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Background: Alzheimer's disease (AD) is the most frequent neurodegenerative disorder worldwide. The great variability in disease evolution and the incomplete understanding of the molecular mechanisms underlying AD make it difficult to predict when a patient will convert from prodromal stage to dementia. We hypothesize that metabolic alterations present at the level of the brain could be reflected at a systemic level in blood serum of patients, and that these alterations could be used as prognostic biomarkers. Methods: This pilot study proposes a serum investigation via nuclear magnetic resonance (NMR) spectroscopy in a consecutive series of AD patients including 57 patients affected by Alzheimer's disease at dementia stage (AD-dem) and 45 patients with mild cognitive impairment (MCI) due to AD (MCI-AD). As control group, we considered 31 subjects with mild cognitive impairment in whom AD and other neurodegenerative disorders were excluded (MCI). A panel of 26 metabolites and 112 lipoprotein-related parameters was quantified and the logistic LASSO regression algorithm was employed to identify the optimal combination of metabolites-lipoproteins and their ratios to discriminate the groups of interest. Results: In the training set, our model classified AD-dem and MCI with an accuracy of 81.7%. These results were reproduced in the validation set (accuracy 75.0%). Evolution of MCI-AD patients was evaluated over time. Patients who displayed a decrease in MMSE < 1.5 point per year were considered at lower progression rate: we obtained a division in 18 MCI-AD at lower progression rate (MCI-AD LR) and 27 at higher progression rate (MCI-AD HR). The model calculated using 4 metabolic features identified MCI-AD LR and MCI-AD HR with an accuracy of 73.3%. Conclusions: The identification of potential novel peripheral biomarkers of Alzheimer's disease, as proposed in this study, opens a new prospect for an innovative and minimally invasive method to identify AD in its very early stages. We proposed a novel approach able to sub-stratify MCI-AD patients identifying those associated with a faster rate of clinical progression. [ABSTRACT FROM AUTHOR]

Most pathogens are generalists capable of infecting multiple host species or strains. Trade‐offs in performance among different hosts are expected to limit the evolution of generalism. Despite the commonness of generalism, the variation in infectivity, transmission, and trade‐offs in performance among host species have rarely been studied in the wild. To understand the ecological and evolutionary drivers of multi‐host pathogen infectivity and transmission potential, I studied disease severity, transmission dynamics, and infectivity variation of downy mildew pathogen Peronospora sparsa on its three host plants Rubus arcticus, R. chamaemorus, and R. saxatilis. In a survey of 20 wild and cultivated sites of the three host species, disease severity varied by host species and by host population size but not among wild and cultivated sites. To understand how alternative host presence and plant diversity affect transmission of the pathogen, I conducted a transmission experiment. In this experiment, alternative host abundance and plant diversity together modified P. sparsa transmission to trap plants. To understand how resistance to P. sparsa varies among host species and genotypes, I conducted an inoculation experiment using 10 P. sparsa strains from different locations and 20 genotypes of the three host species. Significant variation in infectivity was found among host genotypes but not among host species. When trade‐offs for infectivity were tested, high infectivity in one host species correlated with high infectivity in another host species. However, when pathogen transmission‐related life‐history correlations were tested, a positive correlation was found in R. arcticus but not in R. saxatilis. The results suggest that host resistance may shape pathogen life‐history evolution with epidemiological consequences in a multi‐host pathogen. [ABSTRACT FROM AUTHOR]

Objectives: The aims of this study were, to analyze epicardial adipose tissue and pre-sternal adipose tissue thicknesses and the relationship of the ratio of these two parameters with radiological progression, age, gender, concomitant diseases, hospitalization, length of hospital stay, need for intensive care and survival status of COVID-19 patients. Methods: In this retrospective study, a total number of 204 PCR-positive COVID-19 patients, who have initial lung computed tomography (CT) and a second CT within 15 days due to prolonged symptoms or suspected complications were included. According to patterns of lung involvement at the time of diagnosis, patients were divided into 4 groups. In initial CT scans, epicardial adipose tissue and pre-sternal subcutaneous adipose tissue thickness were measured. Progression or regression of the disease is evaluated by comparing the findings in initial and control CTs. Results: The mean age, epicardial adipose tissue thickness (EAT), pre-sternal adipose tissue thickness (PAT), and the EAT/PAT ratio of patients with involvement in both lungs were found to be higher than those in patients with one lung or without lung involvement and there was a statistically significant positive correlation between them. Conclusions: This study is thought to be the first in which epicardial adipose tissue and pre-sternal adipose tissue were evaluated together in COVID-19 patients. Epicardial adipose tissue is a metabolically active organ and measurement in initial CT scans may give an easy and quick idea of the evolution of the disease. [ABSTRACT FROM AUTHOR]

