Global uncertainty in the diagnosis of neurological complications of SARS-CoV-2 infection by both neurologists and non-neurologists: An international inter-observer variability study.

INTRODUCTION: Uniform case definitions are required to ensure harmonised reporting of neurological syndromes associated with SARS-CoV-2. Moreover, it is unclear how clinicians perceive the relative importance of SARS-CoV-2 in neurological syndromes, which risks under- or over-reporting. METHODS: We invited clinicians through global networks, including the World Federation of Neurology, to assess ten anonymised vignettes of SARS-CoV-2 neurological syndromes. Using standardised case definitions, clinicians assigned a diagnosis and ranked association with SARS-CoV-2. We compared diagnostic accuracy and assigned association ranks between different settings and specialties and calculated inter-rater agreement for case definitions as "poor" (κ ≤ 0.4), "moderate" or "good" (κ > 0.6). RESULTS: 1265 diagnoses were assigned by 146 participants from 45 countries on six continents. The highest correct proportion were cerebral venous sinus thrombosis (CVST, 95.8%), Guillain-Barré syndrome (GBS, 92.4%) and headache (91.6%) and the lowest encephalitis (72.8%), psychosis (53.8%) and encephalopathy (43.2%). Diagnostic accuracy was similar between neurologists and non-neurologists (median score 8 vs. 7/10, p = 0.1). Good inter-rater agreement was observed for five diagnoses: cranial neuropathy, headache, myelitis, CVST, and GBS and poor agreement for encephalopathy. In 13% of vignettes, clinicians incorrectly assigned lowest association ranks, regardless of setting and specialty. CONCLUSION: The case definitions can help with reporting of neurological complications of SARS-CoV-2, also in settings with few neurologists. However, encephalopathy, encephalitis, and psychosis were often misdiagnosed, and clinicians underestimated the association with SARS-CoV-2. Future work should refine the case definitions and provide training if global reporting of neurological syndromes associated with SARS-CoV-2 is to be robust.

Problematic White-Tailed Deer Information in Rochlin et al. (2022) Regarding Past and Future Tick (Amblyomma americanum, Acari: Ixodidae) Distributions.

Figure 3 in this Journal of Medical Entomology article is central to the authors' warning about an exploding white-tailed deer population but conflicts in important aspects with the relevant deer research. Among other problems, it shows a 60% increase in the white-tailed deer density from 1500 to 2020 when the research consensus is that the population is about the same. It shows an exploding population from 2000 to 2020 without supporting data when the population peaked around the year 2000 according to evidence-based research.

Predicting the number of reported and unreported cases for the COVID-19 epidemics in China, South Korea, Italy, France, Germany and United Kingdom.

We model the COVID-19 coronavirus epidemics in China, South Korea, Italy, France, Germany and the United Kingdom. We identify the early phase of the epidemics, when the number of cases grows exponentially, before government implementation of major control measures. We identify the next phase of the epidemics, when these social measures result in a time-dependent exponentially decreasing number of cases. We use reported case data, both asymptomatic and symptomatic, to model the transmission dynamics. We also incorporate into the transmission dynamics unreported cases. We construct our models with comprehensive consideration of the identification of model parameters. A key feature of our model is the evaluation of the timing and magnitude of implementation of major public policies restricting social movement. We project forward in time the development of the epidemics in these countries based on our model analysis.

A spatial model of honey bee colony collapse due to pesticide contamination of foraging bees.

We develop a model of honey bee colony collapse based on contamination of forager bees in pesticide contaminated spatial environments. The model consists of differential and difference equations for the spatial distributions of the uncontaminated and contaminated forager bees. A key feature of the model is incorporation of the return to the hive each day of forager bees. The model quantifies colony collapse in terms of two significant properties of honey bee colonies: (1) the fraction of contaminated forager bees that fail to return home due to pesticide contamination, and (2) the fraction of forager bees in the total forager bee population that return to the sites visited on the previous day. If the fraction of contaminated foragers failing to return home is high, then the total population falls below a critical threshold and colony collapse ensues. If the fraction of all foragers that return to previous foraging sites is high, then foragers who visit contaminated sites multiple times have a higher probability of becoming contaminated, and colony collapse ensues. This quantification of colony collapse provides guidance for implementing measures for its avoidance.

