Younger Age Of Onset Research Articles

Practical Guidance on Basal Insulin Initiation and Titration in Asia: A Delphi-Based Consensus.

The global health burden of diabetes is on the rise and has affected more than half a billion people worldwide, particularly in Southeast Asia, North Africa, Africa, and the Western Pacific, Middle East, and South and Central America regions of the International Diabetes Federation (IDF). Despite many new treatments being available for the management of diabetes, glycemic control remains suboptimal in Asia, compared to the rest of the world. Delay in timely insulin initiation and inadequate titration of insulin are regarded to be some of the important reasons for inadequate glycemic control. Additionally, Asian populations have a distinct phenotype, including a younger age of onset and higher glycemic excursions, suggestive of a lower beta-cell function, as compared to non-Asians. Although there are multiple local and international guidelines on insulin initiation and titration, some of these guidelines can be complex. There is an unmet need for guideline recommendations on basal insulin initiation and titration to be simplified and customized for the Asian population with type 2 diabetes mellitus (T2DM). A unified approach would increase adoption of basal insulin initiation by primary care and family medicine physicians, which in turn would help reduce the inertia to insulin initiation. With this background, a consensus-seeking meeting was conducted with 14 experts from seven Asian countries to delineate appropriate practices for insulin initiation and titration in the Asian context. The key objective was to propose a simple insulin titration algorithm, specific for the Asian population, to improve glycemic control and optimize therapeutic outcomes of people with T2DM on basal insulin. Following a detailed review of literature and current guidelines, and potential barriers to insulin initiation and titration, the experts proposed a simplified insulin titration algorithm based on both physician- and patient-led components. The consensus recommendations of the experts related to basal insulin initiation and titration have been summarized in this article, along with the proposed titration algorithm for optimizing glycemic control in the Asian population with T2DM.

Identification of hub genes and pathways in colitis-associated colon cancer by integrated bioinformatic analysis

BackgroundColitis-associated colon cancer (CAC) patients have a younger age of onset, more multiple lesions and invasive tumors than sporadic colon cancer patients. Early detection of CAC using endoscopy is challenging, and the incidence of septal colon cancer remains high. Therefore, identifying biomarkers that can predict the tumorigenesis of CAC is in urgent need.ResultsA total of 275 DEGs were identified in CAC. IGF1, BMP4, SPP1, APOB, CCND1, CD44, PTGS2, CFTR, BMP2, KLF4, and TLR2 were identified as hub DEGs, which were significantly enriched in the PI3K-Akt pathway, stem cell pluripotency regulation, focal adhesion, Hippo signaling, and AMPK signaling pathways. Sankey diagram showed that the genes of both the PI3K-AKT signaling and focal adhesion pathways were upregulated (e.g., SPP1, CD44, TLR2, CCND1, and IGF1), and upregulated genes were predicted to be regulated by the crucial miRNAs: hsa-mir-16-5p, hsa-mir-1-3p, et al. Hub gene-TFs network revealed FOXC1 as a core transcription factor. In ulcerative colitis (UC) patients, KLF4, CFTR, BMP2, TLR2 showed significantly lower expression in UC-associated cancer. BMP4 and IGF1 showed higher expression in UC-Ca compared to nonneoplastic mucosa. Survival analysis showed that the differential expression of SPP1, CFRT, and KLF4 were associated with poor prognosis in colon cancer.ConclusionOur study provides novel insights into the mechanism underlying the development of CAC. The hub genes and signaling pathways may contribute to the prevention, diagnosis and treatment of CAC.

A Novel Intron-Encoded Neuropilin-1 Isoform in Pancreatic Islets Associated With Very Young Age of Onset of Type 1 Diabetes.

Net synthesis of pancreatic β-cells peaks before 2 years of life. β-Cell mass is set within the first 5 years of life. In-frame translational readthrough of the NRP1 gene exon 9 into intron 9 generates a truncated neuropilin-1 protein lacking downstream sequence necessary for binding VEGF that stimulates β-cell replication. VEGF is critical for developing but not adult islet neogenesis. Herein we show that cells in human pancreatic islets containing the full-length neuropilin-1 possess insulin but cells that contain the truncated neuropilin-1 are devoid of insulin. Decreased insulin cells increases susceptibility to onset of type 1 diabetes at a younger age. We also show that the frequency of a genetic marker in NRP1 intron 9 is higher among patients with onset of type 1 diabetes before age 4 years (31.8%), including those with onset at 0.67-2.00 and 2-4 years, compared with that in patients with onset at 4-8 years, at 8-12 years, and after 16 years (16.1%) with frequency equal to that in subjects without diabetes (16.0%). Decreased insulin cells plus the genetic data are consistent with a low effect mechanism that alters the onset of type 1 diabetes to a very young age in some patients, thus supporting the endotype concept that type 1 diabetes is a heterogeneous disease.

