COVID-19 pandemic: Building organisational flexibility to scale transplant programs

The prevailing coronavirus disease 2019 pandemic has challenged our lives in an unprecedented manner. The pandemic has had a significant impact on transplantation worldwide. The logistics of travel restrictions, stretching of available resources, unclear risk of infection in immunosuppressed transplant recipients, and evolving guidelines on testing and transplantation are some of the factors that have unfavourably influenced transplant activity. We must begin to build organisational flexibility in order to restart transplantation so that we can be mindful stewards of organ donation and sincere advocates for our patients. Building a culture of honesty and transparency (with patients, families, colleagues, societies, and authorities), keeping the channels of communication open, working in collaboration with others (at local, regional, national, and international levels), and not restarting without rethinking and appraising all elements of our practice, are the main underlying principles to increase the flexibilit

Anticoagulation in simultaneous pancreas kidney transplantation - On what basis?

BACKGROUND: Despite technical refinements, early pancreas graft loss due to thrombosis continues to occur. Conventional coagulation tests (CCT) do not detect hypercoagulability and hence the hypercoagulable state due to diabetes is left untreated. Thromboelastogram (TEG) is an in-vitro diagnostic test which is used in liver transplantation, and in various intensive care settings to guide anticoagulation. TEG is better than CCT because it is dynamic and provides a global hemostatic profile including fibrinolysis. AIM: To compare the outcomes between TEG and CCT (prothrombin time, activated partial thromboplastin time and international normalized ratio) directed anticoagulation in simultaneous pancreas and kidney (SPK) transplant recipients. METHODS: A single center retrospective analysis comparing the outcomes between TEG and CCT-directed anticoagulation in SPK recipients, who were matched for donor age and graft type (donors after brainstem death and donors after circulatory death). Anticoagulation consisted of intravenous (IV) heparin titrated up to a maximum of 500 IU/h based on CCT in conjunction with various clinical parameters or directed by TEG results. Graft loss due to thrombosis, anticoagulation related bleeding, radiological incidence of partial thrombi in the pancreas graft, thrombus resolution rate after anticoagulation dose escalation, length of the hospital stays and, 1-year pancreas and kidney graft survival between the two groups were compared. RESULTS: Seventeen patients who received TEG-directed anticoagulation were compared against 51 contemporaneous SPK recipients (ratio of 1: 3) who were anticoagulated based on CCT. No graft losses occurred in the TEG group, whereas 11 grafts (7 pancreases and 4 kidneys) were lost due to thrombosis in the CCT group (P = 0.06, Fisher's exact test). The overall incidence of anticoagulation related bleeding (hematoma/ gastrointestinal bleeding/ hematuria/ nose bleeding/ re-exploration for bleeding/ post-operative blood transfusion) was 17.65% in the TEG group and 45.10% in the CCT group (P = 0.05, Fisher's exact test). The incidence of radiologically confirmed partial thrombus in pancreas allograft was 41.18% in the TEG and 25.50% in the CCT group (P = 0.23, Fisher's exact test). All recipients with partial thrombi detected in computed tomography (CT) scan had an anticoagulation dose escalation. The thrombus resolution rates in subsequent scan were 85.71% and 63.64% in the TEG group vs the CCT group (P = 0.59, Fisher's exact test). The TEG group had reduced blood product usage {10 packed red blood cell (PRBC) and 2 fresh frozen plasma (FFP)} compared to the CCT group (71 PRBC/ 10 FFP/ 2 cryoprecipitate and 2 platelets). The proportion of patients requiring transfusion in the TEG group was 17.65% vs 39.25% in the CCT group (P = 0.14, Fisher's exact test). The median length of hospital stay was 18 days in the TEG group vs 31 days in the CCT group (P = 0.03, Mann Whitney test). The 1-year pancreas graft survival was 100% in the TEG group vs 82.35% in the CCT group (P = 0.07, log rank test) and, the 1-year kidney graft survival was 100% in the TEG group vs 92.15% in the CCT group (P = 0.23, log tank test). CONCLUSION: TEG is a promising tool in guiding judicious use of anticoagulation with concomitant prevention of graft loss due to thrombosis, and reduces the length of hospital stay

Genetic algorithm learning as a robust approach to RNA editing site prediction

BACKGROUND: RNA editing is one of several post-transcriptional modifications that may contribute to organismal complexity in the face of limited gene complement in a genome. One form, known as C → U editing, appears to exist in a wide range of organisms, but most instances of this form of RNA editing have been discovered serendipitously. With the large amount of genomic and transcriptomic data now available, a computational analysis could provide a more rapid means of identifying novel sites of C → U RNA editing. Previous efforts have had some success but also some limitations. We present a computational method for identifying C → U RNA editing sites in genomic sequences that is both robust and generalizable. We evaluate its potential use on the best data set available for these purposes: C → U editing sites in plant mitochondrial genomes. RESULTS: Our method is derived from a machine learning approach known as a genetic algorithm. REGAL (RNA Editing site prediction by Genetic Algorithm Learning) is 87% accurate when tested on three mitochondrial genomes, with an overall sensitivity of 82% and an overall specificity of 91%. REGAL's performance significantly improves on other ab initio approaches to predicting RNA editing sites in this data set. REGAL has a comparable sensitivity and higher specificity than approaches which rely on sequence homology, and it has the advantage that strong sequence conservation is not required for reliable prediction of edit sites. CONCLUSION: Our results suggest that ab initio methods can generate robust classifiers of putative edit sites, and we highlight the value of combinatorial approaches as embodied by genetic algorithms. We present REGAL as one approach with the potential to be generalized to other organisms exhibiting C → U RNA editing

