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Quantifying the contribution of genetics and environmental effects on disease initiation and progression, as well as the shared genetics of different diseases, is vital for the understanding of the disease etiology of multimorbidities. In this study, we leverage nationwide Danish registries to provide a granular atlas of the genetic origin of disease phenotypes for a cohort of all Danes 1978-2018 with partially known pedigree (n = 6.3 million). We estimate the heritability and genetic correlation between thousands of disease phenotypes using a novel approach that can be scaled to nationwide data. Our findings confirm the importance of genetics for a number of known associations and increase the resolution of heritability by adding numerous associations, some of which point to shared biologically origin of different phenotypes. We also establish the heritability of disease trajectories and the importance of sex-specific genetic contributions. Results can be accessed at https://h2.cpr.ku.dk/ ., (© 2024. The Author(s).)

We present the Danish Disease Trajectory Browser (DTB), a tool for exploring almost 25 years of data from the Danish National Patient Register. In the dataset comprising 7.2 million patients and 122 million admissions, users can identify diagnosis pairs with statistically significant directionality and combine them to linear disease trajectories. Users can search for one or more disease codes (ICD-10 classification) and explore disease progression patterns via an array of functionalities. For example, a set of linear trajectories can be merged into a disease trajectory network displaying the entire multimorbidity spectrum of a disease in a single connected graph. Using data from the Danish Register for Causes of Death mortality is also included. The tool is disease-agnostic across both rare and common diseases and is showcased by exploring multimorbidity in Down syndrome (ICD-10 code Q90) and hypertension (ICD-10 code I10). Finally, we show how search results can be customized and exported from the browser in a format of choice (i.e. JSON, PNG, JPEG and CSV).

Introduction: Similar symptoms, comorbidities and suboptimal diagnostic tests make the distinction between different types of dementia difficult, although this is essential for improved work-up and treatment optimization., Methods: We calculated temporal disease trajectories of earlier multi-morbidities in Alzheimer's disease (AD) dementia and vascular dementia (VaD) patients using the Danish National Patient Registry covering all hospital encounters in Denmark (1994 to 2016). Subsequently, we reduced the comorbidity space dimensionality using a non-linear technique, uniform manifold approximation and projection., Results: We found 49,112 and 24,101 patients that were diagnosed with AD or VaD, respectively. Temporal disease trajectories showed very similar disease patterns before the dementia diagnosis. Stratifying patients by age and reducing the comorbidity space to two dimensions, showed better discrimination between AD and VaD patients in early-onset dementia., Discussion: Similar age-associated comorbidities, the phenomenon of mixed dementia, and misdiagnosis create great challenges in discriminating between classical subtypes of dementia., (© 2020 The Authors. Alzheimer's & Dementia published by Wiley Periodicals, Inc. on behalf of Alzheimer's Association.)

Purpose: Most chromosome abnormality patients require long-term clinical care. Awareness of mosaicism and comorbidities can potentially guide such health care. Here we present a population-wide analysis of direct and inverse comorbidities affecting patients with chromosome abnormalities., Methods: We extracted direct and inverse comorbidities for the 11 most prevalent chromosome abnormalities from the Danish National Patient Registry (covering 6.9 million patients hospitalized between 1994 and 2015): trisomy 13, 18, and 21, Klinefelter (47,XXY), triple X, XYY, Turner (45,X), Wolf-Hirschhorn, Cri-du-chat, Angelman, and Fragile X syndromes (FXS). We also performed four sub-analyses for male/female Down syndrome (DS) and FXS and non-mosaic/mosaic DS and Turner syndrome., Results: Our data cover 9,003 patients diagnosed with at least one chromosome abnormality. Each abnormality showed a unique comorbidity signature, but clustering of their profiles underlined common risk profiles for chromosome abnormalities with similar genetic backgrounds. We found that DS had a decreased risk for three inverse cancer comorbidities (lung, breast, and skin) and that male FXS and non-mosaic patients have a much more severe phenotype than female FXS and mosaic patients, respectively., Conclusion: Our study underlines the importance of considering mosaicism, sex, and the associated comorbidity profiles of chromosome abnormalities to guide long-term health care of affected patients.

