Miracle-dz/UniFAR-FTUs huggingface dataset:
An Update on Risk Evaluation and Mitigation Strategies in Transplantation

We have recently reported on the management of risk in developing new immunosuppressive agents (1). In particular, we discussed the ever-evolving environment of drug safety and described in detail the process of risk evaluation and mitigation strategies (REMS) and their impact on transplantation. Given the dynamic nature of drug safety, it is not surprising that, since the acceptance of our manuscript, there have been several major developments that must be addressed to provide practitioners with the most upto-date view of REMS. The two developments include the Food and Drug Administration (FDA) approval of belatacept (Nulojix, Bristol-Myers Squibb, Princeton, NJ, USA) for marketing in the United States and the FDA allowing some medications to be released from their REMS requirements.
Transplant Accommodation—Are the Lessons Learned from Xenotransplantation Pertinent for Clinical Allotransplantation?

“Accommodation” refers to a vascularized transplant that has acquired resistance to antibody‐mediated rejection (AMR). The term was coined in 1990, but the phenomenon was first described after clinical ABO‐incompatible (ABOi) renal transplantation in the 1980s and is recognized as a common outcome in this context today. Because of the absence, until recently of reliable animal models of allograft accommodation, it has been studied extensively by investigators in the xenotransplantation field. With recent advances in the ability to recognize and diagnose AMR in human organs, the growth of desensitization programmes for transplantation into sensitized recipients and the availability of therapies that have the potential to promote accommodation, it is timely to review the literature in this area, identifying lessons that may inform preclinical and clinical studies in the future.
Current Status of Organ Transplantation in Japan

To overcome severe donor shortage, Japanese doctors over the years have developed innovative strategies to maximize organs transplanted per brain death donor and expanded the donor pool using living donors. They also used living and marginal organs and drastically improved living donor lung, liver, pancreas and kidney transplantations. Moreover, they initiated ABO blood type incompatible liver transplantation advancements and succeeded in overcoming the blood type barrier in kidney and liver transplantations. Similar efforts are underway for pancreas transplantation. Furthermore, Japanese doctors have developed a nonaggressive step to achieve immunosuppression following organ transplantation by carefully monitoring donor‐specific hyporesponsiveness and infectious immunostatus. However, the institution of amendments to allocation systems and the intensification of efforts to decrease living donor morbidity and to increase the number of brain death donors have remained important issues needing attention. Overall, the strategies Japan has adopted to overcome donor shortage can provide useful insights on how to increase organ transplantations.
Increased microstructural white matter correlations in left, but not right, temporal lobe epilepsy

Microstructural white matter tract correlations have been shown to reflect known patterns of phylogenetic development and functional specialization in healthy subjects. The aim of this study was to establish intertract correlations in a group of controls and to examine potential deviations from normality in temporal lobe epilepsy (TLE). We investigated intertract correlations in 28 healthy controls, 21 left TLE (LTLE) and 23 right TLE (RTLE). Nine tracts were investigated, comprising the parahippocampal fasciculi, the uncinate fasciculi, the arcuate fasciculi, the frontoparietal tracts, and the fornix. An abnormal increase in tract correlations was observed in LTLE, while RTLE showed intertract correlations similar to controls. In the control group, tract correlations increased with increasing fractional anisotropy (FA), while in the TLE groups tract correlations increased with decreasing FA. Cluster analyses revealed agglomeration of bilateral pairs of homologous tracts in healthy subjects, with such pairs separated in our LTLE and RTLE groups. Discriminant analyses aimed at distinguishing LTLE from RTLE, revealing that tract correlations produce higher rates of accurate group classification than FA values. Our results confirm and extend previous work by showing that LTLE compared to RTLE patients display not only more extensive losses in microstructural orientation but also more aberrant intertract correlations. Aberrant correlations may be related to pathologic processes (i.e., seizure spread) or to adaptive processes aimed at preserving key cognitive functions. Our data suggest that tract correlations may have predictive value in distinguishing LTLE from RTLE, potentially moving diffusion imaging to a place of greater prominence in clinical practice. Hum Brain Mapp, 36:85–98, 2015. © 2014 Wiley Periodicals, Inc.
A Risk‐Prediction Model for In‐Hospital Mortality After Heart Transplantation in US Children

