An increased incidence of malignancy is an established complication of organ transplantation and the associated immunosuppression. In this study on cancer incidence in solid organ transplant ...recipients in Britain, we describe the incidence of de novo cancers in the allograft recipient, and compare these incidences following the transplantation of different organs. Data in the UK Transplant Registry held by NHS Blood and Transplant (NHSBT) were linked with data made available by the cancer registries in England, Scotland and Wales. Incidence rates in the transplanted population were then compared with the general population, using standardized incidence ratios matched for age, gender and time period. The 10‐year incidence of de novo cancer in transplant recipients is twice that of the general population, with the incidence of nonmelanoma skin cancer being 13 times greater. Nonmelanoma skin cancer, cancer of the lip, posttransplant lymphoproliferative disease and anal cancer have the largest standardized incidence ratios, but the incidence of different types of malignancy differs according to the organ transplanted. Patterns in standardized incidence ratios over time since transplantation are different for different types of transplant recipient, as well as for different malignancies. These results have implications for a national screening program.
Trends in malignancy incidence over time in transplant recipients varied according to whether a kidney, liver, heart or lung was transplanted and the type of cancer.
The immunoglobulin (IG) loci consist of repeated and highly homologous sets of genes of different types, variable (V), diversity (D) and junction (J), that rearrange in developing B cells to produce ...an individual's highly variable repertoire of expressed antibodies, designed to bind to a vast array of pathogens. This repeated structure makes these loci susceptible to a high frequency of insertion and deletion events through evolutionary time, and also makes them difficult to characterize at the genomic level or assay with high-throughput techniques. Given the central role of antibodies in the adaptive immune system, it is not surprising that early candidate gene approaches showed that germline polymorphisms in these regions correlated with susceptibility to both infectious and autoimmune diseases. However, more recent studies, particularly those using high-throughput genome-wide arrays, have failed to implicate these loci in disease. In this review of the IG heavy chain variable gene cluster (IGHV), we examine how poorly we understand the distribution of haplotype variation in this genomic region, and we argue that this lack of information may mask candidate loci in the IGHV gene cluster as causative factors for infectious and autoimmune diseases.
Chemotherapy‐induced peripheral neuropathy (CIPN) is a common, dose‐limiting side effect of many chemotherapeutic agents. Although many therapies have been investigated for the prevention and/or ...treatment of CIPN, there is no well‐accepted proven therapy. In addition, there is no universally accepted, well‐validated measure for the assessment of CIPN. The agents for which there are the strongest preliminary data regarding their potential efficacy in preventing CIPN are intravenous calcium and magnesium (Ca/Mg) infusions and glutathione. Agents with the strongest supporting evidence for efficacy in the treatment of CIPN include topical pain relievers, such as baclofen/amitriptyline/ketamine gel, and serotonin and norepinephrine reuptake inhibitors, such as venlafaxine and duloxetine. Other promising therapies are also reviewed in this paper. Cutaneous electrostimulation is a nonpharmacological therapy that appears, from an early pilot trial, to be potentially effective in the treatment of CIPN. Finally, there is a lack of evidence of effective treatments for the paclitaxel acute pain syndrome (P‐APS), which appears to be caused by neurologic injury.
Clinical Pharmacology & Therapeutics (2011) 90 3, 377–387. doi:10.1038/clpt.2011.115
The monitoring of adverse drug reactions (ADRs) through pharmacovigilance is vital to patient safety. Spontaneous reporting of ADRs is one method of pharmacovigilance, and in the UK this is ...undertaken through the Yellow Card Scheme (YCS). Yellow Card reports are submitted to the Medicines and Healthcare products Regulatory Agency (MHRA) by post, telephone or via the internet. The MHRA electronically records and reviews information submitted so that important safety issues can be detected. While previous studies have shown differences between patient and health-care professional (HCP) reports for the types of drugs and reactions reported, relatively little is known about the pharmacovigilance impact of patient reports. There have also been few studies on the views and experiences of patients/consumers on the reporting of suspected ADRs.
To evaluate the pharmacovigilance impact of patient reporting of ADRs by analysing reports of suspected ADRs from the UK YCS and comparing reports from patients and HCPs. To elicit the views and experiences of patients and the public about patient reporting of ADRs.
(1) Literature review and survey of international experiences of consumer reporting of ADRs; (2) descriptive analysis of Yellow Card reports; (3) signal generation analysis of Yellow Card reports; (4) qualitative analysis of Yellow Card reports; (5) questionnaire survey of patients reporting on Yellow Cards; (6) qualitative analysis of telephone interviews with patient reporters to the scheme; (7) qualitative analysis of focus groups and usability testing of the patient YCS; and (8) national omnibus telephone survey of public awareness of the YCS.