Adults with Longstanding Strabismus: Psychosocial and Functional Impacts and Reasons behind Surgery Delay.

Purpose The aims of the study were to determine the reasons behind surgical correction delay in adult patients with strabismus, reveal motivations for seeking treatment, and study the psychosocial and functional impacts of strabismus on patients using an Arabic version of the Adult Strabismus-20 (AS-20) questionnaire. Methods and Patients. This study included 79 patients aged ≥18 years and had strabismus for at least one year prior to surgical correction and 40 controls without known visual defects. After a comprehensive ophthalmic exam during their preoperative visit, a validated questionnaire was administered to patients to collect sociodemographic data, reasons for surgery delay, and motivations for seeking treatment now. A translated version of the AS-20 questionnaire was then presented to patients and controls. Total AS-20 (and its subscales: psychosocial and function) scores were calculated and analyzed. All relationships between sociodemographic characteristics, the onset of deviation, presence of diplopia, type and size of deviation, and the changes in the scores of AS-20 (and its subscales) were investigated. Results A total of 79 adult patients with strabismus (cases) and 40 subjects with normal vision (control group) were included in this study. The mean age (SD) was 34.10 (11.5) years for cases (range: 18–61) and 34.20 (11.2) years for controls (range: 18–65) (p=0.964). About half (55.7%, n = 44) of the patients were males compared to (57.5%, n = 23) of the controls. The reasons for strabismus surgery delay reported by the patients were the following: surgery was not offered by an ophthalmologist (35.4%), surgery was offered but declined by the patient due to fear from surgical complications (22.8%), nonaffordability (17.7%), surgery was offered but refused because patients thought they were too old for surgery or patient was not bothered by appearance (15.2%), and patient never sought care (8.9%). The reasons for seeking surgical treatment after this delay were as follows: for cosmetic issues (27.8%), a better understanding of strabismus surgery and its potential complications (20.3%), pressure from family and friends (16.5%), improved economic status (13.9%), relationship/marriage prospects (13.9%), and to improve chances of getting a job (7.6%). When compared to control, patients have significantly lower mean scores of total AS-20 (50.57 vs. 88.01) and its psychosocial (49.59 vs. 87.84) and functional (51.55 vs. 88.19) subscales. AS-20 total score was significantly lower among females and in patients with large deviation size (>25 PD). The psychosocial subscale of AS-20 was significantly lower in females, patients with younger age of onset, and those with large deviation size (>25 PD). Female gender, large deviation size, vertical deviation, and having diplopia correlated significantly with a lower functional score. Conclusion Strabismus has a profound psychosocial and functional impact on affected individuals, especially females and patients with large deviation sizes. Many adult patients with strabismus tend to delay surgical correction; most of these delays could be avoided by better public education, increased awareness among health care providers, and changing health insurance policies to cover the costs of strabismus surgery.

Abstract LB561: Germline mutational profiling of TNBCs in an Indian cohort

Abstract Breast cancer is the most common cancer in Indian women with a high incidence of triple negative breast cancer (TNBC), an aggressive subtype of breast cancer associated with poor prognosis. The high TNBC prevalence (>25%) in India as compared to the western population (10-15%) remains to be a challenge in clinical management. The association of germline BRCA1/2 mutations in TNBCs is well-established as a predisposing factor for hereditary breast cancer risk. However, these studies are predominantly from germline profiling of TNBCs representative of western population. Therefore, we aimed to investigate the germline profiles of breast cancer patients in India using a multi-institutional TNBC cohort based on ACMG consensus multi-gene NGS panel. Of 193 TNBC patients, we identified 57 pathogenic mutations (diagnostic yield = 29.53%) from various genes of which BRCA1 (41/57, 71.93%) and BRCA2 (8/57, 14.03%) were most commonly mutated. We observed a high prevalence of BRCA1 mutations (41/193, 21.24%) and BRCA2 mutations (8/193, 4.14%) in our cohort as compared to published literature. Additionally, 8 pathogenic mutations were also reported in non-BRCA cancer pre-disposing genes associated with the HR pathway like ATM, CHEK2, PALB2. 10 novel mutations were identified in 3 genes namely BRCA1, BRCA2 and PALB2. The most common type of mutations was found to be frame-shift which may cause protein truncation and loss of function. Furthermore, we identified 48 variants of unknown significance (24.9%) of which about 7% were in the BRCA1/2 genes. Data mining from global databases like TCGA, Genome Asia indicated that the novel mutations were unique to the Indian population compared to the germline profiles of different ethnicities. Our study confirms the major contribution of BRCA1/2 genes in TNBCs as reported in the literature. A high percentage of the women were found to be associated with young age onset which may be attributed to BRCA mutations. We have also assessed the association of clinicopathological parameters such as tumor grade, stage, recurrence to the germline mutational status. Our analysis shows significant association of germline mutational status with family history thus underlin the importance of multi-gene panel testing as recommended by NCCN guidelines. Moreover, our results also emphasize the need for designing/implementing guidelines specific to Indian population. In summary our results indicate that Indian TNBCs have a high prevalence of BRCA1/2 mutations. Large scale studies in future are warranted to validate these preliminary findings. Citation Format: Chaitanyanand Koppiker, Ashwini Bapat, Siddharth Gahlaut, Naveen Luke, Jisha John, Rupa Mishra, Aishwarya Konnur, Namrata Namewar, Ruhi Reddy, Shaheen Shaikh, Rituja Banale, Smeeta Nare, Laleh Busheri, Asha Reddy, Ashraf Mannan, Sabarinathan Radhakrishnan, Selvi Radhakrishna, Santosh Dixit. Germline mutational profiling of TNBCs in an Indian cohort [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr LB561.

