Pattern Of Disease Onset Research Articles

Trauma plays an important role in acral melanoma: A retrospective study of 303 patients.

Acral melanoma (AM) is the most common subtype of malignant melanoma in China, with a very poor prognosis. Despite the frequent reporting of trauma events in AM cases, the precise etiology of AM remains elusive. A retrospective analysis was conducted on a cohort of 303 AM patients at Nanjing Drum Tower Hospital. The patients were categorized into four distinct groups based on different patterns of disease onset: trauma type (Type 1), pigmented nevus type (Type 2), pigmented nevi with trauma (Type 3), and pigmented nevi with natural ulceration (Type 4). Differences in clinicopathological features, genetic alterations, and tumor immune microenvironment (TIME) were analyzed. Traumatic events accounted for a large proportion of AM cases. Among these categories, Type 1 patients displayed the least favorable pathological traits and an immunosuppressive TIME. Common copy number variations (CNVs) were observed in CCND1, RB1, FGF19, and IL7R, while CNVs in CDK4 and TERT occurred less frequently in patients with a history of trauma (Type 1 and Type 3). Type 2 patients exhibited the most favorable pathological characteristics and genetic profiles, and demonstrated the lowest incidence of CCDN1 and RB1 CNVs but had the highest CDK4 CNVs. In contrast, the pathological behavior of Type 3 and Type 4 patients was in between Type 1 and Type 2. And patients in Type 3 and Type 4 displayed a more favorable overall microenvironment. This study provides a clinical classification of Chinese AM based on diverse clinical onset characteristics and highlights the important role of trauma in AM. These findings may help to guide the diagnosis, treatment, and prognosis of AM patients. Further investigations are imperative to elucidate the underlying mechanisms governing the association between trauma and AM.

A single center case series of immune checkpoint inhibitor-induced type 1 diabetes mellitus, patterns of disease onset and long-term clinical outcome.

Type 1 diabetes mellitus (T1DM) is a rare, but serious immune-related adverse event (irAE) of immune checkpoint inhibitors (ICIs). Our goal was to characterize treatment outcomes associated with ICI-induced T1DM through analysis of clinical, immunological and proteomic data. This was a single-center case series of patients with solid tumors who received ICIs and subsequently had a new diagnosis of T1DM. ICD codes and C-peptide levels were used to identify patients for chart review to confirm ICI-induced T1DM. Baseline blood specimens were studied for proteomic and immunophenotypic changes. Between 2011 and 2023, 18 of 3744 patients treated at Huntsman Cancer Institute with ICIs were confirmed to have ICI-induced T1DM (0.48%). Eleven of the 18 patients received anti-PD1 monotherapy, 4 received anti-PD1 plus chemotherapy or targeted therapy, and 3 received ipilimumab plus nivolumab. The mean time to onset was 218 days (range 22-418 days). Patients had sudden elevated serum glucose within 2-3 weeks prior to diagnosis. Sixteen (89%) presented with diabetic ketoacidosis. Three of 12 patients had positive T1DM-associated autoantibodies. All patients with T1DM became insulin-dependent through follow-up. At median follow-up of 21.9 months (range 8.4-82.4), no patients in the melanoma group had progressed or died from disease. In the melanoma group, best responses were 2 complete response and 2 partial response while on active treatment; none in the adjuvant group had disease recurrence. Proteomic analysis of baseline blood suggested low inflammatory (IL-6, OSMR) markers and high metabolic (GLO1, DXCR) markers in ICI-induced T1DM cohort. Our case series demonstrates rapid onset and irreversibility of ICI-induced T1DM. Melanoma patients with ICI-induced T1DM display excellent clinical response and survival. Limited proteomic data also suggested a unique proteomic profile. Our study helps clinicians to understand the unique clinical presentation and long-term outcomes of this rare irAE for best clinical management.

