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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).)

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.)

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.

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.)

The quantitative determination of topically applied substances in the skin is severely limited and represents a challenging task. The porcine skin ex vivo was topically treated with a gel containing caffeine (CF) and propylene glycol (PG), and depth‐resolved Raman spectra were recorded with two confocal Raman microscopes. We applied a novel tailored multivariate curve resolution‐alternating least squares method to the selected spectral regions (512–604 and 778–1148 cm−1) of gel‐treated skin and quantitatively determined the concentrations of CF and PG in the stratum corneum (SC). The highest concentration of CF (181 mg/cm3) was found at the surface, while PG (384 mg/cm3) was found at 10% SC depth, indicating the formation of a reservoir at the superficial SC. The concentrations of CF and PG decreased monotonically and reached the detection limit at ≈60% and ≈80% SC depth, respectively, indicating that neither permeate the SC. [ABSTRACT FROM AUTHOR]

Ixodes ricinus is an important vector of infectious human and livestock diseases in Europe. Co-infections of pathogens in ticks and hosts have been reported. Tick cell lines offer a useful model system for study of co-infections. We present a review of the existing literature on co-infections in tick cell lines. Previous studies have demonstrated the usefulness of tick cell lines in studies on co-infection of different pathogens and their interaction with the tick microbiome. We also carried out a preliminary study to investigate the effects of co-culturing Borrelia burgdorferi and Anaplasma phagocytophilum on their growth and interactions with the Ixodes ricinus cell line IRE/CTVM19 over a 13-day period. Replication of both pathogens was quantified by real-time PCR. The presence of A. phagocytophilum appeared to have a slight inhibitory effect on the multiplication of B. burgdorferi, that were added subsequently. In contrast, the prior presence of B. burgdorferi appeared to have a stimulatory effect on A. phagocytophilum after 6 days in culture. We conclude that the IRE/CTVM19 tick cell line is suitable for simultaneous and continuous cultivation of both bacteria and can be applied in future research. [ABSTRACT FROM AUTHOR]

Background: Systemic changes in multiple diseases may influence the onset of dementia. However, the specific temporality between exposure diseases and dementia remains uncertain. Aims: By characterising the full spectrum of temporal disease trajectories before dementia, this study aims to yield a global picture of precursor diseases to dementia and to provide detailed instructions for risk management and primary prevention of dementia. Method: Using the multicentre, community-based prospective UK Biobank, we constructed disease trajectories before dementia utilising the phenome-wide association analysis, paired directional test and association quantification. Stratified disease trajectories were constructed by dementia subtypes, gender, age of diagnosis and Apolipoprotein E (ApoE) status, respectively. Results: Our study population comprised 434 266 participants without baseline dementia and 4638 individuals with all-cause dementia. In total, 1253 diseases were extracted as potential components of the disease trajectory before dementia. We identified three clusters of disease trajectories preceding all-cause dementia, initiated by circulatory, metabolic and respiratory diseases occurring approximately 5–15 years before dementia. Cerebral infarction or chronic renal failure following chronic ischaemic heart disease was the specific trajectory before vascular dementia. Apolipoprotein E (ApoE) ε4 non-carriers exhibited more complex trajectories compared with carriers. Lipid metabolism disorders remained in the trajectories regardless of dementia subtypes, gender, age of diagnosis and ApoE status. Conclusions: This study provides a comprehensive view of the longitudinal disease trajectories before dementia and highlights the potential targets of midlife cardiometabolic dysfunction for dementia screening and prevention. [ABSTRACT FROM AUTHOR]

Fibroblasts are among the most common cell types in the stroma responsible for creating and maintaining the structural organization of the extracellular matrix in the dermis, skin regeneration, and a range of immune responses. Until now, the processes of fibroblast adaptation and functioning in a varying environment have not been fully understood. Modern laser microscopes are capable of studying fibroblasts in vitro and ex vivo. One-photon- and two-photon-excited fluorescence microscopy, Raman spectroscopy/microspectroscopy are well-suited noninvasive optical methods for fibroblast imaging in vitro and ex vivo. In vivo staining-free fibroblast imaging is not still implemented. The exception is fibroblast imaging in tattooed skin. Although in vivo noninvasive staining-free imaging of fibroblasts in the skin has not yet been implemented, it is expected in the future. This review summarizes the state-of-the-art in fibroblast visualization using optical methods and discusses the advantages, limitations, and prospects for future noninvasive imaging., (© 2023 Wiley-VCH GmbH.)