Abstract 1193: Enhancing pediatric cancer variant curation and representation through standardized classification and automation

Abstract Childhood cancers present unique challenges for variant interpretation in a clinical context due to their rarity, low mutation burden, diversity of molecular alterations, and heterogeneity among patients. Consequently, genes and variants associated with childhood tumors are under-represented in public cancer databases and knowledgebases. A focused effort is needed for the structured curation of genetic variant-level data to document diagnostic, prognostic, and therapeutic biomarkers for childhood cancers. The Pediatric Cancer Curation Advancement Subcommittee (PCCAS), a collaboration between the Clinical Interpretations of Variants in Cancer knowledgebase (CIViC; civicdb.org), the ClinGen Somatic Pediatric Cancer Taskforce, Disease Ontology (DO; disease-ontology.org) and CIViCmine (bionlp.bcgsc.ca/civicmine/), is addressing this challenge through enhanced curation, tagging, and automation. PCCAS created a pediatric specific curation standard operating procedure (SOP) to harmonize pediatric evidence entered in CIViC. Our SOP provides general guidance and considerations to define and classify childhood cancers and to represent childhood cancer evidence on a spectrum of age-related incidence and presentation. For instance, pediatric evidence in CIViC is now tagged using Human Phenotype Ontology (HPO) age of onset terms, allowing pediatric evidence to be easily searched, tracked, and sorted. We also initiated the addition of new age of onset terms to enhance the granularity of these tags. WHO ICD-O nomenclature has been chosen for pediatric disease classification in CIViC. ICD-O provides updated terminology including specific genetic subtypes, which are important in pediatric cancers where their underlying molecular profiles often define the disease. To aid curator selection of disease, we verified pediatric relevant ICD-O terms inclusion in DO and restructured DO disease hierarchies to ensure proper mapping. CIViC highlights our pediatric cancer initiative in multiple areas including a homepage feature linking directly to a dedicated pediatric advanced search that returns all evidence tagged with pediatric or young adult age of onset. Most importantly, our childhood specific SOP and initiatives are included in all ClinGen Somatic Cancer and CIViC training sessions for consistent implementation. CIViCmine supports CIViC by using natural language processing to identify important cancer biomarkers in the literature. To better identify pediatric biomarkers, we are adapting and refining CIViCmine to use MeSH terms and other approaches to enhance accuracy in the identification of childhood evidence in both the literature and CIViC. In conclusion, implementation of these procedures, features, and automation are pushing to make childhood cancer variant evidence more accessible and interpretable. Citation Format: Jason Saliba, Jake Lever, Kilannin Krysiak, Arpad Danos, Alex Wagner, Heather E. Williams, Laveniya Satgunaseelan, David Meredith, Cameron J. Grisdale, Chimene Kesserwan, Jianling Ji, Shruti Rao, Catherine Cottrell, Alanna Church, Mark Evans, Yasmina Jaufeerally-Fakim, Lynn M. Schriml, Angshumoy Roy, Gordana Raca, Malachi Griffith, Obi L. Griffith. Enhancing pediatric cancer variant curation and representation through standardized classification and automation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1193.

