Recurrent Loss Research Articles

High level of aneuploidy and recurrent loss of chromosome 11 as relevant features of somatotroph pituitary tumors

BackgroundSomatotroph neuroendocrine pituitary tumors (sPitNET) are a subtype of pituitary tumors that commonly cause acromegaly. Our study aimed to determine the spectrum of DNA copy number abnormalities (CNAs) in sPitNETs and their relevance.MethodsA landscape of CNAs in sPitNETs was determined using combined whole-genome approaches involving low-pass whole genome sequencing and SNP microarrays. Fluorescent in situ hybridization (FISH) was used for microscopic validation of CNAs. The tumors were also subjected to transcriptome and DNA methylation analyses with RNAseq and microarrays, respectively.ResultsWe observed a wide spectrum of cytogenetic changes ranging from multiple deletions, recurrent chromosome 11 loss, stable genomes, to duplication of the majority of the chromosomes. The identified CNAs were confirmed with FISH. sPitNETs with multiple duplications were characterized by intratumoral heterogeneity in chromosome number variation in individual tumor cells, as determined with FISH. These tumors were separate CNA-related sPitNET subtype in clustering analyses with CNA signature specific for whole genome doubling-related etiology. This subtype encompassed GNAS-wild type, mostly densely granulated tumors with favorable expression level of known prognosis-related genes, notably enriched with POUF1/NR5A1-double positive PitNETs. Chromosomal deletions in sPitNETs are functionally relevant. They occurred in gene-dense DNA regions and were related to genes downregulation and increased DNA methylation in the CpG island and promoter regions in the affected regions. Recurrent loss of chromosome 11 was reflected by lowered MEN1 and AIP. No such unequivocal relevance was found for chromosomal gains. Comparisons of transcriptomes of selected most cytogenetically stable sPitNETs with tumors with recurrent loss of chromosome 11 showed upregulation of processes related to gene dosage compensation mechanism in tumors with deletion. Comparison of stable tumors with those with multiple duplications showed upregulation of processes related to mitotic spindle, DNA repair, and chromatin organization. Both comparisons showed upregulation of the processes related to immune infiltration in cytogenetically stable tumors and deconvolution of DNA methylation data indicated a higher content of specified immune cells and lower tumor purity in these tumors.ConclusionssPitNETs fall into three relevant cytogenetic groups: highly aneuploid tumors characterized by known prognostically favorable features and low aneuploidy tumors including specific subtype with chromosome 11 loss.

Exploring the interplay between Porphyromonas gingivalis KGP gingipain, herpes virus MicroRNA-6, and Icp4 transcript in periodontitis: Computational and clinical insights.

Porphyromonas gingivalis, a major pathogen in periodontitis, produces KGP (Lys-gingipain), a cysteine protease that enhances bacterial virulence by promoting tissue invasion and immune evasion. Recent studies highlight microRNAs' role in viral latency, potentially affecting lytic replication through host mechanisms. Herpes virus (HSV) establishes latency via interactions between microRNA-6 (miRH-6) and the ICP4 transcription factor in neural ganglia. This suggests a potential link between periodontitis and HSV-induced latency. This study aims to identify and validate the insilico inhibitory interaction of P. gingivalis KGP with ICP4 transcripts and correlate the presence of viral latency-associated transcript micro-RNA-6 with periodontitis. Computational docking analysis was performed to investigate the potential interaction between ICP4 and KGP gingipain. The binding energy and RMSD ligand values were calculated to determine the interaction's strength. Ten patients with recurrent clinical attachment loss despite conventional therapy were included in the clinical study. Subgingival tissue samples were collected post-phase I therapy, and HSV microRNA-6 presence was detected via polymerase chain reaction and confirmed through gel electrophoresis. Computational docking identified the ICP4-KGP gingipain complex with the lowest binding energy (-288.29 kJ mol^1) and an RMSD ligand of 1.5 Angstroms, indicating strong interaction potential. Gel electrophoresis confirmed miRH-6 presence in all samples. The identification of miRNA-6 in periodontitis patients and the strong interaction potential between P. gingivalis KGP gingipain and ICP4 transcripts indicate a possible link between bacterial virulence factors and viral latency dynamics in periodontal tissues. These results highlight the complex interplay between oral pathogens, viral microRNAs, and host immune responses in periodontitis.

Evolutionary diversity of CXCL16-CXCR6: Convergent substitutions and recurrent gene loss in sauropsids.

