BACKGROUND:Cerebellar ataxia, neuropathy and vestibular are flexia syndrome (CANVAS) and RFC1-related disease are most commonly caused by biallelic AAGGG repeat expansions in RFC1. The high population frequency of this expansion compared to the frequency of CANVAS suggests incomplete penetrance. OBJECTIVE:To determine whether polygenic risk factors influence incomplete penetrance in RFC1-related disease. METHODS:Biallelic RFC1 AAGGG status was profiled in Genomics England (GEL) and the UK Biobank (UKB) discovery cohorts and a replication Australian ataxia cohort (AAC). Polygenic score (PGS) analysis was performed with variants identified in a Huntington's Disease age at onset study. RESULTS:We identified 56 (GEL) and 18 (UKB) biallelic individuals with ataxia and/or neuropathy, and 26 (GEL) and 207 (UKB) age-matched biallelic carriers with no report of ataxia or neuropathy. Meta-analysis of GEL and UKB identified elevated PGS in biallelic affected individuals (OR = 1.43, p = 2.2 × 10-3) compared to controls, but not in the biallelic carriers (OR = 1.01, P = 0.92). The variant rs245100, upstream MSH3, was the biggest contributor to this elevated risk (OR = 2.35, adjusted p = 0.02). Replication in the AAC showed elevated PGS in individuals with molecular confirmation of CANVAS or RFC1-related disease (n = 54) (OR = 1.93, P = 4.4 × 10-5), and enrichment of rs245100 (OR = 4.24, p = 1.0 × 10-4). CONCLUSION:These results indicate that modifier variant burden alters disease penetrance and presentation in RFC1-related disease and determines an increased incidence of ataxia and neuropathy in biallelic individuals. © 2026 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

There is limited data about experiences of people with Parkinson’s (PwP) in Australia. This study, initiated and co-designed by PwP, surveyed 385 participants nationally (335 fully completed the questionnaire). Participants living in capital and regional city centers reported satisfaction with clinical care during diagnostic consultation at approximately 40%, with satisfaction less in rural areas (26%). 68% of participants reported inadequate involvement in discussions about treatment and care planning and 77% were dissatisfied with the support following diagnosis. Respondents reported low referral rates to allied health services such as physiotherapy (22%) and mental health services (17%). Feedback indicated support could improved by increased access to Parkinson’s disease Clinical Nurse Specialists and to educational resources and support. Findings highlight the need to establish Australian guidelines for Parkinson’s clinical management, greater resourcing for clinicians including development of educational programs, and creation of Australian-centric educational resources to improve quality of care for PwP.

Retinal thickness is a marker of retinal health and more broadly, is seen as a promising biomarker for many systemic diseases. Retinal thickness measurements are procured from optical coherence tomography (OCT) as part of routine clinical eyecare. We processed the UK Biobank OCT images using a convolutional neural network to produce fine-scale retinal thickness measurements across > 29,000 points in the macula, the part of the retina responsible for human central vision. The macula is disproportionately affected by high disease burden retinal disorders such as age-related macular degeneration and diabetic retinopathy, which both involve metabolic dysregulation. Analysis of common genomic variants, metabolomic, blood and immune biomarkers, disease PheCodes and genetic scores across a fine-scale macular thickness grid, reveals multiple novel genetic loci including four on the X chromosome; retinal thinning associated with many systemic disorders including multiple sclerosis; and multiple associations to correlated metabolites that cluster spatially in the retina. We highlight parafoveal thickness to be particularly susceptible to systemic insults. These results demonstrate the gains in discovery power and resolution achievable with AI-leveraged analysis. Results are accessible using a bespoke web interface that gives full control to pursue findings. Retinal morphology is emerging as a key biomarker for disease. Here, using AI to create a high-resolution map of retinal thickness from optical coherence tomography images, the authors demonstrate spatial associations with genetic variation, metabolites and disease, with the parafovea showing the highest enrichment

