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For most health professionals who have chosen the challenging path of comprehending classical homeopathy, the theory of miasms is the most intriguing part of our science and is an area where much misunderstanding, criticism and controversy prevails. There are now a large number of opposing ideas and opinions on the subject of miasms, with various classifications, many of which we believe to be erroneous and which confuse many homeopaths and result in incorrect prescriptions. Here we clarify the main postulates of Hahnemann's miasm theory and analyse how his followers transformed his ideas over the next century in the light of medical discoveries. This allows us to understand the limited relevance of miasm theory to modern day prescribing and offer a new and precise definition of the term miasm in relation to modern diseases such as cancer and autoimmune diseases. How we apply this theory to the health challenges of the 21 st century, such as increasing environmental pollution and other toxins, may play an important role in the future wellbeing of the human population. [ABSTRACT FROM AUTHOR]

Background: The aim of this study was to determine whether traumatic dislocation of the patella is provoked by the presence of predisposing factors and examine the role of the mechanism of injury. Methods: Cases diagnosed with dislocation of the patella and covered by the workers' compensation program were identified and classified as traumatic based on insurance regulations. We examined predisposing factors (e.g., frontal axis, torsional deviation, trochlear dysplasia, patella alta) in case groups based on age at dislocation and trauma mechanism. Retrospective cohort study, level of evidence III. Results: Our sample size comprised 104 cases, consisting of 54 children and 50 adults. The most common mechanism of injury in children and adults was rotational trauma. Only 20% of the children and 21% of the adults exhibited no relevant predisposing factors. Group specifically, falls accounted for the highest number of cases exhibiting none of the defined anatomical predisposing factors. Children are more frequently affected by predisposition-related dislocations than adults. Conclusion: The proportion of predispositions is high. A fall, direct impact, or rotational trauma can be viewed as an adequate mechanism of trauma. For successful treatment, it is paramount to analyze the exact mechanism of the trauma and address any underlying predispositions. [ABSTRACT FROM AUTHOR]

Copyright of South African Journal of Art History / Suid-Afrikaanse Tydskrif vir Kunsgeskiedenis is the property of Art Historical Work Group of South Africa and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Aim: For the last 20 years a large amount of data was gathered showing a genetic predisposition to overweight and obesity. The aim of this study was to demonstrate a personalized, genetic-based approach in normalizing the patients’ weight and eating habits.

A family with multiple members diagnosed with prostate cancer was identified, and genetic variants were analyzed. Three brothers were diagnosed with prostate cancer. Germline variants in BRCA1, BRCA2, TINF2, and CD19 were found through next-generation DNA sequencing using a hereditary cancer panel. The BRCA1 G275D variant was present in patients, but absent in the healthy member. An ELAC2 variant was found in 1 patient. Several mutations were predicted to be deleterious by a set of computation programs. Multiple gene mutations might contribute to the overall predisposition to prostate cancer in the family. Even in cases with potentially deleterious variants in BRCA1 or BRCA2, there could be diverse clinical manifestations.

Background: Bone metastasis is the most common metastatic destination in advanced breast cancer, presenting a poor prognosis and clinical challenges in management. To date, the mechanism of bone metastasis in breast cancer remains largely unclear. Methods: Differentially expressed genes in primary tumours that developed bone metastases were systematically analysed using both TCGA-BRCA and E-MTAB-4003 databases. Adaptive phenotype in the subsequent bone lesions was analysed in the GSE46161 database. A series of biomarkers including homing, immune escape, angiogenesis, and factors involved in both osteoblastogenesis and osteoclastogenesis were included to dissect the molecular events underlying bone metastasis in breast cancer. Results: Upregulated expressions of GDF11 expression is positively correlated with colonization, osteoblastogenesis and osteoclastogenesis, whilst CD151 is positively associated with angiogenesis and immune escape. PAFAH1B2 expression is inversely correlated with the angiogenic process. Reduced YTHDF2 may facilitate cancer cell homing, osteoclastogenesis and immune escape in breast cancer. DPP9, FAS, ZNF519, RPP14 and FAU were evaluated for their potential involvement in for the homing to bone, escaping from immune surveillance, angiogenesis, osteoblastic activity and osteoclastic activity in the multi-step process of bone metastasis. Conclusion: GDF11, CD151, PAFAH1B2 and YTHDF2 may play a pivotal role in the predisposition of metastasis to the bone from breast cancer, whilst DPP9, FAS, ZNF519, RPP14 and FAU may be actively involved in the adaptative colonisation of metastatic breast cancer cells in bone.

BackgroundPredisposition to myeloid malignancies is a field at the border of hematology and genetics. Knowledge in this domain has so rapidly increased that WHO defined in 2016 the new “Myeloid Neoplasms with Germline Predisposition” category of tumors. High throughput sequencing is frequently performed in tumors either for diagnosis or prognosis, but this approach may identify potential germline variants that have to be confirmed on non-infiltrated tissues.MethodIn this study, we systematically compared NGS data from genetic analysis performed on all sample types (bone marrow, blood, saliva, skin fibroblasts and hair follicles) in 29 patients, and 44 of their relatives (blood and saliva).ResultsWe showed that saliva was usable for relatives, but only for 24% (7/29) of our patients. Most of patients’ saliva were either “non-contributive” (14/29 i.e., 48% because clearly or probably infiltrated) or “inconclusive” (8/29 corresponding to 28%).ConclusionThe recommendations for the use of saliva we present here focus on the importance of collecting saliva during remission when possible. Moreover, we propose hair follicles as an alternative to skin biopsy, that remains the gold standard especially in case of allogenic hematopoietic stem cells transplantation. Technological progresses have revolutionized the diagnosis of predisposition to solid or hematological malignancies, and it is very likely that new techniques will help to manage the familial predisposition in the future.

Purpose: Besides the multi-layered capsule–ligamentous complex of the elbow joint the high bony congruence in the ulnohumeral joint contributes to elbow stability. Therefore, we assume that specific anatomical configurations of the trochlear notch predispose to dislocation. In case of ligamentous elbow dislocation both conservative and surgical treatment is possible without a clear treatment algorithm. Findings of constitutional bony configurations could help deciding for the best treatment option. Methods: In this retrospective matched-pair analysis we compared MRI imaging from patients sustaining a primary traumatic elbow dislocation (instability group) with patients suffering from chronic lateral epicondylitis (control group), treated between 2009 and 2019. Two independent observers measured different anatomical landmarks of the trochlear notch in a multiplanar reconstructed standardized sagittal trochlear plane (SSTP). Primarily, opening angle and relative depth of the trochlear notch were determined. After adjustment to the proximal ulnar rim in the SSTP, coronoid and olecranon angle, the articular angle as well as the ratio of the tip heights of the trochlear notch were measured. Results: We compared 34 patients in the instability group (age 48 ± 14 years, f/m 19/15) with 34 patients in the control group (age 47 ± 16 years, f/m 19/15). Instability group showed a significantly larger opening angle (94.1° ± 6.9° vs. 88.5° ± 6.9°, p = 0.0002), olecranon angle (60.9° ± 5.3° vs. 56.1° ± 5.1°, p < 0.0001) and articular angle (24.7° ± 6.4° vs. 22.3° ± 5.8°, p = 0.02) compared to the control group. Measuring the height from the coronoid (ch) and olecranon (oh) tip also revealed a significantly larger tip ratio (tr = ch/oh) in the instability group (2.7 ± 0.8 vs. 2.2 ± 0.5, p < 0.0001). The relative depth (61.0% ± 8.3% vs. 62.7% ± 6.0%, p = 0.21) of the trochlear notch as well as the coronoid angle (32.8° ± 4.5° vs. 31.7° ± 5.2°, p = 0.30) showed no significant difference in the instability group compared to the control group. The interrater reliability of all measurements was between 0.83 and 0.94. Conclusion: MRI of patients with elbow dislocation show that there seems to be a bony anatomical predisposition. According to the results, it seems reasonable to include predisposing bony factors in the decision-making process when surgical stabilization and conservative treatment is possible. Further biomechanical studies should prove these assumptions to generate critical bony values helping surgeons with decision making. Level of evidence: III. [ABSTRACT FROM AUTHOR]

