Miracle-dz/UniFAR-FTUs huggingface dataset:
A Systems Medicine approach to multimorbidity. Towards personalised care for patients with Chronic Obstructive Pulmonary Disease

Multimorbidity (i.e. the presence of more than one chronic disease in the same patient) and comorbidity (i.e. the presence of more than one chronic disease in the presence of an index disease) are main sources of dysfunction in chronic patients and avoidable costs in conventional health systems worldwide. By affecting a majority of elderly population worldwide, multimorbidity prompts the need for revisiting the single disease approach followed by contemporary clinical practice and elaborate strategies that target shared mechanisms of associated diseases with the potential of preventing, decelerating or even halting multimorbid disease progression. However, our current understanding on disease interactions is rather limited, and although many disorders have been associated based on their shared molecular traits and their observed co-occurrence in different populations, no comprehensive approach has been outlined to translate this knowledge into clinical practice. This PhD thesis aims to explore multimorbidity from a systems medicine perspective on the specific use-case of chronic obstructive pulmonary disease (COPD), with the outlook of generalising these methods to a broader set of chronic respiratory diseases, and other non-communicable diseases (NCDs). COPD is a major cause of chronic morbidity and mortality worldwide, and its disease manifestations often involves extra-pulmonary effects, including highly prevalent comorbidities (e.g. type 2 diabetes, cardiovascular diseases) and systemic effects. The thesis investigates molecular disturbances at the body system level and identifies signature biological pathways that potentially play key role in systemic effects and comorbidities of patient with COPD. The thesis also analyses from a population health perspective the comorbidity related risks of COPD, indicating its major negative impact on highly relevant clinical events, use of healthcare resources and prognosis. Finally, the thesis identifies personalized health risk prediction and service selection as potential tools for the integration and transfer of scientific evidence on multimorbidity to daily clinical practice and explores real-world implementation strategies in cloud-based environments. Thesis outcomes indicate the need for a novel, systems perspective on COPD that considers non-pulmonary manifestations both at the staging and the management of the disease. Moreover, the thesis provides specific actionable insights for the development of innovative interventions targeting the prevention of non-pulmonary manifestations. The application of the outcomes of the thesis has a credible potential to contribute to personalized care for chronic patients.
Coffee

baked goods and therefore with sugar has constituted but a small proportion of its total intake, most fat being eaten independently of any sweetening. In contrast, the association of sugar with cream on fruit desserts and with fat in cakes, pies and similar foods results in an overwhelming proportion of the sugar that is consumed being eaten together with fat. Even when sugar is used to sweeten tea or coffee, the addition of milk or cream results in some association. It is consequently possible to dissociate the effects of fat consumption from those of sugar, but virtually impossible to dissociate the effects of sugar consumption from those of fat. This would readily help to explain the negative findings of the Keys multivariate analysis. Keys drew attention to the rising incidence of coronary heart disease in both the United Kingdom and the United States during the first half of the twentieth century when fat consumption in both countries rose considerably but sugar consumption changed very little. This does not exonerate sugar as a risk factor. Theoretically, if both sugar and animal fats were risk factors and sugar consumption held constant while fat consumption increased, the incidence of CHD would rise. Longitudinal studies of food consumption would only exonerate sugar if a society could be found in which fat intake was constant, sugar consumption rose but coronary heart disease incidence did not change. Such a society is unlikely ever to exist. The observations of Keys therefore, while not implicating sugar as a risk factor, certainly do not exclude it.107 In conclusion, excessive sugar intake is conducive to obesity and results in surges in serum insulin levels with an eventual increase in insulin resistance. The results of experimental dietary studies suggest that, particularly in the context of a coincidental liberal saturated fat intake, high sugar consumption is followed by elevation of serum cholesterol as well as triglyceride levels. The relation of high cholesterol levels to increasing incidence of coronary heart disease is well established and recent studies have implicated liberal sugar consumption with serum triglyceride elevation, insulin resistance and rising glycosylated levels as well. All of these are established risk factors for CHD. The great increase in English sugar consumption during the Georgian era has been shown to coincide with a sharp increase in consumption of animal fats and reasons for a direct linkage between the effects of these two dietary changes have been demonstrated. The evidence therefore suggests that the dramatic rise in sugar usage in eighteenth-century England could be implicated as an ancillary factor contributing to the initial emergence of angina pectoris and its increasing prevalence thereafter.
National Standards for the prevention and control of healthcare-associated infections in acute healthcare services