Internal Medicine Residents Reject “Longer and Gentler” Training

BACKGROUND: Increasing complexity of medical care, coupled with limits on resident work hours, has prompted consideration of extending Internal Medicine training. It is unclear whether further hour reductions and extension of training beyond the current duration of 3 years would be accepted by trainees. OBJECTIVE: We aimed to determine if further work-hour reductions and extension of training would be accepted by trainees and whether resident burnout affects their opinions. DESIGN: A postal survey was sent to all 143 Internal Medicine residents at the University of Colorado School of Medicine in May 2004. MEASUREMENTS: The survey contained questions related to opinions on work-hour limits using a 5-point Likert scale ranging from strongly agree to strongly disagree. Burnout was measured using the Maslach Burnout Inventory, organized into three subscales: emotional exhaustion (EE), depersonalization (DP), and personal accomplishment, with burnout defined as high EE or DP. RESULTS: Seventy-four percent (106/143) of residents returned the survey. The vast majority (84%) of residents disagreed or strongly disagreed with extending training to 4 or 5 years. Burnout residents were less averse to extending training (strongly agree or agree, 18.9% vs 4.3%, P = .04). The majority of residents (68.9%) disagreed or strongly disagreed with establishing a 60-hour/week limit. Residents who met the criteria for burnout were more likely to agree that a 60-hour limit would be better than an 80-hour limit (strongly agree or agree, 22% vs 8%, P = .02). CONCLUSIONS: In this program, most Internal Medicine residents are strongly opposed to extending their training to 4 or 5 years and would prefer the current 80 hours/week cap. A longer, less intense pace of Internal Medicine training seems to be less attractive in the eyes of current trainees

Maximizing dose reductions with cardiac CT

Multidetector computed tomography has come a long way in a short time, quickly becoming a standard tool in the cardiac imaging armamentarium. The promise of plaque imaging, combined with both anatomical visualization and stenosis detection, has made this a preferred first line test of many cardiologists and radiologists. This test is well suited to rule out coronary artery disease (obstruction) and still diagnosing subclinical plaque, with may be a good target for anti-atherosclerotic therapies. There has been recent criticism against CT imaging, and cardiac CT specifically, due to the high radiation doses that being employed. New advances have allowed for dramatic dose reductions. These include more routinely performed methods such as dose modulation, and newer methods such as prospective gating or minimizing the field of view. This paper will review the different applications to reduce cardiac CT radiation doses to nominal levels, potentially expanding the applications of cardiac CT by removing one of the biggest barriers

Regulation of Mouse Small Heat Shock Protein αb-Crystallin Gene by Aryl Hydrocarbon Receptor

The stress-inducible small heat shock protein (shsp)/αB-crystallin gene is expressed highly in the lens and moderately in other tissues. Here we provide evidence that it is a target gene of the aryl hydrocarbon receptor (AhR) transcription factor. A sequence (−329/−323, CATGCGA) similar to the consensus xenobiotic responsive element (XRE), called here XRE-like, is present in the αBE2 region of αB-crystallin enhancer and can bind AhR in vitro and in vivo. αB-crystallin protein levels were reduced in retina, lens, cornea, heart, skeletal muscle and cultured muscle fibroblasts of AhR−/− mice; αB-crystallin mRNA levels were reduced in the eye, heart and skeletal muscle of AhR−/− mice. Increased AhR stimulated αB-crystallin expression in transfection experiments conducted in conjunction with the aryl hydrocarbon receptor nuclear translocator (ARNT) and decreased AhR reduced αB-crystallin expression. AhR effect on aB-crystallin promoter activity was cell-dependent in transfection experiments. AhR up-regulated αB-crystallin promoter activity in transfected HeLa, NIH3T3 and COS-7 cells in the absence of exogenously added ligand (TCDD), but had no effect on the αB-crystallin promoter in C2C12, CV-1 or Hepa-1 cells with or without TCDD. TCDD enhanced AhR-stimulated αB-crystallin promoter activity in transfected αTN4 cells. AhR could bind to an XRE-like site in the αB-crystallin enhancer in vitro and in vivo. Finally, site-specific mutagenesis experiments showed that the XRE-like motif was necessary for both basal and maximal AhR-induction of αB-crystallin promoter activity. Our data strongly suggest that AhR is a regulator of αB-crystallin gene expression and provide new avenues of research for the mechanism of tissue-specific αB-crystallin gene regulation under normal and physiologically stressed conditions