Clinical characteristics and prognostic analyses of cervical neuroblastoma

Objective: To determine the characteristics of cervical neuroblastoma and the effect of resection extent on survival and outcomes. Methods: We performed a retrospective review of 32 children with cervical neuroblastoma treated at Beijing Children's Hospital between April 2013 and August 2020. Data were collected from the medical record. The individualized therapy was designed based on staging and risk group. Based on the extent of resection, patients were divided into incomplete and complete resection groups. Event free and overall survival rates were compared between two groups using the Kaplan-Meier method. Results: The ages of patients ranged from 1 month to 81 months, with a median age of 11 months, including 7 males and 15 females. Twenty-nine patients (90.6%) presented with cervical painless mass. The average diameter of the primary tumors was (5.12±1.43) cm. Tumors were located in the parapharyngeal space in 25 cases (78.1%) and in the root of the neck in 7 cases (21.9%). None had MYCN amplification. According to International Neuroblastoma Staging System (INSS), 15 patients (46.9%) were identified as stage 1, 11 patients (34.3%) as stage 2B, 3 patients (9.4%) as stage 3 and 3 patients (9.4%) as stage 4. There were 12 patients (37.5%) at low risk, 17 patients (53.1%) at intermediate risk and 3 patients at high risk according to Children's Oncology Group (COG) risk classification system. All patients underwent tumor resection. Postoperatively Horner's syndrome occurred in 13 patients (40.6%), pneumonia in 9 patients (28.1%), pharyngeal dysfunction in 8 patients (25.0%) and transient hoarseness in 4 patients (12.5%). At a median follow-up of 36.5 months, the overall survival rate was 96.4%, with no significant difference between incomplete and complete resection groups (100.0% vs. 96.3%, χ2=0.19, P=0.667); the event free survival rate was 78.1%, with a significant difference between the two groups (40.0% vs. 85.2%, χ²=6.71, P=0.010). Conclusions: Primary cervical neuroblastoma has a young onset age, mostly in low and medium risk groups, and represents favorable lesions with good outcomes after multidisciplinary therapy. Less aggressive surgery with preservation of important structures is recommended. Complete resection should not be attempted if it would compromise vital structures.

VISUAL PROGNOSTIC VALUE OF NEUTROPHIL-TO-LYMPHOCYTE RATIO AND PLATELET-TO-LYMPHOCYTE RATIO IN BEHÇET UVEITIS.

To investigate the significance of systemic indicators, including neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR), as long-term visual prognostic factors in patients with Behçet uveitis. This study comprised 114 eyes from 114 patients diagnosed with Behçet uveitis. Ophthalmologic evaluations and biochemical measurements including NLR and PLR values were consecutively obtained at each visit. Patients were divided into good and poor visual outcome groups, based on the visual acuity of 0.5 logarithm of the minimum angle of resolution in the worse-seeing eyes at the last visit. Factors associated with poor visual outcomes were analyzed, and optimal cutoff values of NLR and PLR were also evaluated. Sixty-six eyes (57.9%) were included in the good visual outcome group. Multivariate regression analysis showed that younger age of onset (odds ratio = 0.939; P = 0.010), longer disease duration (odds ratio = 1.164; P < 0.001), higher maximum NLR (odds ratio = 1.215; P = 0.033), and higher initial PLR (odds ratio = 1.014; P = 0.039) were significantly associated with poor visual outcomes. The optimal cutoff value for patients with poor visual outcome was 5.608 for NLR and 128.078 for PLR. A higher maximum NLR and higher initial PLR, as well as a younger age of onset and longer disease duration, were significantly associated with poor visual outcomes. Systemic inflammatory factors might be important indicators of visual prognosis in Behçet uveitis.

Scenery of multilocus inherited neoplasia alleles syndrome (MINAS) in a single Brazilian institution.

10598 Background: Genetic testing of hereditary cancer using comprehensive gene panels can identify patients with more than one pathogenic mutation in high and/or moderate-risk-associated cancer genes. This phenomenon is known as multilocus inherited neoplasia alleles syndrome (MINAS), which has been potentially linked to more severe clinical manifestations.To determine the prevalence and clinical features of MINAS in a large cohort of adult patients with hereditary cancer homogeneously tested with the same gene panel. Methods: A cohort of 1,234 unrelated patients with suspicion of hereditary cancer was screened using a validated NGS panel including 20 genes associated with hereditary cancer. Results: One hundred and forty two (8.7%) patients harbouring probably pathogenic or pathogenic mutatations and 9 harbouring two pathogenic mutations in dominant cancer-predisposing genes were identified, representing 6.3% (9/142) of patients with pathogenic mutations. All (9/9) of these cases presented clinical manifestations associated with only one of the mutations identified. One case showed mutations in MEN1 and MLH1 and developed tumours associated with both cancer syndromes. Interestingly, three of the double mutants had a young age of onset or severe breast cancer phenotype and carried mutations in moderate to low-risk DNA damage repair-associated genes; two of them presented biallelic inactivation of CHEK2. We included these two patients for the sake of their clinical interest although we are aware that they do not exactly fulfil the definition of MINAS since both mutations are in the same gene. Conclusions: Genetic analysis of a broad cancer gene panel identified the largest series of patients with MINAS described in a single study. Overall, our data do not support the existence of more severe manifestations in double mutants at the time of diagnosis although they do confirm previous evidence of severe phenotype in biallelic CHEK2 and other DNA repair cancer-predisposing genes.

