The expanding clinical and genetic spectrum of DYNC1H1-related disorders.

Intracellular trafficking involves an intricate machinery of motor complexes including the dynein complex to shuttle cargo for autophagolysosomal degradation. Deficiency in dynein axonemal chains as well as cytoplasmic light and intermediate chains have been linked with ciliary dyskinesia and skeletal dysplasia. The cytoplasmic dynein 1 heavy chain protein (DYNC1H1) serves as a core complex for retrograde trafficking in neuronal axons. Dominant pathogenic variants in DYNC1H1 have been previously implicated in peripheral neuromuscular disorders (NMD) and neurodevelopmental disorders (NDD). As heavy-chain dynein is ubiquitously expressed, the apparent selectivity of heavy-chain dyneinopathy for motor neuronal phenotypes remains currently unaccounted for. Here, we aimed to evaluate the full DYNC1H1-related clinical, molecular and imaging spectrum, including multisystem features and novel phenotypes presenting throughout life. We identified 47 cases from 43 families with pathogenic heterozygous variants in DYNC1H1 (aged 0-59 years) and collected phenotypic data via a comprehensive standardized survey and clinical follow-up appointments. Most patients presented with divergent and previously unrecognized neurological and multisystem features, leading to significant delays in genetic testing and establishing the correct diagnosis. Neurological phenotypes include novel autonomic features, previously rarely described behavioral disorders, movement disorders, and periventricular lesions. Sensory neuropathy was identified in nine patients (median age of onset 10.6 years), of which five were only diagnosed after the second decade of life, and three had a progressive age-dependent sensory neuropathy. Novel multisystem features included primary immunodeficiency, bilateral sensorineural hearing loss, organ anomalies, and skeletal manifestations, resembling the phenotypic spectrum of other dyneinopathies. We also identified an age-dependent biphasic disease course with developmental regression in the first decade and, following a period of stability, neurodegenerative progression after the second decade of life. Of note, we observed several cases in whom neurodegeneration appeared to be prompted by intercurrent systemic infections with double-stranded DNA viruses (Herpesviridae) or single-stranded RNA viruses (Ross-River fever, SARS-CoV-2). Moreover, the disease course appeared to be exacerbated by viral infections regardless of age and/or severity of NDD manifestations, indicating a role of dynein in anti-viral immunity and neuronal health. In summary, our findings expand the clinical, imaging, and molecular spectrum of pathogenic DYNC1H1 variants beyond motor neuropathy disorders and suggest a life-long continuum and age-related progression due to deficient intracellular trafficking. This study will facilitate early diagnosis and improve counselling and health surveillance of affected patients.

Mapping the Pathways Between Posttraumatic Stress Disorder, Depression, and Alcohol and Cannabis Use: A Network Analysis.

Objective: The present study examines the network structure and, using Bayesian network analysis, estimates the directional pathways among symptoms of posttraumatic stress disorder (PTSD), major depressive disorder (MDD), and levels of alcohol and cannabis use. Method: A sample of 1471 adults in the United States, who reported at least one potentially traumatic event, completed the PTSD Checklist (PCL-5), Patient Health Questionnaire (PHQ-9), and the Alcohol/Cannabis Use Disorders Identification Test (AUDIT/CUDIT). A regularized partial correlation network provided estimates of symptoms clusters and connections. Directional pathways within the network were then estimated using a directed acyclic graph (DAG). Results: Symptoms clustered in theoretically consistent ways. Risky behavior demonstrated the highest strength centrality and bridge strength. Neither alcohol nor cannabis use appeared central in the network, and DAG results suggested that MDD and PTSD symptoms are more likely to lead to substance use than the other way around. Conclusions: Results suggest that cannabis use is largely connected to alcohol use. Consistent with prior research, risky behavior appeared to be the primary bridge between substance use and PTSD. The direction of associations between substance use and psychological symptoms requires further attention.

High-pressure single-crystal diffraction at the Australian Synchrotron.

A new high-pressure single-crystal diffraction setup has been designed and implemented at the Australian Synchrotron for collecting molecular and protein crystal structures. The setup incorporates a modified micro-Merrill-Bassett cell and holder designed specifically to fit onto the horizontal air-bearing goniometer, allowing high-pressure diffraction measurements to be collected with little to no modification of the beamline setup compared with ambient data collections. Compression data for the amino acid, L-threonine, and the protein, hen egg-white lysozyme, were collected, showcasing the capabilities of the setup.

Respiratory rate monitoring and early detection of deterioration practices.