The CXCL16-CXCR6 axis is crucial for regulating the persistence of CD8 tissue-resident memory T cells (TRM). CXCR6 deficiency lowers TRM cell numbers in the lungs and depletes ILC3s in the lamina propria, impairing mucosal defence. This axis is linked to diseases like HIV/SIV, cancer, and COVID-19. Together, these highlight that the CXCL16-CXCR6 axis is pivotal in host immunity. Previous studies of the CXCL16-CXCR6 axis found genetic variation among species but were limited to primates and rodents. To understand the evolution and diversity of CXCL16-CXCR6 across vertebrates, we compared approximately 400 1-to-1 CXCR6 orthologs spanning diverse vertebrates. The unique DRF motif of CXCR6 facilitates leukocyte adhesion by interacting with cell surface-expressed CXCL16 and plays a key role in G-protein selectivity during receptor signalling; however, our findings show that this motif is not universal. The DRF motif is restricted to mammals, turtles, and frogs, while the DRY motif, typical in other CKRs, is found in snakes and lizards. Most birds exhibit the DRL motif. These substitutions at the DRF motif affect the receptor-Gi/o protein interaction. We establish recurrent CXCR6 gene loss in 10 out of 36 bird orders, including Galliformes and Passeriformes, Crocodilia, and Elapidae, attributed to segmental deletions and/or frame-disrupting changes. Notably, single-cell RNA sequencing of the lung shows a drop in TRM cells in species with CXCR6 loss, suggesting a possible link. The concurrent loss of ITGAE, CXCL16, and CXCR6 in chickens may have altered CD8 TRM cell abundance, with implications for immunity against viral diseases and vaccines inducing CD8 TRM cells.

Prospective Observational Study Of Hyperhomocysteinemia In Patients With Recurrent Pregnancy Loss In Teaching Hospital

Background: Spontaneous pregnancy loss can be physically and emotionally taxing for couples, especially when faced with recurrent losses. Recurrent pregnancy loss (RPL), also referred to as recurrent miscarriage or habitual abortion, is historically defined as 3 consecutive pregnancy losses prior to 20 weeks from the last menstrual period . RPL is also defined by two or more failed consecutive pregnancies. It is estimated that fewer than 5% of women will experience two consecutive miscarriages and only 1% experience three or more. At present, there exists a small number of accepted etiologies for RPL. Most of the diagnosed etiologies include endocrine abnormalities, autoimmune disorders, uterine anomalies, and genetic factors. After evaluation for these causes, approximately half of all cases will still remain unexplained. Hence the present study was taken up to investigate the association between hyperhomocysteinemia and recurrent pregnancy loss, evaluating prevalence, potential mechanisms and implications for management. Materials and Methods: The prospective observational study was conducted on 50 patients in the Department of OBG in Dr. B. R. Ambedkar Medical College and Hospital for a period of 18 months. Prior to the initiation of the study, Ethical and Research Committee clearance was obtained from Institutional Ethical Committee. Results: The majority of participants in both groups were aged 35 to 40 years (32.35% in Group A and 37.5% in Group B).Statistically significant differences were observed between the groups regarding hypertensive disorders of pregnancy, co-morbidities, adverse pregnancy outcomes, the nature of abortion (primary vs. secondary), fetal outcomes, APGAR scores at 1 and 5 minutes, neonatal birth weight, and NICU admissions, with p-values of 0.001 across these measures.Group B (with hyperhomocysteinemia) showed higher instances of hypertensive disorders, co-morbidities, adverse pregnancy and fetal outcomes, abnormal APGAR scores at 1 and 5 minutes, lower neonatal birth weight, and NICU admissions.The mean homocysteine levels were 13.28 ± 1.8 µmol/L in Group A and 73.98 ± 5.1 µmol/L in Group B, with a highly significant difference (p: 0.0001).Most subjects in Group B had intermediately severe hyperhomocysteinemia (50%), with 37.5% experiencing moderately severe hyperhomocysteinemia and 12.5% with severe hyperhomocysteinemia. All abortions in Group A were primary, whereas Group B had 60% primary and 40% secondary abortions. Conclusion: Hyperhomocysteinemia is a risk factor for recurrent pregnancy loss. About 1 in 3 patients of RPL have hyperhomocysteinemia and therefore as a routine workup for RPL serum homocysteine measurement should also be included. Treatment of hyperhomocysteinemia with folic acid and vitamin B12 decreases homocysteine levels significantly.