A COVID-19 epidemic model with latency period.

At the beginning of a COVID-19 infection, there is a period of time known as the exposed or latency period, before an infected person is capable of transmitting the infection to another person. We develop two differential equations models to account for this period. The first is a model that incorporates infected persons in the exposed class, before transmission is possible. The second is a model that incorporates a time delay in infected persons, before transmission is possible. We apply both models to the COVID-19 epidemic in China. We estimate the epidemiological parameters in the models, such as the transmission rate and the basic reproductive number, using data of reported cases. We thus evaluate the role of the exposed or latency period in the dynamics of a COVID-19 epidemic.

Hepatitis E: an expanding epidemic with a range of complications.

BACKGROUND: Hepatitis E virus (HEV) is a common cause of viral hepatitis worldwide. Previously considered a disease of the developing world, it is increasingly recognized that locally acquired HEV infection is common in industrialized countries. OBJECTIVES: The aim was to highlight the changing epidemiology of HEV infection, particularly in the developed world, and inform clinicians of the diverse clinical presentations and extra-hepatic complications associated with the virus. SOURCES: References for this review were identified through searches of MEDLINE/PubMed, and Google Scholar, up to January 2020. Searches were restricted to articles published in English. CONTENT: Hepatitis E virus is an under-recognized, emerging pathogen with important implications for public health in both the developing and developed world. The number of cases reported in resource-rich settings is increasing, in part due to improved case ascertainment but also as a result of increased incidence in some countries. The reasons behind these epidemiological shifts are not currently known. Chronic HEV infection has been reported in immunocompromised patients. A range of extra-hepatic manifestations have also been reported, most notably neurological and renal complications. There is evidence to suggest a causal link with Guillain-Barré syndrome, neuralgic amyotrophy and encephalitis/myelitis. Glomerular disease has been reported in the context of both acute and chronic infection. IMPLICATIONS: HEV should be included in non-invasive liver screens and considered in the differentials for patients presenting with alanine aminotransferase elevation, suspected drug-induced liver injury or decompensated liver disease. Any patients with acute neurological injury and deranged liver function should be tested for hepatitis E, and all patients presenting with Guillain-Barré syndrome or neuralgic amyotrophy should be tested regardless of liver enzymes. Immunocompromised patients with persistently raised liver enzymes should be tested with molecular techniques and offered annual routine screening.

Identifying the number of unreported cases in SIR epidemic models.

An SIR epidemic model is analysed with respect to the identification of its parameters and initial values, based upon reported case data from public health sources. The objective of the analysis is to understand the relationship of unreported cases to reported cases. In many epidemic diseases the reported cases are a small fraction of the unreported cases. This fraction can be estimated by the identification of parameters for the model from reported case data. The analysis is applied to the Hong Kong seasonal influenza epidemic in New York City in 1968-1969.

Non-vitamin K antagonist oral anticoagulants (NOACs) for thromboembolic prevention, are they safe in congenital heart disease? Results of a worldwide study.

