New studies of the treatment of neuropathic pain have increased the need for an updated review of randomized, double-blind, placebo-controlled trials to support an evidence based algorithm to treat ...neuropathic pain conditions. Available studies were identified using a MEDLINE and EMBASE search. One hundred and five studies were included. Numbers needed to treat (NNT) and numbers needed to harm (NNH) were used to compare efficacy and safety of the treatments in different neuropathic pain syndromes. The quality of each trial was assessed. Tricyclic antidepressants and the anticonvulsants gabapentin and pregabalin were the most frequently studied drug classes. In peripheral neuropathic pain, the lowest NNT was for tricyclic antidepressants, followed by opioids and the anticonvulsants gabapentin and pregabalin. For central neuropathic pain there is limited data. NNT and NNH are currently the best way to assess relative efficacy and safety, but the need for dichotomous data, which may have to be estimated retrospectively for old trials, and the methodological complexity of pooling data from small cross-over and large parallel group trials, remain as limitations.
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GEOZS, IJS, IMTLJ, KILJ, OILJ, SBCE, SBJE, UL, UPUK
Climate and environments of the mid-Pliocene warm period (3.264 to 3.025 Ma) have been extensively studied. Whilst numerical models have shed light on the nature of climate at the time, uncertainties ...in their predictions have not been systematically examined. The Pliocene Model Intercomparison Project quantifies uncertainties in model outputs through a coordinated multi-model and multi-model/data intercomparison. Whilst commonalities in model outputs for the Pliocene are clearly evident, we show substantial variation in the sensitivity of models to the implementation of Pliocene boundary conditions. Models appear able to reproduce many regional changes in temperature reconstructed from geological proxies. However, data/model comparison highlights that models potentially underestimate polar amplification. To assert this conclusion with greater confidence, limitations in the time-averaged proxy data currently available must be addressed. Furthermore, sensitivity tests exploring the known unknowns in modelling Pliocene climate specifically relevant to the high latitudes are essential (e.g. palaeogeography, gateways, orbital forcing and trace gasses). Estimates of longer-term sensitivity to CO2 (also known as Earth System Sensitivity; ESS), support previous work suggesting that ESS is greater than Climate Sensitivity (CS), and suggest that the ratio of ESS to CS is between 1 and 2, with a "best" estimate of 1.5.
Ex situ dual hypothermic oxygenated machine perfusion (DHOPE) and normothermic machine perfusion (NMP) of donor livers may have a complementary effect when applied sequentially. While DHOPE ...resuscitates the mitochondria and increases hepatic adenosine triphosphate (ATP) content, NMP enables hepatobiliary viability assessment prior to transplantation. In contrast to DHOPE, NMP requires a perfusion solution with an oxygen carrier, for which red blood cells (RBC) have been used in most series. RBC, however, have limitations and cannot be used cold. We, therefore, established a protocol of sequential DHOPE, controlled oxygenated rewarming (COR), and NMP using a new hemoglobin‐based oxygen carrier (HBOC)‐based perfusion fluid (DHOPE‐COR‐NMP trial, NTR5972). Seven livers from donation after circulatory death (DCD) donors, which were initially declined for transplantation nationwide, underwent DHOPE‐COR‐NMP. Livers were considered transplantable if perfusate pH and lactate normalized, bile production was ≥10 mL and biliary pH > 7.45 within 150 minutes of NMP. Based on these criteria five livers were transplanted. The primary endpoint, 3‐month graft survival, was a 100%. In conclusion, sequential DHOPE‐COR‐NMP using an HBOC‐based perfusion fluid offers a novel method of liver machine perfusion for combined resuscitation and viability testing of suboptimal livers prior to transplantation.
This clinical cohort study indicates that a combination of hypo‐ and normothermic machine perfusion, using a preservation fluid containing an hemoglobin‐based oxygen carrier, is feasible and provides a tool to resuscitate and select initially declined high‐risk donor livers that can be transplanted successfully.