BackgroundDetection of anaemia is crucial for clinical medicine and public health. Current WHO anaemia definitions are based on statistical thresholds (fifth centiles) set more than 50 years ago. We sought to establish evidence for the statistical haemoglobin thresholds for anaemia that can be applied globally and inform WHO and clinical guidelines.MethodsIn this analysis we identified international data sources from populations in the USA, England, Australia, China, the Netherlands, Canada, Ecuador, and Bangladesh with sufficient clinical and laboratory information collected between 1998 and 2020 to obtain a healthy reference sample. Individuals with clinical or biochemical evidence of a condition that could reduce haemoglobin concentrations were excluded. We estimated haemoglobin thresholds (ie, 5th centiles) for children aged 6–23 months, 24–59 months, 5–11 years, and 12–17 years, and adults aged 18–65 years (including during pregnancy) for individual datasets and pooled across data sources. We also collated findings from three large-scale genetic studies to summarise genetic variants affecting haemoglobin concentrations in different ancestral populations.FindingsWe identified eight data sources comprising 18 individual datasets that were eligible for inclusion in the analysis. In pooled analyses, the haemoglobin fifth centile was 104·4 g/L (90% CI 103·5–105·3) in 924 children aged 6–23 months, 110·2 g/L (109·5–110·9) in 1874 children aged 24–59 months, and 114·4 g/L (113·6–115·2) in 1839 children aged 5–11 years. Values diverged by sex in adolescents and adults. In pooled analyses, the fifth centile was 122·2 g/L (90% CI 121·3–123·1) in 1741 female adolescents aged 12–17 years and 128·2 g/L (126·4–130·0) in 1103 male adolescents aged 12–17 years. In pooled analyses of adults aged 18–65 years, the fifth centile was 119·7 g/L (90% CI 119·1–120·3) in 3640 non-pregnant females and 134·9 g/L (134·2–135·6) in 2377 males. Fifth centiles in pregnancy were 110·3 g/L (90% CI 109·5–111·0) in the first trimester (n=772) and 105·9 g/L (104·0–107·7) in the second trimester (n=111), with insufficient data for analysis in the third trimester. There were insufficient data for adults older than 65 years. We did not identify ancestry-specific high prevalence of non-clinically relevant genetic variants that influence haemoglobin concentrations.InterpretationOur results enable global harmonisation of clinical and public health haemoglobin thresholds for diagnosis of anaemia. Haemoglobin thresholds are similar between sexes until adolescence, after which males have higher thresholds than females. We did not find any evidence that thresholds should differ between people of differering ancestries.FundingWorld Health Organization and the Bill & Melinda Gates Foundation.

Purpose: Stuttering is a speech condition that can have a major impact on a person's quality of life. This descriptive study aimed to identify subgroups of people who stutter (PWS) based on stuttering burden and to investigate differences between these subgroups on psychosocial aspects of life. Method: The study included 618 adult participants who stutter. They completed a detailed survey examining stuttering symptomatology, impact of stuttering on anxiety, education and employment, experience of stuttering, and levels of depression, anxiety, and stress. A two-step cluster analytic procedure was performed to identify subgroups of PWS, based on self-report of stuttering frequency, severity, affect, and anxiety, four measures that together inform about stuttering burden. Results: We identified a high- ( n = 230) and a low-burden subgroup ( n = 372). The high-burden subgroup reported a significantly higher impact of stuttering on education and employment, and higher levels of general depression, anxiety, stress, and overall impact of stuttering. These participants also reported that they trialed more different stuttering therapies than those with lower burden. Conclusions: Our results emphasize the need to be attentive to the diverse experiences and needs of PWS, rather than treating them as a homogeneous group. Our findings also stress the importance of personalized therapeutic strategies for individuals with stuttering, considering all aspects that could influence their stuttering burden. People with high-burden stuttering might, for example, have a higher need for psychological therapy to reduce stuttering-related anxiety. People with less emotional reactions but severe speech distortions may also have a moderate to high burden, but they may have a higher need for speech techniques to communicate with more ease. Future research should give more insights into the therapeutic needs of people highly burdened by their stuttering. Supplemental Material: https://doi.org/10.23641/asha.25582980