BACKGROUND: Current guidelines consider vitamin K antagonists (VKA) the oral anticoagulant agents of choice in adults with atrial arrhythmias (AA) and moderate or complex forms of congenital heart disease, significant valvular lesions, or bioprosthetic valves, pending safety data on non-VKA oral anticoagulants (NOACs). Therefore, the international NOTE registry was initiated to assess safety, change in adherence and quality of life (QoL) associated with NOACs in adults with congenital heart disease (ACHD). METHODS: An international multicenter prospective study of NOACs in ACHD was established. Follow-up occurred at 6 months and yearly thereafter. Primary endpoints were thromboembolism and major bleeding. Secondary endpoints included minor bleeding, change in therapy adherence (≥80% medication refill rate, ≥6 out of 8 on Morisky-8 questionnaire) and QoL (SF-36 questionnaire). RESULTS: In total, 530 ACHD patients (mean age 47 SD 15 years; 55% male) with predominantly moderate or complex defects (85%), significant valvular lesions (46%) and/or bioprosthetic valves (11%) using NOACs (rivaroxaban 43%; apixaban 39%; dabigatran 12%; edoxaban 7%) were enrolled. The most common indication was AA (91%). Over a median follow-up of 1.0 [IQR 0.0-2.0] year, thromboembolic event rate was 1.0% [95%CI 0.4-2.0] (n = 6) per year, with 1.1% [95%CI 0.5-2.2] (n = 7) annualized rate of major bleeding and 6.3% [95%CI 4.5-8.5] (n = 37) annualized rate of minor bleeding. Adherence was sufficient during 2 years follow-up in 80-93% of patients. At 1-year follow-up, among the subset of previous VKA-users who completed the survey (n = 33), QoL improved in 6 out of 8 domains (p ≪ 0.05). CONCLUSIONS: Initial results from our worldwide prospective study suggest that NOACs are safe and may be effective for thromboembolic prevention in adults with heterogeneous forms of congenital heart disease.

An Environmental Model of Honey Bee Colony Collapse Due to Pesticide Contamination.

We develop a model of honey bee colony collapse based on the contamination of forager bees in environmental regions contaminated with pesticides. An important feature of the model is the daily homing capacity each day of foragers bees. The model consists of difference equations describing the daily homing of uncontaminated and contaminated forager bees, with an increased homing failure of contaminated bees. The model quantifies colony collapse in terms of the fraction of contaminated bees subject to this increased homing failure. If the fraction is sufficiently high, then the hive falls below a viability threshold population size that leads to rapid disintegration. If the fraction is sufficiently low, then the hive can rise above the viability threshold and attain a stable population level.

New Closures for More Precise Modeling of Landau Damping in the Fluid Framework.

Incorporation of kinetic effects such as Landau damping into a fluid framework was pioneered by Hammett and Perkins, by obtaining closures of the fluid hierarchy, where the gyrotropic heat flux fluctuations or the deviation of the fourth-order gyrotropic fluid moment are expressed through lower-order fluid moments. To obtain a closure of a fluid model expanded around a bi-Maxwellian distribution function, the usual plasma dispersion function Z(ζ) that appears in kinetic theory or the associated plasma response function R(ζ)=1+ζZ(ζ) has to be approximated with a suitable Padé approximant in such a way that the closure is valid for all ζ values. Such closures are rare, and the original closures of Hammett and Perkins are often employed. Here we present a complete mapping of all plausible Landau fluid closures that can be constructed at the level of fourth-order moments in the gyrotropic limit and we identify the most precise closures. Furthermore, by considering 1D closures at higher-order moments, we show that it is possible to reproduce linear Landau damping in the fluid framework to any desired precision, thus showing convergence of the fluid and collisionless kinetic descriptions.

Low risk of hepatotoxicity from rifampicin when used for cholestatic pruritus: a cross-disease cohort study.