Skin moisturizing is important in dermatology and cosmetics. Raman microspectroscopy is a well‐suited method to determine water concentration profiles in the stratum corneum (SC) of untreated and formulation‐treated skin in vivo. Until now, the water in the SC was quantified using the ratio of water to proteins, and other SC components were neglected. Here, we apply the tailored multivariate curve resolution‐alternating least squares (tMCR‐ALS) method to improve the quantitative determination of water in the SC of cosmetic oil‐treated skin accounting Raman spectra of proteins, lipids, and oils in the high wavenumber region. We compared the water concentration profiles in the SC of petrolatum‐treated skin calculated using the tMCR‐ALS method and two existing conventional and extended methods, which are both based on the analysis of the water‐to‐protein‐ratio. The results show that in petrolatum‐treated skin, the conventional method calculates an incorrect water profile in the depth of 0–70% of the SC thickness; the extended method shows an incorrect profile in the depth of 0–10% of the SC thickness; the applied tMCR‐ALS method show results, which coincide well with the modern knowledge of the moisturizing effect of cosmetic oils on the SC. Almond, jojoba, and paraffin oils exhibit a similar moisturizing effect that manifests itself in an increase of water concentration in the intermediate SC depth. However, the effect of petrolatum is more pronounced. In the context of treated skin, the proposed method calculates water concentration profiles throughout the SC correctly and thus has a great potential in dermatology and cosmetics. [ABSTRACT FROM AUTHOR]

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.

Ex vivo porcine lung immersed in e-liquid was investigated in-depth using confocal Raman micro-spectroscopy to assess the e-liquid influence on the lung. It was found that lung-related Raman band intensities at 1002, 1548, 1618 and 1655 cm -1 increased after first and second treatments except the surface, which was attributed to the well-known optical clearing (OC) effect due to alveoli filling with e-liquid resulting in light scattering reduction. The autofluorescence enhancement was explained by oxidative stress induced in lung during exposure to e-liquid. Moreover, e-liquid induced collagen dehydration was revealed by the I 937 /I 926 Raman band intensity ratio change. The effect was enhanced after the second treatment of the same lung tissue that indicates the possibility of multi-step OC treatment. We hypothesize that the nicotine-flavour-free e-liquids containing glycerol and propylene glycol could potentially be used in clinical protocols as OC agent for enhanced in-depth Raman-guided bronchoscopy., (© 2023 Wiley-VCH GmbH.)

In the central nervous system, oligodendrocytes wrap around neuronal axons to form myelin, an insulating layer or sheath that allows for the efficient conductance of action potentials. In addition to structural insulation, myelin provides encased axons with nutrient, metabolic and defensive support. Demyelination, or myelin loss, can therefore cause axonal dysfunction, leading to neurological impairment and disease. In Alzheimer’s disease (AD), progressive white matter demyelination is acknowledged as one of the earliest pathologies preceding symptom onset. Unfortunately, current pharmacotherapy for slowing demyelination or promoting remyelination in AD is nonexistent. Exercise is recognized for its wide-ranging benefits to human health, including improved mental health and the prevention of lifestyle-related diseases. Mounting evidence suggests the contribution of physical activity in delaying the progression of dementia in elderly populations. Recent mechanistic studies have shown that exercise facilitates myelination in the brain through the vitalization of intrinsic pro-myelination cues, such as increased neurotrophic factors and electrical activity. In this review, we summarize and discuss the potential of physical exercise on counteracting aging-associated white matter demyelination, which causes cognitive decline in AD. We highlight the need of further basic and clinical research investigations on this topic to establish novel approaches for healthy and improved brain aging. [ABSTRACT FROM AUTHOR]