Machine learning algorithms are essential for predicting severe outcomes during public health crises like COVID-19. However, the dynamic nature of diseases requires continual evaluation and updating of these algorithms. This study aims to compare three update strategies for predicting severe COVID-19 outcomes postdiagnosis: "naive" (a single initial model), "frequent" (periodic retraining), and "context-driven" (retraining informed by clinical insights). The goal is to determine the most effective timing and approach for adapting algorithms to evolving disease dynamics and emerging data. A dataset of 1.11 million COVID-19 patients from diverse U.S. regions was used to develop and validate an XGBoost algorithm for predicting severe outcomes upon diagnosis. Data included patient demographics, vital signs, comorbidities, and immunity-related factors (prior infection and vaccination status) from January 2007 to November 2021. The study analyzed the performance of the three update strategies from March 2020 to November 2021. Predictive features changed over the pandemic, with comorbidities and vitals being significant initially, and geography, demographics, and immunity-related variables gaining importance later. The "naive" strategy had an average area under the curve (AUC) of 0.77, the "frequent" strategy maintained stability with an average AUC of 0.81, and the "context-driven" strategy averaged an AUC of 0.80, outperforming the "naive" strategy and aligning closely with the "frequent" strategy. A context-driven approach, guided by clinical insights, can enhance predictive performance and offer cost-effective solutions for dynamic public health challenges. These findings have significant implications for efficiently managing healthcare resources during evolving disease outbreaks. [ABSTRACT FROM AUTHOR]

The unexpectable variations of the diagnosed disease symptoms are quite often observed during medical diagnosis. In stochastics, such behavior is called "grey swan" or "black swan" as synonyms of sudden, unpredictable change. Evolution of the disease's symptoms is usually described by means of Markov processes, where dependency on process history is neglected. The common expectation is that such processes are Gaussian. It is demonstrated here that medical observation can be described as a Markov process and is non-Gaussian. Presented non-Gaussian processes have "fat tail" probability density distribution (pdf). "Fat tail" permits a slight change of probability density distribution and triggers an unexpectable big variation of the diagnosed parameter. Such "fat tail" solution is delivered by the anomalous diffusion model applied here to describe disease evolution and to explain the possible presence of "swans" mentioned above. The proposed model has been obtained as solution of the Fractal Fokker–Planck equation (FFPE). The paper shows a comparison of the results of the theoretical model of anomalous diffusion with experimental results of clinical studies using bioimpedance measurements in cardiology. This allows us to consider the practical usefulness of the proposed solutions. [ABSTRACT FROM AUTHOR]

Canine distemper virus (CDV) and phocine distemper virus (PDV) are major pathogens to terrestrial and marine mammals. Yet little is known about the timing and geographical origin of distemper viruses and to what extent it was influenced by environmental change and human activities. To address this, we (i) performed the first comprehensive time-calibrated phylogenetic analysis of the two distemper viruses, (ii) mapped distemper antibody and virus detection data from marine mammals collected between 1972 and 2018, and (iii) compiled historical reports on distemper dating back to the eighteenth century. We find that CDV and PDV diverged in the early seventeenth century. Modern CDV strains last shared a common ancestor in the nineteenth century with a marked radiation during the 1930s–1950s. Modern PDV strains are of more recent origin, diverging in the 1970s–1980s. Based on the compiled information on distemper distribution, the diverse host range of CDV and basal phylogenetic placement of terrestrial morbilliviruses, we hypothesize a terrestrial CDV-like ancestor giving rise to PDV in the North Atlantic. Moreover, given the estimated timing of distemper origin and radiation, we hypothesize a prominent role of environmental change such as the Little Ice Age, and human activities like globalization and war in distemper virus evolution. [ABSTRACT FROM AUTHOR]