Preventing and controlling healthcare-associated infections continues to be a significant challenge to healthcare systems throughout the world, including Ireland. These infections affect on average 1 in 20 people in the acute healthcare service setting, rising in patient care areas with high numbers of vulnerable patients and complex activity. ‡ In addition, antimicrobial resistance presents a serious threat to patients, with an increasing amount of outbreaks related to multidrug-resistant organisms reported in Irish hospitals. In particular, resistant enterobacteriaceae and enterococci have emerged as important causes of healthcare-associated infection. In 2014, Ireland had the highest proportion of vancomycin-resistant Enterococci blood-stream infection in Europe.  The potential risk of transmission and spread of healthcareassociated infection has been observed with increased patient transfer occurring between hospitals in Ireland. ‡ Healthcare-associated infections can have a huge impact on patients and their families, causing serious illness, long-term disability and death. There are also significant impacts on acute healthcare services due to the cost implications of such infections, including prolonged patient stays, isolation requirements and ward closures. However, a significant proportion of healthcare-associated infection is known to be avoidable, if effective structures, systems and processes are in place to manage the potential risks arising from the environment and activities within the hospital. This is best achieved through a well-organised, planned and managed infection prevention and control programme which is integrated with an antimicrobial stewardship programme to effectively coordinate efforts within an acute healthcare service
Local effects of limited recombination in Drosophila

Recent years have witnessed the integration of theoretical advances in population genetics with large-scale analyses of complete genomes. As a result, a growing number of studies suggest the frequent occurrence of deleterious as well as adaptive mutations. Given the evidence for the widespread occurrence of selection, the finite sizes of natural populations, and the limited recombination in every genome, mutations under selection are expected to alter the fate of genetically linked mutations. The consequences of this non-independent behavior of mutations can be described by the Hill-Robertson effect in terms of the reduction in the effective population size (Ne). Reduction in the effective population size has two effects: 1) a reduction in levels of genetic variation and 2) a reduction in the effectiveness of selection that is manifested in an increased probability of fixation of deleterious mutations and a reduced probability of fixation of advantageous mutations. Changes in Ne that have previously been frequently associated with changes in recombination rate can also occur locally, in association with changes in the number of sites under selection even when the recombination rate remains uniform. The main objective of the work presented in this thesis is to investigate these local effects of the non-independent behavior of mutations on patterns of polymorphism and divergence in Drosophila using computer simulation and experimental approaches. A computer simulation approach is developed to investigate the local consequences of linked selection on estimates of selection and the proportion of adaptive substitutions using the McDonald-Kreitman framework. The results suggest that even a high level of recombination is unlikely to remove all the effects of linked selection.
AI-19 T peripheral helper cells are expanded in the circulation of active SLE patients and correlate with CD21low B cells