COVID-19 caused by SARS-CoV-2 has resulted in a global pandemic with a rapidly developing global health and economic crisis. Variations in the disease have been observed and have been associated with the genomic sequence of either the human host or the pathogen. Worldwide scientists scrambled initially to recruit patient cohorts to try and identify risk factors. A resource that presented itself early on was the UK Biobank (UKBB), which is investigating the respective contributions of genetic predisposition and environmental exposure to the development of disease. To enable COVID-19 studies, UKBB is now receiving COVID-19 test data for their participants every two weeks. In addition, UKBB is delivering more frequent updates of death and hospital inpatient data (including critical care admissions) on the UKBB Data Portal. This frequently changing dataset requires a tool that can rapidly process and analyse up-to-date data. We developed an R package specifically for the UKBB COVID-19 data, which summarises COVID-19 test results, performs association tests between COVID-19 susceptibility/severity and potential risk factors such as age, sex, blood type, comorbidities and generates input files for genome-wide association studies (GWAS). By applying the R package to data released in April 2021, we found that age, body mass index, socioeconomic status and smoking are positively associated with COVID-19 susceptibility, severity, and mortality. Males are at a higher risk of COVID-19 infection than females. People staying in aged care homes have a higher chance of being exposed to SARS-CoV-2. By performing GWAS, we replicated the 3p21.31 genetic finding for COVID-19 susceptibility and severity. The ability to iteratively perform such analyses is highly relevant since the UKBB data is updated frequently. As a caveat, users must arrange their own access to the UKBB data to use the R package.

COVID-19 caused by SARS-CoV-2 has resulted in a global pandemic with a rapidly developing global health and economic crisis. Variations in the disease have been observed and have been associated with the genomic sequence of either the human host or the pathogen. Worldwide scientists scrambled initially to recruit patient cohorts to try and identify risk factors. A resource that presented itself early on was the UK Biobank (UKBB), which is investigating the respective contributions of genetic predisposition and environmental exposure to the development of disease. To enable COVID-19 studies, UKBB is now receiving COVID-19 test data for their participants every two weeks. In addition, UKBB is delivering more frequent updates of death and hospital inpatient data (including critical care admissions) on the UKBB Data Portal. This frequently changing dataset requires a tool that can rapidly process and analyse up-to-date data. We developed an R package specifically for the UKBB COVID-19 data, which summarises COVID-19 test results, performs association tests between COVID-19 susceptibility/severity and potential risk factors such as age, sex, blood type, comorbidities and generates input files for genome-wide association studies (GWAS). By applying the R package to data released in April 2021, we found that age, body mass index, socioeconomic status and smoking are positively associated with COVID-19 susceptibility, severity, and mortality. Males are at a higher risk of COVID-19 infection than females. People staying in aged care homes have a higher chance of being exposed to SARS-CoV-2. By performing GWAS, we replicated the 3p21.31 genetic finding for COVID-19 susceptibility and severity. The ability to iteratively perform such analyses is highly relevant since the UKBB data is updated frequently. As a caveat, users must arrange their own access to the UKBB data to use the R package.

Objective: Abnormal changes in metabolite levels in serum or plasma have been highlighted in several studies in age-related macular degeneration (AMD), the leading cause of irreversible vision loss. Specific changes in lipid profiles are associated with an increased risk of AMD. Metabolites could thus be used to investigate AMD disease mechanisms or incorporated into AMD risk prediction models. However, whether particular metabolites causally affect the disease has yet to be established. Design: A 3-tiered analysis of blood metabolites in the United Kingdom (UK) Biobank cohort to identify metabolites that differ in AMD patients with evidence for a putatively causal role in AMD. Participants: A total of 72 376 donors from the UK Biobank cohort including participants with AMD (N = 1353) and non-AMD controls (N = 71 023). Methods: We analyzed 325 directly measured or derived blood metabolites from the UK Biobank for 72 376 donors to identify AMD-associated metabolites. Genome-wide association studies for 325 metabolites in 98 316 European participants from the UK Biobank were performed. The causal effects of these metabolites in AMD were tested using a 2-sample Mendelian randomization approach. The predictive value of these measurements together with sex and age was assessed by developing a machine learning classifier. Main Outcome Measures: Evaluating metabolic biomarkers associated with AMD susceptibility and investigating their potential causal contribution to the development of the disease. Results: This study noted age to be the prominent risk factor associated with AMD development. While accounting for age and sex, we identified 84 metabolic markers as significantly (false discovery rate-adjusted P value < 0.05) associated with AMD. Lipoprotein subclasses comprised the majority of the AMD-associated metabolites (39%) followed by several lipoprotein to lipid ratios. Nineteen metabolites showed a likely causative role in AMD etiology. Of these, 6 lipoproteins contain very small, very low-density lipoprotein (VLDL), and phospholipids to total lipid ratio in medium VLDL. Based on this we postulate that depletion of circulating very small VLDLs is likely causal for AMD. The risk prediction model constructed from the metabolites, age and sex, identified age as the primary predictive factor with a much smaller contribution by metabolites to AMD risk prediction. Conclusions: This study underscores the pronounced role of lipids in AMD susceptibility and the likely causal contribution of particular subclasses of lipoproteins to AMD. Our study provides valuable insights into the metabopathological mechanisms of AMD disease development and progression.