Salivary gland pleomorphic adenoma (SGPA) is the most common type of benign epithelial tumor; it is observed more commonly in females (with a female-to-male ratio of 1.43:1), and the age at diagnosis ranges between 40 and 59 years, with only 2% of cases diagnosed before age 18. Cri du Chat (CdC) is a rare syndrome caused by deletions of various sizes in the short arm of chromosome 5. Tumors in CdC patients are extremely rare: in Danish, Spanish, Australian, and Japanese groups of cases, no tumors have been reported, while a few cases have been described among 321 CdC patients collected in Italy and Germany. These cases all involve tumors that appear at a young age. We here report the case of a parotid pleomorphic adenoma in an 8-year-old boy with CdC. Exome analysis did not identify variants certainly significant for the development of SGPA. A CGH array, analyzed both in peripheral blood and tumor samples, failed to recognize anomalies previously associated with SGPA but identified a de novo duplication in 7p15.2, which contains part of a gene, SKAP2, in which the increased copy number is associated with the development of a different type of tumor such as pancreatic duct adenocarcinoma. The assumption that the duplication in 7p15.2 is relevant for the development of SGPA in our patient implies that CGH array studies must be included early in life in routine work-ups of CdC to identify CNVs with possible pathogenic roles for tumor development. This is particularly also relevant in relation to the severely impaired possibility for patients with CdC to report discomfort or pain related to tumor development. Constitutional CNVs in addition to the deletion in 5p should also be extensively studied to verify if their presence in some patients could explain why, in these cases, tumors develop at an age younger than expected. [ABSTRACT FROM AUTHOR]

Reconstructed epidermal equivalents (REEs) consist of two distinct cell layers – the stratum corneum (SC) and the keratinocyte layer (KL). The interplay of these layers is particularly crucial in pruritic inflammatory disorders, like psoriasis, where a defective SC barrier is associated with immune dysregulation. However, independent evaluation of the skin barrier function of the SC and KL in REEs is highly challenging because of the lack of quantitative methodologies that do not disrupt the counter layer. Here, a non‐invasive impedance spectroscopy technique is introduced for dissecting the distinct contributions of the SC and KL to overall skin barrier function without disrupting the structure. These findings, inferred from the impedance spectra, highlight the individual barrier resistances and maturation levels of each layer. Using an equivalent circuit model, a correlation between impedance parameters and specific skin layers, offering insights beyond traditional impedance methods that address full‐thickness skin only is established. This approach successfully detects subtle changes, such as increased paracellular permeability due to mild irritants and the characterization of an immature SC in psoriatic models. This research has significant implications, paving the way for detailed mechanistic investigations and fostering the development of therapies for skin irritation and inflammatory disorders. [ABSTRACT FROM AUTHOR]

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.

Antioxidants exhibit a powerful defense mechanism against aging and chronic disease. The human skin reflects the overall antioxidant status of the body. The cutaneous carotenoid concentration is a biomarker for individual nutritional intake of antioxidants, as it correlates with the overall antioxidant status. The cutaneous carotenoid concentrations of 44 adults were measured using a multiple spatially resolved reflection spectroscopy. During the first phase of the study, measurements of carotenoid concentrations were performed without revealing the antioxidant status, followed by an intervention phase during which the volunteers were informed about their individual values by biofeedback. During the third phase, biofeedback was combined with an additional intake of fruit juices. Across time points, participants showed increasing levels of carotenoid status. Thus, biofeedback leads to an improvement of the carotenoid value of the skin. Providing a biofeedback measurement to monitor the individual antioxidative status may be an easy and cost-effective way of primary prevention., (© 2023 The Authors. Journal of Biophotonics published by Wiley-VCH GmbH.)

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.

