The kuru infectious agent is a unique geographic isolate distinct from Creutzfeldt–Jakob disease and scrapie agents

Human sporadic Creutzfeldt–Jakob disease (sCJD), endemic sheep scrapie, and epidemic bovine spongiform encephalopathy (BSE) are caused by a related group of infectious agents. The new U.K. BSE agent spread to many species, including humans, and clarifying the origin, specificity, virulence, and diversity of these agents is critical, particularly because infected humans do not develop disease for many years. As with viruses, transmissible spongiform encephalopathy (TSE) agents can adapt to new species and become more virulent yet maintain fundamentally unique and stable identities. To make agent differences manifest, one must keep the host genotype constant. Many TSE agents have revealed their independent identities in normal mice. We transmitted primate kuru, a TSE once epidemic in New Guinea, to mice expressing normal and ≈8-fold higher levels of murine prion protein (PrP). High levels of murine PrP did not prevent infection but instead shortened incubation time, as would be expected for a viral receptor. Sporadic CJD and BSE agents and representative scrapie agents were clearly different from kuru in incubation time, brain neuropathology, and lymphoreticular involvement. Many TSE agents can infect monotypic cultured GT1 cells, and unlike sporadic CJD isolates, kuru rapidly and stably infected these cells. The geographic independence of the kuru agent provides additional reasons to explore causal environmental pathogens in these infectious neurodegenerative diseases.     

Creutzfeldt‐Jakob disease and blood transfusion safety

Transmissible spongiform encephalopathies (TSEs) are untreatable, fatal neurologic diseases affecting mammals. Human disease forms include sporadic, familial and acquired Creutzfeldt‐Jakob disease (CJD). While sporadic CJD (sCJD) has been recognized for near on 100 years, variant CJD (vCJD) was first reported in 1996 and is the result of food‐borne transmission of the prion of bovine spongiform encephalopathy (BSE, ‘mad cow disease’). Currently, 230 vCJD cases have been reported in 12 countries, the majority in the UK (178) and France (27). Animal studies demonstrated highly efficient transmission of natural scrapie and experimental BSE by blood transfusion and fuelled concern that sCJD was potentially transfusion transmissible. No such case has been recorded and case–control evaluations and lookback studies indicate that, if transfusion transmission occurs at all, it is very rare. In contrast, four cases of apparent transfusion transmission of vCJD infectivity have been identified in the UK. Risk minimization strategies in response to the threat of vCJD include leucodepletion, geographically based donor deferrals and deferral of transfusion recipients. A sensitive and specific, high‐throughput screening test would provide a potential path to mitigation but despite substantial effort no such test has yet appeared. The initial outbreak of vCJD appears to be over, but concern remains about subsequent waves of disease among those already infected. There is considerable uncertainty about the size of the infected population, and there will be at least a perception of some continuing risk to blood safety. Accordingly, at least some precautionary measures will remain in place and continued surveillance is necessary.     

Developments in variant Creutzfeldt Jakob disease

The announcement on 17 July 2000 that the rate of increase in the incidence of variant Creutzfeldt Jakob disease (vCJD) in the United Kingdom (UK) had reached statistical significance makes the current issue of Eurosurveillance particularly timely. A clus     

Risk reduction strategies for variant Creutzfeldt–Jakob disease transmission by UK plasma products and their impact on patients with inherited bleeding disorders

Summary. The appearance and rapid evolution of BSE in UK cattle in the mid 1980s, with compelling data supporting variant Creutzfeldt–Jakob disease (vCJD) as its human manifestation, pose a potentially severe threat to public health. Three clinical cases and one asymptomatic case of vCJD infection have been reported in UK recipients of non‐leucodepleted red cell transfusions from donors subsequently diagnosed with vCJD. Plasma from both these and other donors who later developed vCJD has contributed towards plasma pools used to manufacture clotting factor concentrate. The United Kingdom Haemophilia Centre Doctors’ Organisation (UKHCDO) Surveillance Study has detected asymptomatic vCJD postmortem in a haemophilic patient treated with UK plasma products including two batches of clotting factor linked to a donor who subsequently developed vCJD. Over 4000 bleeding disorder patients treated with UK plasma products are recorded on the UKHCDO National Haemophilia Database. The risk of vCJD transmission by plasma products is not known. However, public health precautions have been implemented since 2004 in all UK inherited bleeding disorder patients who received UK‐sourced plasma products between 1980 and 2001 to minimize the possible risk of onward vCJD transmission. We evaluate vCJD surveillance and risk management measures taken for UK inherited bleeding disorder patients, report current data and discuss resultant challenges and future directions.     

