Classification Guidelines Research Articles

PanIN or IPMN? Redefining Lesion Size in 3 Dimensions.

Pancreatic ductal adenocarcinoma (PDAC) develops from 2 known precursor lesions: a majority (∼85%) develops from pancreatic intraepithelial neoplasia (PanIN), and a minority develops from intraductal papillary mucinous neoplasms (IPMNs). Clinical classification of PanIN and IPMN relies on a combination of low-resolution, 3-dimensional (D) imaging (computed tomography, CT), and high-resolution, 2D imaging (histology). The definitions of PanIN and IPMN currently rely heavily on size. IPMNs are defined as macroscopic: generally >1.0cm and visible in CT, and PanINs are defined as microscopic: generally <0.5cm and not identifiable in CT. As 2D evaluation fails to take into account 3D structures, we hypothesized that this classification would fail in evaluation of high-resolution, 3D images. To characterize the size and prevalence of PanINs in 3D, 47 thick slabs of pancreas were harvested from grossly normal areas of pancreatic resections, excluding samples from individuals with a diagnosis of an IPMN. All patients but one underwent preoperative CT scans. Through construction of cellular resolution 3D maps, we identified >1400 ductal precursor lesions that met the 2D histologic size criteria of PanINs. We show that, when 3D space is considered, 25 of these lesions can be digitally sectioned to meet the 2D histologic size criterion of IPMN. Re-evaluation of the preoperative CT images of individuals found to possess these large precursor lesions showed that nearly half are visible on imaging. These findings demonstrate that the clinical classification of PanIN and IPMN fails in evaluation of high-resolution, 3D images, emphasizing the need for re-evaluation of classification guidelines that place significant weight on 2D assessment of 3D structures.

WilsonGenAI a deep learning approach to classify pathogenic variants in Wilson Disease.

Advances in Next Generation Sequencing have made rapid variant discovery and detection widely accessible. To facilitate a better understanding of the nature of these variants, American College of Medical Genetics and Genomics and the Association of Molecular Pathologists (ACMG-AMP) have issued a set of guidelines for variant classification. However, given the vast number of variants associated with any disorder, it is impossible to manually apply these guidelines to all known variants. Machine learning methodologies offer a rapid way to classify large numbers of variants, as well as variants of uncertain significance as either pathogenic or benign. Here we classify ATP7B genetic variants by employing ML and AI algorithms trained on our well-annotated WilsonGen dataset. We have trained and validated two algorithms: TabNet and XGBoost on a high-confidence dataset of manually annotated, ACMG & AMP classified variants of the ATP7B gene associated with Wilson's Disease. Using an independent validation dataset of ACMG & AMP classified variants, as well as a patient set of functionally validated variants, we showed how both algorithms perform and can be used to classify large numbers of variants in clinical as well as research settings. We have created a ready to deploy tool, that can classify variants linked with Wilson's disease as pathogenic or benign, which can be utilized by both clinicians and researchers to better understand the disease through the nature of genetic variants associated with it.

P21 Advancing dermatological care: a comprehensive evaluation of the steroid-free GL-1 formulation

Abstract Introduction and aims The prolonged use of topical steroids introduces notable dermatological risks, including the onset of permanent stretch marks, bruising, discoloration and vascular abnormalities. This study presents an innovative strategy by formulating GL-1, a steroid-free treatment amalgamating seaweed bioactives, sesame oil and naturally occurring salts and minerals. The objective of this study was to address the limitations of conventional topical steroids and introduce pioneering solutions to dermatological care. Methods To assess the safety and efficacy of GL-1 (product 1), a comprehensive battery of in vitro tests was employed. The skin corrosion test (OECD 431) established the noncorrosive nature of GL-1, validating its safety on reconstructed human epidermis. The skin irritation test (OECD 439) demonstrated the nonirritating attributes of GL-1, aligning with the United Nations Globally Harmonized System of Classification and Labelling guidelines. Additionally, the bovine corneal opacity and permeability test (OECD 437) affirmed the noninducing nature of GL-1 in relation to eye irritation or serious eye damage. Results Preliminary outcomes from dermal clinical trials indicate promising Results for GL-1. In vitro experiments on HaCaT and human dermal fibroblasts, adult (HDFa) cell lines highlighted the noncytotoxicity of GL-1, contrasting with the ‘Cortopin’, which exhibited cytotoxicity. GL-1 exhibited a proliferative effect in HDFa cells, signifying its potential for regenerative applications. Furthermore, both GL-1 and ‘Cortopin’ displayed antioxidant activity in HaCaT cells, underscoring the additional merits of our formulation. Conclusions Our steroid-free formulation, GL-1, demonstrates exceptional safety and efficacy through a meticulous series of in vitro assessments and initial clinical trials. These findings position GL-1 as a promising candidate for diverse dermal applications, offering a secure alternative to traditional topical steroids. The potential impact of GL-1 transcends its therapeutic efficacy, emphasizing its robust safety profile validated through multiple in vitro evaluations.