Dementia is a highly prevalent condition with devastating clinical and socioeconomic sequela. It is expected to triple in prevalence by 2050. No treatment is currently known to be effective. Symptomatic late-onset dementia and predementia (SLODP) affects 95% of patients with the syndrome. In contrast to trials of pharmacological prevention, no treatment is suggested to remediate or cure these symptomatic patients. SLODP but not young onset dementia is intensely associated with multimorbidity (MUM), including brain-perturbating conditions (BPCs). Recent studies showed that MUM/BPCs have a major role in the pathogenesis of SLODP. Fortunately, most MUM/BPCs are medically treatable, and thus, their treatment may modify and improve SLODP, relieving suffering and reducing its clinical and socioeconomic threats. Regrettably, the complex system features of SLODP impede the diagnosis and treatment of the potentially remediable conditions (PRCs) associated with them, mainly due to failure of pattern recognition and a flawed diagnostic workup. We suggest incorporating two SLODP-specific conceptual themes into the diagnostic workup: MUM/BPC and multilevel phenomenological themes. By doing so, we were able to improve the diagnostic accuracy of SLODP components and optimize detecting and favorably treating PRCs. These revolutionary concepts and their implications for remediability and other parameters are discussed in the paper. [ABSTRACT FROM AUTHOR]

The dengue virus, the primary cause of dengue fever, dengue hemorrhagic fever, and dengue shock syndrome, is the most widespread mosquito-borne virus worldwide. In recent decades, the prevalence of dengue fever has increased markedly, presenting substantial public health challenges. Consequently, the development of an efficacious vaccine against dengue remains a critical goal for mitigating its spread. Our research utilized Celcradle™, an innovative tidal bioreactor optimized for high-density cell cultures, to grow Vero cells for dengue virus production. By maintaining optimal pH levels (7.0 to 7.4) and glucose concentrations (1.5 g/L to 3.5 g/L) during the proliferation of cells and viruses, we achieved a peak Vero cell count of approximately 2.46 × 109, nearly ten times the initial count. The use of Celcradle™ substantially decreased the time required for cell yield and virus production compared to conventional Petri dish methods. Moreover, our evaluation of the immunogenicity of the Celcradle™-produced inactivated DENV4 through immunization of mice revealed that sera from these mice demonstrated cross-reactivity with DENV4 cultured in Petri dishes and showed elevated antibody titers compared to those from mice immunized with virus from Petri dishes. These results indicate that the dengue virus cultivated using the Celcradle™ system exhibited enhanced immunogenicity relative to that produced in traditional methods. In conclusion, our study highlights the potential of the Celcradle™ bioreactor for large-scale production of inactivated dengue virus vaccines, offering significant promise for reducing the global impact of dengue virus infections and accelerating the development of effective vaccination strategies. [ABSTRACT FROM AUTHOR]

Background: Evidence for substance use‐related problems in individuals with mild intellectual disability is sparse and mainly limited to selected psychiatric populations. We evaluated the risk of substance use‐related problems in individuals with mild intellectual disability compared to the general population. Additionally, we have performed secondary sibling comparison analyses to account for familial confounding. Methods: We conducted a population‐based cohort study of individuals born in Sweden between 1973 and 2003. A total of 18,307 individuals with mild intellectual disability were compared to 915,350 reference individuals from the general population and 18,996 full siblings of individuals with mild intellectual disability. Information on mild intellectual disability and substance use‐related problems was obtained from several Swedish national and regional school and healthcare registers. Substance use‐related problems were measured via corresponding diagnostic and legal codes and included alcohol use disorder, drug use disorder, alcohol‐related somatic disease, conviction for a substance‐related crime, and substance‐related death. Results: Individuals with mild intellectual disability had a higher risk of any substance use‐related problem compared to the general population (HR, 1.81; 95% CI, 1.72–1.91), both in males (HR, 1.76; 95% CI, 1.65–1.89) and females (HR, 1.89; 95% CI, 1.74–2.05). The risks of substance use‐related problems were particularly elevated among individuals with mild intellectual disability and psychiatric comorbidities (HR, 2.21–8.24). The associations were attenuated in the sibling comparison models. Conclusions: Individuals with mild intellectual disability, especially those with psychiatric comorbidity, are at an elevated risk of substance use‐related problems. Familial factors shared by full siblings contribute considerably to the association between mild intellectual disability and substance use‐related problems. [ABSTRACT FROM AUTHOR]