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BFBNIB, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Engineered gene-drive techniques for population modification and/or suppression have the potential for tackling complex challenges, including reducing the spread of diseases and invasive species. ...Gene-drive systems with low threshold frequencies for invasion, such as homing-based gene drive, require initially few transgenic individuals to spread and are therefore easy to introduce. The self-propelled behavior of such drives presents a double-edged sword, however, as the low threshold can allow transgenic elements to expand beyond a target population. By contrast, systems where a high threshold frequency must be reached before alleles can spread-above a fitness valley-are less susceptible to spillover but require introduction at a high frequency. We model a proposed drive system, called "daisy quorum drive," that transitions over time from a low-threshold daisy-chain system (involving homing-based gene drive such as CRISPR-Cas9) to a high-threshold fitness-valley system (requiring a high frequency-a "quorum"-to spread). The daisy-chain construct temporarily lowers the high thresholds required for spread of the fitness-valley construct, facilitating use in a wide variety of species that are challenging to breed and release in large numbers. Because elements in the daisy chain only drive subsequent elements in the chain and not themselves and also carry deleterious alleles ("drive load"), the daisy chain is expected to exhaust itself, removing all CRISPR elements and leaving only the high-threshold fitness-valley construct, whose spread is more spatially restricted. Developing and analyzing both discrete patch and continuous space models, we explore how various attributes of daisy quorum drive affect the chance of modifying local population characteristics and the risk that transgenic elements expand beyond a target area. We also briefly explore daisy quorum drive when population suppression is the goal. We find that daisy quorum drive can provide a promising bridge between gene-drive and fitness-valley constructs, allowing spread from a low frequency in the short term and better containment in the long term, without requiring repeated introductions or persistence of CRISPR elements.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Dual hypothermic oxygenated machine perfusion (DHOPE) of the liver has been advocated as a method to reduce ischemia/reperfusion injury (IRI). This study aimed to determine whether DHOPE reduces IRI ...of the bile ducts in donation after circulatory death (DCD) liver transplantation. In a recently performed phase 1 trial, 10 DCD livers were preserved with DHOPE after static cold storage (SCS; www.trialregister.nl NTR4493). Bile duct biopsies were obtained at the end of SCS (before DHOPE; baseline) and after graft reperfusion in the recipient. Histological severity of biliary injury was graded according to an established semiquantitative grading system. Twenty liver transplantations using DCD livers not preserved with DHOPE served as controls. Baseline characteristics and the degree of bile duct injury at baseline (end of SCS) were similar between both groups. In controls, the degree of stroma necrosis (P = 0.002) and injury of the deep peribiliary glands (PBG; P = 0.02) increased after reperfusion compared with baseline. In contrast, in DHOPE‐preserved livers, the degree of bile duct injury did not increase after reperfusion. Moreover, there was less injury of deep PBG (P = 0.04) after reperfusion in the DHOPE group compared with controls. In conclusion, this study suggests that DHOPE reduces IRI of bile ducts after DCD liver transplantation. Liver Transplantation 24 655–664 2018 AASLD.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Respiratory muscle weakness is an important feature of spinal muscular atrophy (SMA). Progressive lung function decline is the most important cause of mortality and morbidity in patients. The natural ...history of lung function in SMA has, however, not been studied in much detail.
We analysed 2098 measurements of lung function from 170 treatment-naïve patients with SMA types 1c-4, aged 4-74 years. All patients are participating in an ongoing population-based prevalence cohort study. We measured Forced Expiratory Volume in 1 s (FEV
), Forced Vital Capacity (FVC), and Vital Capacity (VC). Longitudinal patterns of lung function were analysed using linear mixed-effects and non-linear models. Additionally, we also assessed postural effects on results of FEV
and FVC tests. In early-onset SMA types (1c-3a), we observed a progressive decline of lung function at younger ages with relative stabilisation during adulthood. Estimated baseline values were significantly lower in more severely affected patients: %FEV
ranged from 42% in SMA type 1c to 100% in type 3b, %FVC 50 to 109%, and %VC 44 to 96%. Average annual decline rates also differed significantly between SMA types, ranging from - 0.1% to - 1.4% for FEV
, - 0.2% to - 1.4% for FVC, and + 0.2% to - 1.7% for VC. In contrast to SMA types 1c-3a, we found normal values for all outcomes in later-onset SMA types 3b and 4 throughout life, although with some exceptions and based on limited available data. Finally, we found no important differences in FVC or FEV
values measured in either sitting or supine position.