The present study was undertaken to determine the predisposition of one transitional disease on the other in various dairy animals of Punjab. For this purpose, a total of 250 respondents were randomly selected and were interviewed personally from various parts of Punjab through a structured interview schedule. Among the various transitional diseases in dairy farms, anoestrus was found to be high (59.00%) followed by mastitis (52.00%). Dystocia was found to be highly significant (p<0.01) with transitional diseases such as Retention of Placenta (ROP) and metritis. ROP had highly significant variation (p<0.01) with diseases such as dystocia, mastitis, ketosis and metritis. Anoestrus was found to be significant (p<0.05) with repeat breeding. Ketosis was found to be highly significant with anoestrus (p<0.01). Milk fever varied significantly with dystocia and ROP (p<0.05). Metritis had significance with dystocia, mastitis, anoestrus and milk fever (p<0.01). Also, repeat breeding was highly significant (p<0.01) with mastitis. Thus, it was concluded that presence of one transitional disease can predispose the dairy animal to other transitional diseases as well. Hence, farmers are educated on transitional disease management through training and other extension and advisory services. [ABSTRACT FROM AUTHOR]

The aim of this systematic review and meta‐analysis was to identify the genetic variants of (inter)national competing long‐distance runners and road cyclists compared with controls. The Medline and Embase databases were searched until 15 November 2021. Eligible articles included genetic epidemiological studies published in English. A homogenous group of endurance athletes competing at (inter)national level and sedentary controls were included. Pooled odds ratios based on the genotype frequency with corresponding 95% confidence intervals (95%CI) were calculated using random effects models. Heterogeneity was addressed by Q‐statistics, and I2. Sources of heterogeneity were examined by meta‐regression and risk of bias was assessed with the Clark Baudouin scale. This systematic review comprised of 43 studies including a total of 3938 athletes and 10 752 controls in the pooled analysis. Of the 42 identified genetic variants, 13 were investigated in independent studies. Significant associations were found for five polymorphisms. Pooled odds ratio [95%CI] favoring athletes compared with controls was 1.42 [1.12–1.81] for ACE II (I/D), 1.66 [1.26–2.19] for ACTN3 TT (rs1815739), 1.75 [1.34–2.29] for PPARGC1A GG (rs8192678), 2.23 [1.42–3.51] for AMPD1 CC (rs17602729), and 2.85 [1.27–6.39] for HFE GG + CG (rs1799945). Risk of bias was low in 25 (58%) and unclear in 18 (42%) articles. Heterogeneity of the results was low (0%–20%) except for HFE (71%), GNB3 (80%), and NOS3 (76%). (Inter)national competing runners and cyclists have a higher probability to carry specific genetic variants compared with controls. This study confirms that (inter)national competing endurance athletes constitute a unique genetic make‐up, which likely contributes to their performance level. [ABSTRACT FROM AUTHOR]

Purpose: Describe clinical characteristics and outcome of Li-Fraumeni syndrome (LFS)-associated osteosarcomas., Methods: TP53 germline pathogenic/likely pathogenic variant carriers diagnosed with osteosarcoma in France between 1980 and 2019 were identified via the French Li-Fraumeni database at Rouen University Hospital. Sixty-five osteosarcomas in 52 patients with available clinical and histological data were included. The main clinical characteristics were compared with data from National Cancer Institute's SEER (Surveillance, Epidemiology, and End Results) for patients of the same age group., Results: Median age at first osteosarcoma diagnosis was 13.7 years (range: 5.9-36.7). Compared to unselected osteosarcomas, LFS-associated osteosarcomas occurred more frequently in patients less than 10 years of age (23% vs. 9%), and when compared with osteosarcomas in patients less than 25 years were characterized by an excess of axial (16% vs. 10%) and jaw sites (15% vs. 3%) and histology with predominant chondroblastic component and periosteal subtypes (17% vs. 1%). Metastases incidence (25%) was as expected in osteosarcomas. After the first osteosarcoma treatment, the rate of good histologic response (62%) and the 5-year progression-free survival (55%, 95% confidence interval [CI]: 42.6-71.1) were as expected in unselected series of osteosarcomas, whereas the 5-year event-free survival was 36.5% [95% CI: 25.3-52.7] due to the high incidence of second malignancies reaching a 10-year cumulative risk of 43.4% [95% CI: 28.5-57.5]., Conclusion: In osteosarcoma, young age at diagnosis, axial and jaw sites, histology with periosteal or chondroblastic subtype, and synchronous multifocal tumors should prompt suspicion of a germline TP53 mutation. Standard treatments are effective, but multiple malignancies impair prognosis. Early recognition of these patients is crucial for tailored therapy and follow-up., (© 2024 The Author(s). Pediatric Blood & Cancer published by Wiley Periodicals LLC.)

Multiple primary lung tumor is garnering attention from clinicians, with adenocarcinoma emerging as the predominant histological type. Because of the heterogeneity and diffuse distribution of lesions in the same patient, the treatment of multiple primary lung adenocarcinoma (MPLA) is a significant challenge. As a kind of variation unaffected by tumor heterogeneity, germline alterations may play a key role in the development of MPLA. Here, whole-exome sequencing (WES) of peripheral blood was employed to obtain germline alteration data. Intergroup comparative analyses on rare and deleterious alterations of MPLA, solitary lung adenocarcinoma, and healthy individuals in a MPLA family were performed to clarify the candidate alterations. WES and targeted Sanger sequencing were performed in 27 disseminated MPLA patients to detect the mutation site that had been screened. A rare and deleterious germline alteration, EPHB4R91H, was found in all of the patients of an MPLA family and a patient with disseminated MPLA. It was revealed that EPHB4R91H was able to enhance the proliferation, migration, and invasion ability of A549 cells through increased binding affinity to ephrinB2, which in turn activated the EPHB4/ERK/JNK/MAPK pathway. Our findings corroborate that germline alterations are involved in the development of MPLA. And it was found for the first time that the EPHB4R91H mutation promotes the development of MPLA by enhancing its affinity for ephrinB2 and thereby active EPHB4/ERK/JNK/MAPK pathway., (© The Author(s) 2024. Published by Oxford University Press.)