P.074 An assessment of next-generation panel testing in epilepsy

Background: With the now routine use of next-generation sequencing it is important to know the baseline outcomes as they relate to clinical care for pediatric epilepsy in Ontario. We sought to assess the diagnostic yield of genetic epilepsy panel testing and characterize the impact on patient care. Methods: We conducted a retrospective chart review of patients with epilepsy seen at CHEO between 2012-2020 with genetic testing. 227 patients met our inclusion criteria. Patient charts were reviewed for clinical details, co-morbidities, genetic testing results, and changes to management. Results: Diagnostic yield was 19% for multi-gene epilepsy panel testing. A further 10% received a diagnosis from additional genetic testing. The diagnostic yield was significantly higher in patients with a younger age of onset of seizures. A direct change in clinical management as a result of the molecular diagnosis was evident for 9% of patients; however, all diagnoses impacted prognosis and family counselling. Conclusions: The diagnostic yield of genetic epilepsy panel testing conducted at CHEO is comparable to other reported rates. Genetic testing resulted in clinical benefits of recurrence risk counselling, prognostic information and though a direct change in management was advised in a minority of individuals, targeted treatment recommendations will continue to increase with ongoing testing.

1139-P: The Association between Age of Onset of Type 2 Diabetes and the Long-Term Risk for Major Diabetes-Related Complications

We evaluated the association between age of onset of type 2 diabetes and the risk for major diabetes complications. We included 1.1 million people with type 2 diabetes from the Australian diabetes registry, followed from 2010-2019. We evaluated the incidence of hospitalization for, or death from, myocardial infarction (MI) , stroke, and heart failure (HF) , and hospitalization for lower extremity amputation (LEA) ; the incidence of end-stage kidney disease (ESKD; including kidney replacement therapy or death from ESKD) ; and all-cause mortality (ACM) . Poisson regression was used to model rates by age of diabetes onset, current age, and diabetes duration. During 6.9 million person-years of follow-up, 72338, 46533, 101023, 20024, 13331, and 203542 MI, stroke, HF, LEA, ESKD, and ACM events occurred, respectively. The risk for all outcomes increased exponentially with diabetes duration (Figure) . The effects of age and duration differed for each: age was the stronger risk factor for MI, stroke, HF, and ACM, while duration was the predominant determinant of ESKD and LEA risk. At a given age, a 10-year younger age of onset was associated with a 1.1-1.5-fold increased risk of stroke and ACM, a 1.5-2-fold increased risk of MI and HF, and a 2-4-fold increased risk of LEA and ESKD. Thus, the increase in prevalence of young-onset type 2 diabetes may shift the burden of diabetes complications in coming decades. Disclosure J.I.Morton: None. P.Lazzarini: None. K.Polkinghorne: None. D.J.Magliano: None. J.E.Shaw: Advisory Panel; Abbott Diagnostics, AstraZeneca, Eli Lilly and Company, Pfizer Inc., Roche Diagnostics, Research Support; AstraZeneca, Boehringer Ingelheim International GmbH, Speaker's Bureau; AstraZeneca, Eli Lilly and Company, Novo Nordisk, Sanofi. Funding JIM is supported by an Australian Government Research Training Program (RTP) Scholarship and Monash Graduate Excellence Scholarship. PAL is supported by a National Health and Medical Research Council Early Career Fellowship. DJM is supported by a National Health and Medical Research Council Senior Research Fellowship. JES is supported by a National Health and Medical Research Council Investigator Grant. This work is partially supported by the Victorian Government’s Operational Infrastructure Support Program.

1290-P: A Rare Case of HNF1A-MODY

Introduction: Maturity onset diabetes of the young (MODY) is a monogenic nonimmune type of diabetes mellitus. It is rare and sometimes misdiagnosed as type 1 or type 2 diabetes (T2DM) . The age of onset is usually below 25 years. It is more common in the European population. Hepatocyte nuclear factor 1-alpha (HNF1A) is one of the most common mutations and is associated with cardiovascular and renal complications.1 Genetic testing in patients with strong hereditary factors results in definitive diagnosis and subsequent appropriate treatment.2 The aim of this report is to emphasize the importance of distinguishing MODY by considering the family history of diabetes and relative clinical features. Case presentation: A 58-year-old Filipino woman was diagnosed with T2DM at age 15. Her mother, 5 of 8 siblings and her daughter all had diabetes. They all died in the 2nd or 3rd decades of their life due to diabetes complications. Her grandfather was European. She has renal insufficiency, coronary heart disease and heart failure. Treatment included glimepiride 2 mg daily and sitagliptin 25 mg daily. The physical exam was unremarkable. Body mass index (BMI) was 21. GAD 65 antibody and Islet cell antibody were negative, C peptide: 3.6 ng/mL, blood sugar: 1mg/dL, HbA1c: 7.3%, creatinine: 2.15 mg/dL and GFR: 25 mL/min/1.73m2. A diagnosis of MODY was considered due to strong family history of diabetes, young age at the onset of diabetes and normal BMI. DNA sequencing demonstrated positive HNF1A mutation compatible with HNF1A-MODY. Due to post prandial hyperglycemia, glimepiride was replaced with pre-meal lispro. Conclusion: This is a rare case of HNF1A-MODY found in a Filipino patient. MODY should be included in the differential diagnosis of diabetic patients with an extensive family history of diabetes, young age of onset of diabetes and negative pancreatic antibodies. Early diagnosis with genetic profiling can guide therapy and hopefully decrease the vascular complications of long-term poor glycemic control. Disclosure S.Velayati: None. M.Shanik: Consultant; Bigfoot Biomedical, Inc., Proteomics International, Research Support; Better Therapeutics, Speaker's Bureau; Abbott, Boehringer Ingelheim International GmbH, Novo Nordisk, Xeris Pharmaceuticals, Inc. I.J.Romao: None.