The risk of variant Creutzfeldt‐Jakob disease among UK patients with bleeding disorders,known to have received potentially contaminated plasma products

Summary. The risk of variant Creutzfeldt‐Jakob disease (vCJD) from potentially infected plasma products remains unquantified. This risk has been assessed for 787 UK patients with an inherited bleeding disorder prospectively followed‐up for 10–20 years through the UK Haemophilia Centre Doctors’ Organisation (UKHCDO) Surveillance Study. These patients had been treated with any of 25 ‘implicated’ clotting factor batches from 1987 to 1999, which included in their manufacture, plasma from eight donors who subsequently developed clinical vCJD. Variant CJD infectivity of these batches was estimated using plasma fraction infectivity estimates and batch‐manufacturing data. Total potential vCJD infectivity received by each patient has been estimated by cumulating estimated infectivity from all doses received during their lifetime. Of 787 patients, 604 (77%) were followed‐up for over 13 years following exposure to an implicated batch. For these 604 patients, the estimated vCJD risk is ≥1% for 595, ≥50% for 164 and 100% for 51. This is additional to background UK population risk due to dietary exposure. Of 604 patients, 94 (16%) received implicated batches linked to donors who developed clinical vCJD within 6 months of their donations. One hundred and fifty‐one (25%) had received their first dose when under 10 years of age. By 1st January 2009, none of these patients had developed clinical vCJD. The absence of clinical vCJD cases in this cohort to date suggests that either plasma fraction infectivity estimates are overly precautionary, or the incubation period is longer for this cohort than for implicated cellular blood product recipients. Further follow‐up of this cohort is needed.     

Risk of variant Creuzfeldt–Jakob disease from factor concentrates: current perspectives

The demonstration of iatrogenic transmission of Creuzfeldt-Jakob disease (CJD) through therapeutic interventions led to substantial concerns in communities requiring blood products in the 1980s and 1990s. These concerns led some regulatory authorities to adopt a very precautionary approach and require recall of plasma products, including factor concentrates, which included donors at risk of CJD. The FDA's approach on recall contributed to a substantial lack of plasma products on the world market in the mid- to late 1990s. Growing epidemiological evidence of non-transmission of CJD to humans through blood, as well as demonstration of the plasma fractionation system's ability to eliminate CJD-type agents, led the FDA to rescind its measures for product recall in 1998. Although no evidence exists that the variant strain of CJD (vCJD) will behave any differently to the classic strain (cCJD) of the disease during fractionation, indications that higher levels of the strain may be present in the blood in vCJD, as well as the uncertainty regarding the epidemiology of the disease, has led to a new round of precautionary measures aimed at minimizing vCJD risk. Currently, the traditional approach to product safety through appropriate donor selection, screening using laboratory tests and systematic pathogen elimination is not completely possible for addressing the risk of vCJD. The only definite risk factor for vCJD is residence in a country where meat products from cattle with bovine spongiform encephalopathy (BSE) have been consumed; currently this is predominantly the United Kingdom but the appearance of BSE in other European countries has stimulated non-European regulatory authorities to defer blood donors from most of Europe. There is currently no screening test available for vCJD. Plasma fractionation techniques fortuitously appear to eliminate substantial amounts of vCJD like agents but only one pathogen eliminating technique, nanofiltration, has been proposed for specifically eliminating vCJD-like agents. Despite the current uncertainty, it is possible to be cautiously optimistic regarding the safety of factor concentrates from the risk of vCJD. An accumulating body of evidence suggests that it is unlikely that the plasma pool from countries with moderate BSE epidemics will contain sufficient levels of vCJD agent to lead to an infective final product. Nevertheless, the development of a blood screening test and more dedicated elimination methods are high priorities for the blood industry as it faces this new threat. The community of blood product users, including people with haemophilia, need to be in a position to make an informed choice regarding the risk of this new agent. Such a choice needs to take into account the alternatives to plasma product therapy such as recombinant concentrates and the risks to product supply ensuing from an excessive reliance on one form of product.     

Clinical implications of emerging pathogens in haemophilia: the variant Creutzfeldt–Jakob disease experience

Summary.  The impact of variant Creutzfeldt–Jakob disease (vCJD) on the clinical practice of haemophilia in the UK is coloured by the haemophilia community's experience of hepatitis C virus and human immunodeficiency virus (HIV) transmission via plasma-derived therapies in the 1980s, when the delay in recognizing and acting on the potential risks cost many patients their lives and left others to manage another chronic disease. This crisis prompted organisations such as the United Kingdom Haemophilia Centre Doctors' Organisation to advocate for the introduction of haemophilia therapies that would not be susceptible to contamination with blood-borne pathogens. After the identification of vCJD in 1996, a number of public health measures were taken in response to a government-sponsored vCJD risk assessment, and following reports of transfusion-transmission of vCJD, additional guidelines have been developed to prevent person-to-person transmission, some of which may impact the quality and availability of medical and surgical care. Variant CJD has had a significant negative effect on the UK haemophilia community, shaking patient confidence in the therapies they have received over the last 21 years, affecting the quality of care and creating the risk of stigmatizing the community as it was in the 1980s. As with HIV and vCJD, emerging blood-borne infectious agents will likely affect blood and blood-derived therapies well before we become aware of its presence. As a result, only therapies with the lowest level of risk should be used for care of patients with haemophilia.     

