Three-dimensional aortic geometry: clinical correlates, prognostic value and genetic architecture.

Aortic structure and function impact cardiovascular health through multiple mechanisms. Aortic structural degeneration increases left ventricular afterload, pulse pressure and promotes target organ damage. Despite the impact of aortic structure on cardiovascular health, aortic 3D-geometry has yet to be comprehensively assessed. Using a convolutional neural network (U-Net) combined with morphological operations, we quantified aortic 3D-geometric phenotypes (AGPs) from 53,612 participants in the UK Biobank and 8,066 participants in the Penn Medicine Biobank. AGPs reflective of structural aortic degeneration, characterized by arch unfolding, descending aortic lengthening and luminal dilation exhibited cross-sectional associations with hypertension and cardiac diseases, and were predictive for new-onset hypertension, heart failure, cardiomyopathy, and atrial fibrillation. We identified 237 novel genetic loci associated with 3D-AGPs. Fibrillin-2 gene polymorphisms were identified as key determinants of aortic arch-3D structure. Mendelian randomization identified putative causal effects of aortic geometry on the risk of chronic kidney disease and stroke.

The value of ultrasound in combination with 99mTc-MIBI imaging department of ultrasound medicine, for the diagnosis of ectopic parathyroid glands in the thyroid gland in patients with secondary hyperparathyroidism.

To investigate the value of preoperative ultrasound combined with 99mTc-MIBI imaging for the diagnosis of ectopic intrathyroid parathyroid gland (ETPG) in patients with secondary hyperparathyroidism (SHPT). One hundred and eleven patients with SHPT who underwent total parathyroidectomy plus forearm transplantation from January 2015 to January 2022 in the Third Hospital of Hebei Medical University were selected. All patients underwent routine preoperative ultrasonography and 99mTc-MIBI imaging, and with pathological diagnosis as the gold standard, the clinical data of ETPG patients were selected, including clinical manifestations, laboratory tests, preoperative ultrasonography and 99mTc-MIBI imaging for localization and diagnosis, intraoperative exploration and postoperative pathology, and postoperative follow-up. To analyze the ultrasound manifestations of preoperative parathyroid hyperplasia and the results of 99mTc-MIBI imaging in patients with ETPG. Among 111 patients with SHPT, there were 5 patients with ETPG, 1 male and 4 females with a mean age of (45.00 ±â€…5.05) years, and 6 ectopic parathyroid glands were located in the thyroid gland. The incidence of ETPG was 4.5% (5/111), 4 were detected by ultrasound, 2 were not detected with a diagnostic accuracy of 66.7% (4/6), 3 were positive for 99mTc-MIBI imaging, 3 were negative with a diagnostic accuracy of 50.0% (3/6). Among them, one was not detected by ultrasound, but was positive for 99mTc-MIBI imaging, 2 with negative 99mTc-MIBI imaging, but all were detected by ultrasound, and one with negative 99mTc-MIBI imaging was detected by ultrasound but misdiagnosed as a thyroid nodule. A total of 5 ETPGs were detected by ultrasound combined with 99mTc-MIBI imaging, with a diagnostic accuracy of 83.3% (5/6). Patients' postoperative serum calcium and serum parathyroid hormone (PTH) levels were normalized or significantly decreased from preoperative levels. Ultrasound combined with 99mTc-MIBI imaging can achieve higher accuracy than either examination alone in the preoperative localization and diagnosis of ETPG in SHPT patients.

The Janus face of HIF-1α in ischemic stroke and the possible associated pathways.

Stroke is the most devastating disease, causing paralysis and eventually death. Many clinical and experimental trials have been done in search of a new safe and efficient medicine; nevertheless, scientists have yet to discover successful remedies that are also free of adverse effects. This is owing to the variability in intensity, localization, medication routes, and each patient's immune system reaction. HIF-1α represents the modern tool employed to treat stroke diseases due to its functions: downstream genes such as glucose metabolism, angiogenesis, erythropoiesis, and cell survival. Its role can be achieved via two downstream EPO and VEGF strongly related to apoptosis and antioxidant processes. Recently, scientists paid more attention to drugs dealing with the HIF-1 pathway. This review focuses on medicines used for ischemia treatment and their potential HIF-1α pathways. Furthermore, we discussed the interaction between HIF-1α and other biological pathways such as oxidative stress; however, a spotlight has been focused on certain potential signalling contributed to the HIF-1α pathway. HIF-1α is an essential regulator of oxygen balance within cells which affects and controls the expression of thousands of genes related to sustaining homeostasis as oxygen levels fluctuate. HIF-1α's role in ischemic stroke strongly depends on the duration and severity of brain damage after onset. HIF-1α remains difficult to investigate, particularly in ischemic stroke, due to alterations in the acute and chronic phases of the disease, as well as discrepancies between the penumbra and ischemic core. This review emphasizes these contrasts and analyzes the future of this intriguing and demanding field.