BACKGROUND: The use of rifampicin for cholestatic pruritus is accompanied by concerns over safety, but the availability of real-world prescribing data is relatively limited. AIM: We sought to describe the rate and characteristics of rifampicin-induced hepatitis in a mixed aetiology cohort of patients with established liver disease and cholestatic pruritus. METHODS: Retrospective review of records for out-patients commenced on rifampicin for pruritus 2012-2016 inclusive. Rifampicin-induced hepatitis was recorded where alanine aminotransferase activity (ALT) increased to both ≥5 × baseline and ≥5 × upper limit of normal (ULN), or to both ≥3 × baseline and ≥3 × ULN with concurrent elevation in serum bilirubin to ≥2 × baseline and ≥2 × ULN, in addition to a Roussel-Uclaf Causality Assessment Method score of "probable" or "highly probable" for rifampicin causality. RESULTS: After exclusions, we reviewed 105 patients who took rifampicin for a median of 131 days. Most had primary biliary cholangitis or primary sclerosing cholangitis; 40 (38.1%) were men and median age was 44 years (IQR: 32-57). 44 (41.9%) patients had baseline serum bilirubin ≥2 × ULN and 28 (26.7%) ALT ≥3 × ULN. 5 (4.8%) developed rifampicin-induced hepatitis at a median of 70(range 27-130) days after drug initiation. No individual or laboratory baseline characteristics were significantly associated with subsequent development of hepatitis. All cases of hepatitis recovered after drug cessation, although one patient was hospitalised and received corticosteroids. CONCLUSIONS: Given the efficacy of rifampicin for an important sub-group of those with cholestatic pruritus, adult patients, including those with jaundice, can be counselled that 95% of prescriptions are safe, and where hepatitis occurs, including at long latency, drug cessation appears effective.

Cellular and Molecular Mechanisms of Autoimmune Hepatitis.

Autoimmune hepatitis is an uncommon idiopathic syndrome of immune-mediated destruction of hepatocytes, typically associated with autoantibodies. The disease etiology is incompletely understood but includes a clear association with human leukocyte antigen (HLA) variants and other non-HLA gene variants, female sex, and the environment. Pathologically, there is a CD4+ T cell-rich lymphocytic inflammatory infiltrate with variable hepatocyte necrosis and subsequent hepatic fibrosis. Attempts to understand pathogenesis are informed by several monogenetic syndromes that may include autoimmune liver injury, by several drug and environmental agents that have been identified as triggers in a minority of cases, by human studies that point toward a central role for CD4+ effector and regulatory T cells, and by animal models of the disease. Nonspecific immunosuppression is the current standard therapy. Further understanding of the disease's cellular and molecular mechanisms may assist in the design of better-targeted therapies, aid the limitation of adverse effects from therapy, and inform individualized risk assessment and prognostication.

Acute high-caffeine exposure increases autophagic flux and reduces protein synthesis in C2C12 skeletal myotubes.

Caffeine is a highly catabolic dietary stimulant. High caffeine concentrations (1-10 mM) have previously been shown to inhibit protein synthesis and increase protein degradation in various mammalian cell lines. The purpose of this study was to examine the effect of short-term caffeine exposure on cell signaling pathways that regulate protein metabolism in mammalian skeletal muscle cells. Fully differentiated C2C12 skeletal myotubes either received vehicle (DMSO) or 5 mM caffeine for 6 h. Our analysis revealed that caffeine promoted a 40% increase in autolysosome formation and a 25% increase in autophagic flux. In contrast, caffeine treatment did not significantly increase the expression of the skeletal muscle specific ubiquitin ligases MAFbx and MuRF1 or 20S proteasome activity. Caffeine treatment significantly reduced mTORC1 signaling, total protein synthesis and myotube diameter in a CaMKKß/AMPK-dependent manner. Further, caffeine promoted a CaMKII-dependent increase in myostatin mRNA expression that did not significantly contribute to the caffeine-dependent reduction in protein synthesis. Our results indicate that short-term caffeine exposure significantly reduced skeletal myotube diameter by increasing autophagic flux and promoting a CaMKKß/AMPK-dependent reduction in protein synthesis.

An outbreak vector-host epidemic model with spatial structure: the 2015-2016 Zika outbreak in Rio De Janeiro.