We sought to develop and validate a quantitative risk‐prediction model for predicting the risk of posttransplant in‐hospital mortality in pediatric heart transplantation (HT). Children <18 years of age who underwent primary HT in the United States during 1999–2008 (n = 2707) were identified using Organ Procurement and Transplant Network data. A risk‐prediction model was developed using two‐thirds of the cohort (random sample), internally validated in the remaining one‐third, and independently validated in a cohort of 338 children transplanted during 2009–2010. The best predictive model had four categorical variables: hemodynamic support (ECMO, ventilator support, VAD support vs. medical therapy), cardiac diagnosis (repaired congenital heart disease [CHD], unrepaired CHD vs. cardiomyopathy), renal dysfunction (severe, mild‐moderate vs. normal) and total bilirubin (≥ 2.0, 0.6 to <2.0 vs. <0.6 mg/dL). The C‐statistic (0.78) and the Hosmer–Lemeshow goodness‐of‐fit (p = 0.89) in the model‐development cohort were replicated in the internal validation and independent validation cohorts (C‐statistic 0.75, 0.81 and the Hosmer–Lemeshow goodness‐of‐fit p = 0.49, 0.53, respectively) suggesting acceptable prediction for posttransplant in‐hospital mortality. We conclude that this risk‐prediction model using four factors at the time of transplant has good prediction characteristics for posttransplant in‐hospital mortality in children and may be useful to guide decision‐making around patient listing for transplant and timing of mechanical support.
Report of a Consensus Conference on Transplant Program Quality and Surveillance

Public reports of organ transplant program outcomes by the US Scientific Registry of Transplant Recipients have been both groundbreaking and controversial. The reports are used by regulatory agencies, private insurance providers, transplant centers and patients. Failure to adequately adjust outcomes for risk may cause programs to avoid performing transplants involving suitable but high‐risk candidates and donors. At a consensus conference of stakeholders held February 13–15, 2012, the participants recommended that program‐specific reports be better designed to address the needs of all users. Additional comorbidity variables should be collected, but innovation should also be protected by excluding patients who are in approved protocols from statistical models that identify underperforming centers. The potential benefits of hierarchical and mixed‐effects statistical methods should be studied. Transplant centers should be provided with tools to facilitate quality assessment and performance improvement. Additional statistical methods to assess outcomes at small‐volume transplant programs should be developed. More data on waiting list risk and outcomes should be provided. Monitoring and reporting of short‐term living donor outcomes should be enhanced. Overall, there was broad consensus that substantial improvement in reporting outcomes of transplant programs in the United States could and should be made in a cost‐effective manner.
Induction of Allograft Tolerance by Monoclonal CD3 Antibodies: A Matter of Timing

Despite remarkable progress in organ transplantation through the development of a wealth of immunosuppressive drugs highly effective at controlling acute rejection, two major problems still remain, the loss of transplants due to chronic rejection and the growing number of sensitized recipients due to previous transplants, transfusions or pregnancies. Induction of immune tolerance appears to be the only way to curb this complex situation. Here we describe that a therapy, already successfully used to restore immune tolerance to self‐antigens in overt autoimmunity, is effective at promoting transplant tolerance. We demonstrate that a short low‐dose course with CD3 antibodies started after transplantation, at the time of effector T cell priming to alloantigens, induces permanent acceptance of fully mismatched islet allografts. Mechanistic studies revealed that antigen‐specific regulatory and effector T cells are differentially affected by the treatment. CD3 antibody treatment preferentially induces apoptosis of activated alloreactive T cells which is mandatory for tolerance induction. In contrast, regulatory T cells are relatively spared from CD3 antibody‐induced depletion and can transfer antigen‐specific tolerance thus arguing for their prominent role in sustaining long‐term graft survival.
Posttransplant De Novo Donor‐Specific HLA Antibodies Identify Pediatric Kidney Recipients at Risk for Late Antibody‐Mediated Rejection