Objectives: Gut microbiota dysbiosis is among the risk factors for breast cancer development, together with genetic background and dietary habits. However, caloric restriction has been shown to remodel the gut microbiota and slow tumor growth. Here, we investigated whether the gut microbiota mediates the preventive effects of long-term chronic or intermittent caloric restriction on breast cancer predisposition., Methods: 10-week-old transgenic breast cancer-prone mice were randomly assigned to dietary groups (ad libitum, chronic caloric restriction, and intermittent caloric restriction groups) and fed up to week 81. Stool samples were collected at weeks 10 (baseline), 17 (young), 49 (adult), and 81 (old). 16S rRNA gene sequencing was performed to identify the gut microbiota profile of the different groups. In order to investigate the breast cancer gut microbiota profile within genetically predisposed individuals regardless of diet, mammary tumor-bearing mice and mammary tumor-free but genetically prone mice were selected from the ad libitum group (n = 6)., Results: Intermittent caloric restriction increased the microbial diversity of adult mice and modified age-related compositional changes. A total of 13 genera were differentially abundant over time. Pathogenic Mycoplasma was enriched in the re-feeding period of the old intermittent caloric restriction group compared with baseline. Furthermore, mammary tumor-free mice showed shared gut microbiota characteristics with mammary tumor-bearing mice, suggesting an early link between genetic predisposition, gut microbiota, and breast cancer development., Conclusions: Our study revealed the role of gut microbes in the preventive effects of caloric restriction against breast cancer development, implying the significance of diet and microbiome interplay., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Plain English Summary The French Bulldog is currently a hugely popular dog breed in the UK. However, the breed is linked with a range of serious health issues. Using veterinary clinical data from the VetCompass Programme at the Royal Veterinary College, this study aimed to compare the frequency of common disorders in French Bulldogs against that of all remaining dogs to identify health strengths and weaknesses in French Bulldogs. This overall view of breed health can assist owners, breeders and veterinarians to take appropriate actions to improve the health of French Bulldogs. From an overall population of 905,544 dogs, random samples of 2,781 French Bulldogs and 21,850 non-French Bulldogs were included in the analysis. French Bulldogs were younger (1.51 years versus 4.48 years) and lighter (12.45 kg versus 13.80 kg) than non-French Bulldogs. French Bulldogs had increased risk of 20/43 (46.5 %) specific disorders and decreased risk of 11/43 (25.6 %) specific disorders compared to non-French Bulldogs. The disorders with greatest relative risk in French Bulldogs compared to non-French Bulldogs were narrowed nostrils (x 42.14), Brachycephalic Obstructive Airway Syndrome (x 30.89), ear discharge (x 14.40), skin fold dermatitis (x 11.18) and difficulty giving birth [dystocia] (x 9.13). When the disorders were grouped into broad disease categories, French Bulldogs had increased risk of 12/32 (37.5 %) disorder groups and reduced risk of 6/32 (18.8 %) disorder groups compared to non-French Bulldogs. This study suggests that the health of French Bulldogs is very different, and largely much poorer, that the health of the wider non-French Bulldog population. Many of these differences are closely associated with the extreme body shape that defines the French Bulldog breed. Shifting the body shape of French Bulldogs to become more moderate, and hence less extreme, is proposed as a logical opportunity to reduce the current serious and common health issues in the French Bulldog breed.

Abstract Background Stratifying patients with sepsis was the basis of the predisposition, infection, response and organ dysfunction (PIRO) concept, an attempt to resolve the heterogeneity in treatment response. The purpose of this study is to perform an independent validation of the PIRO staging system in an international cohort and explore its utility in the identification of patients in whom time to antibiotic treatment is particularly important. Methods Prospective international cohort study, conducted over a 6-month period in five Portuguese hospitals and one Australian institution. All consecutive adult patients admitted to selected wards or the intensive care, with infections that met the CDC criteria for lower respiratory tract, urinary, intra-abdominal and bloodstream infections were included. Results There were 1638 patients included in the study. Patients who died in hospital presented with a higher PIRO score (10 ± 3 vs 8 ± 4, p

Background: Telehealth is comprised of telecommunications and electronic information systems to support and maintain long-distance healthcare services. Although it has not been thoroughly explored, the intention of using the service among the general public is critical to its success. We investigated the factors associated with the intention to utilize telehealth services among the general population of Bangladesh. Methods: This cross-sectional study was conducted between May 22, 2021 and June 15, 2021 in Bangladesh, where the total number of participants was 1038. The Pearson chi-square test and Kruskal-Wallis H tests were used to examine the unadjusted relationship between the explanatory variables and the intention to use telehealth services. A multinomial logistic regression model was fitted to determine the adjusted association. Shapiro-Wilk tests were used to check the normality of continuous data. Data were processed and analyzed by software STATA-16. Results: The probability of utilizing the service increased significantly with increasing knowledge, perceived benefit, and predisposition levels among respondents. However, when perceived concern increased, the likelihood of utilizing the service dropped significantly. Age, marital status, educational status, profession, residence, and perceived health status were significantly associated with the participants’ intention to utilize the telehealth service. Conclusions: The influencing aspects of telehealth service utilization should be recognized by the respective authorities. Possible activities to enhance usability among people are also recommended.

Copyright of Sport-Orthopadie - Sport-Traumatologie is the property of Elsevier B.V. and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Background: Myasthenia gravis (MG) is a very heterogenic chronic autoimmune disease caused by the failure of neuromuscular transmission. The HLA gene complex has conventionally been recognized as its main genetic risk and phenotype modifying factor. Our aim was to investigate the prevalence of HLA class I and II alleles and to identify possible risk factors for sporadic MG in a Spanish cohort. Methods: We designed a clinical case–control study comparing HLA alleles and haplotype frequencies in a cohort of 234 patients with sporadic autoimmune MG with data from a group of 492 randomly selected healthy subjects. Using a high-resolution next-generation sequencing (NGS)–based HLA genotyping assay, we investigated the contribution of HLA genotypes and haplotypes in the resulting phenotype, especially, the age at onset, sex, onset MGFA class, thymic histopathology, and serological status. Results: We found that the DQB1*05:02 and DQB1*05:03 alleles could be novel risk factors for Spanish MG cases. The HLA alleles A*01:01, B*08:01, DRB1*03:01, DRB1*14:54, and DQB1*02:01 were also risk factors for the disease. DQB1*03:01 acted as a risk factor for EOMG in women with AChR-positive antibodies and thymus hyperplasia. Additionally, several alleles were identified as potential phenotype-modifying factors that could exert a protective effect: HLA-B*35:08, DRB1*13:01, and DQB1*06:03 in MG; HLA-A*24:02 in women and DRB1*07:01 and DQB1*02:02 for early onset. HLA-C*07:01 and haplotype A1-B8-C7-DR3-DQ2 were associated with an early-onset phenotype. [ABSTRACT FROM AUTHOR]

