Complex Disease Research Articles

Assessing and managing lower limb oedema: a clinical review.

Lower limb oedema is a common condition in clinical practice, frequently affecting the distal lower limbs. Whereas benign causes such as prolonged sitting or standing are typical, oedema can also indicate serious systemic diseases such as cardiac failure, liver disease, or renal impairment. Identifying the cause is crucial to prevent irreversible skin and tissue changes. This clinical review aims to increase the knowledge of advanced clinical practitioners (ACPs) and generalist practitioners, including practice and community nurses, by providing an overview of how to approach patients with lower limb oedema, encompassing history-taking, examinations, investigations, and management plans. The main focus is on lymphoedema, which can be primary or secondary. Primary lymphoedema results from genetic abnormalities, while secondary lymphoedema arises from acquired defects due to factors such as obesity, infections, neoplasms, and trauma. Effective management includes addressing the underlying cause, ensuring proper skin care, recommending appropriate exercises, and the use of compression garments. Referral to a lymphoedema specialist is recommended for patient education on managing and treating the condition when required. Additionally, the article discusses the importance of regular skin inspections, minor injury management, environmental considerations, and the critical role of compression garments in lymphoedema management. This comprehensive approach aims to enhance patient outcomes and provide a thorough strategy for ACPs and generalist practitioners.

Genetic Insights into Congenital Cardiac Septal Defects—A Narrative Review

Congenital heart diseases (CHDs) are a group of complex diseases characterized by structural and functional malformations during development in the human heart; they represent an important problem for public health worldwide. Within these malformations, septal defects such as ventricular (VSD) and atrial septal defects (ASD) are the most common forms of CHDs. Studies have reported that CHDs are the result of genetic and environmental factors. Here, we review and summarize the role of genetics involved in cardiogenesis and congenital cardiac septal defects. Moreover, treatment regarding these congenital cardiac septal defects is also addressed.

Pathophysiology, molecular mechanisms, and genetics of atrial fibrillation.

The development of atrial fibrillation (AF) is a highly complex, multifactorial process involving pathophysiologic mechanisms, molecular pathway mechanisms and numerous genetic abnormalities. The pathophysiologic mechanisms including altered ion channels, abnormalities of the autonomic nervous system, inflammation, and abnormalities in Ca2 + handling. Molecular pathway mechanisms including, but not limited to, renin-angiotensin-aldosterone (RAAS), transforming growth factor-β (TGF-β), oxidative stress (OS). Although in clinical practice, the distinction between types of AF such as paroxysmal and persistent determines the choice of treatment options. However, it is the pathophysiologic alterations present in AF that truly determine the success of AF treatment and prognosis, but even more so the molecular mechanisms and genetic alterations that lie behind them. One tiny clue reveals the general trend, and small beginnings show how things will develop. This article will organize the development of these mechanisms and their interactions in recent years.

General feature selection technique supporting sex-debiasing in chronic illness algorithms validated using wearable device data

AbstractIn tasks involving human health condition data, feature selection is heavily affected by data types, the complexity of the condition manifestation, and the variability in physiological presentation. One type of variability often overlooked or oversimplified is the effect of biological sex. As females have been chronically underrepresented in clinical research, we know less about how conditions manifest in females. Innovations in wearable technology have enabled individuals to generate high temporal resolution data for extended periods of time. With millions of days of data now available, additional feature selection pipelines should be developed to systematically identify sex-dependent variability in data, along with the effects of how many per-person data are included in analysis. Here we present a set of statistical approaches as a technique for identifying sex-dependent physiological and behavioral manifestations of complex diseases starting from longitudinal data, which are evaluated on diabetes, hypertension, and their comorbidity.

Organoids and organoid extracellular vesicles-based disease treatment strategies.