Objective: Use symptoms to stratify temporal disease trajectories., Materials and Methods: We use data from the Danish National Patient Registry to stratify temporal disease pairs by the symptom distributions they associate to. The underlying data comprise of 6.6 million patients collectively assigned with 7.5 million symptoms from chapter XVIII in the WHO International Classification of Disease version 10 terminology., Results: We stratify 33 disease pairs into 67 temporal disease-symptom-disease trajectories from three main diagnoses (two diabetes subtypes and COPD), where the symptom significantly changes the risk of developing the subsequent diseases. We combine these trajectories into three temporal disease networks, one for each main diagnosis. We confirm apparent relations between diseases and symptoms and discovered that multiple symptoms decrease the risk for diabetes progression., Conclusion: Symptoms can be used to stratify disease trajectories, and we suggest that this approach can be applied to temporal disease trajectories systematically using structured claims data. The method can be extended to also use text-mined symptoms from unstructured data in health records., (Copyright © 2019 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Intensive-care units (ICUs) treat the most critically ill patients, which is complicated by the heterogeneity of the diseases that they encounter. Severity scores based mainly on acute physiology measures collected at ICU admission are used to predict mortality, but are non-specific, and predictions for individual patients can be inaccurate. We investigated whether inclusion of long-term disease history before ICU admission improves mortality predictions., Methods: Registry data for long-term disease histories for more than 230 000 Danish ICU patients were used in a neural network to develop an ICU mortality prediction model. Long-term disease histories and acute physiology measures were aggregated to predict mortality risk for patients for whom both registry and ICU electronic patient record data were available. We compared mortality predictions with admission scores on the Simplified Acute Physiology Score (SAPS) II, the Acute Physiologic Assessment and Chronic Health Evaluation (APACHE) II, and the best available multimorbidity score, the Multimorbidity Index. An external validation set from an additional hospital was acquired after model construction to confirm the validity of our model. During initial model development data were split into a training set (85%) and an independent test set (15%), and a five-fold cross-validation was done during training to avoid overfitting. Neural networks were trained for datasets with disease history of 1 month, 3 months, 6 months, 1 year, 2·5 years, 5 years, 7·5 years, 10 years, and 23 years before ICU admission., Findings: Mortality predictions with a model based solely on disease history outperformed the Multimorbidity Index (Matthews correlation coefficient 0·265 vs 0·065), and performed similarly to SAPS II and APACHE II (Matthews correlation coefficient with disease history, age, and sex 0·326 vs 0·347 and 0·300 for SAPS II and APACHE II, respectively). Diagnoses up to 10 years before ICU admission affected current mortality prediction. Aggregation of previous disease history and acute physiology measures in a neural network yielded the most precise predictions of in-hospital mortality (Matthews correlation coefficient 0·391 for in-hospital mortality compared with 0·347 with SAPS II and 0·300 with APACHE II). These results for the aggregated model were validated in an external independent dataset of 1528 patients (Matthews correlation coefficient for prediction of in-hospital mortality 0·341)., Interpretation: Longitudinal disease-spectrum-wide data available before ICU admission are useful for mortality prediction. Disease history can be used to differentiate mortality risk between patients with similar vital signs with more precision than SAPS II and APACHE II scores. Machine learning models can be deconvoluted to generate novel understandings of how ICU patient features from long-term and short-term events interact with each other. Explainable machine learning models are key in clinical settings, and our results emphasise how to progress towards the transformation of advanced models into actionable, transparent, and trustworthy clinical tools., Funding: Novo Nordisk Foundation and Innovation Fund Denmark., (Copyright © 2019 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Objective: To investigate if early treatment of primary HIV-1 infection (PHI) reduces viral set point and/or increases CD4 lymphocytes., Methods: Analysis of two prospective multi-centre PHI cohorts. HIV-1 RNA and CD4 lymphocytes in patients with transient treatment were compared to those in untreated patients. Time to CD4 lymphocyte decrease below 350/ microl after treatment stop or seroconversion was calculated using Kaplan-Meier and Cox-PH-regression analyses., Results: 156 cases of PHI were included, of which 100 had received transient HAART (median treatment time 9.5 months) and 56 remained untreated. Median viral load (563000 cop/ml vs 240000 cop/ml; p<0.001) and median CD4 lymphocyte (449/ microl vs. 613/ microl; p<0.01) differed significantly between treated and untreated patients. Median viral load was 38056 copies/ml in treated patients (12 months after treatment stop) and 52880 copies/ml in untreated patients (12 months after seroconversion; ns). Median CD4 lymphocyte change was +60/ microl vs. -86/ microl (p = 0.01). Median time until CD4 lymphocytes decreased to <350/ microl (including all patients with CD4 lymphocytes <500/ microl during seroconversion) was 20.7 months in treated patients after treatment stop and 8.3 months in untreated patents after seroconversion (p<0.01). Cox-PH analyses adjusting for baseline VL, CD4 lymphocytes, stage of early infection and symptoms confirmed these differences., Conclusions: Treatment during PHI did not lower viral set point. However, patients treated during seroconversion had an increase in CD4 lymphocytes, whereas untreated patients experienced a decrease in CD4 lymphocytes. Time until reaching CD4 lymphocytes <350/ microl was significantly shorter in untreated than in treated patients including patients with CD4 lymphocytes <500/ microl during seroconversion.