The main components of the stratum corneum (SC), water, lipids, and proteins, are non-homogeneously distributed throughout the depth. The quantitative determination of their concentration profiles and penetration depth of topically applied substances are urgent topics of dermatological and cosmetic research. Confocal Raman micro-spectroscopy has distinct advantages when determining semi-quantitative concentrations of SC components and topically applied substances non-invasively and in vivo. In this work, we applied a tailored multivariate curve resolution-alternating least squares (tMCR-ALS) method to analyze Raman spectra of the SC in the 2000-4000 cm -1 region for quantitatively determining the concentrations of water, lipids, proteins, and topically applied oils using substance-related spectral loadings which were allowed to change depth-dependently from the SC's surface toward its bottom. tMCR-ALS makes matching of depth-dependent signal attenuation, that is, the normalization on keratin, unnecessary and requires only a few additional experiments for calibration - Raman spectra of the pure materials and their densities., (© 2022 The Authors. Journal of Biophotonics published by Wiley-VCH GmbH.)

The epidermal protective functions are closely associated with skin hydration homeostasis. The understanding of different states of water binding is a rising concept in assessing topically applied formulations and their interaction within the stratum corneum (SC). In addition to global water content, primary bound water, partially bound water, and unbound water and barrier-related lipid lateral packing and protein secondary structure can be measured by Raman spectroscopy. This study aimed to establish an in vitro SC model to evaluate differences in the efficacy of a natural sugar-derived complex in combination with glycerol and a botanical extract in modulating SC water binding and structural proteins and barrier lipids. These compounds were selected due to their water-binding and soothing properties. The SC water profiles were assessed at the surface and in 8 μm SC depth. After a 12-hour hyperhydration and subsequent product incubation the measurements were performed during a 6 hours desiccation phase. The maximal water caption and the time until reaching a steady state are measured as well as water retention and resistance against water loss. Global water content, partially bound, and unbound water, as well as lipid and protein structures were assessed with confocal Raman microspectroscopy. Both the natural sugar-derived mixture and more pronounced, the same mixture with additional glycerol increased all three water-binding parameters at the surface and in 8 μm SC depth at the beginning and during the desiccation phase. Further addition of botanical extract did not result in an additional increase of the water-binding. All three formulations showed an increase in the lipid lateral packing values prevented the protein alteration as measured by β-sheets signal compared to blank. The present model is suited for screening studies comparing the specific effects of different compounds on hydration states. The natural sugar-derived mixture Aquaxyl showed evidence for an improvement of all SC hydration states, lipid and protein structure which was further enhanced by the addition of glycerol 5%. This improvement was evidenced at the surface and within the SC for all hydration-related parameters, and the lipid as well the protein structures. The addition of botanical extract phytoessence blue daisy did not show further improvement., (© 2022 The Authors. Journal of Biophotonics published by Wiley-VCH GmbH.)

In addressing challenges such as side reaction and dendrite formation, electrolyte modification with bio-molecule sugar species has emerged as a promising avenue for Zn anode stabilization. Nevertheless, considering the structural variability of sugar, a comprehensive screening strategy is meaningful yet remains elusive. Herein, we report the usage of sugar additives as a representative of bio-molecules to develop a screening descriptor based on the modulation of the hydrogen bond component and electron transfer kinetics. It is found that xylo-oligosaccharide (Xos) with the highest H-bond acceptor ratio enables efficient water binding, affording stable Zn/electrolyte interphase to alleviate hydrogen evolution. Meanwhile, sluggish reduction originated from the steric hindrance of Xos contributes to optimized Zn deposition. With such a selected additive in hand, the Zn||ZnVO full cells demonstrate durable operation. This study is anticipated to provide a rational guidance in sugar additive selection for aqueous Zn batteries., (© 2024 Wiley-VCH GmbH.)