Summary: Myeloproliferative neoplasms (MPN) are mainly sporadic but inherited variants have been associated with higher risk development. Here, we identified an EPOR variant (EPORP488S) in a large family diagnosed with JAK2V617F‐positive polycythaemia vera (PV) or essential thrombocytosis (ET). We investigated its functional impact on JAK2V617F clonal amplification in patients and found that the variant allele fraction (VAF) was low in PV progenitors but increase strongly in mature cells. Moreover, we observed that EPORP488S alone induced a constitutive phosphorylation of STAT5 in cell lines or primary cells. Overall, this study points for searching inherited‐risk alleles affecting the JAK2/STAT pathway in MPN. [ABSTRACT FROM AUTHOR]

Copyright of Przegląd Pedagogiczny is the property of Kazimierza Wielki University in Bydgoszcz and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Feng Xiao, Jianrong Zhou School of Nursing, Chongqing Medical University, Chongqing, 400016, People’s Republic of ChinaCorrespondence: Jianrong ZhouSchool of Nursing, Chongqing Medical University, No. 1 Changda Road, Jiulongpo District, Chongqing, 400016, People’s Republic of ChinaEmail jianrong_zhou@21cn.comBackground: Nasopharyngeal carcinoma (NPC) is mainly concentrated in East and Southeast Asia. This study aims to elucidate the potential associations of functional SNPs in the fat mass and obesity associated gene (FTO) with NPC risk and radiotherapy outcomes in a Chinese population.Methods: Functional SNP rs1477196 G>A, rs9939609 T>A, rs7206790 C>G, and rs8047395 A>G were genotyped and evaluated for their associations with NPC risk and radiotherapy outcomes.Results: Both rs9939609 (allele A versus allele T: OR=1.59; 95% CI=1.17– 2.17; P-value=0.003) and rs8047395 (allele G versus allele A: OR=0.76; 95% CI=0.64– 0.9; P-value=0.002) were significantly associated with risk of NPC. GTEx showed risk allele A of rs9939609 and rs8047395 were significantly associated with higher FTO mRNA levels in skeletal muscle tissue, which also corroborated our findings. Meanwhile, both rs1477196 (allele A versus allele G: OR=1.64; 95% CI=1.09– 2.49; P-value=0.019) and rs9939609 (allele A versus allele T: OR=0.61; 95% CI=0.43– 0.87; P-value=0.006) were significantly associated with complete remission (CR) of NPC.Conclusion: Our study identified that FTO polymorphisms contributed to the susceptibility and radiotherapy efficacy of NPC. These results shed light on the potential of establishing markers for predicting risk and personalized treatment of NPC.Keywords: nasopharyngeal carcinoma, FTO, predisposition, radiotherapy

Background: Epilepsy is a disorder of the brain characterized by an enduring predisposition to generate epileptic seizures that imposes heavy burden on individuals, families, and also on healthcare systems. As the better understanding of economic aspects of epilepsy will lead to better development of epilepsy care this study was conducted to estimate the cost of illness in epilepsy per patient per year in a tertiary care hospital in New Delhi. Aims and Objectives: The aim of study was to study the direct, indirect and total cost of illness in epilepsy per patient per year in a tertiary care hospital. Materials and Methods: Patients with epilepsy attending the Department of Neurology at Batra Hospital and Medical Research Centre in New Delhi were included in this study. All epilepsy patients fulfilling the inclusion and exclusion criteria were included in the study. The cost of illness was estimated as total, direct and indirect costs of illness per year for each patient. The information was collected on a properly formed format which consists of the demographic details of the patient, general biodata of patient, information about the direct medical costs and direct non-medical costs and information about indirect costs. The results are presented in Mean ± SD frequencies and percentages. The Kruskal-Wallis test was used to compare the costs of illness among different strata. The Mann-Whitney U test was used to compare the costs of illness between strata. The p-value

Alexandra Capellini,1,* Matthew Williams,1,* Kenan Onel,1– 3 Kuan-Lin Huang1– 3 1Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, USA, New York, NY, 10029, USA; 2Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, USA, New York, NY, 10029, USA; 3Icahn Institute for Data Science and Genomic Technology, Icahn School of Medicine at Mount Sinai, USA, New York, NY, 10029, USA*These authors contributed equally to this workCorrespondence: Kenan Onel; Kuan-Lin HuangDepartment of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, Box 1498, New York, NY, 10029, USATel +1 212-824-6134Email kenan.onel@mssm.edu; kuan-lin.huang@mssm.eduAbstract: The canonical model for hereditary cancer predisposition is a cancer predisposition gene (CPG) that drives either one or both of two fundamental hallmarks of cancer, defective genomic integrity and deregulated cell proliferation, ultimately resulting in the accumulation of mutations within cells. Thus, the genes most commonly associated with cancer-predisposing genetic syndromes are tumor suppressor genes that regulate DNA repair (eg, BRCA1, BRCA2, MMR genes) and/or cell cycle (eg, APC, RB1). In recent years, however, the spectrum of high-penetrance CPGs has expanded considerably to include genes in non-canonical pathways such as oncogenic signaling, metabolism, and protein translation. We propose here that, given the variety of pathways that may ultimately affect genome integrity and cell proliferation, the model of cancer genetic predisposition needs to be expanded to account for diverse mechanisms. This synthesis calls for modeling and multi-omic studies applying novel experimental and computational approaches to understand cancer genetic predisposition.Keywords: cancer, genetics, predisposition, multi-omics, genomics, oncogenesis

Acute myeloid leukaemia (AML) is a heterogeneous myeloid malignancy characterized by recurrent clonal events, including mutations in epigenetically relevant genes such as DNMT3A, ASXL1, IDH1/2, and TET2. Next-generation sequencing analysis of a mother and son pair who both developed adult-onset diploid AML identified a novel germline missense mutation DNMT3A p.P709S. The p.P709S protein-altering variant resides in the highly conserved catalytic DNMT3A methyltransferase domain. Functional studies demonstrate that the p.P709S variant confers dominant negative effects when interacting with wildtype DNMT3A. LINE-1 pyrosequencing and reduced representation bisulphite sequencing (RBBS) analysis demonstrated global DNA hypomethylation in germline samples, not present in the leukaemic samples. Somatic acquisition of IDH2 p.R172K mutations, in concert with additional acquired clonal DNMT3A events in both patients at the time of AML diagnosis, confirms the important pathogenic interaction of epigenetically active genes, and implies a strong selection and regulation of methylation in leukaemogenesis. Improved characterization of germline mutations may enable us to better predict malignant clonal evolution, improving our ability to provide customized treatment or future preventative strategies.