Background Pathologic T cell-B cell interactions and production of autoantibodies are hallmark features of SLE. T follicular helper (Tfh) cells are generally considered the principal T cell population capable of helping B cells. However, distinct T cell populations can augment B cell responses in chronically inflamed peripheral tissues. We recently described a dramatically expanded population of T peripheral helper (Tph) cells that promotes B cell responses in synovium of patients with seropositive RA. Here we evaluate the frequency, phenotype, and clinical associations of Tph cells in the circulation of patients with lupus. Methods Mass cytometry data from the Accelerating Medicines Partnership RA/SLE Network were used to quantify cell populations in PBMCs from 27 lupus nephritis patients, 27 RA patients, and 25 non-inflammatory controls. Frequencies of Tph cells (PD-1hi CXCR5- CD4+ T cells), Tfh cells (PD-1hi CXCR5+ CD4+ T cells), and CD21low CD19+ B cells were quantified by standardized gating, and associations with SLEDAI and dsDNA titers were assessed. For in vitro T cell-B cell co-cultures, sorted Tph cells, Tfh cells, or control T cell populations from SLE patients were co-cultured with memory B cells and stimulated with SEB +LPS, and CD38hi CD27+ plasmablasts were quantified at day 5. Results We first confirmed that Tph cells (PD-1hi CXCR5- CD4+ T cells) from SLE patients possess B cell helper function, as we previously observed in RA. Tph cells sorted from blood from 5 different lupus patients strongly induced B cell differentiation into CD38hi CD27+ plasmablasts in vitro (figure 1A, n=5 donors). By mass cytometry, Tph cells are markedly expanded in the circulation of SLE patients compared to non-inflammatory controls (4.3-fold increase, p 50 (p=0.017) and with SELENA-SLEDAI >10 (p=0.046) compared to patients with lower disease activity measures. Similar associations with disease activity were not observed for Tfh cells. Expression of surface receptors on Tph cells from SLE and RA patients was similar. A strong positive correlation emerged between the frequencies of Tph cells and CD21low B cells, an activated B cell population highly expanded in SLE (Spearman r=0.56, p=0.0026, figure 1C, gray=SLE patients, black=all other patients). In contrast, no correlation was seen between Tfh cells and CD21low B cells in SLE patients. Conclusions Tph cells are markedly expanded in the circulation of patients with SLE and demonstrate robust B cell helper function. The strong and specific positive correlation between Tph cell and CD21low B cell frequencies suggests that these cells may act coordinately in the pathologic autoimmune response in SLE. Acknowledgements We acknowledge the Accelerating Medicines Partnership RA/SLE Network and its members.
Functional analysis of the threonine motif in the β1 integrin cytoplasmic tail in mice

Integrins are ubiquitously expressed adhesion receptors with important functions in cellular adhesion, proliferation, migration and signaling. These functions are determined by integrin trafficking through endosomal compartments and receptor affinity regulation. In this thesis, we identified the distal NxxY motif of the β1 integrin cytoplasmic tail as a molecular switch modulating a spatiotemporally controlled binding of two FERM-domain proteins in different cellular compartments. Kindlins mediate integrin activation at the plasma membrane and they dislodge upon internalization. In the endosomal compartment, the free cytoplasmic domain is subsequently bound by sorting nexin 17 (SNX17) to inhibit integrin degradation. We identified SNX17 as a new β1 integrin adaptor protein, which uses the kindlin-binding site in endosomal compartments to stabilize integrins and to promote their recycling back to the plasma membrane.
The Use of Matrix-Assisted Laser Desorption/Ionization Time-of-Flight Mass Spectrometry (MALDI-TOF MS) for the Identification of Pathogens Causing Sepsis.

BACKGROUND Sepsis is a life-threatening condition with high rates of morbidity and mortality; effective and appropriate antibiotic therapy is essential for ensuring patient improvement. To aid in the diagnosis of sepsis, blood cultures are drawn and sent to the microbiology laboratory for pathogen growth, identification, and susceptibility testing. The clinical microbiology laboratory can assist the medical team by providing timely identification of the pathogen(s) causing the bloodstream infection through the use of rapid diagnostic technology. One of these rapid diagnostic technologies, MALDI-TOF MS, has been proven to reduce the time required for appropriate antibiotic therapy when used to identify pathogens grown in culture. This technology has also been used to identify pathogens directly from the positive blood cultures with great success. CONTENT In this minireview, we summarize the different methods that have been developed to directly identify pathogens from positive blood cultures by use of MALDI-TOF MS and the effect of this technology on patient outcomes. Additionally, we touch on current research in the field, including the identification of antimicrobial resistance directly from positive blood cultures by MALDI-TOF MS. SUMMARY Rapid identification of pathogens is important in the survival of patients undergoing a septic event. MALDI-TOF MS technology has played an important role in rapid identification, which has led to a reduction in the time to appropriate antibiotic therapy and contributed to the improvement of patient outcomes. The high sensitivity and specificity of MALDI-TOF MS identification, in combination with MALDI-TOF's rapid function and reduced labor costs, make this technology an attractive choice for clinical laboratories.
Kvetiapin brukes for mye