Factors Associated with Development of Ventral Hernias and Healthcare Seeking Behaviors in a Cohort of Pakistani Women

Background: Anterior abdominal wall hernias constitute one of the most common surgical presentations. According to the World Bank data Pakistan has one of the highest birth rates per woman in the region at 3.6 births per woman. In Pakistan there has also been a large increase in C-section rates with nearly 20% of all pregnancies being delivered via C-section, nearly 1 out of every 5 births. Multi-parity is a risk factor for developing paraumbilical hernias and C-sections lead to incisional hernia developments. Methodology: The study conducted was a cross-sectional study at a tertiary care hospital in the department of surgery from 1st June 2021 till 1st September 2021. Any woman presenting with a ventral hernia to the clinic was asked to fill out a questionnaire. 60 women presented over the study period and were enrolled. Results: Fifty five percent paraumbilical hernias and 41.7% incisional hernias were reported. The mean number of pregnancies was 4.10 S.D 1.531 with a range from 0-8. C-sections were 2 times more common than SVDs. Increasing number of pregnancies associated with younger age of onset. Higher number of vaginal deliveries and C-sections were each associated with the development of a ventral hernia. Conclusion: The high fertility rate and C-section rate in Pakistan incurs a huge risk to women developing ventral hernias and poses a burden to the public healthcare system. Keywords: Paraumbilical hernia; parity; Pakistan

Genetic testing enables a precision medicine approach for nephrolithiasis and nephrocalcinosis in pediatrics: a single-center cohort

ObjectiveHereditary factors are the main cause of pediatric nephrolithiasis (NL)/nephrocalcinosis (NC). We summarized the genotype–phenotype correlation of hereditary NL/NC in our center, to evaluate the role of genetic testing in early diagnosis.MethodsThe clinical data of 32 NL/NC cases, which were suspected to have an inherited basis, were retrospectively analyzed from May 2017 to August 2020. The trio-whole exome sequencing was used as the main approach for genetic testing, variants were confirmed by Sanger sequencing, and pathogenicity analysis according to protein function was predicted with custom-developed software.ResultsCausative monogenic mutations were detected in 24 of 32 NL/NC patients, and copy number variation was detected in one patient. A summary of manifestations in patients with inherited diseases revealed a significant degree of growth retardation, increased urinary excretion of the low-molecular weight protein, hypercalciuria, electrolyte imbalances, and young age of onset to be common in heredity disease. In addition, some patients had abnormal renal function (3 ppm 25). The most frequent pathology identified was distal renal tubular acidosis (with inclusion of SLC4A1, ATP6V1B1, and ATP6VOA4 genes), followed by Dent disease (CLCN5 and OCRL1 genes), primary hyperoxaluria (PH) (AGXT and HOGA1 genes) and Kabuki syndrome (KMT2D gene), which was more likely to present as NC or recurrent stone and having a higher correlation with a specific biochemical phenotype and extrarenal phenotype.ConclusionThe etiology of NL/NC is heterogeneous. This study explored in depth the relationship between phenotype and genotype in 32 patients, and confirmed that genetic testing and clinical phenotype evaluation enable the precision medicine approach to treating patients.

The Benefit of Multigene Panel Testing for the Diagnosis and Management of the Genetic Epilepsies.

With the increasing use of genetic testing in pediatric epilepsy, it is important to describe the diagnostic outcomes as they relate to clinical care. The goal of this study was to assess the diagnostic yield and impact on patient care of genetic epilepsy panel testing. We conducted a retrospective chart review of patients at the Children’s Hospital of Eastern Ontario (CHEO) who had genetic testing between the years of 2013–2020. We identified 227 patients that met criteria for inclusion. The majority of patients had their testing performed as “out-of-province” tests since province-based testing during this period was limited. The diagnostic yield for multi-gene epilepsy panel testing was 17% (39/227) and consistent with the literature. Variants of unknown significance (VUS) were reported in a significant number of undiagnosed individuals (77%; 128/163). A higher diagnostic rate was observed in patients with a younger age of onset of seizures (before one year of age; 32%; 29/90). A genetic diagnosis informed prognosis, recurrence risk counselling and expedited access to resources in all those with a diagnosis. A direct change in clinical management as a result of the molecular diagnosis was evident for 9% (20/227) of patients. The information gathered in this study provides evidence of the clinical benefits of genetic testing in epilepsy and serves as a benchmark for comparison with the current provincial Ontario Epilepsy Genetic Testing Program (OEGTP) that began in 2020.