Individual differences in drug use emerge soon after initial exposure, and only a fraction of individuals who initiate drug use go on to develop a substance use disorder. Variability in vulnerability to establishing drug self-administration behavior is also evident in preclinical rodent models. Latent characteristics that underlie this variability and the relationship between early drug use patterns and later use remain unclear. Here, we attempt to determine whether propensity to establish cocaine self-administration is related to subsequent cocaine self-administration behavior in male Sprague-Dawley rats (n = 14). Prior to initiating training, we evaluated basal locomotor and anxiety-like behavior in a novel open field test. We then trained rats to self-administer cocaine in daily 3 h cocaine (0.75 mg/kg/infusion) self-administration sessions until acquisition criteria (≥30 active lever presses with ≥70 % responding on the active lever in one session) was met and divided rats into Early and Late groups by median-split analysis based on their latency to meet acquisition criteria. After each rat met acquisition criteria, we gave them 10 additional daily cocaine self-administration sessions. We then conducted a progressive ratio, cocaine-induced locomotor sensitivity test, and non-reinforced cocaine seeking test after two weeks of forced abstinence. Early Learners exhibited significantly less locomotion after an acute injection of cocaine, but the groups did not differ in any other behavioral parameter examined. These results indicate that cocaine self-administration acquisition latency is not predictive of subsequent drug-taking behavior, but may be linked to physiological factors like drug sensitivity that can predispose rats to learn the operant task. [ABSTRACT FROM AUTHOR]

Obesity is recognized as a significant risk factor for Alzheimer's disease (AD). Studies have supported the notion that obesity accelerates AD-related pathophysiology in mouse models of AD. The majority of studies, to date, have focused on the use of early-onset AD models. Here, we evaluate the impact of genetic risk factors on late-onset AD (LOAD) in mice fed with a high fat/high sugar diet (HFD). We focused on three mouse models created through the IU/JAX/PITT MODEL-AD Center. These included a combined risk model with APOE4 and a variant in triggering receptor expressed on myeloid cells 2 (Trem2R47H). We have termed this model, LOAD1. Additional variants including the M28L variant in phospholipase C Gamma 2 (Plcg2M28L) and the 677C > T variant in methylenetetrahydrofolate reductase (Mthfr 677C >T) were engineered by CRISPR onto LOAD1 to generate LOAD1. Plcg2M28L and LOAD1. Mthfr 677C >T. At 2 months of age, animals were placed on an HFD that induces obesity or a control diet (CD), until 12 months of age. Throughout the study, blood was collected to assess the levels of cholesterol and glucose. Positron emission tomography/computed tomography (PET/CT) was completed prior to sacrifice to image for glucose utilization and brain perfusion. After the completion of the study, blood and brains were collected for analysis. As expected, animals fed a HFD, showed a significant increase in body weight compared to those fed a CD. Glucose increased as a function of HFD in females only with cholesterol increasing in both sexes. Interestingly, LOAD1. Plcg2M28L demonstrated an increase in microglia density and alterations in regional brain glucose and perfusion on HFD. These changes were not observed in LOAD1 or LOAD1. Mthfr 677C >T animals fed with HFD. Furthermore, LOAD1. Plcg2M28L but not LOAD1. Mthfr 677C >T or LOAD1 animals showed transcriptomics correlations with human AD modules. Our results show that HFD affects the brain in a genotype-specific manner. Further insight into this process may have significant implications for the development of lifestyle interventions for the treatment of AD. [ABSTRACT FROM AUTHOR]

The metabolic syndrome is a cluster of heritable and related traits which has been associated with a range of pathophysiological factors including dyslipidaemia, abdominal obesity, increased fasting plasma glucose (FPG) and hypertension. The documented genetic basis of the metabolic syndrome include several chromosomal positions, numerous candidate gene-associated polymorphisms, different genetic variants, which are linked to the syndrome either as a trait or entities mainly linked to metabolic process. Additionally, the latest findings related to the contribution of epigenetic mechanisms, microRNAs, sporadic variants, non-coding RNAs, and assessing the role of genes in molecular systems has enhanced our understanding of the syndrome. Considerable work has been done to understand the underlying disease mechanisms by elucidating its genetic etiology. Nonetheless, a common shared genetic cause has not been established to clarify the coexistence of their components and further investigation is required. While mostly neglected and rarely known, hereditary predisposition needs to be studied, including with the current defective phenotypic condition descriptions. Metabolic syndrome is a multi-faceted characteristic with abundant properties and the condition can arise from interactions between environmental variables such as physical inactivity, caloric obesity and genetic susceptibility. Although there is support for genetic determinants from family and twin research, there is still no recognised genomic DNA marker for genetic association and linkages with quite a long way off potential for clinical application. In the present review efforts have been made to through light on the various genetic determinants with large effects that underlie with the association of these traits to this syndrome. The heterogeneity and multifactorial heritability of MetS, however, has been a challenge towards understanding the factors underlying the association of these traits. [ABSTRACT FROM AUTHOR]

Aim: This study was designed to evaluate the contribution of GBAP1 variants to gastric cancer (GC) risk in a Chinese Han population. Methods: The genotypes of GBAP1 polymorphisms were detected using the Agena MassARRAY platform. Logistic regression analysis was used to calculate odds ratios (ORs) and 95% CIs. Results:GBAP1 rs140081212 (OR = 0.51, p = 4.50 × 10-07), rs1057941 (OR = 0.48, p = 1.19 × 10-08) and rs2990220 (OR = 0.46, p = 7.34 × 10-09) contribute to reduced GC risk, especially gastric adenocarcinoma. Interestingly, the contribution of GBAP1 variants to GC susceptibility was associated with age, sex, BMI, smoking and drinking. Conclusion: This research suggested that GBAP1 polymorphisms might provide a protective effect against GC occurrence in a Chinese Han population. [ABSTRACT FROM AUTHOR]

All cancers are genetic disorders, but not all genetic disorders are inherited. Most cancers are sporadic, independent events that do not affect other family members. There is a population risk of developing any cancer and it mainly depends on the individual’s age and environmental factors. Cancers linked to predisposition syndromes constitute about 5–10% of all cancer cases. Although it is a small group, making the right diagnosis is important, because of the consequences to the individual, his/her relatives and the benefits they can acquire from surveillance, early therapy and/ or surgical interventions. Genetic counselling plays an important role in diagnosing cancer predisposition syndromes. Hereditary cancer risk assessment includes evaluation of personal and family history, as well as other medical and environmental risk factors. Indications for genetic testing, scope of tests, possible results and their consequences for the patient and his/her family should be discussed. [ABSTRACT FROM AUTHOR]

Introduction. Despite a long history of the disease, genital prolapse still have not been definitively solved. A relevance of pelvic organ prolapse in women has been increasing in recent years largely due to a change in the quality of life and desire to sustain their youth. The number of studies pinpointing the cause of the disease in connective tissue dysplasia (CTD) has been increasing annually.Aim: to conduct a systematic analysis and determine most common signs of CTD in women with genital prolapse.Materials and methods. CTD criteria and the relationship with genital prolapse were analyzed. The study was conducted using questionnaires and including clinical studies examining residents of the Belgorod region (135 women). The main group included 91 patients who had signs of pelvic organ prolapse, and control group consisted of 44 healthy women. CTD intensity score proposed by T.Yu. Smolnova et al. (2003) was used to assess signs of dysplasia in women examined allowing to build up three groups in which each symptom was evaluated as severity score.Results. Asthenic constitution was noted in high percentage of women suffering from genital prolapse (16.70 ± 0.38 %) compared with healthy women (2.30 ± 0.15 %; p = 0.016). Mild bruising, increased tissue bleeding tended to rise in main vs. control group (16.50 ± 0.37 % in main group and 0.0 in control group; p = 0.016). Signs of varicose veins and hemorrhoids requiring no surgical treatment were found in 33.00 ± 0.47 % and 4.50 ± 0.21 % in main vs. control group (p = 0.0002), respectively. Genital prolapse and hernia in first-line relatives were recorded in 9.90 ± 0.30 % in main group (p = 0.031), women without signs of prolapse did not indicate prolapse in close relatives.Conclusion. Asthenic constitution, hernias, varicose veins and hemorrhoids, female pelvic and hernial prolapse in close female relatives, a tendency to mild bruising, skeletal anomalies, elastosis skin were among common CTD signs in women with genital prolapse.