A Case of Sporadic Creutzfeldt‐Jakob Disease in an Older Chinese Woman

Abstract. Creutzfeldt‐Jakob disease (CJD) is a rare but fatal transmissible neurodegenerative disease. There are relatively few reported cases among Chinese in the literature. This case report describes a case of sporadic CJD in an older Chinese woman.     

Batch recall of French plasma‐derived products due to variant Creutzfeldt‐Jakob disease risk: the psychological impact on haemophilic patients,changes in their therapeutic demands and behaviour and ethical considerations

The choice of plasma‐derived products (PdP) vs. recombinant products (RP) for treating haemophilia is influenced by the infectious and perceived safety of the products. Batch recall of PdP due to the risk of variant Creutzfeldt‐Jakob disease (vCJD) may have unfavourable psychological impacts on haemophilia patients and influence their product preferences. This study aimed to assess the psychological impact of batch recalls of PdP in six haemophilia patients and their therapeutic demands, and to discuss the ethical problems in physicians’ management of this event. A survey was conducted using a new interview form and an existing anxiety and depression questionnaire. Batch recalls produce recurrent negative emotional outcomes in haemophiliacs and their families. The quality, understanding and efficiency of the batch recall announcements were unsatisfactory in some respects. Only one patient still had some of the vials in question, and only three patients understood the real reason for the batch recall. Four patients asked to change their PdP for RP; a fifth patient was considering doing so. Here, topics for discussion include the delivery of an unclear message to patients about a very uncertain risk of a frightening disease, the reasons to maintain PdP when RP are largely available, except in specific cases, and the related discomfort for caregivers. The ethical questions revealed by batch recalls and the high psychological impact of vCJD risk on patients can no longer be ignored, and require surveys assessing the rationales and choices of the healthcare authorities, manufacturers, prescribers and users.     

Localization of Niemann–Pick C1 protein in astrocytes: Implications for neuronal degeneration in Niemann– Pick type C disease

Niemann–Pick type C disease (NP-C) is an inherited neurovisceral lipid storage disorder characterized by progressive neurodegeneration. Most cases of NP-C result from inactivating mutations of NPC1, a recently identified member of a family of genes encoding membrane-bound proteins containing putative sterol sensing domains. By using a specific antipeptide antibody to human NPC1, we have here investigated the cellular and subcellular localization and regulation of NPC1. By light and electron microscopic immunocytochemistry of monkey brain, NPC1 was expressed predominantly in perisynaptic astrocytic glial processes. At a subcellular level, NPC1 localized to vesicles with the morphological characteristics of lysosomes and to sites near the plasma membrane. Analysis of the temporal and spatial pattern of neurodegeneration in the NP-C mouse, a spontaneous mutant model of human NP-C, by amino–cupric–silver staining, showed that the terminal fields of axons and dendrites are the earliest sites of degeneration that occur well before the appearance of a neurological phenotype. Western blots of cultured human fibroblasts and monkey brain homogenates revealed NPC1 as a 165-kDa protein. NPC1 levels in cultured fibroblasts were unchanged by incubation with low density lipoproteins or oxysterols but were increased 2- to 3-fold by the drugs progesterone and U-18666A, which block cholesterol transport out of lysosomes, and by the lysosomotropic agent NH₄Cl. These studies show that NPC1 in brain is predominantly a glial protein present in astrocytic processes closely associated with nerve terminals, the earliest site of degeneration in NP-C. Given the vesicular localization of NPC1 and its proposed role in mediating retroendocytic trafficking of cholesterol and other lysosomal cargo, these results suggest that disruption of NPC1-mediated vesicular trafficking in astrocytes may be linked to neuronal degeneration in NP-C.     

Wiedemann–Franz Law for Massless Dirac Fermions with Implications for Graphene

In the 2016 experiment by Crossno et al. the electronic contribution to the thermal conductivity of graphene was found to violate the well-known Wiedemann–Franz (WF) law for metals. At liquid nitrogen temperatures, the thermal to electrical conductivity ratio of charge-neutral samples was more than 10 times higher than predicted by the WF law, which was attributed to interactions between particles leading to collective behavior described by hydrodynamics. Here, we show, by adapting the handbook derivation of the WF law to the case of massless Dirac fermions, that significantly enhanced thermal conductivity should appear also in few- or even sub-kelvin temperatures, where the role of interactions can be neglected. The comparison with numerical results obtained within the Landauer–Büttiker formalism for rectangular and disk-shaped (Corbino) devices in ballistic graphene is also provided.     