The emerging role of humoral immunity in the pathogenesis of chronic allograft damage has prompted research aimed at assessing the role of anti‐HLA antibody (Ab) monitoring as a tool to predict allograft outcome. Data on the natural history of allografts in children developing de novo Ab after transplantation are limited. Utilizing sera collected pretransplant, and serially posttransplant, we retrospectively evaluated 82 consecutive primary pediatric kidney recipients, without pretransplant donor‐specific antibodies (DSA), for de novo Ab occurrence, and compared results with clinical–pathologic data. At 4.3‐year follow up, 19 patients (23%) developed de novo DSA whereas 24 had de novo non‐DSA (NDSA, 29%). DSA appeared at a median time of 24 months after transplantation and were mostly directed to HLA‐DQ antigens. Among the 82 patients, eight developed late/chronic active C4d+ antibody‐mediated rejection (AMR), and four C4d‐negative AMR. Late AMR correlated with DSA (p < 0.01), whose development preceded AMR by 1‐year median time. Patients with DSA had a median serum creatinine of 1.44 mg/dL at follow up, significantly higher than NDSA and Ab‐negative patients (p < 0.005). In our pediatric cohort, DSA identify patients at risk of renal dysfunction, AMR and graft loss; treatment started at Ab emergence might prevent AMR occurrence and/or progression to graft failure.
Early Hospital Readmission After Kidney Transplantation: Patient and Center‐Level Associations

Early hospital readmission (EHR) is associated with increased morbidity, costs and transition‐of‐care errors. We sought to quantify rates of and risk factors for EHR after kidney transplantation (KT). We studied 32 961 Medicare primary KT recipients (2000–2005) linked to Medicare claims through the United States Renal Data System. EHR was defined as at least one hospitalization within 30 days of initial discharge after KT. The association between EHR and recipient and transplant factors was explored using Poisson regression; hierarchical modeling was used to account for study center‐level differences. The overall EHR rate was 31%, and 19 independent patient‐level factors associated with EHR were identified: recipient factors included older age, African American race and various comorbidities; transplant factors included ECD, length of stay and lack of induction therapy. The unadjusted rate of EHR by center ranged from 18% to 47%, but conventional center‐level factors (percent African American, percent age > 60, percent deceased donor and percent expanded criteria donor) were not associated with EHR. However, intermediate total volume and average length of stay were associated with increased EHR risk. Better identification of patients at risk for early hospital readmission following KT may guide discharge planning and early posttransplant outpatient monitoring.
Are We Overdoing Pediatric Lower Gastrointestinal Endoscopy?

Introduction: Lower gastrointestinal endoscopy (LGIE)/colonoscopy is frequently performed for rectal bleeding, recurrent abdominal pain, and the diagnosis of inflammatory bowel disease (IBD). Although these are common indications, the causes of isolated rectal bleeding and recurrent abdominal pain in the otherwise well child have not been described. Methods: A retrospective analysis of patients who had had an LGIE/colonoscopy from January 2001 to December 2010 was performed. The following data were collected: demographic data, indication, distance reached, macroscopic findings, microscopic findings, diagnosis, additional procedures, and complications. Results: There were a total of 999 colonoscopies. The colonoscopy was normal in 390 of 999 (39%). The commonest indication for colonoscopy was a diagnosis of suspected IBD, 449 of 999 (45%). IBD was confirmed in 282 of 449 (63%), but colonoscopy was normal in 143 of 449 (32%) of suspected IBD. Colonoscopy was performed for rectal bleeding in 197 of 999 (20%) of whom 141 of 197 (72%) were normal. There were 46 (5%) colonoscopies performed for recurrent abdominal pain, which were all normal. Our completion rate to the cecum and beyond was 521 of 999 (52%). Our perforation rate during the 10 years was 0.2%. Conclusions: Colonoscopy is a safe procedure in pediatrics; however, 39% of colonoscopies in this series were normal. Many of these could have been avoided by eliminating colonoscopy in patients with recurrent abdominal pain in the absence of other clinical features, conservative management with laxatives for those with fresh blood per rectum typical of anal fissures, and fecal calprotectin screening before endoscopy in patients with suspected IBD.
A novel PCR-based technology for rapid and non-sequencing authentication of Bombyx batryticatus using species-specific primers

