Use, variability, and justification of eligibility criteria for phase II and III clinical trials in acute leukemia

Clinical trial eligibility criteria can unfairly exclude patients or unnecessarily expose them to known risks if criteria are not concordant with drug safety. There are few data evaluating the extent to which acute leukemia eligibility criteria are justified. We analyzed criteria and drug safety data for front-line phase II and/or III acute leukemia trials with start dates 1/1/2010-12/31/2019 registered on clinicaltrials.gov. Multivariable analyses assessed concordance between criteria use and safety data (presence of criteria with a safety signal, or absence of criteria without a signal), and differences between criteria and safety-based limits. Of 250 eligible trials, concordant use of ejection fraction criteria was seen in 34.8%, corrected QT level (QTc) in 22.4%, bilirubin in 68.4%, aspartate transaminase/alanine aminotransferase (AST/ALT) in 58.8%, renal function in 68.4%, human immunodeficiency virus (HIV) in 54.8%, and hepatitis B and C in 42.0% and 41.2%. HIV and hepatitis B and C criteria use was concordant with safety data (adjusted Odds Ratios 2.04 [95%CI: 1.13, 3.66], 2.64 [95%CI: 1.38, 5.04], 2.27 [95%CI: 1.20, 4.32]) but organ function criteria were not (all P>0.05); phase III trials were not more concordant. Bilirubin criteria limits were the same as safety-based limits in 16.0% of trials, AST/ALT in 18.1%, and renal function in 13.9%; in 75.7%, 51.4%, and 56.5% of trials, criteria were more restrictive, respectively, by median differences of 0.2, 0.5, and 0.5 times the upper limits of normal. We found limited drug safety justifications for acute leukemia eligibility criteria. These data define criteria use and limits that can be rationally modified to increase patient inclusion and welfare

Leadership in strategic information (LSI) building skilled public health capacity in Ethiopia

<p>Abstract</p> <p>Background</p> <p>In many developing countries, including Ethiopia, few have the skills to use data for effective decision making in public health. To address this need, the U.S. Centers for Disease Control and Prevention (CDC), in collaboration with two local Ethiopian organizations, developed a year long Leadership in Strategic Information (LSI) course to train government employees working in HIV to use data from strategic information sources. A process evaluation of the LSI course examined the impact of the training on trainees' skills and the strengths and weaknesses of the course. The evaluation consisted of surveys and focus groups.</p> <p>Findings</p> <p>Trainees' skill sets increased in descriptive and analytic epidemiology, surveillance, and monitoring and evaluation (M and E). Data from the evaluation indicated that the course structure and the M and E module required revision in order to improve outcomes. Additionally, the first cohort had a high attrition rate. Overall, trainees and key stakeholders viewed LSI as important in building skilled capacity in public health in Ethiopia.</p> <p>Conclusion</p> <p>The evaluation provided constructive insight in modifying the course to improve retention and better address trainees' learning needs. Subsequent course attrition rates decreased as a result of changes made based on evaluation findings.</p

Identification of an N-terminal 27 kDa fragment of Mycoplasma pneumoniae P116 protein as specific immunogen in M. pneumoniae infections