Patients (n = 5180) and HCPs (n = 20,949) submitting Yellow Card reports from October 2005 to September 2007. Respondents to questionnaire survey (n = 1362). Participants at focus groups and usability testing sessions (n = 40). National omnibus telephone survey (n = 2028).
The literature review included studies in English from across the world. All other components included populations from the UK; the omnibus survey was restricted to Great Britain.
None.
Characteristics of patient reports: types of drug and suspected ADR reported; seriousness of reports; and content of reports. The relative contributions of patient reports and of HCP reports to signal generation. Views and experiences of patient reporters. Views of members of the public about the YCS, including user-friendliness and usability of different ways of patient reporting. Public awareness of the YCS. Suggestions for improving patient reporting to the YCS.
Compared with HCPs, patient reports to the YCS contained a higher median number of suspected ADRs per report, and described reactions in more detail. The proportions of reports categorised as 'serious' were similar; the patterns of drugs and reactions reported differed. Patient reports were richer in their descriptions of reactions than those from HCPs, and more often noted the effects of ADRs on patients' lives. Combining patient and HCP reports generated more potential signals than HCP reports alone; some potential signals in the 'HCP-only' data set were lost when combined with patient reports, but fewer than those gained; the addition of patient reports to HCP reports identified 47 new 'serious' reactions not previously included in 'Summaries of Product Characteristics'. Most patient reporters found it fairly easy to make reports, although improvements to the scheme were suggested, including greater publicity and the redesign of web- and paper-based reporting systems. Among members of the public, 8.5% were aware of the YCS in 2009.
Patient reporting of suspected ADRs has the potential to add value to pharmacovigilance by reporting types of drugs and reactions different from those reported by HCPs; generating new potential signals; and describing suspected ADRs in enough detail to provide useful information on likely causality and impact on patients' lives. These findings suggest that further promotion of patient reporting to the YCS is justified, along with improvements to existing reporting systems. In order of priority, future work should include further investigation of (1) the pharmacovigilance impact of patient reporting in a longer-term study; (2) the optimum approach to signal generation analysis of patient and HCP reports; (3) the burden of ADRs in terms of impact on patients' lives; (4) the knowledge and attitudes of HCPs towards patient reporting of ADRs; (5) the value of using patient reports of ADRs to help other patients and HCPs who are seeking information on patient experiences of ADRs; and (6) the impact of increasing publicity and/or enhancements to reporting systems on the numbers and types of Yellow Card reports from patients.
The National Institute for Health Research Health Technology Assessment programme.
Glacial lakes in the Nepal Himalaya can threaten downstream communities and have large socio-economic consequences if an outburst flood occurs. This study identified 131 glacial lakes in Nepal in ...2015 that are greater than 0.1 km2 and performed a first-pass hazard and risk assessment for each lake. The hazard assessment included mass entering the lake, the moraine stability, and how lake expansion will alter the lake’s hazard in the next 15–30 years. A geometric flood model was used to quantify potential hydropower systems, buildings, agricultural land, and bridges that could be affected by a glacial lake outburst flood. The hazard and downstream impacts were combined to classify the risk associated with each lake. 11 lakes were classified as very high risk and 31 as high risk. The potential flood volume was also estimated and used to prioritize the glacial lakes that are the highest risk, which included Phoksundo Tal, Tsho Rolpa, Chamlang North Tsho, Chamlang South Tsho, and Lumding Tsho. These results are intended to assist stakeholders and decision makers in making well-informed decisions with respect to the glacial lakes that should be the focus of future field studies, modeling efforts, and risk-mitigation actions.
Objective: To investigate predictors of mental health help-seeking as well as identify topics for which college student-athletes are most likely to seek help. Participants: Student-athletes (N = 328) ...from three Division II and III universities. Method: Participants completed a survey packet on stigma, attitudes, and intentions toward seeking mental health services as well as willingness to seek help for specific topics. Results: Structural equation modeling indicated public stigma was significantly related to self-stigma, self-stigma was related to attitudes, and attitudes were related to intentions. Using logistic regression analysis, self-stigma and attitudes were associated with an increased likelihood of having sought mental health services in the past. Comment: These results can be used to help sport psychologists and other mental health staff develop programing that might increase service use among student-athletes. Using a multifaceted approach that decreases stigma and improves attitudes could have the most meaningful effect on encouraging service use.