JØRGEN G. BRAMNESS Jørgen G. Bramness er dr.med., spesialist i psykiatri og seniorforsker ved Nasjonal kompetansetjeneste for samtidig rusmisbruk og psykisk lidelse (N-ROP), Sykehuset Innlandet, Hamar og professor II, Institutt for klinisk medisin, Det helsevitenskapelige fakultet, Universitetet i Tromsø – Norges arktiske universitet. Forfatter har fylt ut ICMJE-skjemaet og oppgir ingen interessekonflikter.
Recent progress in gene therapies for mucopolysaccharidoses

ABSTRACT Introduction: Mucopolysaccharidoses (MPSs) are lysosomal storage disorders due to deficiency of enzymes involved in glycosaminoglycan degradation. They present with multi-organ complications of variable severity and progressive neurodegeneration in most cases. Besides supportive treatments, current therapeutic options include enzyme replacement therapy and hematopoietic stem cell transplantation. However, these treatments are hampered by several risks and limitations and more effective therapies are highly needed. Areas covered: Gene therapy has been largely investigated in pre-clinical models and is now under clinical evaluation for several MPSs. This review covers recent pre-clinical data that supported ongoing or planned ex vivo and in vivo gene therapy clinical trials for MPSs. A literature search was performed using PubMed, EudraCT, ClinicalTrials.gov, and ISRCTN.com websites. Expert opinion: Gene therapy is among the most attractive new treatments for MPSs. Potential advantages of gene therapy include reduced risks and complications compared to other treatments, and improved correction of the central nervous system disorder. Nevertheless, there are major challenges to be addressed, including immune responses and possible toxicities. In upcoming years, we will learn from the ongoing trials about the most effective approaches, serotypes, routes of administration and doses to achieve the best possible results in terms of disease correction.
Reoperative Coronary Artery Bypass Grafting: Review of Changing Pattern and Outcomes

Since coronary artery bypass graft (CABG) surgery was introduced for clinical practice in the 1960s, it has demonstrated its efficiency to improve symptoms and prognosis in patients with the advanced coronary atherosclerotic disease [1]. As CABG patients are getting older and living longer, reoperative CABG surgery has become an integrative part of the cardio-surgical daily practice presenting significant challenges in technical and decision-making aspects [2].
Predicting 10-year cardiovascular risk using WHO/ISH risk prediction chart among urban population in Salem

Background: Coronary vascular disease (CVD) risk estimation tools are a simple means of identifying those at high risk in a community and hence a potentially cost-effective strategy for CVD prevention in resource-poor countries. The WHO /ISH risk prediction charts provide approximate estimates of cardiovascular disease risk in people who do not have established coronary heart disease, stroke or other atherosclerotic disease.Methods: A total of 280 subjects between 40 to 70 years of age were included in this cross sectional study. Eligible households was selected randomly (every 5th household) for the interview using systematic random sampling. Age, gender, smoking status, systolic blood pressure, presence or absence of diabetes and total serum cholesterol were used to compute the total CVD risk using WHO/ISH CVD risk prediction chart. The chart stratify an individual into low (<10%), moderate (10% to <20%), high (20% to <30%), and very high (>30%) risk groups.Results: Moderate and high CVD risk were 12.14% and 7.5% respectively. Of total study participants, 2.5% had very high risk (>40%). High risk (binge drinking) alcohol drinkers (p=0.04) and abdominal obesity (p=0.0001) were significantly associated with higher CVD risk. Higher prevalence of behavioral risk factors was also reported in our study population.Conclusions: A large proportion of the population is at moderate and high cardiovascular risk. Risk stratification and identification of individuals with a high risk for CHD who could potentially benefit from intensive primary prevention efforts are critically important in reducing the burden of CVD in India.
Identification of the major characteristics of potato cultivars which affect yield loss caused by late blight.