Paraoxonase 1 (PON1) is a well recognised member of human endogeneous free radical scavenging systems and its polymorphism and enzyme activity are attributed to various different cancer formations. We aimed to study the Paraoxonase 1 (PON1) polymorphism and enzyme activity in colorectal cancer patients. Peripheral blood samples for DNA extraction were collected from 54 colorectal cancer patients and 85 healthy individuals. Polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP) techniques were used for determination of the PON1192 polymorphism. The frequency of AA genotype was greater than BB and AB genotypes in all groups (n:65 with 46.8%; n:15 with 10.8% and n:59 with 42.4%, respectively). In both tumor groups, PON activities were significantly lower than the control group (p

Obesity is recognized as a significant risk factor for Alzheimer’s disease (AD). Studies have supported the notion that obesity accelerates AD-related pathophysiology in mouse models of AD. The majority of studies, to date, have focused on the use of early-onset AD models. Here, we evaluate the impact of genetic risk factors on late-onset AD (LOAD) in mice fed with a high fat/high sugar diet (HFD). We focused on three mouse models created through the IU/JAX/PITT MODEL-AD Center. These included a combined risk model with APOE4 and a variant in triggering receptor expressed on myeloid cells 2 (Trem2R47H). We have termed this model, LOAD1. Additional variants including the M28L variant in phospholipase C Gamma 2 (Plcg2M28L) and the 677C > T variant in methylenetetrahydrofolate reductase (Mthfr677C >T) were engineered by CRISPR onto LOAD1 to generate LOAD1.Plcg2M28L and LOAD1.Mthfr677C >T. At 2 months of age, animals were placed on an HFD that induces obesity or a control diet (CD), until 12 months of age. Throughout the study, blood was collected to assess the levels of cholesterol and glucose. Positron emission tomography/computed tomography (PET/CT) was completed prior to sacrifice to image for glucose utilization and brain perfusion. After the completion of the study, blood and brains were collected for analysis. As expected, animals fed a HFD, showed a significant increase in body weight compared to those fed a CD. Glucose increased as a function of HFD in females only with cholesterol increasing in both sexes. Interestingly, LOAD1.Plcg2M28L demonstrated an increase in microglia density and alterations in regional brain glucose and perfusion on HFD. These changes were not observed in LOAD1 or LOAD1.Mthfr677C >T animals fed with HFD. Furthermore, LOAD1.Plcg2M28L but not LOAD1.Mthfr677C >T or LOAD1 animals showed transcriptomics correlations with human AD modules. Our results show that HFD affects the brain in a genotype-specific manner. Further insight into this process may have significant implications for the development of lifestyle interventions for the treatment of AD.

Herein, we have reviewed the role of glutamate, the major excitatory neurotransmitter in the brain, in a number of neurochemical, -physiological, and -behavioral processes mediating the development of alcohol dependence. The findings discussed include results from both preclinical as well as neuroimaging and postmortem clinical studies. Expression levels for a number of glutamate-associated genes and/or proteins are modulated by alcohol abuse and dependence. These changes in expression include metabotropic receptors and ionotropic receptor subunits as well as different glutamate transporters. Moreover, these changes in gene expression parallel the pharmacologic manipulation of these same receptors and transporters. Some of these gene expression changes may have predated alcohol abuse and dependence because a number of glutamate-associated polymorphisms are related to a genetic predisposition to develop alcohol dependence. Other glutamate-associated polymorphisms are linked to age at the onset of alcohol-dependence and initial level of response/sensitivity to alcohol. Finally, findings of innate and/or ethanol-induced glutamate-associated gene expression differences/changes observed in a genetic animal model of alcoholism, the P rat, are summarized. Overall, the existing literature indicates that changes in glutamate receptors, transporters, enzymes, and scaffolding proteins are crucial for the development of alcohol dependence and there is a substantial genetic component to these effects. This indicates that continued research into the genetic underpinnings of these glutamate-associated effects will provide important novel molecular targets for treating alcohol abuse and dependence.

Herein, we have reviewed the role of glutamate, the major excitatory neurotransmitter in the brain, in a number of neurochemical, -physiological, and -behavioral processes mediating the development of alcohol dependence. The findings discussed include results from both preclinical as well as neuroimaging and postmortem clinical studies. Expression levels for a number of glutamate-associated genes and/or proteins are modulated by alcohol abuse and dependence. These changes in expression include metabotropic receptors and ionotropic receptor subunits as well as different glutamate transporters. Moreover, these changes in gene expression parallel the pharmacologic manipulation of these same receptors and transporters. Some of these gene expression changes may have predated alcohol abuse and dependence because a number of glutamate-associated polymorphisms are related to a genetic predisposition to develop alcohol dependence. Other glutamate-associated polymorphisms are linked to age at the onset of alcohol-dependence and initial level of response/sensitivity to alcohol. Finally, findings of innate and/or ethanol-induced glutamate-associated gene expression differences/changes observed in a genetic animal model of alcoholism, the P rat, are summarized. Overall, the existing literature indicates that changes in glutamate receptors, transporters, enzymes, and scaffolding proteins are crucial for the development of alcohol dependence and there is a substantial genetic component to these effects. This indicates that continued research into the genetic underpinnings of these glutamate-associated effects will provide important novel molecular targets for treating alcohol abuse and dependence.

In this review paper, we discuss the contribution of proteomic studies to the discovery of disease-specific biomarkers to monitor the disease and evaluate available treatment options for psoriasis. Psoriasis is one of the most prevalent skin disorders driven by a Th17-specific immune response. Although potential patients have a genetic predisposition to psoriasis, the etiology of the disease remains unknown. During the last two decades, proteomics became deeply integrated with psoriatic research. The data obtained in proteomic studies facilitated the discovery of novel mechanisms and the verification of many experimental hypotheses of the disease pathogenesis. The detailed data analysis revealed multiple differentially expressed proteins and significant changes in proteome associated with the disease and drug efficacy. In this respect, there is a need for proteomic studies to characterize the role of the disease-specific biomarkers in the pathogenesis of psoriasis, develop clinical applications to choose the most efficient treatment options and monitor the therapeutic response. [ABSTRACT FROM AUTHOR]