EPID-16. SEASONAL INCIDENCE PATTERN COMPARISON BETWEEN PRIMARY AND SECONDARY CENTRAL NERVOUS SYSTEM LYMPHOMAS

Abstract OBJECTIVE To compare primary CNS lymphoma [PCNSL] and secondary CNS lymphoma [SCNSL] incidence by year, month, week, and time between symptom onset, radiographic study, and tissue diagnosis. BACKGROUND PCNSL is a rare non-Hodgkin’s B-cell lymphoma confined to the central nervous system with an increased incidence among immunocompromised patients and immunocompetent patients.1 Epstein Barr Virus [EBV] infection usually accompanies immunocompromised patients with PCNSL. Whether viral infection is etiologic remains uncertain, especially among the immunocompetent, where EBV is not found. A seasonal pattern was described suggesting an infectious etiology.2 We sought to add to the literature our experience regarding patterns of disease onset. Design/ METHODS We retrospectively identified 96 immunocompetent PCNSL patients and 75 SCNSL patients treated here between 2010-20. Complete data was available for 91 PCNSL and 73 SCNSL patients. Variables collected included symptom onset, initial imaging, and tissue collection dates. RESULTS Weekly incidence was noted in both, with peak of incidence in the 10th and 40th week in PCNSL in 9th, 27th, and 31st weeks among SCNSL. Time between symptom onset and first neuroimaging study was significantly different, with PCNSL patients having significantly less time on average. Curiously, the average time between each PCNSL diagnosis was significantly shorter than that for SCNSL diagnosis. CONCLUSION/RELEVANCE Due to the rarity of the disease, larger studies are needed to further elucidate potential viral etiologies underlying PCNSL.

Data-driven identification of ageing-related diseases from electronic health records

Reducing the burden of late-life morbidity requires an understanding of the mechanisms of ageing-related diseases (ARDs), defined as diseases that accumulate with increasing age. This has been hampered by the lack of formal criteria to identify ARDs. Here, we present a framework to identify ARDs using two complementary methods consisting of unsupervised machine learning and actuarial techniques, which we applied to electronic health records (EHRs) from 3,009,048 individuals in England using primary care data from the Clinical Practice Research Datalink (CPRD) linked to the Hospital Episode Statistics admitted patient care dataset between 1 April 2010 and 31 March 2015 (mean age 49.7 years (s.d. 18.6), 51% female, 70% white ethnicity). We grouped 278 high-burden diseases into nine main clusters according to their patterns of disease onset, using a hierarchical agglomerative clustering algorithm. Four of these clusters, encompassing 207 diseases spanning diverse organ systems and clinical specialties, had rates of disease onset that clearly increased with chronological age. However, the ages of onset for these four clusters were strikingly different, with median age of onset 82 years (IQR 82–83) for Cluster 1, 77 years (IQR 75–77) for Cluster 2, 69 years (IQR 66–71) for Cluster 3 and 57 years (IQR 54–59) for Cluster 4. Fitting to ageing-related actuarial models confirmed that the vast majority of these 207 diseases had a high probability of being ageing-related. Cardiovascular diseases and cancers were highly represented, while benign neoplastic, skin and psychiatric conditions were largely absent from the four ageing-related clusters. Our framework identifies and clusters ARDs and can form the basis for fundamental and translational research into ageing pathways.

Longitudinal progression of aspirin-exacerbated respiratory disease: analysis of a national insurance claims database.