BACKGROUND: A deterministic model is developed for the spatial spread of an epidemic disease in a geographical setting. The disease is borne by vectors to susceptible hosts through criss-cross dynamics. The model is focused on an outbreak that arises from a small number of infected hosts imported into a subregion of the geographical setting. The goal is to understand how spatial heterogeneity of the vector and host populations influences the dynamics of the outbreak, in both the geographical spread and the final size of the epidemic. METHODS: Partial differential equations are formulated to describe the spatial interaction of the hosts and vectors. The partial differential equations have reaction-diffusion terms to describe the criss-cross interactions of hosts and vectors. The partial differential equations of the model are analyzed and proven to be well-posed. A local basic reproduction number for the epidemic is analyzed. RESULTS: The epidemic outcomes of the model are correlated to the spatially dependent parameters and initial conditions of the model. The partial differential equations of the model are adapted to seasonality of the vector population, and applied to the 2015-2016 Zika seasonal outbreak in Rio de Janeiro Municipality in Brazil. CONCLUSIONS: The results for the model simulations of the 2015-2016 Zika seasonal outbreak in Rio de Janeiro Municipality indicate that the spatial distribution and final size of the epidemic at the end of the season are strongly dependent on the location and magnitude of local outbreaks at the beginning of the season. The application of the model to the Rio de Janeiro Municipality Zika 2015-2016 outbreak is limited by incompleteness of the epidemic data and by uncertainties in the parametric assumptions of the model.

Low-dose interleukin-2 promotes STAT-5 phosphorylation, Treg survival and CTLA-4-dependent function in autoimmune liver diseases.

CD4+ CD25high CD127low forkhead box protein 3 (FoxP3+ ) regulatory T cells (Treg ) are essential for the maintenance of peripheral tolerance. Impaired Treg function and an imbalance between effector and Tregs contribute to the pathogenesis of autoimmune diseases. We reported recently that the hepatic microenvironment is deficient in interleukin (IL)-2, a cytokine essential for Treg survival and function. Consequently, few liver-infiltrating Treg demonstrate signal transducer and activator of transcription-5 (STAT-5) phosphorylation. To establish the potential of IL-2 to enhance Treg therapy, we investigated the effects of very low dose Proleukin (VLDP) on the phosphorylation of STAT-5 and the subsequent survival and function of Treg and T effector cells from the blood and livers of patients with autoimmune liver diseases. VLDP, at less than 5 IU/ml, resulted in selective phosphorylation of STAT-5 in Treg but not effector T cells or natural killer cells and associated with increased expression of cytotoxic T lymphocyte antigen-4 (CTLA-4), FoxP3 and CD25 and the anti-apoptotic protein Bcl-2 in Treg with the greatest enhancement of regulatory phenotype in the effector memory Treg population. VLDP also maintained expression of the liver-homing chemokine receptor CXCR3. VLDP enhanced Treg function in a CTLA-4-dependent manner. These findings open new avenues for future VLDP cytokine therapy alone or in combination with clinical grade Treg in autoimmune liver diseases, as VLDP could not only enhance regulatory phenotype and functional property but also the survival of intrahepatic Treg .

Post-prophylaxis Toxoplasma chorioretinitis following donor-recipient mismatched liver transplantation.

Toxoplasmosis may be transferred by organ transplantation. The most common clinical presentation is with multisystem disease, although isolated ocular toxoplasmosis has been described. Many centers have suggested that universal use of co-trimoxazole prophylaxis obviates the need for specific Toxoplasma testing. We report a case of donor-acquired ocular toxoplasmosis after liver transplantation despite co-trimoxazole prophylaxis. The diagnosis was confirmed by Toxoplasma polymerase chain reaction assay in conjunction with seroconversion. The fact that the infection was donor acquired was confirmed by serological mismatch and the absence of sporozoite-specific antigen antibody in the recipient.

Using GWAS to identify genetic predisposition in hepatic autoimmunity.