Two new diketopiperazines from the marine sponge Dysidea sp.

A chemical investigation on the marine sponge Dysidea sp. resulted in the isolation of a series of diketopiperazines, including two new compounds, dysidines A (1) and B (2) as well as six known ones (3-8). Their structures with absolute configurations were determined on the basis of UV, IR, HRMS, NMR and calculated ECD method. Additionally, the cytotoxic, anti-inflammatory, antibacterial and antiviral activities of 1-8 were also tested. However, none of them exhibited significant bioactivities.

Analyzing bivariate cross-trait genetic architecture in GWAS summary statistics with the BIGA cloud computing platform.

As large-scale biobanks provide increasing access to deep phenotyping and genomic data, genome-wide association studies (GWAS) are rapidly uncovering the genetic architecture behind various complex traits and diseases. GWAS publications typically make their summary-level data (GWAS summary statistics) publicly available, enabling further exploration of genetic overlaps between phenotypes gathered from different studies and cohorts. However, systematically analyzing high-dimensional GWAS summary statistics for thousands of phenotypes can be both logistically challenging and computationally demanding. In this paper, we introduce BIGA (https://bigagwas.org/), a website that aims to offer unified data analysis pipelines and processed data resources for cross-trait genetic architecture analyses using GWAS summary statistics. We have developed a framework to implement statistical genetics tools on a cloud computing platform, combined with extensive curated GWAS data resources. Through BIGA, users can upload data, submit jobs, and share results, providing the research community with a convenient tool for consolidating GWAS data and generating new insights.

Diagnostic Performance of Radiomics and Deep Learning to Identify Benign and Malignant Soft Tissue Tumors: A Systematic Review and Meta-analysis.

RATIONALE AND OBJECTIVES: To systematically evaluate the application value of radiomics and deep learning (DL) in the differential diagnosis of benign and malignant soft tissue tumors (STTs). MATERIALS AND METHODS: A systematic review was conducted on studies published up to December 11, 2023, that utilized radiomics and DL methods for the diagnosis of STTs. The methodological quality and risk of bias were evaluated using the Radiomics Quality Score (RQS) 2.0 system and Quality Assessment of Diagnostic Accuracy Studies-2 (QUADAS-2) tool, respectively. A bivariate random-effects model was used to calculate the summarized sensitivity and specificity. To identify factors contributing to heterogeneity, meta-regression and subgroup analyses were performed to assess the following covariates: diagnostic modality, region/volume of interest, imaging examination, study design, and pathology type. The asymmetry of Deeks' funnel plot was used to assess publication bias. RESULTS: A total of 21 studies involving 3866 patients were included, with 13 studies using independent test/validation sets included in the quantitative statistical analysis. The average RQS was 21.31, with substantial or near-perfect inter-rater agreement. The combined sensitivity and specificity were 0.84 (95% CI: 0.76-0.89) and 0.88 (95% CI: 0.69-0.96), respectively. Meta-regression and subgroup analyses showed that study design and the region/volume of interest were significant factors affecting study heterogeneity (P < 0.05). No publication bias was observed. CONCLUSION: Radiomics and DL can accurately distinguish between benign and malignant STTs. Future research should concentrate on enhancing the rigor of study designs, conducting multicenter prospective validations, amplifying the interpretability of DL models, and integrating multimodal data to elevate the diagnostic accuracy and clinical utility of soft tissue tumor assessments.

The genetic architecture of multimodal human brain age.