Pursuing Clinical Predictors and Biomarkers for Progression in ILD: Analysis of the Pulmonary Fibrosis Foundation (PFF) Registry

IntroductionPulmonary fibrosis is a characteristic of various interstitial lung diseases (ILDs) with differing etiologies. Clinical trials in progressive pulmonary fibrosis (PPF) enroll patients based on previously described clinical criteria for past progression, which include a clinical practice guideline for PPF classification and inclusion criteria from the INBUILD trial. In this study, we compared the ability of past FVC (forced vital capacity) progression and baseline biomarker levels to predict future progression in a cohort of patients from the PFF Patient Registry.MethodsBiomarkers previously associated with pathobiology and/or progression in pulmonary fibrosis were selected to reflect cellular senescence (telomere length), pulmonary epithelium (SP-D, RAGE), myeloid activation (CXCL13, YKL40, CCL18, OPN) and fibroblast activation (POSTN, COMP, PROC3).ResultsPFF or INBUILD-like clinical criteria was used to separate patients into past progressor and non-past progressor groups, and neither clinical criterion appeared to enrich for patients with greater future lung function decline. All baseline biomarkers measured were differentially expressed in patient groups compared to healthy controls. Baseline levels of SP-D and POSTN showed the highest correlations with FVC slope over one year, though correlations were low.ConclusionsOur findings provide further evidence that prior decline in lung function may not predict future disease progression for ILD patients, and elevate the need for molecular definitions of a progressive phenotype. Across ILD subtypes, certain shared pathobiologies may be present based on the molecular profile of certain biomarker groups observed. In particular, SP-D may be a common marker of pulmonary injury and future lung function decline across ILDs.

Assessing classification system for landslide susceptibility using frequency ratio, analytical hierarchical process and geospatial technology mapping in Aizawl district, NE India

Landslides are a severe geological hazard in northeastern India, particularly in Mizoram’s Aizawl district. To assess this hazard, we conducted a landslide susceptibility mapping study using the frequency ratio (FR) and analytical hierarchy process (AHP) methods. Twelve factors, including slope, elevation, aspect, curvature, topographic wetness index, topographic ruggedness index, rainfall erosivity factor, geology, land use land cover, normalized difference vegetation index (NDVI), and distance to road, were considered. The final susceptibility maps were created by combining these factors, each weighted according to its importance. Since no standard classification guidelines existed, we compared different systems like GIS-based geometric interval (GIC), natural breaks (NBC), and quantile interval (QIC) with mean-standard deviation (MSC). The area was divided into five susceptibility zones: very high, high, moderate, low, and very low. We evaluated the accuracy of these systems using success rate curve (SRC) and quality sum ratio (Qs) techniques. SRC results showed similar performance for GIC, NBC, QIC, and MSC classifications. The AHP method also yielded comparable results. After analyzing the AUC under SRC and Qs, we selected the MSC classification system as the optimal approach for landslide susceptibility mapping. Notably, the distance to roads factor had the highest predictive value, highlighting its importance in identifying slope instability for effective management strategies. As landslides pose significant risks in northeastern India, and our study using FR and AHP methods, along with MSC classification, provides valuable insights for mitigating this geological hazard.