Primary biliary cirrhosis (PBC), primary sclerosing cholangitis (PSC) and autoimmune hepatitis (AIH) represent the three major hepatic autoimmune conditions. Patient morbidity and mortality remain high across these three diseases, and an unmet need for rational therapy exists. Disease understanding has focused on combining clinical and laboratory based science to provide better insights into the joint host and environmental factors necessary for the initiation, and perpetuation, of hepato-biliary inflammation. Twin studies, family studies, population studies and an inter-relationship with other autoimmune phenomena suggest a genetic component to risk for each disease. Until recently, understanding of this genetic risk has been limited to HLA haplotypes. Associations with risk-conferring and protective HLA haplotypes are present in all three diseases. Over the last few years, genome-wide association studies (GWAS), and related genetic association studies, have greatly increased understanding of the genetic risk signature of these three diseases and autoimmunity in general. Here we consider the rationale for GWAS in general and with specific reference to hepatic autoimmunity. We consider the process of GWAS, and highlight major findings to date. Potential functional implications of key findings are discussed including the IL-12/STAT4 pathway in PBC and the CD28/IL-2 pathway in PSC. We describe the marked pleiotropy demonstrated by PBC and PSC, which is consistent with other autoimmune diseases. Further, we focus on specific gene associations including SH2B3, which is common to all three diseases, and FUT2 in PSC, which represents a link between environment and genetics. We review attempts to translate GWAS findings into basic laboratory models including in vivo systems and highlight where clinical observations relate to genetics. Finally we describe deficiencies in GWAS to date and consider future study of genetics in hepatic autoimmunity.

A model of the Ebola epidemics in West Africa incorporating age of infection.

A model of an Ebola epidemic is developed with infected individuals structured according to disease age. The transmission of the infection is tracked by disease age through an initial incubation (exposed) phase, followed by an infectious phase with variable transmission infectiousness. The removal of infected individuals is dependent on disease age, with three types of removal rates: (1) removal due to hospitalization (isolation), (2) removal due to mortality separate from hospitalization, and (3) removal due to recovery separate from hospitalization. The model is applied to the Ebola epidemics in Sierra Leone and Guinea. Model simulations indicate that successive stages of increased and earlier hospitalization of cases have resulted in mitigation of the epidemics.

The immunogenetics of primary biliary cirrhosis: A comprehensive review.

Primary biliary cirrhosis (PBC), a classic autoimmune liver disease, is characterised by a progressive T cell predominant lymphocytic cholangitis, and a serologic pattern of reactivity in the form of specific anti-mitochondrial antibodies (AMA). CD4+ T cells are particularly implicated by PBC's cytokine signature, the presence of CD4+ T cells specific to mitochondrial auto-antigens, the expression of MHC II on injured biliary epithelial cells, and PBC's coincidence with other similar T cell mediated autoimmune conditions. CD4+ T cells are also central to current animal models of PBC, and their transfer typically also transfers disease. The importance of genetic risk to developing PBC is evidenced by a much higher concordance rate in monozygotic than dizygotic twins, increased AMA rates in asymptomatic relatives, and disproportionate rates of disease in siblings of PBC patients, PBC family members and certain genetically defined populations. Recently, high-throughput genetic studies have greatly expanded our understanding of the gene variants underpinning risk for PBC development, so linking genetics and immunology. Here we summarize genetic association data that has emerged from large scale genome-wide association studies and discuss the evidence for the potential functional significance of the individual genes and pathways identified; we particularly highlight associations in the IL-12-STAT4-Th1 pathway. HLA associations and epigenetic effects are specifically considered and individual variants are linked to clinical phenotypes where data exist. We also consider why there is a gap between calculated genetic risk and clinical data: so-called missing heritability, and how immunogenetic observations are being translated to novel therapies. Ultimately whilst genetic risk factors will only account for a proportion of disease risk, ongoing efforts to refine associations and understand biologic links to disease pathways are hoped to drive more rational therapy for patients.