Stuttering is a common speech disorder that interrupts speech fluency and tends to cluster in families. Typically, stuttering is characterized by speech sounds, words or syllables which may be repeated or prolonged and speech that may be further interrupted by hesitations or 'blocks'. Rare variants in a small number of genes encoding lysosomal pathway proteins have been linked to stuttering. We studied a large four-generation family in which persistent stuttering was inherited in an autosomal dominant manner with disruption of the cortico-basal-ganglia-thalamo-cortical network found on imaging. Exome sequencing of three affected family members revealed the PPID c.808C>T (p.Pro270Ser) variant that segregated with stuttering in the family. We generated a Ppid p.Pro270Ser knock-in mouse model and performed ex vivo imaging to assess for brain changes. Diffusion-weighted MRI in the mouse revealed significant microstructural changes in the left corticospinal tract, as previously implicated in stuttering. Quantitative susceptibility mapping also detected changes in cortico-striatal-thalamo-cortical loop tissue composition, consistent with findings in affected family members. This is the first report to implicate a chaperone protein in the pathogenesis of stuttering. The humanized Ppid murine model recapitulates network findings observed in affected family members.

BACKGROUND & AIMS: Patient navigation interventions can improve health outcomes in underserved, low-income, and racial and ethnic minority groups, who often experience health disparities. We examined the effectiveness of patient navigation to improve linkage to hepatitis C virus (HCV) treatment receipt in a socioeconomically disadvantaged, racially diverse patient population. METHODS: We performed a pre-post analysis evaluating the effectiveness of a patient navigation program among baby boomers who tested positive for HCV in a safety-net health system. The usual care group (June 2013 to May 2015) and patient navigation group (January 2016 to December 2017) were balanced using a stabilized inverse probability of treatment weighting approach. We used logistic regression analyses to evaluate associations between patient navigation and linkage to care for HCV treatment evaluation, treatment initiation, and sustained virologic response. RESULTS: Among 1353 patients (62% black, 61% uninsured, 16% homeless), 769 were in the usual care group, and 584 were in the patient navigation group. The patient navigation group had significantly higher odds of linkage to care (odds ratio [OR], 3.7; 95% confidence interval [CI], 2.9-4.8) and treatment initiation (OR, 3.2; 95% CI, 2.3-4.2) within 6 months. The patient navigation group continued to have increased linkage to care (OR, 3.4; 95% CI, 2.7-4.3) and treatment initiation (OR 2.3; 95% CI, 1.7-3.0) at 12 months. However, there was no significant difference in sustained virologic response between the groups (86.9% vs 86.1%; P [ .78). CONCLUSIONS: Patient navigation was associated with significantly increased linkage to care and treatment initiation among patients with HCV infection. Patient navigation programs can be used to promote HCV elimination among traditionally difficult-to-reach patient populations.

Global economic events have had a profound effect upon both businesses and the available workforce. Industries need a more skilful and advanced labour market and individuals who complete tertiary-level education are afforded better protection against economic uncertainties. Consequently, demand for higher education worldwide is growing, due to a rising number of globally mobile students. However, return on investment is important and curriculums offering employability enhancement and work opportunities are motivating factors when international students make their study decisions. This paper details one UK university's approach to enhancing international student employability skills and employment outcomes, using a 3-day experiential learning residential on an MBA programme. Employing a survey design, the research investigates the benefits of this residential to 182 international MBA students (all from the Indian subcontinent region). The findings report that the international students developed key employability skills via the residential which significantly increased their propensity to obtain subsequent employment. The results of this paper provide much needed insight into improving both the employability skills and employment outcomes of international students, especially students from the Indian subcontinent, via immersive experiential learning activities.