Our data illustrate the longitudinal course of lung function in patients with SMA, which is characterised by a progressive decline in childhood and stabilisation in early adulthood. The data do not support an additional benefit of measuring FEV
or FVC in both sitting and supine position. These data may serve as a reference to assess longer-term outcomes in clinical trials.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
The last interglaciation (~130 to 116 ka) is a time period with a strong astronomically induced seasonal forcing of insolation compared to the present. Proxy records indicate a significantly ...different climate to that of the modern, in particular Arctic summer warming and higher eustatic sea level. Because the forcings are relatively well constrained, it provides an opportunity to test numerical models which are used for future climate prediction. In this paper we compile a set of climate model simulations of the early last interglaciation (130 to 125 ka), encompassing a range of model complexities. We compare the simulations to each other and to a recently published compilation of last interglacial temperature estimates. We show that the annual mean response of the models is rather small, with no clear signal in many regions. However, the seasonal response is more robust, and there is significant agreement amongst models as to the regions of warming vs cooling. However, the quantitative agreement of the model simulations with data is poor, with the models in general underestimating the magnitude of response seen in the proxies. Taking possible seasonal biases in the proxies into account improves the agreement, but only marginally. However, a lack of uncertainty estimates in the data does not allow us to draw firm conclusions. Instead, this paper points to several ways in which both modelling and data could be improved, to allow a more robust model-data comparison.
Vaccination against cancer by using dendritic cells has for more than a decade been based on dendritic cells generated ex vivo from monocytes or CD34(+) progenitors. Here, we report on the first ...clinical study of therapeutic vaccination against cancer using naturally occurring plasmacytoid dendritic cells (pDC). Fifteen patients with metastatic melanoma received intranodal injections of pDCs activated and loaded with tumor antigen-associated peptides ex vivo. In vivo imaging showed that administered pDCs migrated and distributed over multiple lymph nodes. Several patients mounted antivaccine CD4(+) and CD8(+) T-cell responses. Despite the limited number of administered pDCs, an IFN signature was observed after each vaccination. These results indicate that vaccination with naturally occurring pDC is feasible with minimal toxicity and that in patients with metastatic melanoma, it induces favorable immune responses.
Background: Screening for prostate cancer advances the time of diagnosis (lead time) and detects cancers that would not have been diagnosed in the absence of screening (overdetection). Both ...consequences have considerable impact on the net benefits of screening. Methods: We developed simulation models based on results of the Rotterdam section of the European Randomized Study of Screening for Prostate Cancer (ERSPC), which enrolled 42 376 men and in which 1498 cases of prostate cancer were identified, and on baseline prostate cancer incidence and stage distribution data. The models were used to predict mean lead times, overdetection rates, and ranges (corresponding to approximate 95% confidence intervals) associated with different screening programs. Results: Mean lead times and rates of overdetection depended on a man’s age at screening. For a single screening test at age 55, the estimated mean lead time was 12.3 years (range = 11.6–14.1 years) and the overdetection rate was 27% (range = 24%–37%); at age 75, the estimates were 6.0 years (range = 5.8–6.3 years) and 56% (range = 53%–61%), respectively. For a screening program with a 4-year screening interval from age 55 to 67, the estimated mean lead time was 11.2 years (range = 10.8–12.1 years), and the overdetection rate was 48% (range = 44%–55%). This screening program raised the lifetime risk of a prostate cancer diagnosis from 6.4% to 10.6%, a relative increase of 65% (range = 56%–87%). In annual screening from age 55 to 67, the estimated overdetection rate was 50% (range = 46%–57%) and the lifetime prostate cancer risk was increased by 80% (range = 69%–116%). Extending annual or quadrennial screening to the age of 75 would result in at least two cases of overdetection for every clinically relevant cancer detected. Conclusions: These model-based lead-time estimates support a prostate cancer screening interval of more than 1 year.
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