BACKGROUND: Growing evidence points to respiratory rate (RR) being the most important vital sign for early detection of patient deterioration. However, RR is the vital sign most likely to be inaccurate or missed. AIMS: To measure prevalence of early detection of deterioration protocols, examine whether RR was perceived as the leading indicator of deterioration, and understand RR monitoring practices used by nurses around the world. METHODS: A double-blinded survey of nurses in Asia Pacific, Middle East, and Western Europe. FINDINGS: 161 nurses responded. Most (80%) reported having an initiative for early detection of patient deterioration; 12% indicated RR was the most important indicator of deterioration, 27% captured RR for all medical/surgical patients, and 56% take 60 seconds or longer to measure RR. CONCLUSION: Nurses across all regions generally underestimated the importance of capturing an accurate RR for all patients' multiple times per day. This study reinforces the need to enhance international nursing education regarding the importance of RR.

Anatomy and dietary specialization influence sensory behaviour among sympatric primates.

Senses form the interface between animals and environments, and provide a window into the ecology of past and present species. However, research on sensory behaviours by wild frugivores is sparse. Here, we examine fruit assessment by three sympatric primates (Alouatta palliata, Ateles geoffroyi and Cebus imitator) to test the hypothesis that dietary and sensory specialization shape foraging behaviours. Ateles and Cebus groups are comprised of dichromats and trichromats, while all Alouatta are trichomats. We use anatomical proxies to examine smell, taste and manual touch, and opsin genotyping to assess colour vision. We find that the frugivorous spider monkeys (Ateles geoffroyi) sniff fruits most often, omnivorous capuchins (Cebus imitator), the species with the highest manual dexterity, use manual touch most often, and that main olfactory bulb volume is a better predictor of sniffing behaviour than nasal turbinate surface area. We also identify an interaction between colour vision phenotype and use of other senses. Controlling for species, dichromats sniff and bite fruits more often than trichromats, and trichromats use manual touch to evaluate cryptic fruits more often than dichromats. Our findings reveal new relationships among dietary specialization, anatomical variation and foraging behaviour, and promote understanding of sensory system evolution.

Detection of brain somatic variation in epilepsy-associated developmental lesions.

OBJECTIVE: Epilepsy-associated developmental lesions, including malformations of cortical development and low-grade developmental tumors, represent a major cause of drug-resistant seizures requiring surgical intervention in children. Brain-restricted somatic mosaicism has been implicated in the genetic etiology of these lesions; however, many contributory genes remain unidentified. METHODS: We enrolled 50 children who were undergoing epilepsy surgery into a translational research study. Resected tissue was divided for clinical neuropathologic evaluation and genomic analysis. We performed exome and RNA sequencing to identify somatic variation and we confirmed our findings using high-depth targeted DNA sequencing. RESULTS: We uncovered candidate disease-causing somatic variation affecting 28 patients (56%), as well as candidate germline variants affecting 4 patients (8%). In agreement with previous studies, we identified somatic variation affecting solute carrier family 35 member A2 (SLC35A2) and mechanistic target of rapamycin kinase (MTOR) pathway genes in patients with focal cortical dysplasia. Somatic gains of chromosome 1q were detected in 30% (3 of 10) of patients with Type I focal cortical dysplasia (FCD)s. Somatic variation in mitogen-activated protein kinase (MAPK) pathway genes (i.e., fibroblast growth factor receptor 1 [FGFR1], FGFR2, B-raf proto-oncogene, serine/threonine kinase [BRAF], and KRAS proto-oncogene, GTPase [KRAS]) was associated with low-grade epilepsy-associated developmental tumors. RNA sequencing enabled the detection of somatic structural variation that would have otherwise been missed, and which accounted for more than one-half of epilepsy-associated tumor diagnoses. Sampling across multiple anatomic regions revealed that somatic variant allele fractions vary widely within epileptogenic tissue. Finally, we identified putative disease-causing variants in genes not yet associated with focal cortical dysplasia. SIGNIFICANCE: These results further elucidate the genetic basis of structural brain abnormalities leading to focal epilepsy in children and point to new candidate disease genes.

Empirical Evaluation of Rainbow Reflections: A Comic Book Anthology on Body Image for Queer Men.