Detection of anaemia is critical for clinical medicine and public health. Current WHO values that define anaemia are statistical thresholds (5 th centile) set over 50 years ago, and are presently <110g/L in children 6-59 months, <115g/L in children 5-11 years, <110g/L in pregnant women, <120g/L in children 12-14 years of age, <120g/L in non-pregnant women, and <130g/L in men. Haemoglobin is sensitive to iron and other nutrient deficiencies, medical illness and inflammation, and is impacted by genetic conditions; thus, careful exclusion of these conditions is crucial to obtain a healthy reference population. We identified data sources from which sufficient clinical and laboratory information was available to determine an apparently healthy reference sample. Individuals were excluded if they had any clinical or biochemical evidence of a condition that may diminish haemoglobin concentration. Discrete 5 th centiles were estimated along with two-sided 90% confidence intervals and estimates combined using a fixed-effect approach. Estimates for the 5 th centile of the healthy reference population in children were similar between sexes. Thresholds in children 6-23 months were 104.4g/L [90% CI 103.5, 105.3]; in children 24-59 months were 110.2g/L [109.5, 110.9]; and in children 5-11 years were 114.1g/L [113.2, 115.0]. Thresholds diverged by sex in adolescents and adults. In females and males 12-17 years, thresholds were 122.2g/L [121.3, 123.1] and 128.2 [126.4, 130.0], respectively. In adults 18-65 years, thresholds were 119.7g/L [119.1, 120.3] in non-pregnant females and 134.9g/L [134.2, 135.6] in males. Limited analyses indicated 5 th centiles in first-trimester pregnancy of 110.3g/L [109.5, 111.0] and 105.9g/L [104.0, 107.7] in the second trimester. All thresholds were robust to variations in definitions and analysis models. Using multiple datasets comprising Asian, African, and European ancestries, we did not identify novel high prevalence genetic variants that influence haemoglobin concentration, other than variants in genes known to cause important clinical disease, suggesting non-clinical genetic factors do not influence the 5 th centile between ancestries. Our results directly inform WHO guideline development and provide a platform for global harmonisation of laboratory, clinical and public health haemoglobin thresholds.

Across the globe, 2-3% of humans carry the p.Ser132Pro single nucleotide polymorphism in MLKL , the terminal effector protein of the inflammatory form of programmed cell death, necroptosis. Here we show that this substitution confers a gain in necroptotic function in human cells, with more rapid accumulation of activated MLKL S132P in biological membranes and MLKL S132P overriding pharmacological and endogenous inhibition of MLKL. In mouse cells, the equivalent Mlkl S131P mutation confers a gene dosage dependent reduction in sensitivity to TNF-induced necroptosis in both hematopoietic and non-hematopoietic cells, but enhanced sensitivity to IFN-β induced death in non-hematopoietic cells. In vivo, Mlkl S131P homozygosity reduces the capacity to clear Salmonella from major organs and retards recovery of hematopoietic stem cells. Thus, by dysregulating necroptosis, the S131P substitution impairs the return to homeostasis after systemic challenge. Present day carriers of the MLKL S132P polymorphism may be the key to understanding how MLKL and necroptosis modulate the progression of complex polygenic human disease.

Childhood apraxia of speech (CAS), the prototypic severe childhood speech disorder, is characterized by motor programming and planning deficits. Genetic factors make substantive contributions to CAS aetiology, with a monogenic pathogenic variant identified in a third of cases, implicating around 20 single genes to date. Here we aimed to identify molecular causation in 70 unrelated probands ascertained with CAS. We performed trio genome sequencing. Our bioinformatic analysis examined single nucleotide, indel, copy number, structural and short tandem repeat variants. We prioritised appropriate variants arising de novo or inherited that were expected to be damaging based on in silico predictions. We identified high confidence variants in 18/70 (26%) probands, almost doubling the current number of candidate genes for CAS. Three of the 18 variants affected SETBP1, SETD1A and DDX3X, thus confirming their roles in CAS, while the remaining 15 occurred in genes not previously associated with this disorder. Fifteen variants arose de novo and three were inherited. We provide further novel insights into the biology of child speech disorder, highlighting the roles of chromatin organization and gene regulation in CAS, and confirm that genes involved in CAS are co-expressed during brain development. Our findings confirm a diagnostic yield comparable to, or even higher, than other neurodevelopmental disorders with substantial de novo variant burden. Data also support the increasingly recognised overlaps between genes conferring risk for a range of neurodevelopmental disorders. Understanding the aetiological basis of CAS is critical to end the diagnostic odyssey and ensure affected individuals are poised for precision medicine trials.