Aspirin-exacerbated respiratory disease (AERD) is a recalcitrant inflammatory disorder defined by asthma, nasal polyposis, and sensitivity to cyclooxygenase-1 inhibitors. The timeline and course of disease progression is unclear. The Truven MarketScan Database, a large American health insurance claims repository, was queried to identify patients meeting criteria for AERD from 2009 to 2015. Included patients had associated International Classification of Diseases, 9th edition (ICD-9) codes consistent with all 3 components of AERD: asthma, nasal polyposis, and drug allergy. Patterns of disease onset and time to progression were analyzed. A total of 5628 patients were identified for study inclusion. Of the 3 components of AERD, 3303 patients (59%) were initially diagnosed with asthma, 1408 (25%) were initially diagnosed with nasal polyps, and 917 (16%) were first diagnosed with drug sensitivity. The most common (36%) sequence of diagnoses was asthma, followed by nasal polyps, followed by drug allergy. The median interval between diagnosis of upper or lower airway involvement (ie, nasal polyps and/or asthma) to recognition of drug sensitivity was 259 days (quartiles Q1 to Q3: 92 to 603 days). In patients with both asthma and nasal polyps diagnoses, the risk of developing drug sensitivity during the study time period was 6%. Upper and lower airway disease is often initially recognized in patients with AERD, whereas drug sensitivity presents month to years later. This delay may be due to the pathophysiology of AERD and disease progression or due to practice patterns in diagnostic testing and coding. Further work is warranted to identify these patients at early stages in their disease progression.

Five-year risk of incident disease following a diagnosis of chronic rhinosinusitis.

Chronic rhinosinusitis (CRS) has a broad range of comorbidities. Due to a lack of longitudinal studies, it is not known whether these comorbidities cause CRS, are promoted by CRS, or share a systemic disease process with CRS. The objective of this study was to determine the risk of incident disease within 5 years after a new diagnosis of CRS with nasal polyps (CRSwNP) and without nasal polyps (CRSsNP). We conducted a case-control study nested within the longitudinal cohort of primary care patients in the Geisinger Clinic using electronic health record data. We evaluated incident disease over 5 years in newly diagnosed CRSwNP and CRSsNP cases compared to controls using multivariable Cox regression models. CRSsNP (n = 3612) cases were at greater risk (HR, 95% confidence interval) than controls for incidence of: upper airway diseases, including adenotonsillitis (3.29, 2.41-4.50); lower aerodigestive tract diseases, including asthma (2.69, 2.14-3.38); epithelial conditions, including atopic dermatitis (2.75, 1.23-6.16); and hypertension (1.38, 1.19-1.61). CRSwNP (n = 241) cases were at greater risk for obesity than controls (1.74, 1.08-2.80), but CRSwNP was not associated with other diseases. The risk of other diseases associated with CRS adds to the burden of an already highly burdensome condition, and suggests either that CRS promotes onset of other diseases or is an indicator of systemic disease processes. Different patterns of association with diseases by CRS phenotype may be due to CRSwNP sample size limitations or reflect a different pattern of disease onset by phenotype. These findings have implications for screening guidelines and care of CRS patients.

Study of motor asymmetry in ALS indicates an effect of limb dominance on onset and spread of weakness, and an important role for upper motor neurons

In amyotrophic lateral sclerosis (ALS), onset and spread of upper motor neuron (UMN) and lower motor neuron (LMN) dysfunction is typically asymmetric. Our aim was to investigate the relationship between limb dominance and the onset and spread of clinical UMN and LMN dysfunction in ALS. We studied 138 ALS subjects with unilateral and concordant limb dominance, from two tertiary centres. A questionnaire was used to determine the pattern of disease onset and spread. The clinical severity of UMN and LMN signs in each limb was quantified using a validated scoring system. Results showed that onset of weakness was more likely to occur in the dominant upper limb (p = 0.02). In subjects with initial weakness in a non-dominant limb, spread of weakness was more likely to be to the other limb on that side (p = 0.008). The relative distribution of upper limb UMN signs was affected by whether weakness first occurred on the dominant or non-dominant side (p = 0.03). These findings support limb dominance as a significant factor underlying onset and spread of ALS, with UMN processes playing an important role. The effect of limb dominance on the presentation of ALS may reflect underlying neuronal vulnerabilities, which become exposed by the disease.