Given the negative environmental impacts of intensive agriculture, there is an urgent need to reduce the impact of food production on biodiversity. Ecological restoration of farmland could ...potentially contribute to this goal. While the positive impacts of ecological restoration on biodiversity are well established, less evidence is available regarding impacts on economic development and employment. Potentially, prospects for economic development could be enhanced by ecological restoration though increased provision of ecosystem services, on which some economic activity depends. Here we examined this issue through the development of contrasting land use scenarios for the county of Dorset, southern England. Two scenarios of future agricultural expansion were compared with two scenarios of landscape-scale ecological restoration and the current situation. Impacts on provision of multiple ecosystem services (ES) were explored using InVEST models and proxy values for different land cover types. Impacts on economic employment were examined using an economic input-output model, which was adjusted for variation in ES flows using empirically determined ES dependency values for different economic sectors. Using the unadjusted input-output model, the scenarios had only a slight economic impact (≤ 0.3% Gross Value Added, GVA). Conversely, when the input-output model was adjusted to take account of ES flows, GVA increased by up to 5.4% in the restoration scenarios, whereas under the scenario with greatest agricultural expansion, GVA was reduced by -4.5%. Similarly, employment increased by up to 6.7% following restoration, compared to declines of up to -5.6% following maximum agricultural expansion. These results show that the economic contribution of rural land is far greater than that attributable to agricultural production alone. Landscape-scale restoration of agricultural land can potentially increase the contribution of farmland to economic development and employment, by increasing flows of multiple ES to the many economic sectors that depend on them.
Abstract
The time-variable velocity fields of solar-type stars limit the precision of radial-velocity determinations of their planets’ masses, obstructing detection of Earth twins. Since 2015 July, ...we have been monitoring disc-integrated sunlight in daytime using a purpose-built solar telescope and fibre feed to the HARPS-N stellar radial-velocity spectrometer. We present and analyse the solar radial-velocity measurements and cross-correlation function (CCF) parameters obtained in the first 3 yr of observation, interpreting them in the context of spatially resolved solar observations. We describe a Bayesian mixture-model approach to automated data-quality monitoring. We provide dynamical and daily differential-extinction corrections to place the radial velocities in the heliocentric reference frame, and the CCF shape parameters in the sidereal frame. We achieve a photon-noise-limited radial-velocity precision better than 0.43 m s−1 per 5-min observation. The day-to-day precision is limited by zero-point calibration uncertainty with an RMS scatter of about 0.4 m s−1. We find significant signals from granulation and solar activity. Within a day, granulation noise dominates, with an amplitude of about 0.4 m s−1 and an autocorrelation half-life of 15 min. On longer time-scales, activity dominates. Sunspot groups broaden the CCF as they cross the solar disc. Facular regions temporarily reduce the intrinsic asymmetry of the CCF. The radial-velocity increase that accompanies an active-region passage has a typical amplitude of 5 m s−1 and is correlated with the line asymmetry, but leads it by 3 d. Spectral line-shape variability thus shows promise as a proxy for recovering the true radial velocity.
One third of deceased donor kidneys for transplantation in the UK are donated following cardiac death (DCD). Such kidneys have a high rate of delayed graft function (DGF) following transplantation. ...We conducted a multicenter, randomized controlled trial to determine whether kidney preservation using cold, pulsatile machine perfusion (MP) was superior to simple cold storage (CS) for DCD kidneys. One kidney from each DCD donor was randomly allocated to CS, the other to MP. A sequential trial design was used with the primary endpoint being DGF, defined as the necessity for dialysis within the first 7 days following transplant. The trial was stopped when data were available for 45 pairs of kidneys. There was no difference in the incidence of DGF between kidneys assigned to MP or CS (58% vs. 56%, respectively), in the context of an asystolic period of 15 min and median cold ischemic times of 13.9 h for MP and 14.3 h for CS kidneys. Renal function at 3 and 12 months was similar between groups, as was graft and patient survival. For kidneys from controlled DCD donors (with mean cold ischemic times around 14 h), MP offers no advantage over CS, which is cheaper and more straightforward.
Machine perfusion and simple cold storage of DCD kidneys produce equivalent transplant outcome in a UK multicentre randomised controlled trial. See editorial by Irish & Katz on page 1955.
Extracellular vesicles (EVs), including exosomes and microvesicles, are 30-800 nm vesicles that are released by most cell types, as biological packages for intercellular communication. Their ...importance in cancer and inflammation makes EVs and their cargo promising biomarkers of disease and cell-free therapeutic agents. Emerging high-resolution cytometric methods have created a pressing need for efficient fluorescent labeling procedures to visualize and detect EVs. Suitable labels must be bright enough for one EV to be detected without the generation of label-associated artifacts. To identify a strategy that robustly labels individual EVs, we used nanoFACS, a high-resolution flow cytometric method that utilizes light scattering and fluorescence parameters along with sample enumeration, to evaluate various labels. Specifically, we compared lipid-, protein-, and RNA-based staining methods and developed a robust EV staining strategy, with the amine-reactive fluorescent label, 5-(and-6)-Carboxyfluorescein Diacetate Succinimidyl Ester, and size exclusion chromatography to remove unconjugated label. By combining nanoFACS measurements of light scattering and fluorescence, we evaluated the sensitivity and specificity of EV labeling assays in a manner that has not been described for other EV detection methods. Efficient characterization of EVs by nanoFACS paves the way towards further study of EVs and their roles in health and disease.
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