Pediatric Moyamoya Disease and Syndrome in Italy: A Multicenter Cohort.

BackgroundMoyamoya is a rare progressive cerebral arteriopathy, occurring as an isolated phenomenon (moyamoya disease, MMD) or associated with other conditions (moyamoya syndrome, MMS), responsible for 6–10% of all childhood strokes and transient ischemic attacks (TIAs).MethodsWe conducted a retrospective multicenter study on pediatric-onset MMD/MMS in Italy in order to characterize disease presentation, course, management, neuroradiology, and outcome in a European country.ResultsA total of 65 patients (34/65 women) with MMD (27/65) or MMS (38/65) were included. About 18% (12/65) of patients were asymptomatic and diagnosed incidentally during investigations performed for an underlying condition (incMMS), whereas 82% (53/65) of patients with MMD or MMS were diagnosed due to the presence of neurological symptoms (symptMMD/MMS). Of these latter, before diagnosis, 66% (43/65) of patients suffered from cerebrovascular events with or without other manifestations (ischemic stroke 42%, 27/65; TIA 32%, 21/65; and no hemorrhagic strokes), 18% (12/65) of them reported headache (in 4/12 headache was not associated with any other manifestation), and 26% (17/65) of them experienced multiple phenotypes (≥2 among: stroke/TIA/seizures/headache/others). Neuroradiology disclosed ≥1 ischemic lesion in 67% (39/58) of patients and posterior circulation involvement in 51% (30/58) of them. About 73% (47/64) of patients underwent surgery, and 69% (45/65) of them received aspirin, but after diagnosis, further stroke events occurred in 20% (12/61) of them, including operated patients (11%, 5/47). Between symptom onset and last follow-up, the overall patient/year incidence of stroke was 10.26% (IC 95% 7.58–13.88%). At last follow-up (median 4 years after diagnosis, range 0.5–15), 43% (26/61) of patients had motor deficits, 31% (19/61) of them had intellectual disability, 13% (8/61) of them had epilepsy, 11% (7/61) of them had behavioral problems, and 25% (13/52) of them had mRS > 2. The proportion of final mRS > 2 was significantly higher in patients with symptMMD/MMS than in patients with incMMS (p = 0.021). Onset age <4 years and stroke before diagnosis were significantly associated with increased risk of intellectual disability (p = 0.0010 and p = 0.0071, respectively) and mRS > 2 at follow-up (p = 0.0106 and p = 0.0009, respectively).ConclusionsMoyamoya is a severe condition that may affect young children and frequently cause cerebrovascular events throughout the disease course, but may also manifest with multiple and non-cerebrovascular clinical phenotypes including headache (isolated or associated with other manifestations), seizures, and movement disorder. Younger onset age and stroke before diagnosis may associate with increased risk of worse outcome (final mRS > 2).

Age of onset of social anxiety disorder and psychiatric and mental health outcomes: Results from a nationally representative study

ObjectivePrior studies support that younger age of onset would be associated with poorer psychiatric and mental health outcomes for many psychiatric disorders. However, such relationship has never been examined for social anxiety disorder (SAD) in a nationally representative sample. MethodsUsing data from the second Wave of the National Epidemiologic Survey on Alcohol and Related Conditions (NESARC), we have identified four groups of participants with a lifetime DSM-IV diagnosis of SAD based on the self-reported age of onset (childhood onset (<12 years, N = 658), adolescence onset (12–17 years, N = 663), early-adulthood onset (18–39 years, N = 663), and late-adulthood onset (>39 years, N = 415)), and a control group without a lifetime history of SAD (N = 32,205). We performed multinomial logistic regression models to compare lifetime DSM-IV psychiatric disorders and current mental health-related quality of life (assessed with the mental component summary score (MSC) of the SF-12) across these groups. ResultsThe lifetime prevalence rates of panic disorder, agoraphobia and post-traumatic stress disorder were significantly higher in the adulthood onset groups than in groups with an onset during childhood or adolescence (p < 0.01 for most models). MCS score was significantly higher in the childhood (46.0 (SE = 0.5)) or adolescence (46.5 (SE = 0.5)) onset groups than in the groups with an onset during adulthood (early-adulthood onset: 43.5 (SE = 0.6), and late-adulthood onset: 43.0 (SE = 0.8)). LimitationsOur results relied on retrospective self-reported data. ConclusionAmong individuals with SAD, a later age of onset was significantly associated with greater lifetime rates of psychiatric disorders and diminished quality of life.