This article discusses the evolving nature of eosinophilic esophagitis (EoE) and the challenges in diagnosing and managing the condition. EoE is characterized by symptoms such as dysphagia, food impaction, heartburn, and chest pain. The study analyzed a cohort of 1187 patients diagnosed with EoE over a 20-year period and found that the age at diagnosis, frequency of dysphagia, and endoscopic severity increased over time. However, there was no clear trend in diagnostic delay. The authors emphasize the importance of recognizing and diagnosing EoE promptly, as early intervention can reduce complications and improve patient outcomes. They also highlight the need for phenotyping patients with EoE to tailor treatment strategies effectively. Overall, the study underscores the need for healthcare providers to remain vigilant in evaluating and managing EoE across all patient populations. [Extracted from the article]

Introduction: Efficient evaluation with an early surrogate endpoint, taking into account the process of disease evolution, may not only clarify inconsistent or underpowered results but also provide a new insight into the exploration of a new antiviral therapy for treating COVID-19 patients. Methods: We assessed the dynamics of COVID-19 disease spectrum, commencing from low-risk (no or low oxygen supplement), medium-risk (non-invasive ventilator or high oxygen supplement), and high-risk (extracorporeal membrane oxygenation or invasive ventilator) risk state on enrollment, and then the subsequent progression and regression of risk states until discharge or death. The efficacy of antiviral therapy in altering the dynamics was assessed by using the high-risk state as a surrogate endpoint based on the data retrieved from the two-arm Adaptive Covid-19 Treatment Trial. Results: Using the high-risk state as a surrogate endpoint, remdesivir treatment led to a decrease in the high-risk COVID-19 state by 34.8% (95% CI 26.7–42.0%) for a 14-day period and 29.3% (95% CI 28.8–29.8%) up to 28 days, which were consistent with a statistically significant reduction of death by 30.5% (95% CI 6.6, 50.9%) up to a 28-day period. The estimates of numbers needed to be treated were 100.9 (95% CI 88.1, 115.7) for using the high-risk COVID-19 state as a surrogate endpoint for a 14-day period and 133.3 (95% CI 112.5, 158.0) were required for averting one death from COVID-19 up to 28 days. Conclusions: We demonstrate the expedient use of the high-risk COVID-19 disease status as a surrogate endpoint for evaluating the primary outcome of the earliest death. [ABSTRACT FROM AUTHOR]

Introduction Tuberculosis affects commonly the lungs, but any other organs can be affected as well. Urogenital tuberculosis is usually misdiagnosed. In this perspective, we aimed to give an update on the epidemiological, clinical and evolutionary features of urogenital tuberculosis in Southern Tunisia. Methods We conducted a retrospective study including all patients with extrapulmonary tuberculosis notified during the period from 1992 to 2017 in Southern Tunisia. We specified the particularities of urogenital tuberculosis cases, and we compared them with other extrapulmonary tuberculosis cases. Results Overall, we analyzed 240 cases with urogenital tuberculosis, among 1702 patients with extrapulmonary tuberculosis (14.1%). There were 121 women (50.4%). The mean age was 49±17 years. Multifocal tuberculosis was noted in 29 cases (12.1%). There were 169 cases with urinary tract tuberculosis (70.4%). Chronological trends analysis showed that the median age at diagnosis increased significantly (Rho=0.41; p=0.039) and the number of urogenital tuberculosis declined during the study period, without a statistical significance (Rho = -0.07; p=0.721). Compared to other extrapulmonary tuberculosis sites, patients aged 60 years and above (OR=2.7; p<0.001) and coming from rural areas (OR=1.4; p=0.021) were more frequently diagnosed with urogenital tuberculosis. Treatment duration was significantly longer in patients with urogenital tuberculosis (10.13±3.79 vs 9.20±3.77 months; p<0.001). As for the disease evolution, relapse was significantly more frequent in patients with urogenital tuberculosis (OR=4.1; p=0.045). Conclusions Although decreasing trends over time were noted, the prognosis of urogenital tuberculosis was more severe compared to other extrapulmonary tuberculosis sites. [ABSTRACT FROM AUTHOR]

Mixed connective tissue disease was first described as a new autoimmune rheumatic disease in 1972 based on the claim of a distinct clinical picture associated with anti-RNP antibody positivity. Subsequently, this new entity has divided opinions in the rheumatology community. We have reviewed recent cohort studies with more than 100 patients, comparing the clinical and immunological features, treatment, prognosis and evolution to well-defined autoimmune rheumatic diseases. We also reviewed clinical features of undifferentiated autoimmune rheumatic diseases based on the most recent studies. After gathering and reviewing these data, we discuss whether the designation "mixed connective tissue disease" should be maintained. [ABSTRACT FROM AUTHOR]

