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Background: 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., Methods: 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., Results: 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., Conclusions: 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., (Copyright © 2024 Elsevier Inc. All rights reserved.)

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., Competing Interests: The author has declared no competing interests., (© 2024 The Authors. Evolutionary Applications published by John Wiley & Sons Ltd.)

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.

Background and Aims: The aims of this study were to describe the trends in the behavior of pediatric CD during the last decade and to describe the seasonal variation of disease presentation., Methods: Patients under 18 years old and diagnosed between 2009 and 2019 were included. The clinical, endoscopic, histological, and laboratory data were collected from the medical records. We analyzed the trends of these parameters according to the year and season of diagnosis., Results: 654 patients were included in the study. The number of incident CD cases increased yearly. Patients diagnosed between 2015 and 2019 were younger at diagnosis (OR 2.53, p = 0.02), had more perianal diseases (OR: 2.30, p < 0.0001) and more granulomas (OR: 1.61, p = 0.003), but fewer eosinophils (OR: 0.35, p < 0.0001) and less chronic lymphoplasmacytic infiltrate (OR: 0.56, p = 0.008) as compared to the 2009-2014 cohort. There was fewer CD diagnosis during winter. Patients diagnosed in the fall had lower PCDAIs, less failure to thrive and less extensive digestive involvement. Colonic disease was significantly more frequent during summer and fall., Conclusion: The clinical and histological phenotype of CD has changed over time and there are important seasonal trends in the frequency and severity on disease behavior suggesting possible disease triggers., Competing Interests: Declaration of Competing Interest None declared., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

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.

High-risk neuroblastoma (HR-NB) is branded with hematogenous metastasis, relapses, and dismal long-term survival. Intensification of consolidation therapy with tandem/triple autologous stem cell (SC) rescue (with bone marrow [BM]/peripheral blood [PB] CD34 + selection) after myeloablative chemotherapy has improved long-term survival. However, the benefit is limited by the indication of NB cells in CD34 + PBSCs, CD34 expression in NB cells, and the risk of reinfusing NB cancer stem cells (NB CSCs) that could lead to post-transplant relapse. We investigated the association of CD34 surface expression (92 patients) with NB evolution/clinical outcomes. CD34 gene-level status in NB was assessed through RNA-Seq data mining (18 cohorts, n, 3324). Genetic landscape of CD34-expressing NB CSCs (CD133 + CD34 + ) was compared with CD34 - CSCs (CD133 + CD34 - ). RNA-seq data revealed equivocal association patterns of CD34 expression with patient survival. Our immunohistochemistry data revealed definite, but rare (mean, 0.73%; range 0.00-7.87%; median, 0.20%) CD34 positivity in NB. CD34 + significantly associated with MYCN amplification (p, 0.003), advanced disease stage (p, 0.016), and progressive disease (PD, p < 0.0009) after clinical therapy. A general high-is-worse tendency was observed in patients with relapsed disease. High CD34 + correlated with poor survival in patients with N-MYC-amplified HR-NB. Gene expression analysis of CD34 + -NB CSCs identified significant up (4631) and downmodulation (4678) of genes compared with NB CSCs that lack CD34. IPA recognized the modulation of crucial signaling elements (EMT, stemness maintenance, differentiation, inflammation, clonal expansion, drug resistance, metastasis) that orchestrate NB disease evolution in CD34 +  CSCs compared with CD34 - CSCs. While the function of CD34 in NB evolution requires further in-depth investigation, careful consideration should be exercised for autologous stem cell rescue with CD34 + selection in NB patients. Graphical abstract.

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.

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 PrP C to PrP Sc 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., Competing Interests: Declaration of Competing Interest The author declares no conflict of interest., (Copyright © 2020 Elsevier B.V. All rights reserved.)

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., Competing Interests: Conflicts of interest: All authors – none to declare., (GERMS.)

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.