Organoids are "mini-organs" that self-organize and differentiate from stem cells under in vitro 3D culture conditions, mimicking the spatial structure and function of tissues in vivo. Extracellular vesicles (EVs) are nanoscale phospholipid bilayer vesicles secreted by living cells, rich in bioactive molecules, with excellent biocompatibility and low immunogenicity. Compared to EVs, organoid-derived EVs (OEVs) exhibit higher yield and enhanced biological functions. Organoids possess stem cell characteristics, and OEVs are capable of delivering active substances, making both highly promising for medical applications. In this review, we provide an overview of the fundamental biological principles of organoids and OEVs, and discuss their current applications in disease treatment. We then focus on the differences between OEVs and traditional EVs. Subsequently, we present methods for the engineering modification of OEVs. Finally, we critically summarize the advantages and challenges of organoids and OEVs. In conclusion, we believe that a deeper understanding of organoids and OEVs will provide innovative solutions to complex diseases.

The Influence of Skin Microbial Ecology on γδ T Cell Immune Pathways in Allergic Dermatitis Models in Mice.

Atopic dermatitis (AD) is a complex disease influenced by alterations in the skin microbiome and immune dysregulation. Despite the recognized role of these factors, the specific pathways by which distinct microbial populations affect skin immunity remain insufficiently understood. On a molecular level, the pathogenesis of AD involves critical cytokines such as IL-4, IL-17, interferon-γ (IFN-γ), and IL-10, which contribute to the imbalance in T helper (Th) cell responses. Importantly, gamma-delta (γδ) T cells, which produce these cytokines and infiltrate affected epithelial cells in AD, have been underexplored. This study seeks to alleviate AD symptoms in mice by adjusting both peripheral and local immune environments through the transplantation of skin microbiota. By employing 16S rRNA sequencing, we characterized the skin microbiome of the mouse model. Our results demonstrate that microbiota intervention significantly reduces skin thickening and serum IgE levels in DNFB-induced AD mice. Additionally, changes in skin microbiota modulated immune cell dynamics, restoring the Th1/Th2 balance and leading to clinical improvement. These findings highlight the critical role of skin microbiota in shaping immune responses, positioning microbiota-based therapies as a potential treatment for AD.

Hypospadias Associated With Fetal Growth Restriction: A Multicentric Descriptive and Prognostic Cohort Study.

To determine the prevalence of genetic and endocrine abnormalities and to assess fetal, neonatal and surgical outcomes in cases of hypospadias associated with fetal growth restriction. A multicentric retrospective study was conducted across five prenatal diagnosis centers in Paris. The cohort encompassed all fetuses diagnosed with the combination of fetal growth restriction < 10th percentile (FGR) and hypospadias from 2013 to 2021. Maternal data, fetal outcome and results of prenatal investigations were collected, along with postnatal data, encompassing endocrinological and genetic assessments, functional aspects and surgical outcomes. Among the 82 patients included in the cohort, there were 14 (17%) terminations of pregnancy and four (5%) in utero deaths, leaving 64 (78%) live neonates, including five (6%) with early neonatal death. Among the 52 (63%) cases where hypospadias and FGR were considered as ultrasound-isolated anomalies, six (12%, [3.2%-20.8%]) exhibited chromosomic, genetic, or endocrinological abnormalities diagnosed half prenatally and half postnatally. Fifty percent of the overall hypospadias were proximal. Most children underwent surgical intervention before reaching 2years of age, with 50% encountering complications and often required reintervention. The association of FGR and hypospadias should not be underestimated as genetic or endocrinological abnormalities were identified even when hypospadias and FGR initially appear isolated. Additionally, the overall prognosis may be worsened using complex and iterative surgical procedures.

Molecular and morphofunctional bases of development of the horse multiple congenital eye anomalies with the silver gene presence on the example of the &lt;i&gt;Soviet draft&lt;/i&gt; breed