Low Socioeconomic Indicators Correlate with Critical Pre-Operative Glenoid Bone Loss and Care Delays

BackgroundChronic and recurrent shoulder dislocations prior to stabilization can increase the risk of glenoid bone loss. Glenoid bone loss exceeding critical levels can lead to further instability and decreased outcomes following arthroscopic labral repair. Indicators of low socioeconomic status (SES), such as high Area Deprivation Index (ADI) and non-commercial insurance, are related to generalized delays to orthopedic care, which can cause recurrent instability and increase glenoid bone loss. Hypothesis/PurposeHigher national ADI and non-commercial insurance would be associated with greater levels of radiographic glenoid bone loss after glenoid instability. MethodsA retrospective study was performed with patients who underwent anterior labral repair. Chart review included demographics, course of care data, preoperative instability data, national ADI, and insurance status. The Neighborhood Atlas Website and patients’ home addresses were used to obtain national ADI. Glenoid bone loss was measured using the Best-fit circle Pico method on three-dimensionally aligned magnetic resonance images (MRIs). Researchers were blinded to SES indicators during radiographic analysis. Glenoid bone loss was compared between SES indicators using one-way ANOVAs. Results146 patients met inclusion criteria and had complete datasets (23.3% female; 22.4±7.0-years-old; national ADI=16.1±15.3). Patients experienced on average 9.12±6.63% glenoid bone loss. A curve fitting tool determined a quadratic non-linear regression best characterized the association of glenoid bone loss and ADI (R2 = 0.392, p < 0.001). Individuals with commercial insurance experienced 8.58%±6.69% glenoid bone loss as compared to 11.78%±6.30% in individuals with Medicaid insurance (p=0.03). Critical bone loss at a threshold of 13.5% was more likely with higher national ADI (p<0.001) and Medicaid insurance (OR=2.49, CI=1.02-6.09). However, only national ADI was predictive of subcritical bone loss at a threshold of 10% (p<0.001). ConclusionPatients with greater national ADI and Medicaid insurance status had greater rates of critical preoperative glenoid bone loss at a threshold of 13.5%. Greater national ADI is also predictive of subcritical glenoid bone loss at a threshold of 10% and overall glenoid bone loss. Further study is needed to assess the postoperative implications of these findings in this population.

Pregnancy loss in individuals with von Willebrand disease and unspecified mucocutaneous bleeding disorders: A multicentre cohort study

BackgroundWhile bleeding around pregnancy is well described in von Willebrand disease (VWD), risk of pregnancy loss is less certain. We aimed to describe the frequency of pregnancy loss in females with VWD, compared with those with a similar mucocutaneous bleeding phenotype and no VWD, or compared with non-bleeding disorder controls. MethodsFemale patients were consecutively approached in 8 specialty bleeding disorder clinics between 2014-2023. The VWD group was defined as having VWF:Antigen (Ag) and VWF:Activity (Act) levels, each <0.50 IU/mL on ≥2 occasions, and a Condensed MCMDM-1 score of ≥4. The non-VWD mucocutaneous bleeding disorder group had VWF levels ≥0.50 IU/mL on ≥2 occasions and a MCMDM-1 score ≥4. A non-bleeding disorder control group was recruited in pregnancy from a low-risk maternity clinic. ResultsThere were 150 females in the VWD group, 145 in the non-VWD mucocutaneous bleeding disorder group, and 137 in the control group. There was a similar frequency of individuals with ≥1 loss in the VWD group (45.3%, 68/150), the non-VWD group (56.6%, 82/145) (-11.2%, 97.5% CI -24.2, 1.8%), and the non-bleeding disorder control group (37.2%, 51/137) (8.1%, 97.5% CI -4.9%, 21.1%). Using a logistic regression, the odds ratio of pregnancy losses in the VWD group versus non-VWD group was 0.94 (95% CI 0.65, 1.36). All groups experienced more recurrent losses compared to the literature. ConclusionsThere was no statistically significant difference in risk of pregnancy loss between females with VWD, females with a similar mucocutaneous bleeding phenotype, and with non-bleeding disorder controls.

Deciphering Developmental Epileptic Encephalopathies (DEE): Unravelling the Key Signs

&lt;p&gt;&lt;strong&gt;Background:&lt;/strong&gt; Epilepsy, a chronic neurological disorder affecting over 50 million people worldwide, is marked by recurrent seizures and loss of consciousness. It is categorized based on EEG features, etiologies, and comorbidities. Developmental Encephalopathy (DE) involves developmental delays and early-onset seizures without causing developmental regression. In contrast, Epileptic Encephalopathy (EE) features severe epilepsy syndromes where frequent seizures result in developmental delays or regression.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Methods:&lt;/strong&gt; This review explores the clinical definitions, epidemiology, and diagnostic criteria for DE, EE, and DEEs. It covers their etiologies, clinical features, diagnostic methods, and treatment strategies, including genetic, structural, metabolic, and immune-related factors.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Results:&lt;/strong&gt; DE features developmental impairment with epilepsy, while EE involves severe epilepsy causing cognitive and behavioral dysfunction. DEEs are marked by early-onset severe epilepsy and EEG abnormalities that worsen developmental impairments. Essential diagnostic tools include EEG, neuroimaging, and genetic testing. Effective management requires personalized interventions to control seizures and address cognitive deficits.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Conclusion:&lt;/strong&gt; DEEs are a complex epilepsy subset with major developmental and cognitive challenges. Early diagnosis and targeted treatments are crucial for improving outcomes. Ongoing research into DEEs' genetic and pathophysiological mechanisms is key to enhancing understanding and management.&lt;/p&gt;