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., Level of Evidence: Level II Prognostic Study., (Copyright © 2020, The author(s).)

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.

Upon entering clinical medicine in the 1940s, antibiotic therapy seemed to complete a transformation of hospitals that originated in the late nineteenth century. Former death sinks had become harbingers of therapeutic progress. Yet this triumph was short-lived. The arrival of pathologies caused by resistant bacteria, and of nosocomial infections whose spread was helped by antibiotic therapies, seemed to be intimately related to modern anti-infective therapy. The place where such problems culminated were hospitals, which increasingly appeared as dangerous environments where attempts to combat infectious diseases had instead created hothouses of disease evolution. This paper will focus on one aspect of that history. It caused clinical medicine and hospital hygiene in particular to pay attention to a dimension of infectious disease it had previously paid little attention to thus far: The evolution of infectious disease-previously a matter of mostly theoretical interest-came to be useful in explaining many phenomena observed. This did not turn hospital hygienists into geneticists, though it did give them an awareness that the evolution of infectious disease in a broad sense was something that did matter to them. The paper advances its argument by looking at three phases: The growing awareness of the hospital as a dangerous environment in the 1950s, comprehensive attempts at improving antibiotic therapy and hospital hygiene that followed from the 1960s and lastly the framing of such challenges as risk factors from the 1970s. In conclusion, I will argue that hospital hygiene, being inspired in particular by epidemiology and risk factor analysis, discussed its own specific version of disease emergence and therefore contributed to the 1980s debates around such topics. Being loosely connected to more specialized studies, it consisted of a re-interpretation of infectious disease centred around the temporality of such phenomena as they were encountered in day-to-day dealings of clinical wards.

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.

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., (© 2014 EAN.)

Cancer cells have the unusual capacity to limit the cost of the mutation load that they harbor and simultaneously harness its evolutionary potential. This property fuels drug resistance, a key failure mode in oncogene-directed therapy. However, the factors that regulate this capacity might also provide an Achilles' heel that could be exploited therapeutically. Recently, insight has come from a seemingly distant field: protein folding. It is now clear that protein homeostasis broadly supports malignancy and fuels the rapid evolution of drug resistance. Among protein homeostatic mechanisms that influence cancer biology, the essential ATP-driven molecular chaperone heat-shock protein 90 (Hsp90) is especially important. Hsp90 catalyzes folding of many proteins that regulate growth and development. These "client" kinases, transcription factors, and ubiquitin ligases often play critical roles in human disease, especially cancer. Studies in a wide range of systems-from single-celled organisms to human tumor samples-suggest that Hsp90 can broadly reshape the map between genotype and phenotype, acting as a "capacitor" and "potentiator" of genetic variation. Indeed, it has likely done so to such a degree that it has left an impress on diverse genome sequences. Hsp90 can constitute as much as 5% of total protein in transformed cells and increased levels of heat-shock activation correlate with poor prognosis in breast cancer. These findings and others have motivated a flurry of interest in Hsp90 inhibitors as cancer therapeutics, which have met with rather limited success as single agents, but may eventually prove invaluable in limiting the emergence of resistance to other chemotherapeutics, both genotoxic and molecularly targeted. Here, we provide an overview of Hsp90 function, review its relationship to genetic variation and the evolution of new traits, and discuss the importance of these findings for cancer biology and future efforts to drug this pathway., (© 2016 Elsevier Inc. All rights reserved.)

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., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Drug-resistant bacteria are a huge and growing threat to public health. A solution exists in theory, but had not yet been put to a practical test. The accompanying paper by Ross-Gillespie et al., the theory is put to a test and performs successfully. As predicted, using a drug that targets bacteria's shared secreted 'public goods' molecules instead of cell components did not drive the bacterial evolution of drug resistance, and therefore retained its effectiveness. This result holds great promise for better drugs and vaccines against many infectious diseases, and also for better cancer therapies.

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 © 2013 Elsevier B.V. All rights reserved.)