Proton batteries are promising candidates for next-generation large-scale energy storage in extreme conditions due to the small ionic radius and efficient transport of protons. Hydrogen gas, with its low working potentials, fast kinetics, and stability, further enhances the performance of proton batteries but necessitates the development of novel electrolytes with low freezing points and reduced corrosion. This work introduces a localized water restriction strategy by incorporating a tertiary component with a high donor number, which forms strong bonds with water molecules. This approach restricts free water molecules and reduces the average hydrogen bond ratio and strength. As-prepared ternary eutectic electrolytes lowered the freezing point to -103 °C, significantly lower than the traditional binary electrolyte (9.5 m H 3 PO 4 , -93 °C). This electrolyte is highly compatible with the Cu 0.79 Co 0.21 [Fe(CN) 6 ] 0.64  ⋅ 4H 2 O (CoCuHCF) cathode, reducing material dissolution and current collector corrosion. The H 2 ||CoCuHCF battery using this electrolyte demonstrated a high-power density of 23664.3 W kg -1 , excellent performance at -80 °C, and stable cyclability over 1000 cycles (>30 days) at -50 °C. These findings provide a framework for proton electrolytes, highlighting the potential of hydrogen batteries in challenging environments., (© 2024 Wiley-VCH GmbH.)

The utilization of thin zinc (Zn) anodes with a high depth of discharge is an effective strategy to increase the energy density of aqueous Zn metal batteries (ZMBs), but challenged by the poor reversibility of Zn electrode due to the serious Zn-consuming side reactions at the Zn||electrolyte interface. Here, we introduce 2-bromomethyl-1,3-dioxolane (BDOL) and methanol (MeOH) as electrolyte additive into aqueous ZnSO 4 electrolyte. In the as-formulated electrolyte, BDOL with a strong electron-withdrawing group (-CH 2 Br) tends to pair with the H 2 O-Zn-MeOH complex, leading to the formation of organobromine-partnered H 2 O-Zn-MeOH cluster ions. During the Zn electrodeposition process, the formed ZnO-dominated by-products induce the polymerization of BDOL monomers, which are previously adsorbed on the electrode. As a result, a uniform dual-layer SEI with ZnO-dominated outer layer and polyether-dominated inner layer is built on the surface of Zn electrode. With such an in situ formed dual-layer SEI, the Zn||Mg 0.9 Mn 3 O 7  ⋅ 2.7H 2 O pouch cell using a 10-um Zn anode (corresponding to a low negative to positive areal capacity ratio of 3.56) successfully operated for 300 cycles with a high capacity retention of 86 %, promising a high practical energy density of >120 Wh/kg (based on the total mass of Zn and Mg 0.9 Mn 3 O 7  ⋅ 2.7H 2 O)., (© 2024 Wiley-VCH GmbH.)

Metabolic syndrome (MetS) has been linked to accelerated cognitive decline and Alzheimer's disease and related dementias (ADRDs) via cerebral small vessel disease (CSVD); however, this relation in MetS without overt cardiometabolic disease comorbidities is unknown and may represent a population amenable to preventative strategies. Our study aimed to determine risk profiles for neurocognitive decline and ADRDs in early-stage MetS with evidence of CSVD using the TriNetX electronic health records (EHR) research network. Patients aged 50 to 80 years old meeting MetS criteria were identified utilizing TriNetX data from 76 healthcare organizations. Propensity score matching controlled for demographic and confounding factors. Cohorts included MetS-only, non-MetS, and a MetS subset with evidence of CSVD (MetS-CSVD) created by clustering relevant ICD-codes for diagnoses, imaging, and lab work. Contingency analyses determined odds of developing neurocognitive decline, ADRDs, and CSVD in MetS vs non-MetS and MetS-CSVD vs. MetS-only, using odd ratios with 95% confidence intervals (p-value < 0.05). After propensity score matching, there were 57,347 men and 52,259 women in each of the MetS and non-MetS cohorts and 2,810 men and 2,862 women in each of the MetS-CSVD and MetS-only cohorts. Compared to non-MetS, the MetS cohort exhibited higher odds of developing neurocognitive decline (men: RR = 1.82, p < 0.001; women: RR = 1.34, p = 0.015) and CSVD (men: RR = 2.83, p < 0.001; women: RR = 2.14, p < 0.001), but only women exhibited significantly higher odds of developing ADRDs (men: RR = 1.13, p = 0.38; women: RR = 1.52, p < 0.001). Compared to MetS-only, the MetS-CSVD showed elevated odds in developing neurocognitive decline (men: RR = 1.81, p = 0.040; women: RR = 1.87, p = 0.018) and ADRDs (men: RR = 2.39, p = 0.009; women: RR = 1.65, p = 0.041). A large, predominantly US, sample of subclinical MetS demonstrated heightened odds for developing neurocognitive decline and ADRDs, with even higher odds when evidence of CSVD was also present. TriNetX facilitated a robust exploration of these associations, and our findings warrant further investigation of interventions that target this subclinical at-risk population., Competing Interests: Declarations. Conflict of interest: The authors declare no competing interests., (© 2024. The Author(s), under exclusive licence to American Aging Association.)