NKG2D (Natural Killer Group 2, Member D) ligand expression and ameloblastoma recurrence: a retrospective immunohistological pilot study

Background/PurposeThis retrospective immunohistological pilot study aimed to investigate the influence of natural killer group 2, member D (NKG2D) ligand expression on ameloblastoma recurrence after surgical resection. It also aimed to elucidate additional clinical factors that could serve as predictors of ameloblastoma recurrence.Materials and methodsThis study included 96 patients who were histologically diagnosed with ameloblastoma after surgical resection. The expression of NKG2D ligands, including UL16-binding proteins (ULBPs) 1–3 and major histocompatibility complex class I chain-related molecule (MIC) A/B, was evaluated in formalin-fixed paraffin-embedded tumor tissues via immunohistochemistry assays. Furthermore, the patients’ electronic medical records were reviewed. Multivariate Cox regression analysis was conducted, and data were expressed as adjusted hazard ratios [HRs] with 95% confidence intervals [95% CIs].ResultsMultivariate analysis revealed that recurrent tumors (ref.: primary; adjusted HR [95% CI]: 2.780 [1.136, 6.803], p = 0.025) and positive MICA/B expression (ref.: negative; adjusted HR [95% CI]: 0.223 [0.050, 0.989], p = 0.048) independently affected recurrence-free survival in ameloblastoma.ConclusionThis study identified recurrent cases and loss of MICA/B expression as independent predictors of early ameloblastoma recurrence following surgical resection. The findings suggest that decreased MICA/B expression might undermine NKG2D-mediated tumor immunosurveillance, thereby influencing early recurrence.

Recurrent evolution of small body size and loss of the sword ornament in Northern swordtail fish.

Across the tree of life, species have repeatedly evolved similar phenotypes. While well-studied for ecological traits, there is also evidence for recurrent evolution of sexually selected traits. Swordtail fish (Xiphophorus) are a classic model system for studying sexual selection, and female Xiphophorus exhibit strong mate preferences for large male body size and a range of sexually dimorphic ornaments. Interestingly, sexually selected traits have also been lost multiple times in the genus. However, there has been uncertainty over the number of losses of ornamentation and large body size because phylogenetic relationships between species in this group have historically been controversial, partially due to prevalent gene flow. Here, we use whole-genome sequencing approaches to re-examine phylogenetic relationships within a Xiphophorus clade that varies in the presence and absence of sexually selected traits. Using wild-caught individuals, we determine the phylogenetic placement of a small, unornamented species, X. continens, confirming an additional loss of ornamentation and large body size in the clade. With these revised phylogenetic relationships, we analyze evidence for coevolution between body size and other sexually selected traits using phylogenetic comparative methods. These results provide insights into the evolutionary pressures driving the recurrent loss of suites of sexually selected traits.

Impact of Psychoeducation Applied to The Spouses of Bipolar Patients on Their Emotional Expression, Stigmatization, and Loneliness Levels

Objective: Bipolar disorder (BD) is a serious burden for patients and family members due to recurrent mood episodes, hospitalizations, and loss of productivity. The goal of this study is to examine how psychoeducation affected the caregivers of bipolar patients' levels of emotional expression, stigmatization, loneliness, and mood symptoms. Method: This research is a quasi-experimental intervention study applied as a pretest-posttest design with a control group. The study included 20 patients with bipolar diagnosis and 20 caregiver spouses who were followed up in our outpatient clinic. Participants were divided into 2 groups as study and control group. The spouses in the control group were interviewed only to evaluate their situation. The study group received a 6-session (15 hours) psychoeducation intervention. We administered the Emotion Expression Scale (EES), Self-Stigma Scale-Family (SSI-F), UCLA Loneliness Scale (UCLA-LS), and DASS-21 Scale to the spouses of bipolar patients in the study and control groups before and after the psychoeducation program. Results: The mean age of the spouses in the study group was 43.4±7.04 years, the mean age of the spouses in the control group was 39±8.29 years and all of them were female. There was no significant difference between the mean scores of the SSI-F, EES, and DASS-21 scales of the spouses in the study and control groups before the training (p&gt;0.05). After the psychoeducation program was applied to the spouses in the intervention group, a significant decrease was observed in the SSI-F, EES, and DASS-21 scale scores (p

Evolutionary and functional analyses reveal a role for the RHIM in tuning RIPK3 activity across vertebrates.