Polymorphism of the parasite lactate dehydrogenase gene from Plasmodium vivax Korean isolates

BackgroundAssaying for the parasitic lactate dehydrogenase (pLDH) is widely used as a rapid diagnostic test (RDT), but the efficacy of its serological effectiveness in diagnosis, that is antibody detection ability, is not known. The genetic variation of Korean isolates was analysed, and recombinant protein pLDH was evaluated as a serodiagnostic antigen for the detection of Plasmodium vivax malaria.MethodsGenomic DNA was purified, and the pLDH gene of P. vivax was amplified from blood samples from 20 patients. The samples came from five epidemic areas: Bucheon-si, Gimpo-si, and Paju-si of Gyeonggi Province, Gangwha-gun of Incheon metropolitan city, and Cheorwon-gun of Gangwon Province, South Korea, from 2010 to 2011. The antigenicity of the recombinant protein pLDH was tested by western blot and enzyme-linked immunosorbent assay (ELISA).ResultsSequence analysis of 20 Korean isolates of P. vivax showed that the open reading frame (ORF) of 951 nucleotides encoded a deduced protein of 316 amino acids (aa). This ORF showed 100% identity with the P. vivax Belem strain (DQ060151) and P. vivax Hainan strain (FJ527750), 89.6% homology with Plasmodium falciparum FCC1_HN (DQ825436), 90.2% homology with Plasmodium berghei (AY437808), 96.8% homology with Plasmodium knowlesi (JF958130), and 90.2% homology with Plasmodium reichenowi (AB122147). A single-nucleotide polymorphism (SNP) at nucleotide 456 (T to C) was also observed in the isolate from Bucheon, but it did not change in the amino acid sequence. The expressed recombinant protein had a molecular weight of approximately 32 kDa, as analysed by sodium dodecyl sulphate-polyacrylamide gel electrophoresis (SDS-PAGE) analysis. Of the 40 P. vivax patients, 34 (85.0%) were positive by ELISA.ConclusionsThe pLDH genes of 19 isolates of P. vivax were identical, except one for SNP at nucleotide 456. This observation indicates that this gene is relatively stable. Based on these results, the relationship between antibody production against pLDH and the pattern of disease onset should be investigated further before using pLDH for serodiagnosis.

A11 Induced pluripotent stem cells for basic and translational research on HD

<h3>Background</h3> The expression of mutant HTT leads to many cellular alterations, including abnormal vesicle recycling, loss of signalling by brain-derived neurotrophic factor, excitotoxicity, perturbation of Ca²⁺ signalling, decreases in intracellular ATP, alterations of gene transcription, inhibition of protein clearance pathways, mitochondrial and metabolic disturbances, and ultimately cell death. While robust mammalian systems have been developed to model disease and extensive mechanistic insights have emerged, significant differences between rodent and human cells and between non-neuronal cells and neurons limit the utility of these models for accurately representing human disease. Human pluripotent stem cells can generate highly specified cell populations, including DARPP32-positive MSNs of the striatum, and provide a method for modelling HD in human neurons carrying the mutation. As it is caused by one single gene, HD is an ideal disorder for exploring the utility of modelling disease in induced pluripotent stem cells (iPSCs) through reprogramming adult cells from HD patients with known patterns of disease onset and duration. <h3>Aims</h3> Generate iPSC lines from HD patients and controls and identify CAG-repeat expansion associated phenotypes. <h3>Methods/techniques</h3> Through the efforts of an international consortium effort, 14 lines were generated, differentiated into neuronal populations and assessed for CAG-repeat dependent outcome measures. <h3>Results/outcomes</h3> HD iPSC lines have reproducible CAG expansion–associated phenotypes upon differentiation, including CAG expansion-associated changes in gene expression patterns and alterations in electrophysiology, metabolism, cell adhesion, and ultimately an increased risk of cell death. While the lines with the longest repeats (HD180) showed a phenotype across all assays, those with shorter repeats (HD60) showed phenotypes in a specific sub set of assays. The most sensitive assay for establishing repeat dependent effects was found to be calcium responses to stress. <h3>Conclusions</h3> This HD iPSC collection represents a unique and well-characterised resource to elucidate disease mechanisms in HD and provides a novel human stem cell platform for screening new candidate therapeutics. <h3>Funding</h3> NIH, CHDI, CIRM.