The detours of pancreatic ducts, internal pancreatic fistulas: a rare complication of chronic pancreatitis

Internal pancreatic fistula occurs due to the disruption of the pancreatic duct, resulting in communication with it and another epithelial surface. A rare variant is the pancreaticopleural and pancreaticogastric fistula, typically associated with chronic necrotising pancreatitis, resulting from posterior disruption of the pancreatic duct. It is a complex disease with different aetiologies, varied clinical presentations and multiple management options. Unlike postoperative pancreatic fistula, internal pancreatic fistula lacks guidelines for classification and management. Once an internal fistula is suspected, further imaging work-up and biochemical analysis needs to be performed. Here, we present an unprecedented case of pancreaticopleural fistula on a background of chronic necrotising pancreatitis, and an asymptomatic pancreatico-gastric fistula. To our knowledge, no such case has been previously reported.

Domains, competences and learning outcomes for undergraduate education in periodontology.

This review is intended to adapt the current conceptual framework in dental education based on four domains to propose a set of competences, learning outcomes and methods of teaching, learning and assessment for undergraduate education in periodontology. Based on the current framework of competences and learning outcomes recommended by the Association for Dental Education in Europe (ADEE), undergraduate education in periodontology has been updated using the classification and clinical practice guidelines for the diagnosis and treatment of periodontal and peri-implant diseases. Specific learning outcomes have been proposed within each competence area, that is in Domain I (n = 10), Domain II (n = 13), Domain III (n = 33) and Domain IV (n = 12). Teaching methods and learning activities based on the different dimensions of the cognitive process have been proposed. Additionally, 10 key learning outcomes have been proposed as exit outcomes, which implies their accomplishment within the final assessment of any graduating student.

P033 Online educational resources in paediatric and adolescent rheumatology- what’s new?

Abstract Background/Aims Paediatric and adolescent rheumatology (PAR) is a small sub-specialty, and due to the rarity of some conditions, UK trainees find it difficult to access relevant educational materials. Furthermore, due to the wide geographical distribution of paediatric rheumatology centres, regional educational opportunities are limited. A 2022 survey of the UK PAR trainee group confirmed that the creation of more PAR specific online educational materials and signposting of current guidelines/ resources was needed. Survey participants were supportive of a range of delivery methods, including webinars, e-learning, case studies and podcasts. Methods A PAR trainee education team was formed in 2022, with the aim of promoting learning opportunities, by developing and collating educational resources. The PAR trainee education team has been working both independently and in conjunction with the British Society of Rheumatology (BSR) education team and Digital Learning Board (DLB) to achieve this aim. Activities have included the following: a) Creation of a BSR hosted Teams channel to store PAR specific educational information; b) PAR trainee inclusion on the BSR DLB, which creates digital education resources including podcasts and the monthly blended learning Spotlight topic series; c) Creation of PAR focused podcasts within the BSR Talking Rheumatology podcast series; d) Organisation of webinars on PAR relevant topics; e) Creation of a PAR podcast playlist on the Spotify platform; f) Production of a resource list and education newsletter to signpost relevant existing/upcoming learning opportunities and events. Results A 2023 follow up survey of the PAR trainee group (n = 16 respondents), showed the most used resources were podcasts (69%), the newsletter (63%) and resource list (43%). Webinars (38%), the Teams channel (38%) and the BSR Spotlight series (31%) had been accessed less. BSR podcast download data illustrated that PAR relevant podcasts from the Talking Rheumatology/ Talking Rheumatology Spotlight series have a UK and international audience. There have been over 2500 downloads from six PAR relevant podcasts covering myositis guidelines, biologics in PAR, HLH, antiphospholipid syndrome and ultrasound in PAR. Feedback from those who have used the various educational resources has been extremely positive, although comments have indicated a barrier in terms of awareness of the materials and how to access them. Conclusion Good progress has been made, however maximising means and opportunities to disseminate available resources within the PAR community is vital. Work to develop, collate and signpost more PAR educational content is ongoing. A project is in progress to create condition-specific lists of classification criteria, guidelines and key studies. The PAR trainee group are very grateful to all of those who have supported this work including the professionals who have shared their knowledge and expertise via podcasts and webinars, members of the BSR DLB and the education team at BSR. Disclosure J. Lemon: Other; Unpaid member of the BSR Digital Learning Board. R. Close: None. G. Dobson: None. K. Maxey: Other; Works for the BSR as Events and Education Officer. J. May: None. D. McLaughlin: None. I. Rajarathinam: None. S. Saadalla: None. L. Yeo: None. P.A. Watson: Other; Works for the BSR in a paid role (2PA per week ) as digital learning editor.