The complex biological mechanisms underlying human brain aging remain incompletely understood. This study investigated the genetic architecture of three brain age gaps (BAG) derived from gray matter volume (GM-BAG), white matter microstructure (WM-BAG), and functional connectivity (FC-BAG). We identified sixteen genomic loci that reached genome-wide significance (P-value < 5×10-8). A gene-drug-disease network highlighted genes linked to GM-BAG for treating neurodegenerative and neuropsychiatric disorders and WM-BAG genes for cancer therapy. GM-BAG displayed the most pronounced heritability enrichment in genetic variants within conserved regions. Oligodendrocytes and astrocytes, but not neurons, exhibited notable heritability enrichment in WM and FC-BAG, respectively. Mendelian randomization identified potential causal effects of several chronic diseases on brain aging, such as type 2 diabetes on GM-BAG and AD on WM-BAG. Our results provide insights into the genetics of human brain aging, with clinical implications for potential lifestyle and therapeutic interventions. All results are publicly available at https://labs.loni.usc.edu/medicine .

Thymoquinone regulates microglial M1/M2 polarization after cerebral ischemia-reperfusion injury via the TLR4 signaling pathway.

Acute ischemic stroke followed by microglia activation, and the regulation of neuroinflammatory responses after ischemic injury involves microglia polarization. microglia polarization is involved in the regulation of neuroinflammatory responses and ischemic stroke-related brain damage. Thymoquinone (TQ) is an anti-inflammatory agent following ischemic stroke onset. However, the significance of TQ in microglia polarization following acute ischemic stroke is still unclear. We predicted that TQ might have neuroprotective properties by modulating microglia polarization. In this work, we mimicked the clinical signs of acute ischemic stroke using a mouse middle cerebral artery ischemia-reperfusion (I/R) model. It was discovered that TQ treatment decreased I/R-induced infarct volume, cerebral oedema, and promoted neuronal survival, as well as improved the histopathological changes of brain tissue. The sensorimotor function was assessed by the Garica score, foot fault test, and corner test, and it was found that TQ could improve the motor deficits caused by I/R. Secondly, real-time fluorescence quantitative PCR, immuno-fluorescence, ELISA, and western blot were used to detect the expression of M1/M2-specific markers in microglia to explore the role of TQ in the modulation of microglial cell polarization after cerebral ischemia-reperfusion. We found that TQ was able to promote the polarization of microglia with extremely secreted inflammatory factors from M1 type to M2 type. Furthermore, TQ could block the TLR4/NF-κB signaling pathway via Hif-1α activation which subsequently may attenuate microglia differentiation following the cerebral ischemia, establishing a mechanism for the TQ's beneficial effects in the cerebral ischemia-reperfusion model.

A multi-cohort genome-wide association study in African ancestry individuals reveals risk loci for primary open-angle glaucoma.

Primary open-angle glaucoma (POAG), the leading cause of irreversible blindness worldwide, disproportionately affects individuals of African ancestry. We conducted a genome-wide association study (GWAS) for POAG in 11,275 individuals of African ancestry (6,003 cases; 5,272 controls). We detected 46 risk loci associated with POAG at genome-wide significance. Replication and post-GWAS analyses, including functionally informed fine-mapping, multiple trait co-localization, and in silico validation, implicated two previously undescribed variants (rs1666698 mapping to DBF4P2; rs34957764 mapping to ROCK1P1) and one previously associated variant (rs11824032 mapping to ARHGEF12) as likely causal. For individuals of African ancestry, a polygenic risk score (PRS) for POAG from our mega-analysis (African ancestry individuals) outperformed a PRS from summary statistics of a much larger GWAS derived from European ancestry individuals. This study quantifies the genetic architecture similarities and differences between African and non-African ancestry populations for this blinding disease.

Identification and validation of supervariants reveal novel loci associated with human white matter microstructure.

As an essential part of the central nervous system, white matter coordinates communications between different brain regions and is related to a wide range of neurodegenerative and neuropsychiatric disorders. Previous genome-wide association studies (GWASs) have uncovered loci associated with white matter microstructure. However, GWASs suffer from limited reproducibility and difficulties in detecting multi-single-nucleotide polymorphism (multi-SNP) and epistatic effects. In this study, we adopt the concept of supervariants, a combination of alleles in multiple loci, to account for potential multi-SNP effects. We perform supervariant identification and validation to identify loci associated with 22 white matter fractional anisotropy phenotypes derived from diffusion tensor imaging. To increase reproducibility, we use United Kingdom (UK) Biobank White British (n = 30,842) data for discovery and internal validation, and UK Biobank White but non-British (n = 1927) data, Europeans from the Adolescent Brain Cognitive Development study (n = 4399) data, and Europeans from the Human Connectome Project (n = 319) data for external validation. We identify 23 novel loci on the discovery set that have not been reported in the previous GWASs on white matter microstructure. Among them, three supervariants on genomic regions 5q35.1, 8p21.2, and 19q13.32 have P-values lower than 0.05 in the meta-analysis of the three independent validation data sets. These supervariants contain genetic variants located in genes that have been related to brain structures, cognitive functions, and neuropsychiatric diseases. Our findings provide a better understanding of the genetic architecture underlying white matter microstructure.

