fatigue (CFS) are syndromes of unknown etiology. They share features of fatigue and cognitive dysfunction, making it difficult to differentiate them. Unresolved is whether nPTLS is a subset of CFS. Methods and Principal Findings: Pooled cerebrospinal fluid (CSF) samples from nPTLS patients, CFS patients, and healthy volunteers were comprehensively analyzed using high-resolution mass spectrometry (MS), coupled with immunoaffinity depletion methods to reduce protein-masking by abundant proteins. Individual patient and healthy control CSF samples were analyzed directly employing a MS-based label-free quantitative proteomics approach. We found that both groups, and individuals within the groups, could be distinguished from each other and normals based on their specific CSF proteins (p&0.01). CFS (n = 43) had 2,783 non-redundant proteins, nPTLS (n = 25) contained 2,768 proteins, and healthy normals had 2,630 proteins. Preliminary pathway analysis demonstrated that the data could be useful for hypothesis generation on the pathogenetic mechanisms underlying these two related syndromes. Conclusions: nPTLS and CFS have distinguishing CSF protein complements. Each condition has a number of CSF proteins that can be useful in providing candidates for future validation studies and insights on the respective mechanisms of pathogenesis. Distinguishing nPTLS and CFS permits more focused study of each condition, and can lead to novel diagnostics and therapeutic interventions

The Epidemiology and Clinical Spectrum of Melioidosis: 540 Cases from the 20 Year Darwin Prospective Study

Melioidosis is an occupationally and recreationally acquired infection important in Southeast Asia and northern Australia. Recently cases have been reported from more diverse locations globally. The responsible bacterium, Burkholderia pseudomallei, is considered a potential biothreat agent. Risk factors predisposing to melioidosis are well recognised, most notably diabetes. The Darwin prospective melioidosis study has identified 540 cases of melioidosis over 20 years and analysis of the epidemiology and clinical findings provides important new insights into this disease. Risk factors identified in addition to diabetes, hazardous alcohol use and chronic renal disease include chronic lung disease, malignancies, rheumatic heart disease, cardiac failure and age ≥50 years. Half of patients presented with pneumonia and septic shock was common (21%). The decrease in mortality from 30% in the first 5 years of the study to 9% in the last five years is attributed to earlier diagnosis and improvements in intensive care management. Of the 77 fatal cases (14%), all had known risk factors for melioidosis. This supports the most important conclusion of the study, which is that melioidosis is very unlikely to kill a healthy person, provided the infection is diagnosed early and resources are available to provide appropriate antibiotics and critical care where required

Organization, Evolution, Cognition and Dynamic Capabilities

Using insights from ‘embodied cognition’ and a resulting ‘cognitive theory of the firm’, I aim to contribute to the further development of evolutionary theory of organizations, in the specification of organizations as ‘interactors’ that carry organizational competencies as ‘replicators’, within industries as ‘populations’. Especially, I analyze how, if at all, ‘dynamic capabilities’ can be fitted into evolutionary theory. I propose that the prime purpose of an organization is to serve as a cognitive ‘focusing device’. Here, cognition has a wide meaning, including perception, interpretation, sense making, and value judgements. I analyse how this yields organizations as cohesive wholes, and differences within and between industries. I propose the following sources of variation: replication in communication, novel combinations of existing knowledge, and a path of discovery by which exploitation leads to exploration. These yield a proposal for dynamic capabilities. I discuss in what sense, and to what extent these sources of variation are ‘blind’, as postulated in evolutionary theory.

Obtaining Adequate Surgical Margins in Breast-Conserving Therapy for Patients with Early-Stage Breast Cancer: Current Modalities and Future Directions

Inadequate surgical margins represent a high risk for adverse clinical outcome in breast-conserving therapy (BCT) for early-stage breast cancer. The majority of studies report positive resection margins in 20% to 40% of the patients who underwent BCT. This may result in an increased local recurrence (LR) rate or additional surgery and, consequently, adverse affects on cosmesis, psychological distress, and health costs. In the literature, various risk factors are reported to be associated with positive margin status after lumpectomy, which may allow the surgeon to distinguish those patients with a higher a priori risk for re-excision. However, most risk factors are related to tumor biology and patient characteristics, which cannot be modified as such. Therefore, efforts to reduce the number of positive margins should focus on optimizing the surgical procedure itself, because the surgeon lacks real-time intraoperative information on the presence of positive resection margins during breast-conserving surgery. This review presents the status of pre- and intraoperative modalities currently used in BCT. Furthermore, innovative intraoperative approaches, such as positron emission tomography, radioguided occult lesion localization, and near-infrared fluorescence optical imaging, are addressed, which have to prove their potential value in improving surgical outcome and reducing the need for re-excision in BCT

Autoantibodies neutralizing type I IFNs are present in ~4% of uninfected individuals over 70 years old and account for ~20% of COVID-19 deaths

Publisher Copyright: © 2021 The Authors, some rights reserved.Circulating autoantibodies (auto-Abs) neutralizing high concentrations (10 ng/ml; in plasma diluted 1:10) of IFN-alpha and/or IFN-omega are found in about 10% of patients with critical COVID-19 (coronavirus disease 2019) pneumonia but not in individuals with asymptomatic infections. We detect auto-Abs neutralizing 100-fold lower, more physiological, concentrations of IFN-alpha and/or IFN-omega (100 pg/ml; in 1:10 dilutions of plasma) in 13.6% of 3595 patients with critical COVID-19, including 21% of 374 patients >80 years, and 6.5% of 522 patients with severe COVID-19. These antibodies are also detected in 18% of the 1124 deceased patients (aged 20 days to 99 years; mean: 70 years). Moreover, another 1.3% of patients with critical COVID-19 and 0.9% of the deceased patients have auto-Abs neutralizing high concentrations of IFN-beta. We also show, in a sample of 34,159 uninfected individuals from the general population, that auto-Abs neutralizing high concentrations of IFN-alpha and/or IFN-omega are present in 0.18% of individuals between 18 and 69 years, 1.1% between 70 and 79 years, and 3.4% >80 years. Moreover, the proportion of individuals carrying auto-Abs neutralizing lower concentrations is greater in a subsample of 10,778 uninfected individuals: 1% of individuals 80 years. By contrast, auto-Abs neutralizing IFN-beta do not become more frequent with age. Auto-Abs neutralizing type I IFNs predate SARS-CoV-2 infection and sharply increase in prevalence after the age of 70 years. They account for about 20% of both critical COVID-19 cases in the over 80s and total fatal COVID-19 cases.Peer reviewe