Purpose This prospective study was undertaken to describe patterns of fragmentation of the femoral epiphysis following a proximal femoral varus osteotomy (PFVO) done during stage I of LCPD and to assess the disease duration and outcome in each pattern. Methods A total of 25 children treated by a PFVO in stage I of LCPD were followed until healing. The MRI Perfusion Index, radiographic changes in the femoral epiphysis, disease duration and the Sphericity Deviation Score (SDS) at healing were documented. The reproducibility of classification of the pattern of fragmentation, estimation of disease duration and SDS were assessed. The duration of the disease and SDS in the patterns of fragmentation were compared. Results Four patterns of fragmentation were noted, namely, typical fragmentation, bypassing fragmentation, abortive fragmentation and atypical fragmentation with horizontal fissuring. The reproducibility of classifying the pattern of fragmentation was moderate (Kappa: 0.48) while the reproducibility of other continuous variables was excellent. The Perfusion Index was less than 50% in every affected hip. The duration of the disease and SDS were lowest in children in whom the stage of fragmentation was bypassed but these differences were not statistically significant. Conclusion Following a proximal femoral osteotomy during stage I of LCPD the fragmentation stage may be bypassed partially or completely and the chances of a good outcome appear to be very good if fragmentation is bypassed. [ABSTRACT FROM AUTHOR]

Background: The mechanism of many complex diseases has not been detected accurately in terms of their stage evolution. Previous studies mainly focus on the identification of associations between genes and individual diseases, but less is known about their associations with specific disease stages. Exploring biological modules through different disease stages could provide valuable knowledge to genomic and clinical research. Results: In this study, we proposed a powerful and versatile framework to identify stage-specific cancer related genes and their dynamic modules by integrating multiple datasets. The discovered modules and their specific-signature genes were significantly enriched in many relevant known pathways. To further illustrate the dynamic evolution of these clinical-stages, a pathway network was built by taking individual pathways as vertices and the overlapping relationship between their annotated genes as edges. Conclusions: The identified pathway network not only help us to understand the functional evolution of complex diseases, but also useful for clinical management to select the optimum treatment regimens and the appropriate drugs for patients. [ABSTRACT FROM AUTHOR]

Abstract: More is not automatically better. Generation and accumulation of information reflecting the complexity of zoonotic diseases as ecological systems do not necessarily lead to improved interpretation of the obtained information and understanding of these complex systems. The traditional conceptual framework for analysis of diseases ecology is neither designed for, nor adaptable enough, to absorb the mass of diverse sources of relevant information. The multidirectional and multidimensional approaches to analyses form an inevitable part in defining a role of zoonotic pathogens and animal hosts considering the complexity of their inter‐relations. And the more data we have, the more involved the interpretation needs to be. The keyword for defining the roles of microbes as pathogens, animals as hosts, and environmental parameters as infection drivers is “functional importance.” Microbes can act as pathogens toward their host only if/when they recognize the animal organism as the target. The same is true when the host recognizes the microbe as a pathogen rather than harmless symbiont based on the context of its occurrence in that host. Here, we propose conceptual tools developed in the realm of the interdisciplinary sciences of complexity and biosemiotics for extending beyond the currently dominant mindset in ecology and evolution of infectious diseases. We also consider four distinct hierarchical levels of perception guiding how investigators can approach zoonotic agents, as a subject of their research, representing differences in emphasizing particular elements and their relations versus more unified systemic approaches. [ABSTRACT FROM AUTHOR]

Background and purpose: Deep brain stimulation (DBS) for severe Parkinson's disease (PD) outperforms the best medical treatment in controlling motor symptoms and improving quality of life. Nevertheless disease progression cannot be controlled, and the development of dementia over time is nearly inevitable, often resulting in nursing home placement. Ten-year survival, development of hallucinations, dementia and nursing home placement were examined and adverse events were assessed. Method: Patient files were scrutinized from baseline up to 10 years of treatment or death on all 79 PD patients treated with DBS of the subthalamic nucleus from 1998 to 2003 at Aarhus University Hospital. Results: Twenty-four patients died during the follow-up period of 10 years. Age above 60 years at surgery increased mortality 2.3-fold (P = 0.04). Of the 55 surviving patients 29 (53%) were demented and 19 (35%) were in nursing homes. Average time from operation to dementia was 5.6 ± 2.9 years. Hallucinations and nursing home placement were associated with increased mortality. Conclusion: Survival of 70% after a mean of 25 years of PD including 10 years with DBS illustrates that this is a selected group of PD patients. The prevalence of dementia steadily increased after surgery as expected from disease progression and can be an early event. Compared with the few similar long-term studies, the present study presents a larger cohort followed at the same DBS center for a longer period of time and none was lost to follow-up, making conclusions more valid. The present findings are of significant prognostic help for the patient, caregiver and physician when treatment with DBS has to be decided. [ABSTRACT FROM AUTHOR]