The Genetic Architecture of Biological Age in Nine Human Organ Systems.

Understanding the genetic basis of biological aging in multi-organ systems is vital for elucidating age-related disease mechanisms and identifying therapeutic interventions. This study characterized the genetic architecture of the biological age gap (BAG) across nine human organ systems in 377,028 individuals of European ancestry from the UK Biobank. We discovered 393 genomic loci-BAG pairs (P-value<5×10-8) linked to the brain, eye, cardiovascular, hepatic, immune, metabolic, musculoskeletal, pulmonary, and renal systems. We observed BAG-organ specificity and inter-organ connections. Genetic variants associated with the nine BAGs are predominantly specific to the respective organ system while exerting pleiotropic effects on traits linked to multiple organ systems. A gene-drug-disease network confirmed the involvement of the metabolic BAG-associated genes in drugs targeting various metabolic disorders. Genetic correlation analyses supported Cheverud's Conjecture1 - the genetic correlation between BAGs mirrors their phenotypic correlation. A causal network revealed potential causal effects linking chronic diseases (e.g., Alzheimer's disease), body weight, and sleep duration to the BAG of multiple organ systems. Our findings shed light on promising therapeutic interventions to enhance human organ health within a complex multi-organ network, including lifestyle modifications and potential drug repositioning strategies for treating chronic diseases. All results are publicly available at https://labs-laboratory.com/medicine.

(+)- and (-)-Tedanine, a pair of new enantiomeric indolone alkaloids from the marine sponge Tedania sp.

(+)- and (-)-Tedanine [(+)-1 and (-)-1], a pair of new enantiomeric indolone alkaloids, along with nine compounds (2-10) were isolated from the marine sponge Tedania sp. The structures of (+)-1 and (-)-1 including absolute configurations were determined by spectroscopic analysis and quantum chemical calculation. Compounds (+)-1 and (-)-1 were the first examples of indolone alkaloids isolated from this genus. In addition, the cytotoxic and antibacterial activities of these compounds were also evaluated.

The diagnostic performance of salivary gland ultrasound elastography in Sjögren's syndrome and sicca symptoms: a systematic review and meta-analysis.

OBJECTIVE: To systematically evaluate the diagnostic performance of ultrasound elastography (USE) in distinguishing primary Sjögren's syndrome (pSS) from healthy/disease controls. METHODS: We searched the PubMed, Embase, Web of Science, and Cochrane Library databases for published literature on USE for diagnosing pSS. Bivariate random effects models were used to calculate the pooled sensitivity and specificity of USE. To determine the factors influencing heterogeneity, meta-regression and subgroup analyses were performed to assess country, diagnostic criteria, imaging mechanisms, shear wave elastography techniques, measurement location, control group category, and patient age. Publication bias was assessed using the asymmetry of the Deeks funnel plot. RESULTS: Fifteen articles covering 816 patients and 735 control participants were included. USE showed a pooled sensitivity of 0.80 (95% CI: 0.71-0.87) and specificity of 0.87 (95% CI: 0.78-0.92). Meta-regression and subgroup analyses revealed that shear wave elastography techniques, measurement location, and patient age were significant factors that affected study heterogeneity (p < 0.05). Elastography performs better in diagnosing patients aged ≤ 51 years compared to patients aged > 51 years. There was no significant publication bias. CONCLUSION: USE demonstrates high accuracy in differentiating between pSS and healthy/disease control groups. CLINICAL RELEVANCE STATEMENT: Ultrasound elastography, as a non-invasive and cost-effective technique, can be used to distinguish primary Sjögren's syndrome from disease/healthy control groups by measuring the stiffness of salivary glands. KEY POINTS: • Ultrasound elastography is an acceptable technique for the diagnosis of primary Sjögren's syndrome. • The pooled sensitivity and specificity of ultrasound elastography for diagnosing primary Sjögren's syndrome were 0.80 and 0.87, respectively. • In patients aged ≤ 51 years with primary Sjögren's syndrome, ultrasound elastography showed good diagnostic performance.