Background: The co-administration of drugs known to interact greatly impacts morbidity, mortality, and health economics. This study aims to examine the drug–drug interaction (DDI) phenomenon with a large-scale longitudinal analysis of age and gender differences found in drug administration data from three distinct healthcare systems. Methods: This study analyzes drug administrations from population-wide electronic health records in Blumenau (Brazil; 133 K individuals), Catalonia (Spain; 5.5 M individuals), and Indianapolis (USA; 264 K individuals). The stratified prevalences of DDI for multiple severity levels per patient gender and age at the time of administration are computed, and null models are used to estimate the expected impact of polypharmacy on DDI prevalence. Finally, to study actionable strategies to reduce DDI prevalence, alternative polypharmacy regimens using drugs with fewer known interactions are simulated. Results: A large prevalence of co-administration of drugs known to interact is found in all populations, affecting 12.51%, 12.12%, and 10.06% of individuals in Blumenau, Indianapolis, and Catalonia, respectively. Despite very different healthcare systems and drug availability, the increasing prevalence of DDI as patients age is very similar across all three populations and is not explained solely by higher co-administration rates in the elderly. In general, the prevalence of DDI is significantly higher in women — with the exception of men over 50 years old in Indianapolis. Finally, we show that using proton pump inhibitor alternatives to omeprazole (the drug involved in more co-administrations in Catalonia and Blumenau), the proportion of patients that are administered known DDI can be reduced by up to 21% in both Blumenau and Catalonia and 2% in Indianapolis. Conclusions: DDI administration has a high incidence in society, regardless of geographic, population, and healthcare management differences. Although DDI prevalence increases with age, our analysis points to a complex phenomenon that is much more prevalent than expected, suggesting comorbidities as key drivers of the increase. Furthermore, the gender differences observed in most age groups across populations are concerning in regard to gender equity in healthcare. Finally, our study exemplifies how electronic health records' analysis can lead to actionable interventions that significantly reduce the administration of known DDI and its associated human and economic costs. [ABSTRACT FROM AUTHOR]

The effect of tissue optical clearing (TOC) to increase the probing depth and observe in-depth structure of the ex vivo porcine dura mater was studied by confocal Raman microspectroscopy (CRM). Raman intensities were significantly increased at the depth of 250 μm for all collagen bands after treatment with glycerol. The influence of glycerol on collagen hydration was also investigated. The results indicate that the process of TOC can be divided into three main steps. The first one is a fast process of tissue dehydration accompanied by collagen shrinkage while the second relatively slow process is related to the glycerol penetration into the interfibrillar space of collagen combined with swelling of tissue. The third step is collagen dissociation caused by the high concentration of glycerol. To the best of our knowledge, this study is the first example to introduce the TOC technique in assisting CRM of ex vivo dura mater in-depth probing., (© 2021 Wiley-VCH GmbH.)