<p>Abstract</p> <p>Background</p> <p><it>Mycoplasma pneumoniae </it>is an important cause of respiratory tract infection and is increasingly being associated with other diseases such as asthma and extra-pulmonary complications. Considerable cross-reactivity is known to exist between the whole cell antigens used in the commercial serological testing assays. Identification of specific antigens is important to eliminate the risk of cross-reactions among different related organisms. Adherence of <it>M. pneumoniae </it>to human epithelial cells is mediated through a well defined apical organelle to which a number of proteins such as P1, P30, P116 and HMW1-3 have been localized, and are being investigated for adhesion, gliding and immunodiagnostic purposes.</p> <p>Methods</p> <p>A 609 bp fragment P116_(N-27),corresponding to the N-terminal region of <it>M. pneumoniae </it>P116 gene was cloned and expressed. A C-terminal fragment P1_(C-40),of P1 protein of <it>M. pneumoniae </it>was also expressed. Three IgM ELISA assays based on P116_(N-27),P1_(C-40)and (P116 _(N-27)+ P1_(C-40)) proteins were optimized and a detailed analysis comparing the reactivity of these proteins with a commercial kit was carried out. Comparative statistical analysis of these assays was performed with the SPSS version 15.0.</p> <p>Results</p> <p>The expressed P116_(N-27)protein was well recognized by the patient sera and was immunogenic in rabbit. P1_(C-40)of <it>M. pneumoniae </it>was also immunogenic in rabbit. In comparison to the reference kit, which is reported to be 100% sensitive and 75% specific, ELISA assay based on purified P116_(N-27),P1_(C-40)and (P116_(N-27)+ P1_(C-40)) proteins showed 90.3%, 87.1% and 96.8% sensitivity and 87.0%, 87.1% and 90.3% specificity respectively. The p value for all the three assays was found to be < 0.001, and there was a good correlation and association between them.</p> <p>Conclusion</p> <p>This study shows that an N-terminal fragment of P116 protein holds a promise for serodiagnosis of <it>M. pneumoniae </it>infection. The IgM ELISA assays based on the recombinant proteins seem to be suitable for the use in serodiagnosis of acute <it>M. pneumoniae </it>infections. The use of short recombinant fragments of P116 and P1 proteins as specific antigens may eliminate the risk of cross-reactions and help to develop a specific and sensitive immunodiagnostic assay for <it>M. pneumoniae </it>detection.</p

Secure Virtual Mobile Small Cells: A Stepping Stone Towards 6G

YesAs 5th Generation research reaches the twilight, the research community must go beyond 5G and look towards the 2030 connectivity landscape, namely 6G. In this context, this work takes a step towards the 6G vision by proposing a next generation communication platform, which aims to extend the rigid coverage area of fixed deployment networks by considering virtual mobile small cells (MSC) that are created on demand. Relying on emerging computing paradigms such as NFV (Network Function Virtualization) and SDN (Software Defined Networking), these cells can harness radio and networking capability locally reducing protocol signalling latency and overhead. These MSCs constitute an intelligent pool of networking resources that can collaborate to form a wireless network of MSCs providing a communication platform for localized, ubiquitous and reliable connectivity. The technology enablers for implementing the MSC concept are also addressed in terms of virtualization, lightweight wireless security, and energy efficient RF. The benefits of the MSC architecture towards reliable and efficient cell-offloading are demonstrated as a use-case.This project has received funding from the European Union's H2020 research and innovation program under grant agreement H2020-MCSAITN- 2016-SECRET 722424 [2]

Cholangiocyte organoids can repair bile ducts after transplantation in the human liver.

Organoid technology holds great promise for regenerative medicine but has not yet been applied to humans. We address this challenge using cholangiocyte organoids in the context of cholangiopathies, which represent a key reason for liver transplantation. Using single-cell RNA sequencing, we show that primary human cholangiocytes display transcriptional diversity that is lost in organoid culture. However, cholangiocyte organoids remain plastic and resume their in vivo signatures when transplanted back in the biliary tree. We then utilize a model of cell engraftment in human livers undergoing ex vivo normothermic perfusion to demonstrate that this property allows extrahepatic organoids to repair human intrahepatic ducts after transplantation. Our results provide proof of principle that cholangiocyte organoids can be used to repair human biliary epithelium

The Effects of cognitive appraisals of communication competence in conflict interactions : a study involving western and chinese cultures

This study investigated differences between people from Western and Chinese cultures on perceived competence (effectiveness and appropriateness) of the other party's communication during conflict. First, a pilot study with 30 employees in Singapore examined appraisals of communication competence in recalled intercultural conflict incidents. Western expatriates judged competence of the other party mainly on whether the communication style was direct and engaged, deemed to be judgments of effectiveness. However, host-nationals judged competence mainly on interactional skills and cultural knowledge, deemed to be judgments of appropriateness. Following the pilot study, a quasi-experimental study (128 Australian and 108 Chinese university students) showed that Australians discriminated between four different types of conflict styles more distinctly with effectiveness than appropriateness judgments and vice versa for Chinese. This supports the pilot work. Furthermore, both effectiveness and appropriateness judgments predicted relationship outcomes postconflict for both groups. For Australians, the trend of effectiveness judgments across the four conflict styles paralleled exactly the trend of their predictions for how much the relationship would improve postconflict, whereas their appropriateness judgments did not. For Chinese, neither competency judgments mirrored predictions on relationship improvement. However, their appropriateness judgments paralleled their predictions for level of status quo maintenance, but their effectiveness judgments did not. The evidence supports the hypothesis that people from different cultures hold dissimilar implicit cognitive theories of what defines in/competent communication in interpersonal conflict. The potent association of competency judgments with relational outcomes signals a new cognitive direction for conflict research, long fixated on behavioral manifestations.19 page(s