Dental calculus (calcified tartar or plaque) is today widespread on modern human teeth around the world. A combination of soft starchy foods, changing acidity of the oral environment, genetic pre-disposition, and the absence of dental hygiene all lead to the build-up of microorganisms and food debris on the tooth crown, which eventually calcifies through a complex process of mineralisation. Millions of oral microbes are trapped and preserved within this mineralised matrix, including pathogens associated with the oral cavity and airways, masticated food debris, and other types of extraneous particles that enter the mouth. As a result, archaeologists and anthropologists are increasingly using ancient human dental calculus to explore broad aspects of past human diet and health. Most recently, high-throughput DNA sequencing of ancient dental calculus has provided valuable insights into the evolution of the oral microbiome and shed new light on the impacts of some of the major biocultural transitions on human health throughout history and prehistory. Here, we provide a brief historical overview of archaeological dental calculus research, and discuss the current approaches to ancient DNA sampling and sequencing. Novel applications of ancient DNA from dental calculus are discussed, highlighting the considerable scope of this new research field for evolutionary biology and modern medicine. [ABSTRACT FROM AUTHOR]

Environmental change is contributing to change the pattern of diseases in aquatic settings. In this study we have analyzed the disease outbreaks that occurred in North Spanish Salmonid hatcheries during the last two decades. Six pathogens were considered: Aeromonas hydrophila, Aeromonas salmonicida, Flavobacterium psychrophilum, Lactococcus garvieae, infectious pancreatic necrosis virus and Yersinia ruckeri. Vaccines against Lactococcus and Yersinia are currently applied in the region. A shift in the dominant pathogen from Y. ruckeri to F. psychrophilum occurred after the year 2000, coincident with application of vaccines and climate warming in the region. Positive association of vaccines against some pathogens and prevalence of other pathogens was found, as well as a significant change in the temperature range at which outbreaks occurred. Both environmental perturbations and opportunistic development of pathogens when others are controlled by vaccines contribute to explain the stability of disease outbreaks in the region despite the introduction of vaccines. [ABSTRACT FROM AUTHOR]

Abstract: In order to understand contemporary natural history of Duchenne muscular dystrophy (DMD), we report 6-minute walk distance (6MWD) and its change over time from a large single centre population of corticosteroid treated DMD boys. Sixty-five boys on daily corticosteroid treatment were identified with a mean (SD) age of 9.5 (2.3) years at first observation. 6MWD was described for 1year age groupings. In addition, changes in 6MWD at 1, 1.5 and 2years (±12weeks) of follow-up were evaluated. The same evaluations were applied to 6MWD data converted to percent predicted values based on the Geiger equation. 6MWD showed an increase from age group 4.5–5.5years to age group 6.5–7.5years, followed by a decline, which became precipitous from 12.5years onwards. From 15.5years, all boys were unable to perform the 6-min test. Changes in 6MWD demonstrated a mean (median, SD) decline of −43 (−14, 90) m at 1year (N =25, mean baseline age 9.5years), −64 (−56, 99) m at 1.5years (N =18, mean baseline age 9.6years), −125 (−106, 139) m at 2years (N =14, mean baseline age 10.0years). Conversion to percent predicted values showed the same pattern of evolution.This study provides data on the ambulatory capacity and its changes over time in a homogenous cohort of 65 DMD boys on daily corticosteroids. The variability, the age-related aspects and the slope of decline of the 6MWD should be considered in the design and interpretation of therapeutic trials in ambulant DMD patients. [Copyright &y& Elsevier]