Receptor interacting protein kinases (RIPK) RIPK1 and RIPK3 play important roles in diverse innate immune pathways. Despite this, some RIPK1/3-associated proteins are absent in specific vertebrate lineages, suggesting that some RIPK1/3 functions are conserved while others are more evolutionarily labile. Here, we perform comparative evolutionary analyses of RIPK1-5 and associated proteins in vertebrates to identify lineage-specific rapid evolution of RIPK3 and RIPK1 and recurrent loss of RIPK3-associated proteins. Despite this, diverse vertebrate RIPK3 proteins are able to activate NF-κB and cell death in human cells. Additional analyses revealed a striking conservation of the RIP homotypic interaction motif (RHIM) in RIPK3, as well as other human RHIM-containing proteins. Interestingly, diversity in the RIPK3 RHIM can tune activation of NF-κB while retaining the ability to activate cell death. Altogether, these data suggest that NF-κB activation is a core, conserved function of RIPK3, and the RHIM can tailor RIPK3 function to specific needs within and between species.

Diagnostic Signs and Symptoms of Cyanocobalamin Deficiency at Rural Setting in India: Novel Method of Supplementation.

Cyanocobalamin or B12 deficiency is common in the Indian population, and responsible for anemia. Various clinical manifestations include central nervous system and cardiovascular manifestations, secondary to a rise in serum homocysteine levels. In a routine outpatient department at Bawaskar Hospital and Clinical Research Centre, Mahad, patients with suspected clinical signs and symptoms suggestive of cyanocobalamin deficiency were studied in detail regarding their dietary habits, serum hemoglobin, B12, and homocysteine levels. A total of 1,992 (female 1,009, 50.75%) were clinically examined in detail. Of these, 945 (49.94%), 999 (50.17%), and 48 (2.40%) were strict vegetarians, both vegetarian and nonvegetarian, and strict nonvegetarians, respectively. Common occupations associated with B12 deficiency include 666 (33.4%) housewives, 396 (19.9%) service workers, 316 (15.9%) businesspeople, 180 (9%), and 198 (9.9%) retired and industrial populations, respectively. Clinical manifestations include recurrent scalp hair loss in 268 (13.5%), poor memory in 240 (12%), tingling and numbness in 200 (10%), and generalized weakness in 387 (19.4%) patients. Additionally, 541 (27.15%) patients had pigmentation of the nail bed, knuckles, oral mucosa, and tongue, while 237 (10.81%) suffered from hypertension and ischemic heart disease. During the process of preparation of vegetarian and nonvegetarian food, there is a 30-48% reduction in vitamin content. Supplementation of vitamin by adding table salt to food on a plate at the time of eating improves the vitamin level in the blood. In the absence of laboratory investigations in rural settings, clinical signs and symptoms are helpful in detecting B12 deficiency. Directly adding vitamin powder, similar to table salt, to cooked food on the plate improved blood vitamin levels.

A Comparative Genomic Analysis of Parathyroid Adenomas and Carcinomas Harboring Heterozygous Germline CDC73 Mutations.

Parathyroid cancer has been linked to germline mutations of the CDC73 gene. However, carriers harboring cancer-associated germline CDC73 mutations may develop only parathyroid adenoma or no parathyroid disease. This incomplete penetrance indicates that additional genomic events are required for parathyroid tumorigenesis. (1) Determine the status of the second CDC73 allele in parathyroid tumors harboring germline CDC73 mutations, and (2) compare the genomic landscapes between parathyroid carcinomas and adenomas. Whole-exome and RNA sequencing of 12 parathyroid tumors harboring germline CDC73 mutations (6 adenomas and 6 carcinomas) and their matched normal tissues. All 12 parathyroid tumors had gained one somatic event predicted to cause a complete inactivation of the second CDC73 allele. Several distinctive genomic features were identified in parathyroid carcinomas compared to adenomas, including more single nucleotide variants bearing the C>G transversion and APOBEC deamination signatures, frequent mutations of the genes involved in the PI-3K/mTOR signaling, a greater number of copy number variations, and substantially more genes with altered expression. Parathyroid carcinomas also share some genomic features with adenomas. For instance, both have recurrent somatic mutations and copy number loss that impact the genes involved in T-cell receptor signaling and tumor antigen presentation, suggesting a shared strategy to evade immune surveillance. Biallelic inactivation of CDC73 is essential for parathyroid tumorigenesis in carriers harboring germline mutations of this gene. Despite sharing some genomic features with adenomas, parathyroid carcinomas have more distinctive alterations in the genome, some of which may be critical for cancer formation.