Fabrication of MXene/cellulose composite-based flexible supercapacitor: synthesis, properties, and future perspectives

MXenes have attracted considerable research interest in the field of energy storage due to their unique structure and favourable surface functional group properties. Recent efforts are focused extensively on synthesizing MXene composites for fabricating ideal electrode materials for energy storage applications. To fully exploit the characteristic features of MXene nanosheets and to ensure superb mechanical properties, cellulose is frequently used in combination with MXene to design high-potential functional nanocomposites. Cellulose serves as a promising reinforcing filler and flexible substrate due to its excellent mechanical strength. Its one-dimensional filamentous structure minimizes insulating contacts between 2D materials, enhancing both supercapacitive and mechanical properties. Furthermore, the 3D printing of micro-supercapacitors (MSCs) using MXene/cellulose inks yields desired printed interdigitated patterns with higher geometric accuracy, resulting in superior mechanical strength and capacitive performance. In this article, we present a comprehensive and timely review of recent research efforts and their outcomes related to the fabrication of flexible supercapacitors (SCs) based on MXene/cellulose composites. The scope extends to the fabrication of MXene/cellulose MSCs and electrodes that are wearable or free-standing. The initial sections of the article delve into the current synthesis methodologies for MAX phase and MXene, highlighting structural variations resulting from different synthesis procedures. Subsequently, we discuss the synthesis procedures for MXene/cellulose composites, the fabrication of MXene/cellulose based SCs, and their performance. Towards the end, we address existing research gaps and provide insights into future perspectives regarding MXene/cellulose SCs, drawing from the latest research findings. This review underscores the pivotal role played by MXene/cellulose composites in advancing the field of energy storage

Ovarian Endometrioid Adenocarcinoma: Incidence and Clinical Significance of the Morphologic and Immunohistochemical Markers of Mismatch Repair Protein Defects and Tumor Microsatellite Instability

A subset of women with uterine cancer exhibiting defective mismatch repair (MMR) proteins and microsatellite instability (MSI) may have Lynch syndrome, which also confers a risk for colorectal cancer and other cancers in the patient and in her family. Screening algorithms based on clinical and pathologic criteria are effective in determining which patients with uterine cancer are most likely to benefit from definitive genetic testing for Lynch syndrome. Ovarian cancer, particularly endometrioid adenocarcinoma, is also associated with Lynch syndrome, although the risk is much smaller than for uterine cancer. This study evaluated whether the morphologic criteria [tumor-infiltrating lymphocytes (TILs), peritumoral lymphocytes (PTLs), dedifferentiated morphology)] currently used to screen uterine cancer for further Lynch syndrome testing can be applied to ovarian cancer. Among 71 patients with pure ovarian endometrioid adenocarcinoma treated at a single institution, 13% had a tumor with TILs, 3% had PTLs, and none had dedifferentiated morphology. Overall, 10% of tumors had abnormal MMR protein status, defined as complete immunohistochemical loss of expression of MLH1, MSH2, MSH6, and/or PMS2. Each of these tumors with abnormal MMR status demonstrated MSI using a polymerase chain reaction-based assay evaluating 5 mononucleotide repeat markers. No relationship was found between patient age, TILs, PTLs, or a spectrum of other morphologic variables and MMR protein status/MSI. Only 1/7 tumors with abnormal MMR/MSI had TILs/PTLs. Among 14 patients who died, 12 (86%) had normal MMR status. Among 7 patients with tumors with abnormal MMR/MSI, 5 (71%) were alive without disease. Concurrent uterine tumor was present in 5/7 patients whose ovarian tumor had abnormal MMR/MSI. This study suggests that the morphologic criteria used to screen patients with uterine cancer for further Lynch syndrome testing are not applicable in patients with ovarian cancer. Although abnormal MMR/MSI did not carry prognostic value in this study, it did predict the involvement of the uterus by the tumor. Thus, in patients with ovarian endometrioid adenocarcinoma who undergo uterus-sparing surgery, abnormal MMR/MSI should prompt further diagnostic evaluation of the endometrium for tumor