Abstract: Background: Active smoking has been associated with a higher risk of developing Crohn''s disease (CD). However, its impact on clinical outcomes has been controversial among studies. Aims: To evaluate the influence of active smoking on initial manifestations of CD, the development of disease-related complications, and therapeutic requirements. Methods: Patients diagnosed with CD within a ten-year period (1994–2003) were identified. Clinical and therapeutic features until October 2008 or loss of follow-up were recorded. Smoking status was assessed at each major disease-related event (e.g. penetrating and stricturing complications, perianal disease, intestinal resection, introduction of immunomodulators or biological agents). Results: A total of 259 patients were included in the study with a median follow-up period of 91months. At diagnosis, 50.5% were active smokers and only 12% of them quit smoking during follow-up, mostly after a major disease-related event occurred. Smoking at diagnosis was not associated with a particular CD presentation. Active smoking did not influence the development of strictures, intraabdominal and perianal penetrating complications, or increased resectional surgery, biological therapy or immunomodulators requirements. Conclusions: Patients who develop CD while smoking seem to have a similar disease course to those who never smoked. [Copyright &y& Elsevier]

Rheumatoid arthritis (RA) is an inflammatory autoimmune disease of unknown etiology. Many cytokines have been found to be associated with RA pathogenesis and among them is macrophage migration inhibitory factor (MIF). The aim of this study was to determine whether MIF serum levels are associated with RA course, clinical activity, and clinical biomarkers of the disease. MIF levels were determined in serum samples of 54 RA patients and 78 healthy subjects (HS) by enzyme-linked immunosorbent assay (ELISA). Disease activity was evaluated using the DAS28 score. Patients were subgrouped according to disease activity and years of evolution of disease. Statistical analysis was carried out by SPSS 10.0 and GraphPad Prism 5 software. RA patients presented increased levels of MIF as compared to HS. MIF levels were raised on early stages of RA and tend to decrease according to years of evolution. Moreover, MIF levels positively correlated with rheumatoid factor in RA patients and with C reactive protein in all individuals studied. Our findings suggest that MIF plays a role in early stages of RA. [ABSTRACT FROM AUTHOR]

Abstract: Background: Patients with ulcerative colitis (UC) and concomitant perianal disease (PAD) are occasionally seen, but the impact of PAD on UC outcome has been scarcely assessed. Aims: To evaluate the prevalence, clinical features and outcomes of PAD among UC patients. Methods: Patients with an initial diagnosis of UC who ever developed PAD were identified from three IBD hospital databases. Each case was matched by age, disease extent at diagnosis, and year of diagnosis, with two UC patients who never developed PAD. Results: Thirty-seven UC patients (5% of the whole series) developed PAD (complex in about a half of them), being more frequent among men (62%), with distal (50%) or extense (34%) disease. Proximal spread of UC occurred in 19% of cases. No differences in demographic features, rate of proximal spread or colectomy during follow-up were found as compared to controls, but greater requirements of steroids (P=0.019) were detected in UC-PAD patients. A change in disease diagnosis occurred in 6 patients mainly because of transmural involvement in colectomy specimen, small intestinal involvement, and/or endoscopic appearance. Conclusions: PAD may occur in up to 5% of UC patients. When complex it leads to a change in disease diagnosis in one third of cases. UC-related therapeutic requirements are not increased in these patients, except for steroids. [Copyright &y& Elsevier]

Genetic data from field isolates of foot-and-mouth disease virus (FMDV) have been used to trace the source of recent outbreaks of FMD, to design better vaccines and diagnostic tests for FMDV, and to make conclusions regarding the general variability in the FMDV genome. Though epidemiologic data associated with FMDV isolates are available, these data have been used rarely to explore possible associations of epidemiologic factors with evolution or variation of the FMDV genome. In this study, factors associated with variation in the primary immunogenic peptide gene of FMDV (VP1), for a sample of 147 serotype O, Pan Asia strain sequences were explored using traditional analytical epidemiologic methods: logistic regression and multinomial-response logistic regression. Hypothesized factors included host type (bovine, ovine, buffalo, or porcine) and geographical region (Middle East, South Asia, East Asia, Southeast Asia, and Europe). Results of two regression analyses suggest that host type and region, considered to be possible surrogates for host management, may be associated with selection in the VP1 amino acid sequence in FMDV. For example, isolates from cattle and sheep in South Asia appear to converge with a proposed ancestor sequence, whereas isolates from the same species in the Middle East and Southeast Asia appear to diverge. The methods demonstrated here could be used on a more detailed dataset to explore the selective pressure of host immunity on the evolution of FMDV antigens in an endemic setting. More broadly, epidemiologic methods could be applied extensively to molecular data to explore the causes of genomic variation in disease-causing organisms. [ABSTRACT FROM AUTHOR]