Osteonecrosis of the femoral and Humoral heads in sickle disease patients: Risk factor, Comorbiditis

ObjectivesAVN is the most common in Sickle Cell Disease patients, as SCD is common in the Jazan region of Saudi Arabia. The risk factors, and comorbidity regarding AVN of hip and shoulder joints in SCD patients were investigated in this study. MethodsThis retrospective cohort study was conducted at the two biggest hospitals in the Jazan region. A valid data collection sheet was used to collect information of SCD patients admitted to the wards or during follow-up. Staging for HAVN and SAVN was based on FICAT classification guidelines. Descriptive statistics and multivariate logistic regression were utilized. Resultstotal number of participants is 257, and 99 (38.5%) were under 14 years of age. About half of the participants are (134) females. Regarding participants' hemoglobin type, 78.6% had SCD, while 21.4% had sickle thalassemia. The occurrence of HAVN and SAVN is 14.8% and 5.4%, respectively. Of the 38 HAVN participants, 26.3% had comorbidities, and 5.3% had hypertension. The SAVN participants didn't report diabetes or hypertension. The vascular occlusive crisis is the most significant complication associated with SCD. Multivariate logistic regression determined some risk factors for SAVN and HAVN. ConclusionAVN is a frequent consequence of SCD, where the incidence rises with age. The vascular necrosis is the most significant complications. Continuing research on the prevention and non-surgical treatments of AVN caused by SCD must remain a top focus.

Clinical Relevance of Plasma Lactic Acid in the Onset and Prognosis of Sudden Deafness.

Sudden deafness poses a significant threat to patients' quality of life, yet effective indicators for evaluating its onset and prognosis remain elusive. The inner ear is primarily supplied by the labyrinthine artery, which lacks collateral circulation. Changes in coagulation function and hemorheology can cause spasm or thrombosis of the labyrinthine artery, leading to ischemia, hypoxia, and microcirculation disorders in the inner ear, ultimately resulting in sudden deafness. This retrospective study examined 196 patients with sudden deafness, utilizing the 2015 Chinese guideline for diagnosis and treatment classification. Coagulation system analysis used the STA-R Evolution automatic coagulation analyzer, measuring activated partial thromboplastin time (APTT), prothrombin time (PT), and fibrinogen (FIB). Plasma lactate concentration was determined using a Johnson and Johnson Fusion 5.1 model plasma lactate detector. Results of the study revealed a correlation between the degree of hearing loss and disease prognosis. Patients with higher grade hearing loss exhibited elevated plasma lactate levels upon admission compared with those with lower grade hearing loss. Importantly, elevated plasma lactate levels at admission served as predictive indicators for treatment outcomes. In addition, patients with ineffective treatment demonstrated a more coagulable blood state, as evidenced by the lower APTT (ineffective treatment: 31.47 ± 4.55 seconds, effective treatment: 35.17 ± 5.38 seconds) and PT on admission, but higher plasma FIB. In conclusion, plasma lactate levels upon admission hold promise as prognostic markers for sudden deafness treatment outcomes, providing valuable insights for clinical management.

Significant but partial lipoprotein lipase functional loss caused by a novel occurrence of rare LPL biallelic variants