Edaravone dexborneol alleviates cerebral ischemia-reperfusion injury through NF-κB/NLRP3 signal pathway.

Inflammatory injury following ischemia-reperfusion (I/R) severely limits the efficacy of stroke treatment. Edaravone dexborneol (C.EDA) has been shown to reduce inflammation following a cerebral hemorrhage. However, the precise anti-inflammatory mechanism of C.EDA is unknown. In this study, we investigated whether C.EDA provides neuroprotection after I/R in rats, as well as the potential mechanisms involved. A middle cerebral artery occlusion/reperfusion (I/R) model was created using Sprague-Dawley rats. The blood flow of the central cerebral artery was monitored by a laser speckle imaging system. The neurological score was used to assess behavioral improvement. Cerebral infarction volume was measured by TTC staining. And the integrity of the blood-brain barrier was detected by Evan's blue staining. The expression of the nuclear factor kappa-B (NF-κB)/ the NOD-like receptor protein (NLRP3) inflammasome signal pathway and microglia polarization were detected by immunofluorescence and Western blotting. The cerebral blood flow ratio indicates that the cerebral I/R model was successfully established. After reperfusion for 72 h, the improvement of neurological scores, infarct volume reduction, and integrity of the blood-brain barrier was observed in I/R rats with C.EDA treatment. Meanwhile, the immunofluorescence result showed that the expression of iNOS, NLRP3, and NF-κB protein was decreased and the level of Arg1 was increased. Western blot analysis showed that the expression of NF-κB/NLRP3 signal pathway-related protein was decreased. In conclusion, this study indicates that C.EDA alleviates I/R injury by blocking the activation of the NLRP3 inflammasome and regulating the polarization of M1/M2 microglia via the NF-κB signal pathway.

The interaction effects of age, APOE and common environmental risk factors on human brain structure.

Mounting evidence suggests considerable diversity in brain aging trajectories, primarily arising from the complex interplay between age, genetic, and environmental risk factors, leading to distinct patterns of micro- and macro-cerebral aging. The underlying mechanisms of such effects still remain unclear. We conducted a comprehensive association analysis between cerebral structural measures and prevalent risk factors, using data from 36,969 UK Biobank subjects aged 44-81. Participants were assessed for brain volume, white matter diffusivity, Apolipoprotein E (APOE) genotypes, polygenic risk scores, lifestyles, and socioeconomic status. We examined genetic and environmental effects and their interactions with age and sex, and identified 726 signals, with education, alcohol, and smoking affecting most brain regions. Our analysis revealed negative age-APOE-ε4 and positive age-APOE-ε2 interaction effects, respectively, especially in females on the volume of amygdala, positive age-sex-APOE-ε4 interaction on the cerebellar volume, positive age-excessive-alcohol interaction effect on the mean diffusivity of the splenium of the corpus callosum, positive age-healthy-diet interaction effect on the paracentral volume, and negative APOE-ε4-moderate-alcohol interaction effects on the axial diffusivity of the superior fronto-occipital fasciculus. These findings highlight the need of considering age, sex, genetic, and environmental joint effects in elucidating normal or abnormal brain aging.

Secondary hyperparathyroidism combined with thyroid disease.

To retrospectively analyze the diagnosis and treatment of secondary hyperparathyroidism (SHPT) combined with thyroid disease, and to investigate the correlation between SHPT and papillary thyroid carcinoma (PTC), SHPT and thyroid disease, and the importance of preoperative localization diagnosis in patients with SHPT. Clinical data of 101 patients who underwent surgical treatment for SHPT at the Third Hospital of Hebei Medical University were collected from August 2014 to May 2023, and patients were divided into SHPT without PTC group (n = 94) and SHPT with PTC group (n = 7) according to their postoperative pathology. Patients were divided into SHPT without thyroid disease group (n = 32) and SHPT with thyroid disease group (n = 69) according to their preoperative ultrasound diagnosis and postoperative pathology. The differences between the 2 groups were compared to explore the association between SHPT and PTC and between SHPT and thyroid disease. Of the 101 patients with SHPT, 65 were male and 36 were female with a mean age of (44.26 ±â€…11.16) years. There were 69 patients (68.32%) with concomitant thyroid disease and 32 patients (31.68%) without concomitant thyroid disease, including 7 patients (6.93%) with PTC. The results of univariate analysis showed that the differences in age and preoperative PTH levels between the SHPT without PTC group and the SHPT with PTC group were statistically significant (P < 0. 05),There were no significant differences in age, gender, preoperative PTH, preoperative alkaline phosphatase, preoperative serum calcium, preoperative serum phosphorus, preoperative serum creatinine, duration of dialysis disease, and whether they were accompanied by hypertension or not between the SHPT without thyroid disease group and the SHPT with thyroid disease group (P > 0. 05), logistic regression analysis showed that there was a correlation between the age of patients with SHPT and the level of preoperative PTH with PTC. In patients with SHPT, concomitant thyroid disease is more common, so patients with SHPT should be screened for thyroid disease at the same time as routine preoperative ultrasonography combined with nuclear scan for localized diagnosis, and surgical resection is preferred if concomitant PTC is present.