Variant Creutzfeldt–Jakob disease: risk of transmission by blood and blood products

Summary.  Variant Creutzfeldt–Jakob disease (CJD) is a novel acquired human prion disease apparently resulting from exposure to the bovine spongiform encephalopathy (BSE) agent. Variant CJD differs from other human prion diseases in that the disease-associated form of the prion protein and infectivity are readily detectable in lymphoid tissues throughout the body. Lymphoid tissues and lymphocytes are implicated in the peripheral pathogenesis of prion diseases (where infectivity may be detected during the preclinical phase of the illness), giving rise to concerns that blood and blood products may also contain infectious particles, representing a possible source of iatrogenic spread of variant CJD. This concern has been reinforced following the experimental transmission of BSE in a sheep model by transfusion of blood and buffy coat from animals in the preclinical phase of the illness, and the recent identification of a UK case of variant CJD in a patient who had received packed red blood cells that had been donated by an individual who subsequently died from variant CJD. Studies in animal models suggest that most prion infectivity in blood may be cell-associated, with lower levels in the plasma, and there is evidence to suggest that any infectivity present may be reduced during the process of plasma fractionation. However, the possibility that plasma or blood products could transmit the disease cannot be excluded. Further studies are required to develop more sensitive means to detect disease-associated prion protein in blood; such techniques could be employed for screening purposes to reduce exposure to contaminated products and to assist with risk management in potentially exposed individuals.     

Variant Creutzfeldt–Jakob disease: risk of transmission by blood transfusion and blood therapies

Summary.  In the last decade, a new variant of the human prion disease Creutzfeldt–Jakob disease (now known as variant CJD or vCJD) was identified and causally linked to dietary exposure to bovine spongiform encephalopathy (BSE) during the 1980s and early 1990s. Preliminary studies in animal models suggest that prions can be transmitted by blood. Based on two recent reports of iatrogenic vCJD transmission by blood transfusion in humans, a Department of Health-sponsored risk assessment warned that recipients of plasma therapies are now at risk of contracting vCJD from potentially infected donors. It is believed that all the population may be susceptible to vCJD infection, although clinical cases have so far occurred only in methionine homozygotes at codon 129 in the human prion protein gene. A non-invasive blood-based diagnostic assay is urgently needed. Because the incubation period may be upwards of 40 years and there is no reliable screening test, it is currently unknown how many people may be in an asymptomatic phase of vCJD infection in the UK. However, there remains a distinct possibility that some infected patients may never develop clinical symptoms but will remain asymptomatic carriers who can potentially transmit the disease to other individuals. Therefore, screening of infectious individuals will be a critical component for individuals who rely on blood transfusions and/or blood therapies. In the absence of screening tests or effective therapies to treat this disease, a formidable worldwide public health challenge lies ahead to prevent new infections, accurately assess infection rates and treat infected patients.     

A PCA–EEMD–CNN–Attention–GRU–Encoder–Decoder Accurate Prediction Model for Key Parameters of Seawater Quality in Zhanjiang Bay

In order to effectively solve the problem of low accuracy of seawater water quality prediction, an optimized water quality parameter prediction model is constructed in this paper. The model first screened the key factors of water quality data with the principal component analysis (PCA) algorithm, then realized the de-noising of the key factors of water quality data with an ensemble empirical mode decomposition (EEMD) algorithm, and the data were input into the two-dimensional convolutional neural network (2D-CNN) module to extract features, which were used for training and learning by attention, gated recurrent unit, and an encoder–decoder (attention–GRU–encoder–decoder, attention–GED) integrated module. The trained prediction model was used to predict the content of key parameters of water quality. In this paper, the water quality data of six typical online monitoring stations from 2017 to 2021 were used to verify the proposed model. The experimental results show that, based on short-term series prediction, the root mean square error (RMSE), mean absolute percentage error (MAPE), and decision coefficient (R²) were 0.246, 0.307, and 97.80%, respectively. Based on the long-term series prediction, RMSE, MAPE, and R² were 0.878, 0.594, and 92.23%, respectively, which were all better than the prediction model based on an enhanced clustering algorithm and adam with a radial basis function neural network (ECA–Adam–RBFNN), a prediction model based on a softplus extreme learning machine method with partial least squares and particle swarm optimization (PSO–SELM–PLS), and a wavelet transform-depth Bi–S–SRU (Bi-directional Stacked Simple Recurrent Unit) prediction model. The PCA–EEMD–CNN–attention–GED prediction model not only has high prediction accuracy but can also provide a decision-making basis for the water quality control and management of aquaculture in the waters around Zhanjiang Bay.