BackgroundLipoprotein lipase (LPL) plays a crucial role in triglyceride hydrolysis. Rare biallelic variants in the LPL gene leading to complete or near-complete loss of function cause autosomal recessive familial chylomicronemia syndrome. However, rare biallelic LPL variants resulting in significant but partial loss of function are rarely documented. This study reports a novel occurrence of such rare biallelic LPL variants in a Chinese patient with hypertriglyceridemia-induced acute pancreatitis (HTG-AP) during pregnancy and provides an in-depth functional characterization.MethodsThe complete coding sequences and adjacent intronic regions of the LPL, APOC2, APOA5, LMF1, and GPIHBP1 genes were analyzed by Sanger sequencing. The aim was to identify rare variants, including nonsense, frameshift, missense, small in-frame deletions or insertions, and canonical splice site mutations. The functional impact of identified LPL missense variants on protein expression, secretion, and activity was assessed in HEK293T cells through single and co-transfection experiments, with and without heparin treatment.ResultsTwo rare LPL missense variants were identified in the patient: the previously reported c.809G > A (p.Arg270His) and a novel c.331G > C (p.Val111Leu). Genetic testing confirmed these variants were inherited biallelically. Functional analysis showed that the p.Arg270His variant resulted in a near-complete loss of LPL function due to effects on protein synthesis/stability, secretion, and enzymatic activity. In contrast, the p.Val111Leu variant retained approximately 32.3% of wild-type activity, without impacting protein synthesis, stability, or secretion. Co-transfection experiments indicated a combined activity level of 20.7%, suggesting no dominant negative interaction between the variants. The patient’s post-heparin plasma LPL activity was about 35% of control levels.ConclusionsThis study presents a novel case of partial but significant loss-of-function biallelic LPL variants in a patient with HTG-AP during pregnancy. Our findings enhance the understanding of the nuanced relationship between LPL genotypes and clinical phenotypes, highlighting the importance of residual LPL function in disease manifestation and severity. Additionally, our study underscores the challenges in classifying partial loss-of-function variants in classical Mendelian disease genes according to the American College of Medical Genetics and Genomics (ACMG)’s variant classification guidelines.

Insufficiency of Laboratory Data in Reflecting Allergic Rhinitis Severity Based on the Allergic Rhinitis and Its Impact on Asthma Guideline in Korean Patients

Background and Objectives: This retrospective study, conducted at a single tertiary medical center, aimed to investigate the correlation between the severity of allergic rhinitis (AR) based on subjective symptoms and the severity assessed through laboratory data.Methods: In total, 584 patients who were diagnosed with AR by a multiple-allergen simultaneous test were included. Patients were classified into four groups according to the Allergic Rhinitis and its Impact on Asthma (ARIA) classification guideline. The visual analog scale (VAS) score for overall discomfort and laboratory parameters, including the serum total immunoglobulin E (IgE) level and peripheral blood eosinophil count, were evaluated in all patients. An analysis was conducted to examine the differences in VAS scores and laboratory findings among the four groups. Additionally, the correlations between the laboratory findings and VAS score were analyzed.Results: The serum total IgE level and the percentage and count of peripheral blood eosinophils showed no significant differences among the groups. However, the VAS score for overall discomfort exhibited notable between-group differences. The average VAS score was 6.14 (95% confidence interval 5.94–6.34) in the overall group. The mean scores of each group showed a noticeable increasing trend from the mild intermittent group to the mild persistent, moderate to severe intermittent, and moderate to severe persistent groups (p&lt;0.001), although there was no clear correlation between the increase in VAS scores and laboratory parameters.Conclusion: Neither the symptom-based ARIA guideline nor the VAS score correlated with the AR laboratory test measurements. The current laboratory data alone may not be sufficient to reflect the severity of AR based on subjective symptoms.

Analysis of the Effects of Maternal Body Mass Index and Gestational Weight Gain on Maternal and Neonatal Outcomes in Twin Pregnancy

Objective: To investigate the effects of maternal body mass index (BMI) and gestational weight gain on maternal and neonatal outcomes in twin pregnancies. Methods: Five hundred cases of twin pregnancies were divided into a low body weight group (68 cases), a normal weight group (355 cases), an overweight group (65 cases), and an obesity group (12 cases) according to the World Health Organization (WHO) Body Mass Index (BMI) classification guidelines Results: Comparison of weight gain during different pregnancies revealed that pregnant women were mainly of low weight and average weight. The higher the BMI before pregnancy, the higher the incidence of excessive weight gain during pregnancy. The incidences of gestational diabetes mellitus (GDM) and premature rupture of membranes in women with low weight gain were significantly higher than those in women with average weight gain and high weight gain (P &lt; 0.05). The incidences of gestational hypertension, preeclampsia, and anemia in women with high weight gain were significantly higher than those in women with low weight gain and average weight gain (P &lt; 0.05). The incidence of neonatal birth weight, fetal distress, and macrosomia in the high weight gain group was significantly higher than those in the low weight gain and average weight gain groups (P &lt; 0.05). The birth weight of newborns in low-weight gain mothers was significantly lower than that of normal-weight gain mothers (P &lt; 0.05). Conclusion: Poor maternal and infant outcomes were common in women with insufficient or excessive weight gain during pregnancy. Therefore, for women with twin pregnancies, weight management is crucial to ensure maternal and infant health.