Yield loss caused by late blight varies among potato cultivars. This thesis reports experiments and models aimed at identifying the plant characteristics that explain the variation. In the experiments, blight did not affect the efficiency with which twenty potato cultivars used intercepted light to produce biomass. The rate of photosynthesis of green parts was not impaired by lesions in other parts. Yield loss thus was fully explained by reduced light interception, i.e. reduced green leaf area. Blight decreased green leaf area mainly by lesion coverage of leaves, but also by accelerating leaf senescence. Simulation analysis showed that the acceleration of senescence accounted for less than 15% of the yield loss in every cultivar, and no genetic variation for this trait was found. The marked genotypic differences observed in foliage area thus were due to differences in lesion coverage, caused by different levels of partial resistance and by maturity class-related differences in foliage growth. It is concluded that breeding for components of partial resistance is more promising than breeding for tolerance, but should be done separately for early and late cultivars. The literature was reviewed and found conflicting about the relation between yield loss and components of resistance to the fungus. The limitations of published epidemiological models as instruments for identification of the most important components are discussed. An improved epidemiological model was constructed and used to identify infection efficiency and radial lesion growth rate as the main determinants of disease progress in potato. Resistance breeding should therefore focus on these components.
Factors Correlated with Relapse among Substance Abuse Patients

Background: Substance abuse is a chronic and relapsing disorder with different genetic, mental, social and environmental factors, influencing its commencement and continuation. Aim: The study aimed to assess factors correlated with relapse among substance abuse patients. Setting: The present study carried out at institute of psychiatry affiliated to Ain Shams university hospitals and El Khanka Hospital Sample: A convenient sample of 120 relapse patients from institute of psychiatry and El Khanka Hospital. Tools of data collection:: Structured questionnaire was utilized. It included two parts. Part I: to assess socio-demographic characteristics. Part 2: Questionnaire about factors correlated with relapse among substance abuse patients Results: It was founded that relapse dimensions represented from the greatest to the lowest mean score as the following; Unpleasant feelings, good feelings, disruption of relationships with others, mental, physical and debilitating pains, desire and real estate hints, test the ability to control the abuse, the pressure of the co-workers, and the least of them for Family problems Conclusion: It was concluded that, there was a significant positive correlation between all dimensions of relapse and socio-demographic characteristics as age, place of birth, level of education and economic status. Recommendation: Developing future prevention programs for protection against substance abuse
Adult height and risk of gastric cancer: a pooled analysis within the Stomach cancer Pooling Project

Background The association between height and risk of gastric cancer has been studied in several epidemiological studies with contrasting results. The aim of this study is to examine the association between adult height and gastric cancer within a large pooled analysis of case-control studies members of the Stomach cancer Pooling (StoP) Project consortium. Methods Data from 18 studies members of the StoP consortium were collected and analyzed. A multivariable logistic regression model was used to estimate the study-specific odds ratios (ORs) and 95% confidence intervals (CIs) for the association between 10-cm increase in height and risk of gastric cancer. Age, sex, tobacco smoking, alcohol consumption, social class, geographical area and Helicobacter pylori (H. pylori) status were included in the regression model. Resulting estimates were then pooled with random-effect model. Analyses were conducted overall and in strata of selected variables. Results A total of 7562 cases and 19 033 controls were included in the analysis. The pooled OR was 0.96 (95% CI 0.87–1.05). A sensitivity analysis was performed restricting the results to the studies with information on H. pylori status, resulting in an OR of 0.97 (95% CI 0.79–1.20). Conclusion Our study does not support a strong and consistent association between adult height and gastric cancer.