Genetic variation of aldolase from Korean isolates of Plasmodium vivax and its usefulness in serodiagnosis

BackgroundThe malaria aldolase is widely used as rapid diagnostic test (RDT), but the efficacy in aspect of its serological effectiveness in diagnosis is not known. The genetic variation of Korean isolates was analysed and recombinant aldolase was evaluated as a serological antigen in Plasmodium vivax malaria.MethodsGenomic DNA was purified and the aldolase gene of P. vivax from 25 patients’ blood samples was amplified. The samples came from 5 epidemic areas; Bucheon-si, Gimpo-si, Paju-si of Gyeonggido, Gangwha-gun of Incheon metropolitan city, and Cheorwon of Gangwon-do, South Korea. The antigenicity of the recombinant aldolase was tested by western blot and enzyme-linked immunosorbent assay (ELISA).ResultsSequence analysis of 25 Korean isolates of P. vivax showed that the open reading frame (ORF) of 1,110 nucleotides encoded a deduced protein of 369 amino acids (aa). This ORF showed 100% homology with the P. vivax Sal I strain (XM_00165894) and P. vivax WDK strain (AF247063), 87.4% homology with Plasmodium falciparum (AF179421), 90.6% homology with Plasmodium chabaudi (AF247060), 89.5% homology with Plasmodium vinckei (AF247061), and 96.7% homology with Plasmodium knowlesi. A single nucleotide polymorphism (SNP) at nucleotide 180 (G to A, n = 5) was also observed in the isolates. The expressed recombinant protein had a molecular weight of approximately 31 kDa (monomeric form) and 62 kDa (dimeric form) as analysed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) analysis. Among 109 P. vivax patients, 32 (29.4%) had positive in an enzyme-linked absorbance assay (ELISA). This result showed significant correlation between ELISA and an indirect fluorescent antibody test (IFAT) (P < 0.0001).ConclusionsThe aldolase gene from Korean isolates of P. vivax showed one SNP at nucleotide position 180; this SNP mutant was discovered in only the western part of Han River, and included the regions of Ganghwa, Gimpo, and Bucheon. Based on the results, the relationship between antibody production against aldolase and the pattern of disease onset should be more investigated before using aldolase for serodiagnosis.

Post‐transplant lymphoproliferative disorders: clinicopathological analysis of 43 cases in a single center, 1990–2009

Post-transplant lymphoproliferative disorders (PTLDs) are a heterogeneous set of complications of organ transplantation associated with poor patient prognosis. We analyzed the clinicopathological features of PTLDs in 43 adult and pediatric recipients of solid organ or bone marrow transplantation at a large transplant service in the Republic of Korea between 1990 and 2009. Of 4545 solid organ and 747 bone marrow transplant recipients, 37 (0.81%) and 6 (0.8%), respectively, developed heterogeneous types of PTLDs. The cumulative incidences of PTLDs during this period were 1.79% (4/223) for heart transplant recipients, 0.78% (17/2192) for kidney transplant recipients, and 0.77% (16/2067) for liver transplant recipients. The patterns of disease onset, histology, and patient survival were associated with the types of organs transplanted. There is a trend for shorter overall survival (OS) in recipients with early-onset PTLDs and monomorphic PTLD histology, while kidney transplant recipients showed favorable OS. This study may be the first comprehensive analysis of the characteristics of PTLDs in Korean patients.