The Impact of Revascularization Strategy on Clinical Failure, Hemodynamic Failure and Chronic Limb Threatening Ischemia Symptoms in the BEST-CLI Trial

ObjectivesSustained clinical and hemodynamic benefit following revascularization for chronic limb-threatening ischemia (CLTI) is needed to resolve symptoms and prevent limb loss. We sought to compare rates of clinical and hemodynamic failure as well as resolution of initial and prevention of recurrent CLTI following endovascular (ENDO) vs bypass (OPEN) revascularization in the BEST-CLI trial. MethodsAs planned secondary analyses of the BEST-CLI trial, we examined the rates of A) clinical failure (a composite of all-cause death, above-ankle amputation, major reintervention, and degradation of WIfI stage); B) hemodynamic failure (a composite of above-ankle amputation, major and minor reintervention to maintain index limb patency, failure to initially increase or a subsequent decrease in ankle brachial index of 0.15 or toe brachial index of 0.10, and radiographic evidence of treatment stenosis or occlusion); C) time to resolution of presenting CLTI symptoms; and D) incidence of recurrent CLTI. Time-to-event analyses were by intention-to-treat assignment in both trial cohorts (cohort 1: suitable single segment great saphenous vein [SSGSV], N=1434; cohort 2: lacking suitable SSGSV, N= 396) and multivariate stratified Cox regression models were created. ResultsIn cohort 1, there was a significant difference in time to clinical failure (log-rank p<0.001), hemodynamic failure (log-rank p<0.001), and resolution of presenting symptoms (log-rank p=0.009) in favor of OPEN. In cohort 2, there was a significantly lower rate of hemodynamic failure (log-rank p=0.006) favoring OPEN, and no significant difference in time to clinical failure or resolution of presenting symptoms. Multivariate analysis revealed that assignment to OPEN was associated with significantly lower risk of clinical and hemodynamic failure in both cohorts, and a significantly higher likelihood of resolving initial and preventing recurrent CLTI symptoms in cohort 1, including after adjustment for key baseline patient covariates (end stage renal disease (ESRD), prior revascularization, smoking, diabetes, age>80, WIfI stage, tissue loss, infrapopliteal disease). Factors independently associated with clinical failure included age>80 in cohort 1 and ESRD across both cohorts. ESRD was associated with hemodynamic failure in cohort 1. Factors associated with slower resolution of presenting symptoms included diabetes in cohort 1 and WIfI stage in cohort 2. ConclusionsDurable clinical and hemodynamic benefit following revascularization for CLTI is important to avoid persistent and recurrent CLTI, reinterventions and limb loss. When compared with ENDO, initial treatment with OPEN surgical bypass, particularly with available saphenous vein, is associated with improved clinical and hemodynamic outcomes and enhanced resolution of CLTI symptoms.

Comparative Study on the Clinicopathologic and Molecular Characteristics of Primary and Secondary Diffuse Large B-cell Lymphoma in the Central Nervous System.

Diffuse large B-cell lymphoma of the central nervous system (CNS-DLBCL) is an aggressive B-cell lymphoma with clinical and molecular heterogeneity. Primary CNS-DLBCL (PCNSL) affects the brain, eyes, leptomeninges, or spinal cord without systemic involvement. Secondary CNS-DLBCL (SCNSL) manifests concurrently with systemic lymphoma or as an isolated CNS relapse with poor prognosis. Next-generation sequencing (NGS) was used to identify genomic alterations in 32 PCNSL and 9 SCNSL cases. Single nucleotide variants and copy number variations in addition to the clinicopathologic data and proposed risk predictive values were compared to aid in diagnostic differentiation between the two types of lymphomas. The MCD genotype, characterized by mutations in MYD88 and CD79B, is the most common alteration in PCNSL and is associated with lower survival rates. The frequency of MYD88 mutation was significantly higher in PCNSL compared to SCNSL (75.0% vs. 33.3%; p=0.042). Recurrent copy number loss of 6p21 occurred in 56.1% of cases, more often in PCNSL (65.6%) than in SCNSL (22.2%) (p=0.028). Diagnostic positive predictive values (PPV) of MYD88 mutation and 6p21 loss for PCNSL were 89% and 91%, respectively. PPV of both alterations was 93% for the diagnosis of PCNSL. MYD88 mutation and 6p21 loss were significantly higher in PCNSL than in SCNSL, and novel risk prediction models based on these distinct genomic profiles can aid in the clinical differentiation of PCNSL and SCNSL.