Isolation and total synthesis of dysidone A: a new piperidone alkaloid from the marine sponge Dysidea sp.

A new piperidone alkaloid, dysidone A (1), was isolated from the marine sponge Dysidea sp. The structure of 1 was elucidated by the method of spectroscopic analysis. Compound 1 represented the first example of piperidone alkaloid isolated from the sponge of the genus Dysidea with the exocyclic double bond. Furthermore, the total synthesis of 1 was also carried out, which was started with piperidine proceeding a PIDA/I2-mediated α and ß-C (sp3) -H bond dual oxygenation to achieve a 5-steps synthesis in a total yield of 10.6%. In addition, the anti-inflammatory activities of 1 and its derivative dysidone B (1d) were evaluated, which suggested that 1 showed weak anti-inflammatory activity.

The pivotal role of the X-chromosome in the genetic architecture of the human brain.

Genes on the X-chromosome are extensively expressed in the human brain, resulting in substantial influences on brain development, intellectual disability, and other brain-related disorders. To comprehensively investigate the X-chromosome's impact on the cerebral cortex, white matter tract microstructures, and intrinsic and extrinsic brain functions, we examined 2,822 complex brain imaging traits obtained from n=34,000 subjects in the UK Biobank. We unveiled potential autosome-X-chromosome interaction, while proposing an atlas of dosage compensation (DC) for each set of traits. We observed a pronounced X-chromosome impact on the corticospinal tract and the functional amplitude and connectivity of visual networks. In association studies, we identified 50 genome-wide significant trait-locus pairs enriched in Xq28, 22 of which replicated in independent datasets (n=4,900). Notably, 13 newly identified pairs were in the X-chromosome's non-pseudo-autosomal regions (NPR). The volume of the right ventral diencephalon shared genetic architecture with schizophrenia and educational attainment in a locus indexed by rs2361468 (located ~3kb upstream of PJA1, a conserved and ubiquitously expressed gene implicated in multiple psychiatric disorders). No significant associations were identified in the pseudo-autosomal regions (PAR) or the Y-chromosome. Finally, we explored sex-specific associations on the X-chromosome and compared differing genetic effects between sexes. We found much more associations can be identified in males (33 versus 9) given a similar sample size. In conclusion, our research provides invaluable insights into the X-chromosome's role in the human brain, contributing to the observed sex differences in brain structure and function.

Direct and indirect effects of age on dengue severity: The mediating role of secondary infection.

Severe dengue occurrence has been attributed to increasing age and different dengue virus (DENV) serotypes that cause secondary infections and immune-enhancing phenomena. Therefore, we examined if the effect of age on dengue severity was mediated by infectivity status while controlling for sex and region. Further, we assessed the spatial clustering of dengue severity for individuals with primary and secondary infection across Mexican municipalities. Health data from 2012 to 2017 was retrieved from Mexico's Ministry of Health. A mediation analysis was performed using multiple logistic regression models based on a directed acyclic graph. The models were explored for the direct effect of age on dengue severity and its indirect impact through secondary infection. In addition, severe dengue clusters were determined in some Northeastern and Southeastern municipalities through spatial analysis. We observed a nonlinear trend between age and severe dengue. There was a downward trend of severe dengue for individuals between 0 and 10 years and an upward trend above 10 years. The effect of age on dengue severity was no longer significant for individuals between 10 and 60 years after introducing infectivity status into the model. The mediating role of infectivity status in the causal model was 17%. Clustering of severe dengue among individuals with primary infection in the Northeastern region may point to the high prevalence of DENV-3 in the region. Public health efforts may prevent secondary infection among infants and the aged. In addition, there should be a further investigation into the effect of DENV-3 in individuals with primary disease.