The article concretizes clinical data on the molecular and morphofunctional foundations of the development of multiple congenital eye abnormalities (MСOA) linked to the silver gene, using the example of the Soviet heavy-duty horse breed. Recommendations for owners on their maintenance and medical support and work with them are provided. The study was conducted on the basis of data from the VNIIK breeding center for the specified horse breed, genetic testing and ophthalmological examination. The focus group included 26 horses of the Soviet heavy-duty breed, examined for the presence of the silver gene. The results of the study showed that horses of the Soviet heavy-duty breed should undergo genetic testing for the presence of a silver gene in the genotype. However, the presence of MCOA linked to the silver gene is not an indication for the culling of horses due to the status of this breed as endangered, if it is necessary to select a mate for mating without genetic abnormalities so that they do not spread during uncontrolled crossing. Regular observation of an ophthalmologist and strict implementation of his recommendations are necessary to prevent the development of infectious complications and rapid progression of the disease with the onset of blindness. Horses homozygous for the silver gene should be kept in conditions that limit the possibility of injury to the eyeballs, including secondary damage to eye structures by the UV spectrum of solar radiation, for which translucent/opaque masks or sunglasses should be used. Working on homozygous horses with partial or complete loss of vision is potentially dangerous and possible only if a number of conditions are met and the owner is ready to bear legal responsibility for possible consequences.

Association between different proportions of crescents and the progression of IgA nephropathy (IgAN): a systematic review and meta-analysis.

Immunoglobulin A nephropathy (IgAN) is a complex renal disease with a highly variable clinical course. Identifying reliable prognostic markers is crucial for risk stratification and treatment decisions. This study aimed to understand the influence of different proportions of crescents (Cs) on the progression of IgAN. Four databases (PubMed, Web of Science, Embase, and Cochrane Library) were searched until September 25, 2023. The study encompassed IgAN patients, focusing on kidney outcomes and end-stage kidney disease (ESKD). Statistical analysis included calculating hazard ratios (HR) for binary outcomes and examining publication bias. The meta-analysis involved thirteen studies comprising 11,849 patients. For kidney outcomes, crescent formation may be linked to an elevated risk (HR = 2.01, 95%CI 1.40-2.87, P < 0.001). Furthermore, significantly increased risks of kidney outcomes were observed with a crescent proportion > 10 (HR = 1.8, 95%CI 1.32-2.45, P < 0.001) and > 25%(HR = 2.11, 95% CI 1.47-3.02, P < 0.001). Regarding ESKD, a proportion > 25% also displayed an elevated risk (HR = 1.70, 95% CI 1.18-2.44, P = 0.004). However, a proportion > 10% (including > 25%) did not show a significant association with ESKD (HR = 1.12, 95% CI 0.36-3.47, P = 0.842) versus less. This systematic review and meta-analysis established a strong association between crescent proportions and the progression of IgAN. Higher proportions, notably exceeding 25%, were reliable prognostic markers, indicating a greater risk of adverse kidney outcomes and ESKD. These findings have significant clinical implications, offering the potential for more precise risk stratification in IgAN patients.

Optimal incubation duration of liquid cultures for assessing culture negative conversion in patients with Mycobacterium avium complex and Mycobacterium abscessus pulmonary diseases.

Mycobacterial liquid culturing typically requires six weeks or longer, primarily because of the slow growth rate of Mycobacterium tuberculosis. This study aimed to evaluate the potential of shortening the duration of mycobacterial liquid culturing in healthcare settings with high prevalence rates of non-tuberculous mycobacteria. We retrospectively analyzed the relationship between mycobacterial species and time to positive testing of liquid cultures from sputum samples using the Mycobacteria Growth Indicator Tube system over a 3.5-year period beginning in July 2020 at a university hospital in Japan. We analyzed 15,147 sputum culture samples and found a 1.1% positivity rate for Mycobacterium tuberculosis complex, while the rates for Mycobacterium avium complex and Mycobacterium abscessus were 17.6% and 2.1%, respectively. The median time to positivity was 17 days for Mycobacterium tuberculosis complex, 9 days for Mycobacterium avium complex, and 4 days for Mycobacterium abscessus. Comparing a 4-week culture period with an eight-week period, the positivity rates for Mycobacterium avium complex and Mycobacterium abscessus were 97.0% and 99.4%, respectively. In settings with a high incidence of non-tuberculous mycobacteria, the basic liquid culturing period can be safely shortened to 4 weeks without significantly compromising detection sensitivity, except for the samples that are highly suspected to contain tuberculosis, extremely slow-growing mycobacteria, smear-positive, or nucleic acid amplification testing positive.