To assess the value of clinical and MRI variables in predicting short-term brain atrophy accumulation and clinical evolution in a large cohort of patients with RRMS, we studied a cohort of 548 patients, previously enrolled as a placebo arm of a 14-month, double-blind trial of oral glatiramer acetate (GA). A logistic regression model with EDSS progression as the dependent variable was built to assess baseline clinical and MRI variables associated with clinical worsening during follow-up. In 466 patients with complete central brain atrophy assessment, another linear regression model with percentage central brain volume change (PCBVC) as the dependent variable was built to assess baseline clinical and MRI variables associated with atrophy development. A total of 80 patients (15 %) had EDSS progression over the follow-up period. Factors independently predicting the probability to have a clinical progression were lower EDSS (OR = 0.78, 95 % CI = 0.62–0.97 p = 0.02) and higher T2 LL (OR = 1.022, 95 % CI = 1.006–1.038, p = 0.007) at baseline. In the 466 patients with atrophy assessment, PCBVC declined, on average, by –2.0 % (SD = 2.8) (p < 0.001) over the follow-up. The multivariate PCBVC analysis revealed that the PCBVC decrease was independently correlated with higher EDSS (p = 0.03) and T2 LL (p = 0.005) at baseline. The squared correlation coefficients of the composite scores made up of EDSS and T2 LL considered together were able to explain only 3 % of the variance in disability progression and only 4 % of the variance of PCBVC. In RRMS patients, clinical and conventional MRI findings at baseline only modestly predict shortterm accumulation of brain atrophy and disability. These data confirm the need to develop clinical and MRI measures more sensitive towards the more disabling aspects of the disease. [ABSTRACT FROM AUTHOR]

To define the extent of overall brain damage in patients with clinically isolated syndromes (CIS) suggestive of multiple sclerosis (MS) and to identify non-conventional magnetic resonance (MR) metrics predictive of evolution to definite MS. Brain conventional and magnetization transfer (MT) MRI scans were obtained from 208 CIS patients and 55 matched healthy controls, recruited in four centres. Patients were assessed clinically at the time of MRI acquisition and after a median period of 3.1 years from disease onset. The following measures were derived: T2, T1 and gadolinium (Gd)- enhancing lesion volumes (LV), normalized brain volume (NBV), MTR histogram-derived quantities of the normal-appearing white matter (NAWM) and grey matter (GM). During the follow-up, 43 % of the patients converted to definite MS. At baseline, a significant inter-centre heterogeneity was detected for T2 LV (p = 0.003), T1 LV (p = 0.006), NBV (p < 0.001) and MTR histogram-derived metrics (p < 0.001). Pooled average MTR values differed between CIS patients and controls for NAWM (p = 0.003) and GM (p = 0.01). Gdactivity and positivity of International Panel (IP) criteria for disease dissemination in space (DIS), but not NAWM and GM MTR and NBV, were associated with evolution to definite MS. The final multivariable model retained only MRI IP criteria for DIS (p = 0.05; HR = 1.66, 95 % CI = 1.00–2.77) as an independent predictor of evolution to definite MS. Although irreversible tissue injury is present from the earliest clinical stages of MS, macroscopic focal lesions but not "diffuse" brain damage measured by MTR are associated to an increased risk of subsequent development of definite MS in CIS patients. [ABSTRACT FROM AUTHOR]

Emerging infectious diseases, most of which are considered zoonotic in origin, continue to exact a significant toll on society. The origins of major human infectious diseases are reviewed and the factors underlying disease emergence explored. Anthropogenic changes, largely in land use and agriculture, are implicated in the apparent increased frequency of emergence and re-emergence of zoonoses in recent decades. Special emphasis is placed on the pathogen with likely the greatest zoonotic potential, influenzavirus A. [ABSTRACT FROM AUTHOR]

Abstract: A number of recent magnetic resonance imaging studies have challenged the classical view of multiple sclerosis (MS) as a “two-stage” disease where an early inflammatory demyelinating phase with focal macroscopic lesions formed in the white matter (WM) of the central nervous system is followed by a late neurodegenerative phase, which is believed to be a mere consequence of repeated inflammatory insults and irreversible demyelination. These studies have consistently shown the presence of diffuse normal-appearing WM damage, marked gray matter involvement and significant cortical functional reorganization, as well as the occurrence of the neurodegenerative component of MS from the earliest clinical stages of the disease with only a partial relation to MRI markers of inflammatory demyelination. The present review argues that MS can no longer be viewed as a “two-stage” disease, which suggests that the two pathological components are dissociated in time, but rather as a “simultaneous two-component” disease, where the relative contributions of the various pathological processes of the disease to the development of “fixed” disability, their relationship and their evolution over time need to be clarified. This new view of MS should inform the development of future research protocols to define its actual physiopathology and prompt the institution of early treatment which should ideally target not only inflammatory demyelination, but also the neurodegenerative aspects of the disease, as well as promote neuroprotection and enhance reparative mechanisms and adaptive functional reorganization of the cortex. [Copyright &y& Elsevier]