The AFLOW Fleet for Materials Discovery

The traditional paradigm for materials discovery has been recently expanded to incorporate substantial data driven research. With the intent to accelerate the development and the deployment of new technologies, the AFLOW Fleet for computational materials design automates high-throughput first principles calculations, and provides tools for data verification and dissemination for a broad community of users. AFLOW incorporates different computational modules to robustly determine thermodynamic stability, electronic band structures, vibrational dispersions, thermo-mechanical properties and more. The AFLOW data repository is publicly accessible online at aflow.org, with more than 1.7 million materials entries and a panoply of queryable computed properties. Tools to programmatically search and process the data, as well as to perform online machine learning predictions, are also available.Comment: 14 pages, 8 figure

Malignant melanoma of the mandibular gingiva

Oral malignant melanoma is an infrequent neoplasia making up less than 1% of all melanomas, which exhibits much more aggressive behavior than those found on the skin. We present an aggressive case of oral malignant melanoma located on the mandibular gingiva in a 24-year-old male patient, who developed metastases to not only the regional lymph nodes but also the lungs and liver. The advanced stage of the disease contraindicated any surgical intervention and palliative chemotherapy was planned

Extent of non-publication in cohorts of studies approved by research ethics committees or included in trial registries

BACKGROUND: The synthesis of published research in systematic reviews is essential when providing evidence to inform clinical and health policy decision-making. However, the validity of systematic reviews is threatened if journal publications represent a biased selection of all studies that have been conducted (dissemination bias). To investigate the extent of dissemination bias we conducted a systematic review that determined the proportion of studies published as peer-reviewed journal articles and investigated factors associated with full publication in cohorts of studies (i) approved by research ethics committees (RECs) or (ii) included in trial registries. METHODS AND FINDINGS: Four bibliographic databases were searched for methodological research projects (MRPs) without limitations for publication year, language or study location. The searches were supplemented by handsearching the references of included MRPs. We estimated the proportion of studies published using prediction intervals (PI) and a random effects meta-analysis. Pooled odds ratios (OR) were used to express associations between study characteristics and journal publication. Seventeen MRPs (23 publications) evaluated cohorts of studies approved by RECs; the proportion of published studies had a PI between 22% and 72% and the weighted pooled proportion when combining estimates would be 46.2% (95% CI 40.2%-52.4%, I2 = 94.4%). Twenty-two MRPs (22 publications) evaluated cohorts of studies included in trial registries; the PI of the proportion published ranged from 13% to 90% and the weighted pooled proportion would be 54.2% (95% CI 42.0%-65.9%, I2 = 98.9%). REC-approved studies with statistically significant results (compared with those without statistically significant results) were more likely to be published (pooled OR 2.8; 95% CI 2.2-3.5). Phase-III trials were also more likely to be published than phase II trials (pooled OR 2.0; 95% CI 1.6-2.5). The probability of publication within two years after study completion ranged from 7% to 30%. CONCLUSIONS: A substantial part of the studies approved by RECs or included in trial registries remains unpublished. Due to the large heterogeneity a prediction of the publication probability for a future study is very uncertain. Non-publication of research is not a random process, e.g., it is associated with the direction of study findings. Our findings suggest that the dissemination of research findings is biased

Cerebral activations related to ballistic, stepwise interrupted and gradually modulated movements in parkinson patients

Patients with Parkinson's disease (PD) experience impaired initiation and inhibition of movements such as difficulty to start/stop walking. At single-joint level this is accompanied by reduced inhibition of antagonist muscle activity. While normal basal ganglia (BG) contributions to motor control include selecting appropriate muscles by inhibiting others, it is unclear how PD-related changes in BG function cause impaired movement initiation and inhibition at single-joint level. To further elucidate these changes we studied 4 right-hand movement tasks with fMRI, by dissociating activations related to abrupt movement initiation, inhibition and gradual movement modulation. Initiation and inhibition were inferred from ballistic and stepwise interrupted movement, respectively, while smooth wrist circumduction enabled the assessment of gradually modulated movement. Task-related activations were compared between PD patients (N = 12) and healthy subjects (N = 18). In healthy subjects, movement initiation was characterized by antero-ventral striatum, substantia nigra (SN) and premotor activations while inhibition was dominated by subthalamic nucleus (STN) and pallidal activations, in line with the known role of these areas in simple movement. Gradual movement mainly involved antero-dorsal putamen and pallidum. Compared to healthy subjects, patients showed reduced striatal/SN and increased pallidal activation for initiation, whereas for inhibition STN activation was reduced and striatal-thalamo-cortical activation increased. For gradual movement patients showed reduced pallidal and increased thalamo-cortical activation. We conclude that PD-related changes during movement initiation fit the (rather static) model of alterations in direct and indirect BG pathways. Reduced STN activation and regional cortical increased activation in PD during inhibition and gradual movement modulation are better explained by a dynamic model that also takes into account enhanced responsiveness to external stimuli in this disease and the effects of hyper-fluctuating cortical inputs to the striatum and STN in particular