Introduction: Cancer predisposition syndromes are germline pathogenic variants in genes that greatly raise the risk of developing neoplastic diseases. One of the most well-known is Li-Fraumeni syndrome (LFS), which is due to pathogenic variants in the TP53 gene. Children with LFS have higher risks for multiple malignancies before adulthood, often with rare and aggressive subtypes. Objective: To examine head and neck manifestations of LFS in children treated at a tertiary children's hospital over a 20-year period. Methods: A retrospective review of LFS children with neoplastic disease presenting in traditional Otolaryngologic head and neck subsites from 2000 to 2019, with patient charts reviewed for relevant clinical, imaging, and operative data. Results: Of the 40 LFS patients initially identified, 27 neoplastic tumors were identified in 20 children within this cohort (20 primary, 7 second primary). Head and neck subsites aside from the brain or orbit were involved in 22% (6/27) of these tumors, representing 20% (4/20) of primary tumors and 29% (2/7) of second primary tumors. Both second primaries within the head and neck were within the radiation fields of the first primary tumor. The mean ages at primary and second primary diagnosis were 4.6 years (SD 3.5) and 12 years (SD 1.4), respectively. The male/female ratio was 1:6 among all patients with head and neck tumors. All 6 head and neck tumors were sarcomas. Rhabdomyosarcoma (N = 3, 50%) was the most common pathology, and the other 3 demonstrated rare tumor pathological subtypes (synovial cell sarcoma, pleomorphic myxoid liposarcoma, mandibular osteosarcoma). The neck was the most common subsite (75%) within this group for primary tumor presentation. Conclusion: This study identifies a high potential for head and neck involvement in children with LFS, which has not been previously described in the literature. Otolaryngological care should be included in a multidisciplinary care team surveilling these patients. [ABSTRACT FROM AUTHOR]

A family with multiple members diagnosed with prostate cancer was identified, and genetic variants were analyzed. Three brothers were diagnosed with prostate cancer. Germline variants in BRCA1, BRCA2, TINF2, and CD19 were found through next-generation DNA sequencing using a hereditary cancer panel. The BRCA1 G275D variant was present in patients, but absent in the healthy member. An ELAC2 variant was found in 1 patient. Several mutations were predicted to be deleterious by a set of computation programs. Multiple gene mutations might contribute to the overall predisposition to prostate cancer in the family. Even in cases with potentially deleterious variants in BRCA1 or BRCA2, there could be diverse clinical manifestations. [ABSTRACT FROM AUTHOR]

Desmopathy of the collateral ligaments of the distal interphalangeal joint (CL-DIPJ) has been increasingly relevant in equine sports medicine. However, the risk factors for the development of such desmopathy are not well established. In the literature, what has been described about it, is based on the clinical conditions observed in animals diagnosed with this disorder. Considering this scenario, the aim of this study was to verify which possible extrinsic or intrinsic risk factors may influence the occurrence of disorders in the collateral ligaments of the distal interphalangeal joint in polo horses. Twenty-five horses from the same equestrian team, all competing in polo, were evaluated via ultrasonography. The outcome was defined as changes in echogenicity and/or boundaries of the CL-DIPJ of the thoracic limbs of the horses evaluated. The intrinsic factors considered in this study were age, the presence of angular deviations and gender. As extrinsic factors, the parameters taken into consideration were the handicap in which the animals played and the type of training to which these horses were previously submitted in their professional athletic career. The prevalence ratio was used to verify the association between risk factor and outcome. The result of this evaluation was considered significant when the confidence interval value did not involve the value 1. Positive and significant association was observed only for age. Playing in different handicaps did not influence the presence of ligament disorders. The other factors evaluated revealed a positive but not significant association. Thus, it was concluded that animals aged nine years or older present a higher risk of CL-DIPJ disorders.

This study aimed at investigating the reasons of Indonesia EFL learners in using morphologically- changed English words in writing and finding out the number of Morphologically Changed English Words tend to be used by Indonesian EFL learners at English study Program at FKIP UMP. The number of sample was 36 Indonesian EFL Learners at the third semester of English Study Program at FKIP UMP. This research was a descriptive study. The technique used for collecting the data was distributing questionnaire. The data was analyzed by using percentage analysis and explained descriptively. The results of this study showed that the majority of respondents had more than one reason for a predisposition using morphologically changed English Words in writing. What triggers the use of them was classified into 9 categories; Entertainment, Habit, Efficiency; Saving time and space, Simplification (Easeness), Esthetics, Narsistics, Self-Contentment, Uniqueness, and Trend/Environment. Self-contentment Reasoning is the most dominant reason that the respondents had. There were 1 sentence, 8 phrases, and 20 words tend to be changed morphologically by Indonesian EFL learners as language users. This research was hoped to give the contribution to sociolinguistic aspect that tries to investigate personal use of the language in society in written and it might be dealt with discourse analysis either. It also informed the language phonemenom happened among Indonesian EFL learners as language users and hoped to help other people understand the original language intention by EFL learners when writing such forms for avoiding misunderstanding.

In our philosophical exploration we shall originally analyze dialectical contradictions of predispositions and skills as a source of memory phenomenon development; the patterns leading to the human professional activity evolution, as well as the identification of obstacles and barriers. The area of human orientation in the world of changing opportunities under the influence of the information society formation, hyper-reality and Smart Society in the cognitive innovation perspective, which is defined in the twenty-first century in the novelties of the labor market, new professions, in the processes of technological development, digitization, and transition to the virtual world of communication networks and the Internet, is justified. Moreover, studies of the memory environment reveal a search for "a certain space of inclination," as well as "corresponding features of each block" of the memory environment, determining the patterns of individual professional selection and prospects of a figure, as the subject not only of professional activity in particular, but of life in general. The correlation of the activity approach developments within the development of the subject’s life as well as the model of predisposition realization by M. Achtnich mentioned as holistic and optimal one, maintained by the specific-historical conditions of the figure, have mostly determined the key problem, which this article is devoted to. The purpose of this scientific exploration is the philosophical understanding of predisposition and skill dialectic in human professional activity (on the example of models by Martin Achtnich and Gregory Popov). The achievements of the theoretical model of Gregory Popov represent the significant results of the solution of the issue, to which P. Drucker reached himself in his formulation of "Smart Approach." It is the aforementioned concept that stands now decisive for the prospects of a "smart society" dispute in various activity spheres. Furthermore, the following disposition considers the praxeological perspective of knowledge of the patterns of the "inclination-skills" contradiction resolving application based on the models of G. Popov and P. Druker.

We tested the association between PON1 L55M, Q192R and I102V polymorphic variants and PC risk in Polish men. DNA from 110 consecutive, newly diagnosed patients hospitalized because of PC and DNA from 110 men – volunteers, healthy at the time of the study. PCR-RFLP method. In our study the average age at PC diagnosis of 55MM genotype carriers from families fulfilling Hereditary Prostate Criteria (HPC) was statistically significantly lower (by 7 years) than the average age at the disease diagnosis of 55MM carriers from families without HPC (54.6 ±6.7 vs. 61.9 ±5.4, respectively, p = 0.03). The probability of 5-year survival for the 55MM carriers was 81.3%, compared to 95.7% for non-carriers (p = 0.08, tendency). This is the first study in Polish men evaluating the impact of PON1 genetic polymorphisms on prostate cancer development and its clinical course. PON1 55MM variant may be probably associated with younger age at PC onset in men from families with HPC and with a shorter survival. However, more extensive studies on a larger number of PC patients, possibly from various populations, are necessary to confirm, and extend our findings.