Abstract 7325: Integration of functional data to classify BRCA1/2 missense variants: An ENIGMA project

Abstract The success of precision cancer prevention and treatment hinges on accurate discrimination between benign and pathogenic germline alleles in cancer susceptibility genes. Variants of uncertain clinical significance (VUS) present a challenge for cancer risk assessment and functional data will be essential to resolve many VUS. To address this, we developed a cloud-based environment to collate, curate, integrate and analyze all published functional data related to BRCA1 and BRCA2 missense VUS. Then, functional evidence criteria for pathogenicity were determined for each assay using the American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) classification guidelines and ClinGen criteria. Our approach involved retrieving published articles reporting one or more functional assays of BRCA1/2 missense variants reporting variant impact on various biochemical and cell biological functions. Functional results were recorded using original authors' thresholds and categories, then converted to ordinal variables to harmonize: [0 = no functional impact], [1 = intermediate impact], and [2 = functional impact]. For BRCA1, we updated our previous published integration (Genet Med. 2021;23:306-315) with 14 additional publications, collating results from 53 instances of functional assays reporting functional data on 3,219 unique missense variants. For BRCA2, 28 publications were identified reporting data from 141 instances of functional assays on 4,759 unique missense variants. Utilizing a panel of 542 and 396 known pathogenic and benign reference variants for BRCA1 and BRCA2, respectively, we determined the sensitivity, specificity, and ACMG/AMP odds of pathogenicity for each instance of the assay. The remaining variants were assigned a relevant functional assay code weight for each assay instance. Our study successfully derived ACMG/AMP evidence strength from functional data for 3,040 BRCA1 (94% of 3,219) and 2,704 BRCA2 (57% of 4,759) missense variants. This comprehensive work underscores the utility of functional data in informing classification of BRCA1 and BRCA2 missense VUS. Citation Format: Paulo Lyra, Lucas Dalcolmo, Michael Parsons, Thales Nepomuceno, Samuel Brito, Nam Phuong N. Nguyen, Geise de Oliveira, Joao Paulo da Siva, Laura Caleca, Tanisha Taneja, Chunling Hu, Marcy Richardson, Maria Rossing, Aditi Hazra, Alexandra Martins, Sandrine Caputo, Gael A. Millot, Joanne NgeowYuen Yie, Marcelo A. Carvalho, Melissa Cline, Paolo Radice, Rachael Carlsen, Romy Mesman, Valentina Zampiga, Rehan Villani, Vijay Josef, Shyam Sharan, Kyriaki Michailidou, Amanda B. Spurdle, Fergus Couch, Maaike P.G. Vreeswijk, Alvaro N. Monteiro. Integration of functional data to classify BRCA1/2 missense variants: An ENIGMA project [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7325.

Methods of measurement for pneumothorax in pediatric patients: a systematic review.

Accurate measurement of pneumothorax (PTX) size is necessary to guide clinical decision making; however, there is no consensus as to which method should be used in pediatric patients. This systematic review seeks to identify and evaluate the methods used to measure PTX size with CXR in pediatric patients. A systematic review of the literature through 2021 following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) was conducted using the following databases: Ovid/MEDLINE, Scopus, Cochrane Database of Controlled Trials, Cochrane Database of Systematic Reviews, and Google Scholar. Original research articles that included pediatric patients (< 18years old) and outlined the PTX measurement method were included. 45 studies were identified and grouped by method (Kircher and Swartzel, Rhea, Light, Collins, Other) and societal guideline used. The most used method was Collins (n = 16; 35.6%). Only four (8.9%) studies compared validated methods. All found the Collins method to be accurate. Seven (15.6%) studies used a standard classification guideline and 3 (6.7%) compared guidelines and found significant disagreement between them. Pediatric-specific measurement guidelines for PTX are needed to establish consistency and uniformity in both research and clinical practice. Until there is a better method, the Collins method is preferred.

Analysis of four hereditary protein C deficiencies associated with vascular thromboembolism.