Detailed risks and characteristics of postepilepsy stroke in non-traumatic adult-onset epilepsy

Patients with epilepsy have an increased risk of stroke. However, the detailed risk and characteristics of postepilepsy stroke have not been investigated. This study utilized the National Health Insurance Research Database in Taiwan. We classified adult patients with newly diagnosed epilepsy from 2003 to 2016 as the epilepsy cohort. Patients in the nonepilepsy cohort were selected with propensity score matching at a case-control ratio of 1:5. The incidence, hazard ratio (HR), period-specific HR, recurrent HR in the Wei-Lin-Weissfeld model, stroke severity index, complications, and mortality of all stroke, ischemic stroke (IS) and hemorrhagic stroke events in the two cohorts were analyzed. We enrolled 23,810 patients in the epilepsy cohort and 119,050 persons in the nonepilepsy cohort. The period-specific HRs of all stroke, IS and hemorrhagic stroke peaked immediately after epilepsy diagnosis and trended downward [Adjusted HRs of all stroke: 4.88 (3.88-6.14), 4.47 (3.50-5.70), 3.17 (2.62-3.84), 2.81 (2.27-3.48), 2.81 (2.36-3.34) and 2.33 (2.07-2.62) in 0-0.5, 0.5-1, 1-2, 2-3, 3-5 and ≥5 years after epilepsy diagnosis, respectively]. The recurrent stroke HRs in the epilepsy cohort were >1 from the first [3.06 (2.71-3.34)] to the fourth events [6.33 (1.08-37.03)]. IS events in the epilepsy cohort were associated with a younger onset age, a higher IS severity index, a higher rate of urinary tract infection, a lower in-hospital mortality, while 90-day stroke mortality was similar between the 2 cohorts. Since the increased risk of stroke in epilepsy cohort peaked immediately after epilepsy diagnosis, early implementation of prevention strategies is considered.

Risk factors for motor complications in female patients with Parkinson's disease.

To investigate the risk factors of motor complications in female patients with Parkinson's disease (PD) and the correlation between the occurrence of motor complications and sex hormone levels. According to the occurrence and types of motor complications, 103 female PD patients were divided into two groups: patients with or without the wearing-off phenomenon, patients with or without dyskinesia. Binary logistic regression analysis was performed respectively to screen for the risk factors of the wearing-off phenomenon and dyskinesia in female PD patients. Among 103 female PD patients, 44 (42.72%) had motor complications. Patients with the wearing-off phenomenon and patients with dyskinesia had higher prolactin levels than patients without the wearing-off phenomenon and patients without dyskinesia, respectively. However, the difference was no longer significant when the two groups were corrected for multiple comparisons (P < 0.0028). Multivariate analysis found that younger age at onset and higher Hoehn-Yahr (H&Y) stage were identified as independent risk factors for the wearing-off phenomenon and younger age of onset was an independent risk factor for dyskinesia in female PD patients (P < 0.05). Female PD patients have a higher incidence of motor complications. Younger age of onset and higher H&Y stage were the risk factors of the wearing-off phenomenon, and younger onset age was the risk factor of dyskinesia in female PD patients. There may be a certain correlation between the occurrence of motor complications and sex hormone levels in female PD patients, which requires further verification.

Clinical and Genetic Analysis in Neurological Wilson's Disease Patients With Neurological Worsening Following Chelator Therapy.

Objectives: None of the previous studies have focused on the genetic effect on neurological worsening in neurological Wilson’s disease (WD) patients following chelator therapy. We aimed to evaluate the clinical and genetic role in the occurrence of neurological worsening. Methods: We retrospectively reviewed the medical records of neurological WD patients who received initial chelator therapy and genetic test. Clinical, laboratory, and genetic data were collected. The genotype was classified into two types: 1) severe mutation genotype: patients who carried at least one of the following three types of mutations: frameshift mutation, splicing mutation, or nonsense mutation; 2) non-severe mutation genotype: patients who only carried missense mutations. Then, the clinical features and genotype of the patients with and without neurological worsening were investigated. Results: Forty-seven neurological WD patients were identified with a median age at onset of 16.17 years (range 7.75–47 years) and 35 (74.5%) males. The mean interval from onset to diagnosis was 0.6 years (range: 0.5 months-6.25 years). Neurological deterioration was observed in 29 patients (61.7%) and the other 18 patients (38.3%) were stable or improved during anti-copper treatment. The neurological worsening was completely irreversible in 6 cases (20.7%) and partially irreversible in 16 cases (55.2%). The common deteriorated symptoms were as follows: rigidity in 20 cases (69%), speech difficulties in 20 cases (69%)), walking difficulties in 13 cases (44.8%), dysphagia in 9 cases (31%), and salivation in 9 cases (31%). The patients with neurological worsening had significantly younger age (p = 0.028), shorter delayed diagnosis time (p = 0.011), higher rate of dystonia (p = 0.003), and severe mutation genotype (p = 0.036), compared to those without neurological worsening. Conclusion: We found that younger age of onset, the presence of dystonia, and genotype with severe mutations may be predictive of neurological worsening in the neurological WD patients that received chelator therapy. For those patients, chelator therapy should be given with caution and needs closer observation during follow-up.