Purpose: To our knowledge, there are no data examining the agreement between self-reported and clinician-rated stuttering severity. In the era of big data, self-reported ratings have great potential utility for large-scale data collection, where cost and time preclude in-depth assessment by a clinician. Equally, there is increasing emphasis on the need to recognize an individual's experience of their own condition. Here, we examined the agreement between self reported stuttering severity compared to clinician ratings during a speech assessment. As a secondary objective, we determined whether self-reported stuttering severity correlated with an individual's subjective impact of stuttering. Method: Speech-language pathologists conducted face-to-face speech assessments with 195 participants (137 males) aged 5-84 years, recruited from a cohort of people with self-reported stuttering. Stuttering severity was rated on a 10 point scale by the participant and by two speech-language pathologists. Participants also completed the Overall Assessment of the Subjective Experience of Stuttering (OASES). Clinician and participant ratings were compared. The association between stuttering severity and the OASES scores was examined. Results: There was a strong positive correlation between speech-language pathologist and participant-reported ratings of stuttering severity. Participant reported stuttering severity correlated weakly with the four OASES domains and with the OASES overall impact score. Conclusions: Participants were able to accurately rate their stuttering severity during a speech assessment using a simple one-item question. This finding indicates that self-report stuttering severity is a suitable method for large-scale data collection. Findings also support the collection of self-report subjective experience data using questionnaires, such as the OASES, which add vital information about the participants' experience of stuttering that is not captured by overt speech severity ratings alone.

Polycythemia Vera (PV) is a myeloproliferative neoplasm driven by activating mutations in JAK2 that result in unrestrained erythrocyte production, increasing patients' hematocrit and hemoglobin concentration, placing them at risk of life-threatening thrombotic events. Our GWAS of 440 PV cases and 403,351 controls utilizing UK Biobank data found that SNPs in HFE known to cause hemochromatosis are highly associated with PV diagnosis, linking iron regulation to PV. Analysis of the FinnGen dataset independently confirmed over-representation of homozygous HFE variants in PV patients. HFE influences the expression of hepcidin, the master regulator of systemic iron homeostasis. Through genetic dissection of PV mouse models, we show that the PV erythroid phenotype is directly linked to hepcidin expression: endogenous hepcidin upregulation alleviates erythroid disease whereas hepcidin ablation worsens it. Further, we demonstrate that in PV, hepcidin is not regulated by expanded erythropoiesis but is likely governed by inflammatory cytokines signaling via GP130 coupled receptors. These findings have important implications for understanding the pathophysiology of PV and offer new therapeutic strategies for this disease.

PurposeThis study aims to investigate the influence of the interrelationship between the deployment of Industry 4.0 (I4.0) technologies and the application of lean production (LP) practices on the degree of organizational sustainability performance (SP) enhancement of the Bangladeshi ready-made garment (RMG) sector. Design/methodology/approachPreviously, researchers have applied the resource-based view (RBV) or dynamic capability view (DCV) to describe the interaction of resources and capacities (technologies, management practices, SP) to analyze their effectiveness. However, in light of several contemporary academic discussions, this study contends that these organizational views are inappropriate for explicating SP. Hence, as the foundation of this study's theoretical framework, the authors used the practice-based view (PBV), which is recommended as a useful window to evaluate the function of practices that are common and simple to emulate in execution. To test the theoretical framework and research hypothesis, this study used partial least square (PLS) analysis. For that, the authors carried out a systematic survey to collect data from 80 Bangladeshi RMG factories. FindingsThe results of this research imply that LP is a crucial factor in enhancing organizational SP. Moreover, the results also indicate that the adoption of I4.0 technologies along with LP can assist in delivering the lean objectives more efficiently and, therefore, the combined application of LP practices and I4.0 technologies play a significant role in enhancing organizational SP. Originality/valueThough the present literature indicates the probable significant association between LP and SP or I4.0 technologies and SP, no study, with the best of the authors' knowledge, has empirically examined the combined impacts of correlation between LP and I4.0 on SP. This is also a unique study to apply the PBV theory to explain the organizational SP through the combination of common resources and technologies.