Many significant diseases of human civilization are thought to have arisen concurrently with the advent of agriculture in human society. It has been hypothesised that the food produced by farming increased population sizes to allow the maintenance of virulent pathogens, i.e. civilization pathogens, while domestic animals provided sources of disease to humans. To determine the relationship between pathogens in humans and domestic animals, I examined phylogenetic data for several human pathogens that are commonly evolutionarily linked to domestic animals: measles, pertussis, smallpox, tuberculosis, taenid worms, and falciparal malaria. The majority arc civilization pathogens, although I have included others whose evolutionary origins have traditionally been ascribed to domestic animals. The strongest evidence for a domestic-animal origin exists for measles and pertussis, although the data do not exclude a non-domestic origin. As for the other pathogens, the evidence currently available makes it difficult to determine if the domestic-origin hypothesis is supported or refuted; in fact, intriguing data for tuberculosis and taenid worms suggests that transmission may occur as easily from humans to domestic animals. These findings do not abrogate the importance of agriculture in disease transmission; rather, if anything, they suggest an alternative, more complex series of effects than previously elucidated. Rather than domestication, the broader force for human pathogen evolution could be ecological change, namely anthropogenic modification of the environment. This is supported by evidence that many current emerging infectious diseases are associated with human modification of the environment. Agriculture may have changed the transmission ecology of pre-existing human pathogens, increased the success of pre-existing pathogen vectors, resulted in novel interactions between humans and wildlife, and, through the domestication of animals, provided a stable conduit for human infection by wildlife diseases. [ABSTRACT FROM AUTHOR]

Medical observers during the American Civil War were happily surprised to find that typhus fever rarely made an appearance, and was not a major killer in the prisoner-of-war camps where the crowded, filthy, and malnourished populations appeared Io offer an ideal breeding ground for the disease. Through a review of typhus outbreaks in America north of the Mexican border this article argues that typhus fever rarely if ever extended to the established population of the United States, even when imported on immigrant ships into densely populated and unsanitary slums. It suggests that something ill the American environment was inhospitable to the extensive spread of the disease, most likely all unrecognized difference in the North American louse population compared to that Europe. [ABSTRACT FROM AUTHOR]

Transmissible spongiform encephalopathies can jump species barriers. In relatively few cases is the possible route of transmission thought to be known, mostly involving humans, cattle and sheep. It is thought that sheep might be the cause of Bovine Spongiform Encephalopathy (BSE) and Chronic Wasting Disease (CWD) in cervids, and that humans might have gotten prion disease (e.g., vCJD) from eating meat from BSE+ cows. A looming societal question is whether humans will acquire a prion disease from ingesting prions from CWD+ deer. On an evolutionary tree of the PRNP gene in mammals, deer, sheep and cow are relatively closely related, whereas these three species are relatively distant from humans. If a prion disease jumped the species barrier from cow to humans, the phylogenetic gap from deer to humans is no greater, and sheer evolutionary distance alone cannot explain a CWD species barrier in humans. Aspects of the PRNP gene were compared among these species to search for genetic differences that might influence the permeability of the species barrier. Human prion disease has been associated with having more than four copies of the octarepeat unit (PHGGGWG), whereas deer, sheep and cow all have three copies. Two amino acid positions in the metal-binding region (96 and 97) have been implicated in species barriers (Breydo and Uversky, 2011), whereas no variation was detected in white-tailed deer and mule deer with and without CWD, or in black-tailed deer, Key deer or Coues deer. Four out of 10 differences between deer and human in the β2-α2 loop might preclude CWD prions from converting human PrPC to PrPSc because of disruption of a steric zipper. The reasons for a CWD species barrier between deer and humans, if there is one, is still unresolved. • It is unknown why Chronic Wasting Disease has not caused a prion disease in humans. • If BSE has jumped the species barrier to humans, it appears that CWD could as well. • There are no obvious genetic reasons why humans have not contracted a prion disease from eating infected deer. [ABSTRACT FROM AUTHOR]