To analyze the clinical features and gene mutations in four families with hereditary protein C (PC) deficiency and explore their association with vascular thromboembolism. The clinical data of four patients with PC deficiency were retrospectively analyzed. Venous blood samples were collected from the four affected patients and their family members, and relevant coagulation indexes and thrombin production and inhibition tests were performed. PCR was used to amplify and directly sequence the PROC gene of the probands. Software analysis was conducted to assess the conservativeness and pathogenicity of the mutated loci. Protein models were constructed to analyze the spatial structure before and after the mutation. Thrombin generation and inhibition assays demonstrated impaired anticoagulation in all four probands. Proband 1 and 4 presented clinically with pulmonary embolism and lower extremity deep vein thrombosis (DVT), Proband 2 with cerebral infarction, and Proband 3 with DVT. Genetic analysis revealed the presence of the following mutations: c.541T > G heterozygous missense mutation, c.577-579delAAG heterozygous deletion mutation, c.247-248insCT heterozygous insertion mutation, c.659G > A heterozygous missense mutation, and a new variant locus c.1146_1146delT heterozygous deletion mutation in the four probands, respectively. In particular, c.1146_1146delT heterozygous deletion mutations not reported previously. Conservativeness and pathogenicity analyses confirmed that most of these amino acid residues were conserved, and all the mutations were found to be pathogenic. Analysis of protein modeling revealed that these mutations induced structural alterations in the protein or led to the formation of truncated proteins. According to the American College of Medical Genetics and Genomics (ACMG) classification criteria and guidelines for genetic variants, c.1146_1146delT was rated as pathogenic (PVS1 + M2 + PM4 + PP1 + PP3 + PP4). The identified mutations are likely associated with decreased PC levels in each of the four families. The clinical manifestations of hereditary PC deficiency exhibit considerable diversity.

ClinGen variant curation expert panel recommendations for classification of variants in GAMT, GATM and SLC6A8 for cerebral creatine deficiency syndromes

Cerebral creatine deficiency syndromes (CCDS) are inherited metabolic phenotypes of creatine synthesis and transport. There are two enzyme deficiencies, guanidinoacetate methyltransferase (GAMT), encoded by GAMT and arginine-glycine amidinotransferase (AGAT), encoded by GATM, which are involved in the synthesis of creatine. After synthesis, creatine is taken up by a sodium-dependent membrane bound creatine transporter (CRTR), encoded by SLC6A8, into all organs. Creatine uptake is very important especially in high energy demanding organs such as the brain, and muscle. To classify the pathogenicity of variants in GAMT, GATM, and SLC6A8, we developed the CCDS Variant Curation Expert Panel (VCEP) in 2018, supported by The Clinical Genome Resource (ClinGen), a National Institutes of Health (NIH)-funded resource. We developed disease-specific variant classification guidelines for GAMT-, GATM-, and SLC6A8-related CCDS, adapted from the American College of Medical Genetics/Association of Molecular Pathology (ACMG/AMP) variant interpretation guidelines. We applied specific variant classification guidelines to 30 pilot variants in each of the three genes that have variants associated with CCDS. Our CCDS VCEP was approved by the ClinGen Sequence Variant Interpretation Working Group (SVI WG) and Clinical Domain Oversight Committee in July 2022. We curated 181 variants including 72 variants in GAMT, 45 variants in GATM, and 64 variants in SLC6A8 and submitted these classifications to ClinVar, a public variant database supported by the National Center for Biotechnology Information. Missense variants were the most common variant type in all three genes. We submitted 32 new variants and reclassified 34 variants with conflicting interpretations. We report specific phenotype (PP4) using a points system based on the urine and plasma guanidinoacetate and creatine levels, brain magnetic resonance spectroscopy (MRS) creatine level, and enzyme activity or creatine uptake in fibroblasts ranging from PP4, PP4_Moderate and PP4_Strong. Our CCDS VCEP is one of the first panels applying disease specific variant classification algorithms for an X-linked disease. The availability of these guidelines and classifications can guide molecular genetics and genomic laboratories and health care providers to assess the molecular diagnosis of individuals with a CCDS phenotype.

Retrospective analysis of clinical characteristics and outcomes of patients with carcinoma of unknown primary from three tertiary centers in Australia.