Network medicine informed multiomics integration identifies drug targets and repurposable medicines for Amyotrophic Lateral Sclerosis

Amyotrophic Lateral Sclerosis (ALS) is a devastating, immensely complex neurodegenerative disease by lack of effective treatments. We developed a network medicine methodology via integrating human brain multi-omics data to prioritize drug targets and repurposable treatments for ALS. We leveraged non-coding ALS loci effects from genome-wide associated studies (GWAS) on human brain expression quantitative trait loci (QTL) (eQTL), protein QTL (pQTL), splicing QTL (sQTL), methylation QTL (meQTL), and histone acetylation QTL (haQTL). Using a network-based deep learning framework, we identified 105 putative ALS-associated genes enriched in known ALS pathobiological pathways. Applying network proximity analysis of predicted ALS-associated genes and drug-target networks under the human protein-protein interactome (PPI) model, we identified potential repurposable drugs (i.e., Diazoxide and Gefitinib) for ALS. Subsequent validation established preclinical evidence for top-prioritized drugs. In summary, we presented a network-based multi-omics framework to identify drug targets and repurposable treatments for ALS and other neurodegenerative disease if broadly applied.

A Narrative Review of Congenital Syphilis in the United States: Innovative Perspectives on a Complex Public Health and Medical Disease.

Over the past two decades, congenital syphilis cases have risen 11-fold in the United States. While disparities across geography, race, and ethnicity exist, lack of timely screening or treatment is identified in 88% of cases nationally. Congenital syphilis is a public health and medical problem rooted in systematic and societal structural determinants of health and healthcare limitations. Early syphilis in pregnancy leads to congenital syphilis if untreated in 50 - 70% of cases, with risk for fetal demise, and among survivors, congenital anomalies, organ damage, and central nervous system disease. Prevention of congenital syphilis lies in early detection and treatment in pregnant persons. In this narrative review, we describe the evolving epidemiology of syphilis and congenital syphilis, highlighting unique aspects among women. We explore the role of novel screening and treatment strategies, public health policy, and medical considerations in terms of congenital syphilis prevention. Readers of this review will understand CS as a complex public health and medical disease that can be prevented through innovative and coordinated strategies in public health policy, expanded screening and research opportunities.

Evaluation of the anticancer properties of the phytochemicals present in &lt;em&gt;Annona muricata&lt;/em&gt;

Cancer is a complex disease characterized by the unrestrained proliferation and dissemination of abnormal cells. The issue continues to be a notable public health concern on a global scale, with millions of new cases and fatalities being reported annually. Despite significant advances in cancer treatment, it remains a major challenge due to the high cost and toxicity of current therapies. Phytochemicals naturally found in plants are crucial resources for developing novel drugs and potential cancer therapies. The clinical efficacy of these anti-cancer agents has been demonstrated against diverse neoplastic cell lines. Additional investigation in this field can result in improved cancer therapies. Among many other plants effective against cancer, this literature review explores the anti-cancer properties of Annona muricata, a plant commonly known as soursop, which is a tropical plant species native to Central and South America, the Caribbean, and West Africa known for its edible fruit which has some medicinal merits, but also some toxicological effects. Annona muricata has been traditionally used for medicinal purposes, including cancer treatment. Acetogenins, alkaloids, phenolic compounds, and other active compounds are only a few of the phytochemicals that this review cites as being present in A. muricata. The review also looks into A. muricata’s biological abilities to fight lung, liver, prostate, colon, pancreas, and breast cancers. The toxicity of A. muricata and possible adverse effects are also covered in the review. The review also looks at the usage of nanoparticles with A. muricata as a cancer treatment. Overall, this literature review provides valuable insights into the potential anti-cancer properties of A. muricata and its potential as a therapeutic agent in cancer treatment.

Evaluating Advanced Machine Learning Models for Histopathological Diagnosis of Hansen Disease.