Introduction: Obstructive jaundice in young patients generally prompts a focused differential based on distal biliary obstruction, but proximal obstructions require a more extensive workup. Here, we present a perplexing case of proximal biliary obstruction in a young man. Case Description/Methods: A 34-year-old male industrial worker with IBS-D but no significant personal/family history presented with epigastric abdominal pain, weight loss, and jaundice. Labs were significant for AST 95 U/dl, ALT 221 U/dl, Total bilirubin 4.9 mg/dl, and ALP 277 U/L. Toxicology and testing for HIV, Hepatitis A/B/C, extractable nuclear antigen antibodies, ANCA, autoimmune hepatitis, Wilson’s, A1AT deficiency, and hereditary hemochromatosis were unrevealing except for an IgG4 of 133 mg/dl and a CA 19-9 of 133 U/ml. Phase CT liver and MRI showed a 2.8 x 2.8 cm mass at the left/right liver lobe confluence with significant intrahepatic biliary ductal dilatation but were nondiagnostic for hepatocellular carcinoma (HCC), cholangiocarcinoma, or lymphoma (Figure 1, left). Multifocal lymphadenopathy in the porta hepatis was also noted and suspicious for inflammatory pseudotumor. ERCP showed a right-sided hepatic duct inflammatory stricture that was sampled and stented (Figure 1, middle). Lymph node pathology showed malignant gland-forming cells with intracytoplasmic mucin and staining compatible with cancer of hepatobiliary origin (CK19 and CDX2 positive, CK7 and CK20 negative). Bile duct brushings were benign. PET-CT revealed hypermetabolic retroperitoneal, supraclavicular, and left mediastinal lymphadenopathy concerning for metastases (Figure 1, right). Given the lack of criteria to satisfy the diagnosis of HCC, cholangiocarcinoma, or lymphoma, he is undergoing initiation with FOLFOX chemotherapy for a working diagnosis of cancer of unknown primary. Discussion: Pseudoinflammatory tumor from IgG4 disease, supported by his imaging and serologies, was initially our working diagnosis1-6. IgG4 disease, given its nonspecific presentation and rarity, is misdiagnosed as cancer2,3,5. Alternatively, cholangiocarcinoma, feared for its variable presentation in the absence of primary sclerosing cholangitis (PSC), was also considered. We pondered whether the patient’s IBS had been misdiagnosed ulcerative colitis with PSC8. This patient illustrates that consideration of both common and obscure diagnoses is crucial in evaluating obstructive jaundice, especially in young adults without risk factors for liver disease or malignancy.Figure 1.: Figure 1, left. MRI Contrast (A-B) CT Liver Triple Phase (C) Images showing ill-defined mass (arrows) at left/right hepatic lobe confluence causing intrahepatic biliary dilatation, as seen on MRI T2 Coronal (A) and Axial (B) views, and iterative model reconstruction coronal CT Liver view (C). Figure 1, middle. ERCP showing inflammatory stricture occupying right and common hepatic duct (A-C), also visualized on fluoroscopy(D). Figure 1, right. PET CT image showing multifocal liver lesions surrounding central mass in left liver lobe, as well as distant hypermetabolic activity in the retroperitoneal mediastinal, and supraclavicular lymph nodes (arrows) concerning for distant metastasis.

This study examines the impact of Total Quality Management (TQM) and Industry 4.0 (I4.0) on the sustainability performance (SP) of the ready-made garments (RMG) sector in Bangladesh. Furthermore, this research aimed to analyze the potential of TQM to transfer the impact of I4.0 on sustainability performance. The information was gathered using an online survey that was completed by 240 individuals working in nine different ready-made garments industries located in Dhaka, Bangladesh, to investigate the proposed model of this research. Analyzing the data was accomplished through the use of the Structural Equation Modelling (SEM) approach. Research findings demonstrate that both TQM and I4.0 technologies have a significant influence on the sustainability of the RMG sector in Bangladesh. The finding also demonstrates that TQM act as a positive mediator between I4.0 and sustainability performance. The outcomes will help management best in the decision-making process when deciding to adopt TQM principles and I4.0 technologies in their organizations. The findings also offer useful information to industrial executives on how to secure the sustainability of their organizations through TQM and I4.0. This study is a one-of-a-kind study that examines the probable association between TQM, I4.0, and sustainability performance. In addition, it also investigates the role of TQM in mediating the relationship between I4.0 and sustainability performance.