Abstract A novel PCR technology was developed to detect short DNA fragments using species-specific primers for rapid and non-sequencing authentication of Bombyx batryticatus based on differences in the mitochondrial genome. Three specifically designed primer reactions were established to target species for the reliable identification of their commercial products. They were confirmed to have a high inter-species specificity and intra-species stability. The limit of detection was estimated as 1 ng of genomes for Beauveria bassiana and 100 pg for Bombyx mori and Metarhizium anisopliae. Furthermore, validation results demonstrated that raw materials and their processed products can be conveniently authenticated with good sensitivity and precision using this newly proposed approach. In particular, when counterfeits were assayed, these primer sets performed well, whereas COI barcoding technology did not. These could also assist in the discrimination and identification of adulterates of other animal-derived medicines in their pulverized and processed forms and even in complexes.
Parkinson's disease‐related network topographies characterized with resting state functional MRI

Spatial covariance mapping can be used to identify and measure the activity of disease‐related functional brain networks. While this approach has been widely used in the analysis of cerebral blood flow and metabolic PET scans, it is not clear whether it can be reliably applied to resting state functional MRI (rs‐fMRI) data. In this study, we present a novel method based on independent component analysis (ICA) to characterize specific network topographies associated with Parkinson's disease (PD). Using rs‐fMRI data from PD and healthy subjects, we used ICA with bootstrap resampling to identify a PD‐related pattern that reliably discriminated the two groups. This topography, termed rs‐MRI PD‐related pattern (fPDRP), was similar to previously characterized disease‐related patterns identified using metabolic PET imaging. Following pattern identification, we validated the fPDRP by computing its expression in rs‐fMRI testing data on a prospective case basis. Indeed, significant increases in fPDRP expression were found in separate sets of PD and control subjects. In addition to providing a similar degree of group separation as PET, fPDRP values correlated with motor disability and declined toward normal with levodopa administration. Finally, we used this approach in conjunction with neuropsychological performance measures to identify a separate PD cognition‐related pattern in the patients. This pattern, termed rs‐fMRI PD cognition‐related pattern (fPDCP), was topographically similar to its PET‐derived counterpart. Subject scores for the fPDCP correlated with executive function in both training and testing data. These findings suggest that ICA can be used in conjunction with bootstrap resampling to identify and validate stable disease‐related network topographies in rs‐fMRI. Hum Brain Mapp 38:617–630, 2017. © 2016 Wiley Periodicals, Inc.
The physical health challenges in patients with severe mental illness: cardiovascular and metabolic risks

This supplement is the output of a roundtable discussion, attended by a multidisciplinary panel with a broad range of expertise, which includes the treatment of severe mental illness, cardiovascular disease, diabetes and pharmaceutical prescribing. The roundtable and writing of the supplement were organised and paid for by MSD, including the payment of Steve Titmarsh, a medical writer who was involved in the preparation and editing of this document
Abnormal functional connectivity and cortical integrity influence dominant hand motor disability in multiple sclerosis: a multimodal analysis