Pattern of Disease Onset, Diagnostic Delay, and Clinical Features in Juvenile Onset and Adult Onset Ankylosing Spondylitis

To assess the frequency of juvenile onset ankylosing spondylitis (JOAS) in Turkish patients with AS and to compare with adult onset AS (AOAS) in a cross-sectional study design. A total of 322 patients were recruited from the joint database of 5 university hospitals in eastern Turkey. Patients with JOAS (n = 43, 13.4%) had significantly longer diagnostic delay (9.21 vs 5.08 yrs), less severe axial involvement and more prevalent uveitis (OR 2.92, 95% CI 1.25-6.79), and peripheral involvement at onset (OR 3.25, 95% CI 1.51-6.98, adjusted for current age; and OR 2.26, 95% CI 1.07-4.76, adjusted for disease duration). Patients with AOAS had higher radiographic scores and more restricted clinimetrics but similar functional limitations and quality of life. JOAS and AOAS had distinctive courses and Turkish patients with AS had similar features compared to other Caucasian patient populations.

An epidemiological approach for the estimation of disease onset in Central Europe in central and peripheral monogenic retinal dystrophies

To study clinical patterns of disease onset in monogenic retinal dystrophies (MRD), using an epidemiological approach. Records of patients with MRD, seen at the University Eye Hospital Tuebingen from 1994 to 1999, were selected from a database and retrospectively reviewed. For analysis, patients were divided into 2 groups by predominant part of visual field (VF) involvement: group 1 (predominantly central involvement) included Stargardt disease (ST), macular dystrophy (MD), and central areolar choroidal dystrophy (CACD), and group 2 (predominantly peripheral involvement) included Bardet-Biedl syndrome (BBD), Usher syndrome (USH) I and II, and choroideremia (CHD). Age, sex, age of first diagnosis, age of visual acuity (VA) decrease and VF emergence, night blindness and photophobia onset, types of VF defects and age of its onset, color discrimination defects and best corrected VA were analyzed. Records of 259 patients were studied. Men were more prevalent than women. Mean age of the patients was 47.2 (SD = 15.6) years old. Forty-five patients in the first group and 40 in the second were first diagnosed between 21 and 30 years of age. Ninety-four patients in the first group had VA decrease before 30 years of age; in the second group, 68 patients had VA decrease onset between 21 and 40 years of age. Forty-four patients in the first group noticed VF at an age between 21 and 30 years, and 74 patients between 11 and 30 years in the second group. Central scotoma was typical for the first group, and was detected in 115 patients. Concentric constriction was typical for the second group, and was found in 81 patients. Half of patients in both groups preserved best-corrected VA in the better eye at a level of 20/40 or better; 7% in the first group and 6% in the second group were registered as legally blind according to WHO criteria, having VA <1/50 or VF <5 degrees . Diagnosis frequency was USH I and II-34%, ST-31%, MD-18%, CHD-14%, BBD-5%. An epidemiological approach to the estimation of the disease onset of various subtypes of monogenic retinal degenerations will be useful for detection of disease duration, its prognosis, rehabilitation and the researching of future treatment possibilities.

Seasonality of birth in children (0-14 years) with type 1 diabetes mellitus in Slovenia.

The aim of this study was to find out whether there is seasonality of month of birth of children with diabetes in Slovenia and if so whether it differs from that of the general population. A cohort of 849 children and adolescents (0-14 years) with type 1 diabetes mellitus born between 1956 and 1998 were included in the study. Monthly and seasonal patterns of birth of the patients with diabetes were compared with the pattern of normal live births (n = 1,345,921) and the pattern of disease onset. Statistical analysis was made using Student's t-test to compare the means between the four seasons of the year, and single cosinor analysis for a period of 12 months. The children and adolescents with diabetes had a statistically significant different seasonality of month of birth compared to that of the general population, and an opposite pattern from the seasonality of month of onset of disease. The observations made are in accordance with observations made recently in other countries and support the hypothesis that a virus infection transmitted by the mother to the fetus during the annual viral epidemic induces the autoimmune process in the pancreatic beta-cells in genetically susceptible individuals who will subsequently develop clinical diabetes during childhood.