Leprosy is a neglected infectious disease caused by Mycobacterium leprae and Mycobacterium lepromatosis and remains a public health challenge in tropical regions. Therefore, the development of technological tools such as machine learning (ML) offers an opportunity to innovate strategies for improving the diagnosis of this complex disease. To validate the utility of different ML models for the histopathological diagnosis of Hansen disease. An observational study was conducted where 55 H&E-stained tissue slides from leprosy patients and 51 healthy skin controls were analyzed using microphotographs captured at various magnifications. These images were categorized based on histopathological findings and processed using the Cross-Industry Standard Process for Data Mining methodology for designing and training ML models. Five types of ML models were evaluated using standard metrics such as accuracy, sensitivity, and specificity, emphasizing data normalization as a fundamental step in optimizing model performance. The artificial neural network (ANN) model demonstrated an accuracy of 70%, sensitivity of 74%, and specificity of 65%, demonstrating its ability to identify leprosy cases with moderate precision. The receiver operating characteristic curve of the ANN model showed an area under the curve of 0.71. Conversely, models such as decision trees, logistic regression, and random forests showed similar accuracy results but with slightly lower sensitivity, potentially indicating a higher risk of false negatives in detecting leprosy-positive cases. The ANN model emerges as a promising alternative for leprosy detection. However, further refinement of these models is necessary to enhance their adaptability across different clinical settings and participation in patient care.

Triangulation for causal loop diagrams: constructing biopsychosocial models using group model building, literature review, and causal discovery

AbstractThe complex nature of many health problems necessitates the use of systems thinking tools like causal loop diagrams (CLDs) to visualize the underlying causal network and facilitate computational simulations of potential interventions. However, the construction of CLDs is limited by the constraints and biases of specific sources of evidence. To address this, we propose a triangulation approach that integrates expert and theory-driven group model building, literature review, and data-driven causal discovery. We demonstrate the utility of this triangulation approach using a case example focused on the trajectory of depressive symptoms in response to a stressor in healthy adults. After triangulation with causal discovery, the CLD exhibited (1) greater comprehensiveness, encompassing multiple research fields; (2) a modified feedback structure; and (3) increased transparency regarding the uncertainty of evidence in the model structure. These findings suggest that triangulation can produce higher-quality CLDs, potentially advancing our understanding of complex diseases.

A rare case of splenic marginal zone lymphoma with MYD88 mutation transformed into diffuse large B-cell lymphoma: case report and literature review.

In indolent lymphomas, histological transformation (HT) often results in a poor prognosis and presents a significant challenge in the management of these lymphomas. Previous studies have indicated that MYD88 mutations are associated with transformation in certain haematologic malignancies. We report a rare case of splenic marginal zone lymphoma (SMZL) harbouring an MYD88 mutation, which was transformed into diffuse large B-cell lymphoma (DLBCL) and accompanied by newly emerging genetic abnormalities. The role of the MYD88 gene in SMZL is currently unclear. Through this case, we reviewed relevant studies, which indicated that MYD88 mutations, along with other genetic anomalies, may play a significant role in this process. In the future, it is essential to collect more of these rare cases for further research.

Evaluation of Bayesian Linear Regression models for gene set prioritization in complex diseases.

Genome-wide association studies (GWAS) provide valuable insights into the genetic architecture of complex traits, yet interpreting their results remains challenging due to the polygenic nature of most traits. Gene set analysis offers a solution by aggregating genetic variants into biologically relevant pathways, enhancing the detection of coordinated effects across multiple genes. In this study, we present and evaluate a gene set prioritization approach utilizing Bayesian Linear Regression (BLR) models to uncover shared genetic components among different phenotypes and facilitate biological interpretation. Through extensive simulations and analyses of real traits, we demonstrate the efficacy of the BLR model in prioritizing pathways for complex traits. Simulation studies reveal insights into the model's performance under various scenarios, highlighting the impact of factors such as the number of causal genes, proportions of causal variants, heritability, and disease prevalence. Comparative analyses with MAGMA (Multi-marker Analysis of GenoMic Annotation) demonstrate BLR's superior performance, especially in highly overlapped gene sets. Application of both single-trait and multi-trait BLR models to real data, specifically GWAS summary data for type 2 diabetes (T2D) and related phenotypes, identifies significant associations with T2D-related pathways. Furthermore, comparison between single- and multi-trait BLR analyses highlights the superior performance of the multi-trait approach in identifying associated pathways, showcasing increased statistical power when analyzing multiple traits jointly. Additionally, enrichment analysis with integrated data from various public resources supports our results, confirming significant enrichment of diabetes-related genes within the top T2D pathways resulting from the multi-trait analysis. The BLR model's ability to handle diverse genomic features, perform regularization, conduct variable selection, and integrate information from multiple traits, genders, and ancestries demonstrates its utility in understanding the genetic architecture of complex traits. Our study provides insights into the potential of the BLR model to prioritize gene sets, offering a flexible framework applicable to various datasets. This model presents opportunities for advancing personalized medicine by exploring the genetic underpinnings of multifactorial traits.