Functional reorganization and structural damage occur in the brains of people with multiple sclerosis (MS) throughout the disease course. However, the relationship between resting‐state functional connectivity (FC) reorganization in the sensorimotor network and motor disability in MS is not well understood. This study used resting‐state fMRI, T1‐weighted and T2‐weighted, and magnetization transfer (MT) imaging to investigate the relationship between abnormal FC in the sensorimotor network and upper limb motor disability in people with MS, as well as the impact of disease‐related structural abnormalities within this network. Specifically, the differences in FC of the left hemisphere hand motor region between MS participants with preserved (n = 17) and impaired (n = 26) right hand function, compared with healthy controls (n = 20) was investigated. Differences in brain atrophy and MT ratio measured at the global and regional levels were also investigated between the three groups. Motor preserved MS participants had stronger FC in structurally intact visual information processing regions relative to motor impaired MS participants. Motor impaired MS participants showed weaker FC in the sensorimotor and somatosensory association cortices and more severe structural damage throughout the brain compared with the other groups. Logistic regression analysis showed that regional MTR predicted motor disability beyond the impact of global atrophy whereas regional grey matter volume did not. More importantly, as the first multimodal analysis combining resting‐state fMRI, T1‐weighted, T2‐weighted and MTR images in MS, we demonstrate how a combination of structural and functional changes may contribute to motor impairment or preservation in MS. Hum Brain Mapp 37:4262–4275, 2016. © 2016 Wiley Periodicals, Inc.
How do we measure adherence to anti-tuberculosis treatment?

ABSTRACT Introduction: Completion of anti-tuberculosis (TB) treatment is of paramount importance for TB patients, as well as for the global efforts of TB control. However, there is neither a gold-standard measure to monitor adherence to TB treatment nor a widely used definition for different levels of adherence. Areas covered: in this review we aim to describe the different methods used to measure patients’ adherence to anti-TB treatment, identifying their main strengths and limitations, with a focus on low resource settings. Expert commentary: there is a need for continuing the quest for a low cost, reliable and acceptable measure of adherence to TB treatment. We should harmonize treatment adherence measurement to allow adequate comparison of different interventions aimed at increasing adherence to TB treatment, although the way we ensure adherence can affect adherence endpoints themselves. The accuracy of adherence measurement is of importance in the context of drug clinical development.
Factors affecting onchocerciasis transmission: lessons for infection control

ABSTRACT Introduction: Onchocerca volvulus infects in excess of 15 million people. The vectors are Simulium blackflies, varieties of which differ in their ecologies, behavior and vectorial abilities. Control of the vectors and mass administrations of ivermectin have succeeded in reducing prevalences with elimination achieved in some foci, particularly in Central and southern America. In Africa, progress towards elimination has been less successful. Areas covered: Even with community directed treatment with ivermectin (CDTI), control has been difficult in African areas with initial prevalences in excess of 55%, especially if only annual treatments are dispensed. This is partly attributable to insufficient coverage, but the appearance of incipiently resistant non-responding parasites and lack of attention to vector biology in modeling and planning outcomes of intervention programmes have also played their parts, with recrudescence now appearing in some treated areas. Expert commentary: The biology of onchocerciasis is complex involving different vectors with differing abilities to transmit parasites, diverse pathologies related to geographical and parasite variations and endosymbionts in both parasite and vector. Modeling to predict epidemiological and control outcomes is addressing this complexity but more attention needs to be given to the vectors’ roles to further understanding of where and when control measures will succeed.
Application of critical thinking diagnostics in the renal setting

Lack of critical thinking was at the core of an incidence of an avoidable diabetic coma in a renal surgical ward. Here Anita Farrell, Kay Riley, Susan Wheeler and Scott McLean describe the actions that were taken afterwards and how the use of a critical thinking methodology enabled the nurses at the ward to develop new strategies for smarter working and better patient care.
Sports experts criticise school PE lessons for failing to keep children fit

Physical education (PE) lessons in UK schools are failing to develop good general levels of fitness and often do not give children the aerobic workout they need to stay fit, sports experts claim. The British Association of Sports and Exercise Medicine has called for short, intense exercise routines to be built into the school day to encourage children to develop good “functional joint movement. ” Richard Budgett, the association’s chairman, told the BMJ that he believed physical education in schools at present to be “completely disastrous. ” At the annual UK sports and exercise medicine conference last week the association backed the …