Neurologic complications in the course of Plasmodium falciparum infections are commonly diagnosed as cerebral malaria, but bacterial or viral meningitis may exhibit similar symptoms. One to three weeks after P. falciparum malaria, acute disseminated encephalomyelitis (ADEM) can also mimick the symptoms of cerebral malaria. We describe a 31-year-old woman with life-threatening ADEM five days after successful treatment of P. falciparum malaria. The detection of IgG and IgM antibodies in serum and cerebrospinal fluid (CSF) against multiple viruses and bacteria reflected a non-specific polyclonal B cell activation and was more confusing than helpful for diagnostic decisions. Varicella zoster virus was identified with a reverse transcriptase multiplex polymerase chain reaction in the initially obtained and frozen CSF. This case and findings from the literature indicate that P. falciparum-associated ADEM might not be immune mediated, but of infectious origin. With unclear cerebral complications during or after P. falciparum malaria, prompt initiation of empirical antiviral and antibacterial treatment in addition to antimalarials may reduce mortality.

Tick-borne encephalitis is a neurotropic viral disease transmitted by ticks, and occasionally by the drinking of milk. Its incidence in Central and Eastern Europe has increased sharply, supposedly due--among other things--to climate warming and changes in leisure activities. The probability of contracting the disease following viral infection is about 30%. Some 70% of victims manifest a biphasic course with two fever peaks. Some 10% will have lasting, sometimes severe, neurological deficits, and 1 to 2% will die. The diagnosis is based on confirmed exposure to ticks in a high-risk area, a tick bite within the previous three weeks, clinical symptomatology, infected CSF, and FSME-specific IgM and IgG antibodies in the serum. Causal treatment is not possible, but the disease can be effectively avoided by prophylactic (anti-exposure) measures and vaccination. The vaccines currently available in Germany are highly effective and well tolerated, and a vaccine for children became available in 2002. Medical counselling of travellers should give consideration to vaccination against the condition--in particular for destinations in the south east or east of Europe.

Case History: Four males (age 25 to 40 years) and one female (age 25) were admitted to our hospital almost simultaneously with symptoms of fever up to 38 degrees C, dry cough, thoracodynia, dyspnoea, myalgia and arthralgia. All patients belonged to a team of eight German bat researchers who had returned from Cuba 10 days before, where they had investigated bats in caves. Another member of the team had only mild histoplasmosis and was followed in our outpatient clinic. Two scientists who wore their breathing masks continuously during their work in the caves did not fall ill., Examinations: Chest X-rays of all in-patients showed pulmonary infiltrates correlating with the severity of their illness. In all patients specific IgG antibodies against Histoplasma capsulatum-antigen were found in the Western Blot assay, confirming the diagnosis of histoplasmosis., Treatment: Treatment with oral itraconazole 200 mg b.d was given to four inpatients for 6 weeks, in the fifth patient itraconazole was discontinued because of an increase of liver transaminases., Conclusion: Antimycotic treatment of advancing histoplasmosis seems appropriate also in immunocompetent patients. The high number of patients within this group suggests high numbers of Histoplasma capsulatum in the caves. Wearing breathing masks throughout the work in the caves may prevent histoplasmosis even in case of high infectious doses. Pre-travel recommendations for cave researchers have to emphasize the continuous use of breathing masks and vaccination against tetanus and rabies.

The rise in off-track tourism and the spread of schistosomiasis in previously non-endemic areas results in an increasing number of imported schistosomiasis cases. - Detection of eggs in stool or urine and specific serology supports the diagnosis, however eosinophilia in early infection is low. In travel groups with a single index case all members of the group with similar risk behaviour should be examined since more than 50% of group members with similar risk behaviour are likely to be infected. Asymptomatic, atypical and late presentation of the disease might delay diagnosis. Praziquantel is not effective against immature worms, therefore treatment of returning travellers with single dose praziquantel is effective when started not earlier than 2 months after infection. A combination of praziquantel plus artemether is thought to be effective also in early stages of infection. Vaccination trials in endemic areas are in progress but a single vaccine for travellers covering all schistosoma species will not be available in the near future. Advising the traveller to avoid risk behaviour like wading, bathing and swimming in endemic fresh waters and about the risk of acquiring schistosomiasis through surface or spray water during boat tours will help to reduce imported schistosomiasis.

By means of 5 case reports the successful use of an new blood schizontocide against plasmodium falciparum infections is demonstrated. The local patients with severe malaria were treated in the German UN-hospital in Cambodia. Cerebral, pulmonary and haemolytic complications dominated. Intramuscularly artemether, a synthetic Qinghaosu-derivative, was combined with already used antimalarials. All patients survived, regained consciousness and were without fever after administering artemether within 48 to 72 hours. The complications were controlled by mandatory ventilation, blood transfusions, fluid balance and blood sugar monitoring. With artemether we will get a well tolerated and quickly effective schizontocide. In order to avoid recrudenscence and fast drug resistance it should be combined with a tetracycline and in consequence supplemented through a second schizontocide.