GRIN2A and Schizophrenia: Scientific Evidence and Biological Mechanisms.

Schizophrenia is a severe psychiatric disorder and a complex polygenic inherited disease that affects nearly 1% of the global population. Although considerable progress has been made over the past 10 years in the treatment of schizophrenia, antipsychotics are not universally effective and may have serious side effects. The hypofunction of glutamate NMDA receptors (NMDARs) in GABAergic interneurons has long been postulated to be the principal pathophysiology of schizophrenia. A recent study has shown that GRIN2A pathogenic variants are closely related to the aetiology of the disorder. GRIN2A encodes the GluN2A protein, which is a subunit of NMDAR. Most GRIN2A variants have been predicted to cause protein truncation, which results in reduced gene expression. Preclinical studies have indicated that GRIN2A mutations lead to NMDAR loss of function and substantially increase the risk of schizophrenia; however, their role in schizophrenia is not well understood. We hypothesise that the heterozygous loss of GRIN2A induces NMDAR hypofunction sufficient to confer a substantial risk of schizophrenia. Therefore, this review focuses on GRIN2A as a target for novel antipsychotics and discusses the mechanisms by which GRIN2A modulates antischizophrenic activities. Moreover, our review contributes to the understanding of the pathophysiology of schizophrenia to facilitate finding treatments for the cognitive and negative symptoms of schizophrenia.

Development of Novel 3D Spheroids for Discrete Subaortic Stenosis.

In this study, we propose a new method for bioprinting 3D Spheroids to study complex congenital heart disease known as discrete subaortic stenosis (DSS). The bioprinter allows us to manipulate the extrusion pressure to change the size of the spheroids, and the alginate porosity increases in size over time. The spheroids are composed of human umbilical vein endothelial cells (HUVECs), and we demonstrated that pressure and time during the bioprinting process can modulate the diameter of the spheroids. In addition, we used Pluronic acid to maintain the shape and position of the spheroids. Characterization of HUVECs in the spheroids confirmed their uniform distribution and we demonstrated cell viability as a function of time. Compared to traditional 2D cell cultures, the 3D spheroids model provides more relevant physiological environments, making it valuable for drug testing and therapeutic applications.

Leveraging Organ-on-Chip Models to Investigate Host-Microbiota Dynamics and Targeted Therapies for Inflammatory Bowel Disease.

Inflammatory bowel disease (IBD) is an idiopathic gastrointestinal disease with drastically increasing incidence rates. Due to its multifactorial etiology, a precise investigation of the pathogenesis is extremely difficult. Although reductionist cell culture models and more complex disease models in animals have clarified the understanding of individual disease mechanisms and contributing factors of IBD in the past, it remains challenging to bridge research and clinical practice. Conventional 2D cell culture models cannot replicate complex host-microbiota interactions and stable long-term microbial culture. Further, extrapolating data from animal models to patients remains challenging due to genetic and environmental diversity leading to differences in immune responses. Human intestine organ-on-chip (OoC) models have emerged as an alternative in vitro model approach to investigate IBD. OoC models not only recapitulate the human intestinal microenvironment more accurately than 2D cultures yet may also be advantageous for the identification of important disease-driving factors and pharmacological interventions targets due to the possibility of emulating different complexities. The predispositions and biological hallmarks of IBD focusing on host-microbiota interactions at the intestinal mucosal barrier are elucidated here. Additionally, the potential of OoCs to explore microbiota-related therapies and personalized medicine for IBD treatment is discussed.