Abstract Background Multigene panels are routinely used to assess for predisposing germline mutations in families at high breast cancer risk. The number of variants of unknown significance thereby identified increases with the number of sequenced genes. We aimed to determine whether tumor sequencing can help refine the analysis of germline variants based on second somatic genetic events in the same gene. Methods Whole-exome sequencing (WES) was performed on whole blood DNA from 70 unrelated breast cancer patients referred for genetic testing and without a BRCA1, BRCA2, TP53, or CHEK2 mutation. Rare variants were retained in a list of 735 genes. WES was performed on matched tumor DNA to identify somatic second hits (copy number alterations (CNAs) or mutations) in the same genes. Distinct methods (among which immunohistochemistry, mutational signatures, homologous recombination deficiency, and tumor mutation burden analyses) were used to further study the role of the variants in tumor development, as appropriate. Results Sixty-eight patients (97%) carried at least one germline variant (4.7 ± 2.0 variants per patient). Of the 329 variants, 55 (17%) presented a second hit in paired tumor tissue. Of these, 53 were CNAs, resulting in tumor enrichment (28 variants) or depletion (25 variants) of the germline variant. Eleven patients received variant disclosure, with clinical measures for five of them. Seven variants in breast cancer-predisposing genes were considered not implicated in oncogenesis. One patient presented significant tumor enrichment of a germline variant in the oncogene ERBB2, in vitro expression of which caused downstream signaling pathway activation. Conclusion Tumor sequencing is a powerful approach to refine variant interpretation in cancer-predisposing genes in high-risk breast cancer patients. In this series, the strategy provided clinically relevant information for 11 out of 70 patients (16%), adapted to the considered gene and the familial clinical phenotype.

Infection is a commonplace, usually self-limiting, condition but can lead to sepsis, a severe life-threatening dysregulated host response. We investigate the individual phenotypic predisposition to developing uncomplicated infection or sepsis in a large cohort of non-infected patients undergoing major elective surgery. Whole-blood RNA sequencing analysis was performed on preoperative samples from 267 patients. These patients developed postoperative infection with (n = 77) or without (n = 49) sepsis, developed non-infectious systemic inflammatory response (n = 31), or had an uncomplicated postoperative course (n = 110). Machine learning classification models built on preoperative transcriptomic signatures predict postoperative outcomes including sepsis with an area under the curve of up to 0.910 (mean 0.855) and sensitivity/specificity up to 0.767/0.804 (mean 0.746/0.769). Our models, confirmed by quantitative reverse-transcription PCR (RT-qPCR), potentially offer a risk prediction tool for the development of postoperative sepsis with implications for patient management. They identify an individual predisposition to developing sepsis that warrants further exploration to better understand the underlying pathophysiology., Competing Interests: Declaration of interests E.J.G.-B. has received honoraria from Abbott Products Operations AG, bioMérieux, Brahms GmbH, GSK, InflaRx GmbH, Sobi, and Xbiotech Inc; independent educational grants from Abbott Products Operations, bioMérieux, Inc, InflaRx GmbH, Johnson & Johnson, MSD, UCB, and Swedish Orphan Biovitrum AB; and funding from the Horizon 2020 European Grants ImmunoSep and RISCinCOVID and the Horizon Health grant EPIC-CROWN-2 (granted to the Hellenic Institute for the Study of Sepsis). M.S. received grants from NewB, Apollo Therapeutics, and UCL Technology Fund and others from Abbott, Amormed, bioMérieux, Biotest, Deltex Medical, Fresenius, Mindray, NewB, Pfizer, Radiometer, Roche Diagnostics, Safeguard Biosystems, Shionogi, and Spiden outside of this project. M.S. is an unpaid advisor to Presymptom Health Ltd, hemotune, deepUll, and Santersus, and R.L. is a part-time advisor to Presymptom Health Ltd., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Introduction: Children with WAGR (Wilms tumor, aniridia, genitourinary anomalies, and range of development delays) syndrome are predisposed to Wilms tumor (WT) and intrinsic kidney disease. Using the comprehensive International WAGR Syndrome Association (IWSA) survey of children with WAGR syndrome, we analyzed tumor characteristics, treatment and congenital risk factors, and kidney function in children with WAGR and WT., Methods: Descriptive statistics were utilized including demographics, treatment strategies, and patient outcomes. Comparisons were made between patients with WAGR and WT to those with WAGR alone. A multivariable logistic regression was completed for risk of developing WT and to identify predictors of chronic kidney disease (CKD)., Results: Sixty-four of 145 children with WAGR developed WT (44.1%). Three relapsed and one died. CKD developed in five children with WAGR without WT (5/81, 6.2%), and in 34 with WAGR and WT (34/64, 28.3%). Children with WAGR and WT were younger (p = .017), and had a greater association with CKD than WAGR children without WT (p < .0001). Two children with WT required hemodialysis, and one underwent kidney transplantation. By univariate analysis, CKD at any stage was associated with complete nephrectomy for the WT surgery (p < .0001), chemotherapy duration greater than 12 months, and three-drug therapy. Upon multivariate analysis, prior nephrectomy was the only significant variable (p = .0002)., Conclusions: Epidemiological analysis of children with WAGR demonstrated favorable oncologic outcomes, but high rate of early CKD in those who developed WT. Further study of the use of nephron-sparing surgery in children with WAGR and strategies to delay or treat early CKD are needed., (© 2024 Wiley Periodicals LLC.)

Context: Pheochromocytoma and paraganglioma (PPGL) are rare neuroendocrine tumors with high heritability, justifying systematic genetic screening for a germline variant in one of the twenty predisposing genes described to date., Purpose: To describe the experience of one endocrine oncogenetic laboratory over a period of 21 years (2001-2022), from the beginning of PPGL genotyping with Sanger sequencing in 2001 to the implementation of next-generation sequencing (NGS)., Method: The activity database of an academic oncogenetic laboratory was searched to extract patients/relatives identified with a pathogenic variant/likely pathogenic variant (PV/LPV) over a period of 21 years. Clinical and genetic data were compared., Results: In total, 606 index cases with PPGL and 444 relatives were genotyped. Genotyping of index cases was performed by Sanger sequencing and gene deletion analysis in 327 cases and by NGS in 279. Germline PV/LPV spanning 10 genes was identified in 165 index cases (27.2%). Several recurrent PV/LPVs in SDHx were observed in non-related index cases, the most frequent being SDHD, c.170-1G>T (n=28). This subgroup showed great phenotypic variability both between and within families in terms of both tumor location and number. Four patients (1.1%) with PV/LPV in SDHx had 3PA (Pituitary Adenoma and pheochromocytoma/paraganglioma) syndrome. 258 relatives (58.1%) had inherited a PV/LPV in one driver gene. The rate of PV/LPV carriers who were symptomatic at first imaging evaluation was 32%, but varied between<20% in SDHB and SDHC and >50% in SDHD, VHL and MAX., Conclusion: Our experience confirmed previously established genotype-phenotype correlations, but also highlights atypical clinical presentations, even for the same genetic variant. These data must be taken into account for optimal patient follow-up and management., (Copyright © 2024 The Author(s). Published by Elsevier Masson SAS.. All rights reserved.)