EPEN-08. MULTI-OMICS PROFILES REVEAL UNIQUE DEFINING MOLECULAR FEATURES OF POSTERIOR FOSSA EPENDYMOMA SUBTYPE A FROM INFANTS

Abstract BACKGROUND Ependymoma is a heterogeneous brain cancer with multiple subgroups based on locations and molecular profiles. Tumours of the methylation class, posterior fossa group A (PF-EPN-A) represent the most common and aggressive neoplasms and have a poor outcome. PF-EPN-A tumours in infants (under three years of age) are understudied; this project aimed to characterise these infant tumours. METHODS We collected DNA methylation (n=570) and gene expression (n=56) profiles of PF-EPN-A tumours, and single-cell RNA sequencing data of human fetal cerebellum from published studies. RESULTS Analysis of copy number profiles derived from DNA methylation arrays showed that infants with PF-EPN-A have relatively quiescent genomes when compared to children aged four to eighteen years (mean fraction of changes in infants (n=300) = 0.018 and children (n=270) = 0.055; p-value &amp;lt; 2.2 × 10-16). No recurrent focal amplifications or losses were detected, however, copy number loss involving chromosome arms, 12q (12%), 7q (9.7%), 5p (8.3%), and 16p (6%) were relatively common in infants, while 1q gain, 6q loss, and 22q loss were more frequent in children. When we stratified PF-EPN-A based on copy number alterations, infants with altered genomes were associated with poor outcomes compared to infants with stable genomes (fraction of changes = 0), which in turn showed poor overall survival compared to children with stable genomes. Gene set enrichment analysis using data from microarrays showed that infant tumours were specifically enriched with genes involved in the extracellular matrix organization, interferon gamma signaling, neuronal system, autophagy, and signaling by Interleukins, VEGF and PDGF. Integration with single-cell data from the human fetal cerebellum revealed that infants in PF-EPN-A had significantly higher proportions of glial progenitor cells and decreased granule cell progenitor subpopulations. CONCLUSIONS Together, our study identifies distinct genetic and transcriptional programs among infants in PF-EPN-A tumours, representing opportunities to refine future treatment.

Clinical and radiological outcome following arthroscopic Latarjet with cerclage FiberTape fixation with a minimum 1-year follow-up

The rates of implant-related complications are significant following the Latarjet procedure using metal screws in patients with recurrent shoulder dislocation and bone loss. The purpose of this study is to evaluate the short-term outcome following the arthroscopic Latarjet procedure using cerclage FiberTape (Arthrex, Naples, FL, USA) combined with remplissage and capsulolabral repair. It was hypothesized that performing the procedure with cerclage FiberTape would provide sturdy fixation, comparable to the conventional method of using metal screws, while averting hardware-related complications attributed to the latter in published literature. A prospective study was performed in a single institution between 2020 and 2022, with all surgeries performed by a single fellowship-trained shoulder surgeon who has ample experience in performing arthroscopic screw Latarjet procedures. Patient demographics, number of dislocations before surgery, arm dominance, ligamentous laxity, type of sporting activity, Instability Severity Index Score, and percentage of bone loss on the glenoid and humeral sides were recorded. The patients were followed up with visual analog scale, American Shoulder and Elbow Surgeons score, Rowe score, and Walch-Duplay score preoperatively and postoperatively. The coracoid graft position, healing, and remodeling were assessed with computed tomography scans at 3 months postoperatively. Minimum clinical follow-up was for a period of one year. Overall, 10 patients (all males, average age 28±8.8 years) were operated on with an arthroscopic Latarjet procedure using cerclage FiberTape. The minimum follow-up period was 12 months, and the mean follow-up was 13.2 months. The median and individual visual analog scores during arm motion, American Shoulder and Elbow Surgeons scores, Rowe scores, and Walch-Duplay scores improved in the follow-up period. Computed tomography scans at 3 months showed flushed graft position in 5 patients, medial graft position in two patients, and three patients showed graft nonunion with migration. Out of 10 patients, seven had good graft union in follow-up scans. None of the patients required revision surgery. All three patients with graft nonunion were kept under follow-up beyond the study period for recurrence of instability. Our study demonstrated that arthroscopic Latarjet using cerclage FiberTape fixation combined with remplissage and capsulolabral repair resulted in high rate of graft loosening and migration (30%). Nonetheless, patients in whom the coracoid graft had united, as well as those in whom it had not, all had good to excellent functional and clinical outcomes, no complications, and did not require any revision surgery.