Carcinoma of unknown primary (CUP) remains an important tumor entity and a disproportionate cause of cancer mortality. Little is known about the contemporary clinical characteristics, treatment patterns, and outcomes of CUP patients based on updated international classification guidelines. We evaluated a contemporary CUP cohort to provide insight into current clinical practice and the impact of tissue of origin assignment, site-specific and empirical therapy in a real-world setting. We conducted a retrospective cohort study of CUP patients, as defined by the updated European Society of Medical Oncology (ESMO) 2023 guidelines, across three tertiary referral centers in Australia between 2015 and 2022. We analyzed clinical characteristics, treatment patterns, and survival outcomes using the Kaplan-Meier method and Cox regression proportional hazard model between favorable and unfavorable risk groups. We identified a total of 123 CUP patients (n = 86 unfavorable, n = 37 favorable risk as per the 2023 ESMO guidelines). Sixty-four patients (52%) were assigned a tissue of origin by the treating clinician. Median progression free survival (PFS) was 6.8 (95% confidence interval (CI) 5.1-12.1) months and overall survival (OS) 10.2 (95% CI 6.0-18.5) months. Unfavorable risk (hazard ratio [HR] 2.9, p = 0.006), poor performance status (HR 2.8, p < 0.001), and non-squamous histology (HR 2.5, p < 0.05) were associated with poor survival outcome. A total of 70 patients (57%) proceeded to systemic therapy. In patients with non-squamous histology and unfavorable risk, site-specific therapy compared to empirical chemotherapy did not improve outcome (median OS 8.2 vs. 11.8 months, p = 0.7). In this real-world cohort, CUP presentations were heterogenous. Overall survival and rates of systemic treatment were poor. Poor performance status and unfavorable risk were associated with worse survival. For most patients, site-specific therapy did not improve survival outcome. Improved and timely access to diagnostic tests and therapeutics for this group of patients is urgently required.

Pattern-Moving-Modelling and Analysis Based on Clustered Generalized Cell Mapping for a Class of Complex Systems

Considering a class of complex nonlinear systems whose dynamics are mostly governed by statistical regulations, the pattern-moving theory was developed to characterise such systems and successfully estimate the outputs or states. However, since the pattern class variable is not computable directly, this study establishes a clustered generalized cell mapping (C-GCM) to reveal system characteristics. C-GCM is a two-stage approach consisting of a pattern-moving-based description and analysis method. First, a density algorithm, named density-based spatial clustering of applications with noise (DBSCAN), is designed to obtain cell space Ω and the corresponding classification guidelines; this algorithm is initiated after the initial pre-image cells, and the total number of entity cells amounts to Ns. Then, the GCM provides several image cells based on a cell mapping function that refers to the multivariate ARMAX model. The global dynamic analysis employing both searching and storing algorithms depend on the attractor, domain of attraction, and periodic cell groups. At last, simulation results of two examples emphasise the practicality as well as efficacy of the technique suggested. The chief aim of this study was to offer a new perspective for a class of complex systems that could inspire research into nonmechanistic principles modelling and application to nonlinear systems.

Patterns of antibiotic administration in Chinese neonates: results from a multi-center, point prevalence survey

ObjectivesIn this study, we describe the patterns of antibiotic prescription for neonates based on World Health Organization’s (WHO) Essential Medicines List Access, Watch, and Reserve (AWaRe), and the Management of Antibiotic Classification (MAC) Guidelines in China.MethodsOne-day point-prevalence surveys (PPS) on antimicrobial prescriptions were conducted on behalf of hospitalized neonates in China from September 1 and November 30, annually from 2017 to 2019.ResultsData was collected for a total of 2674 neonatal patients from 15 hospitals in 9 provinces across China of which 1520 were newborns who received at least one antibiotic agent. A total of 1943 antibiotic prescriptions were included in the analysis. The most commonly prescribed antibiotic was meropenem (11.8%). The most common reason for prescribing antibiotic to neonates was pneumonia (44.2%). There were 419 (21.6%), 1343 (69.1%) and 6 (0.3%) antibiotic prescriptions in the Access, Watch and Reserve groups, respectively. According to MAC Guidelines in China, there were 1090 (56.1%) antibiotic agents in the Restricted and 414 (21.3%) in the Special group.ConclusionBroad-spectrum antibiotics included in the Watch and Special groups were likely to be overused in Chinese neonates.