Recurrent Duplication and Diversification of a Vital DNA Repair Gene Family Across Drosophila.

Maintaining genome integrity is vital for organismal survival and reproduction. Essential, broadly conserved DNA repair pathways actively preserve genome integrity. However, many DNA repair proteins evolve adaptively. Ecological forces like UV exposure are classically cited drivers of DNA repair evolution. Intrinsic forces like repetitive DNA, which also imperil genome integrity, have received less attention. We recently reported that a Drosophila melanogaster-specific DNA satellite array triggered species-specific, adaptive evolution of a DNA repair protein called Spartan/MH. The Spartan family of proteases cleave hazardous, covalent crosslinks that form between DNA and proteins ("DNA-protein crosslink repair"). Appreciating that DNA satellites are both ubiquitous and universally fast-evolving, we hypothesized that satellite DNA turnover spurs adaptive evolution of DNA-protein crosslink repair beyond a single gene and beyond the D. melanogaster lineage. This hypothesis predicts pervasive Spartan gene family diversification across Drosophila species. To study the evolutionary history of the Drosophila Spartan gene family, we conducted population genetic, molecular evolution, phylogenomic, and tissue-specific expression analyses. We uncovered widespread signals of positive selection across multiple Spartan family genes and across multiple evolutionary timescales. We also detected recurrent Spartan family gene duplication, divergence, and gene loss. Finally, we found that ovary-enriched parent genes consistently birthed functionally diverged, testis-enriched daughter genes. To account for Spartan family diversification, we introduce a novel mechanistic model of antagonistic coevolution that links DNA satellite evolution and adaptive regulation of Spartan protease activity. This framework promises to accelerate our understanding of how DNA repeats drive recurrent evolutionary innovation to preserve genome integrity.

Genomic signatures associated with recurrent scale loss in cyprinid fish.

Scale morphology represents a fundamental feature of fish and a key evolutionary trait underlying fish diversification. Despite frequent and recurrent scale loss throughout fish diversification, comprehensive genome-wide analyses of the genomic signatures associated with scale loss in divergent fish lineages remain scarce. In the current study, we investigated genome-wide signatures, specifically convergent protein-coding gene loss, amino acid substitutions, and cis-regulatory sequence changes, associated with recurrent scale loss in two divergent Cypriniformes lineages based on large-scale genomic, transcriptomic, and epigenetic data. Results demonstrated convergent changes in many genes related to scale formation in divergent scaleless fish lineages, including loss of P/Q-rich scpp genes (e.g. scpp6 and scpp7), accelerated evolution of non-coding elements adjacent to the fgf and fgfr genes, and convergent amino acid changes in genes (e.g. snap29) under relaxed selection. Collectively, these findings highlight the existence of a shared genetic architecture underlying recurrent scale loss in divergent fish lineages, suggesting that evolutionary outcomes may be genetically repeatable and predictable in the convergence of scale loss in fish.

Risk Management Techniques on Financial Performance of State-Owned Sugar Companies in Kenya

Financial performance of sugar companies in Kenya is generally poor and has been fluctuating over a long period. The state-owned sugar companies are worse compared to the privately owned companies. The sugar sector has been orbiting around sugar scarcity, inefficiencies, failure to pay farmers, failure to renovate and modernize production unit, failure to battle with imported sugar, recurrent losses and political interference. The main objective of this study was to evaluate the effect of risk management techniques on financial performance of state-owned sugar companies in Kenya. The specific objectives guiding the study were; to establish the effect of risk avoidance on financial performance of state-owned sugar companies in Kenya, and to assess the effect of risk acceptance on financial performance of state-owned sugar companies in Kenya. The study was anchored on the risk management theory, model risk management and the theory of financial control. The study adopted a descriptive research design with a target population of fifty four respondents being employees from the six state-owned sugar companies in Kenya. Questionnaires were the main data collection tool. Data was analyzed with the help of statistical package for social science version 28, Analysis of Variances, Correlation and regression analysis tools were used to establish the relationship between the variables. The findings of the study revealed a statistically significant regression effect and indicative of accomplished prediction of financial performance of state-owned sugar factories through the F-calculated value which showed that the model was significant. Risk avoidance explained 53.9% of financial performance and risk acceptance explained 61.9% of financial performance of state-owned sugar factories in western Kenya. The findings of the study will provide an insight to finance practitioners on the risk management techniques and their relationship with organizational financial performance as well as contributing to the scholarly literature on risk management techniques in other sectors of the economy. Keywords: Risk, Risk Avoidance, Risk Acceptance, Financial Performance, Risk management Techniques