Gay, bisexual, and queer (GBQ) men are at higher risk of negative body image. As having a negative body image is related to negative mood, sexual, and health outcomes, identifying and providing community-friendly tools for GBQ men is important. This paper describes the creation and evaluation of Rainbow Reflections, a comic anthology developed to promote awareness of and communication about body image. Rainbow Reflections includes comics from 38 trans- and cis-GBQ artists who drew inspiration from personal narratives based on pre-determined themes in the empirical literature and interactive inserts based on evidence-based practice. To evaluate Rainbow Reflections, 167 trans- and cis-GBQ men completed pre-post measures before/after viewing a selection of comics and responded to an open-ended question about their experience. Overall, participants rated the comic book positively, with a majority (61.1%) indicating that they would recommend the book to a friend. After viewing the comics, participants reported greater comfort with initiating conversations about body image, greater satisfaction with their bodies, and reported higher estimates of how common body image concerns are for queer men. Themes that emerged from open-ended responses included participants reflecting on personal struggles (~ 30%), relating with the stories of others (~ 22%), reflecting on the standards of queer men (~ 18%), recognizing cis-privilege (~ 11%), reflecting on others' struggles (~ 9%), negative feedback about the comics (~ 7%), and balancing masculine and feminine (~ 3%). Results of the study provide preliminary evidence for Rainbow Reflections as an effective community-friendly tool to promote awareness of and communication about body image for GBQ men.

Non-invasive risk scores do not reliably identify future cirrhosis or hepatocellular carcinoma in Type 2 diabetes: The Edinburgh type 2 diabetes study.

BACKGROUND: The incidence of cirrhosis and hepatocellular carcinoma (HCC) is increased in Type 2 diabetes, primarily secondary to non-alcoholic fatty liver disease (NAFLD). European guidelines recommend screening for NAFLD in Type 2 diabetes. American guidelines, while not advocating a screening protocol, suggest using non-invasive markers of fibrosis for risk-stratification and guiding onward referral. AIMS: To test the ability of individual fibrosis scores and the European screening algorithm to predict 11-year incident cirrhosis/HCC in an asymptomatic community cohort of older people with Type 2 diabetes. METHODS: The Edinburgh Type 2 Diabetes Study investigated men and women with Type 2 diabetes (n = 1066, aged 60-75 at baseline). Liver markers were measured at baseline and year 1; steatosis and fibrosis markers were calculated according to independently published calculations. During 11 years of follow-up, cases of cirrhosis and HCC were identified. RESULTS: Forty-three out of 1059 participants with no baseline cirrhosis/HCC developed incident disease. All scores were significantly associated with incident liver disease by odds ratio (P < .05). The ability of the risk-stratification tools to accurately identify those who developed incident cirrhosis/HCC was poor with low-positive predictive values (5-46%) and high false-negative and -positive rates (up to 60% and 77%) respectively. When fibrosis risk scores were used in conjunction with the European algorithm, they performed modestly better than when applied in isolation. CONCLUSIONS: In a cohort with a moderately low incidence of cirrhosis/HCC, existing risk scores did not reliably identify participants at high risk. Better prediction models for cirrhosis/HCC in people with Type 2 diabetes are required.

Using Item Response Theory to Develop a 60-Item Representation of the NEO PI-R Using the International Personality Item Pool: Development of the IPIP-NEO-60.

Given advantages of freely available and modifiable measures, an increase in the use of measures developed from the International Personality Item Pool (IPIP), including the 300-item representation of the Revised NEO Personality Inventory (NEO PI-R; Costa & McCrae, 1992a ) has occurred. The focus of this study was to use item response theory to develop a 60-item, IPIP-based measure of the Five-Factor Model (FFM) that provides equal representation of the FFM facets and to test the reliability and convergent and criterion validity of this measure compared to the NEO Five Factor Inventory (NEO-FFI). In an undergraduate sample (n = 359), scores from the NEO-FFI and IPIP-NEO-60 demonstrated good reliability and convergent validity with the NEO PI-R and IPIP-NEO-300. Additionally, across criterion variables in the undergraduate sample as well as a community-based sample (n = 757), the NEO-FFI and IPIP-NEO-60 demonstrated similar nomological networks across a wide range of external variables (rICC = .96). Finally, as expected, in an MTurk sample the IPIP-NEO-60 demonstrated advantages over the Big Five Inventory-2 (Soto & John, 2017 ; n = 342) with regard to the Agreeableness domain content. The results suggest strong reliability and validity of the IPIP-NEO-60 scores.

MX2: a high-flux undulator microfocus beamline serving both the chemical and macromolecular crystallography communities at the Australian Synchrotron.

MX2 is an in-vacuum undulator-based crystallography beamline at the 3 GeV Australian Synchrotron. The beamline delivers hard X-rays in the energy range 4.8-21 keV to a focal spot of 22 × 12 µm FWHM (H × V). At 13 keV the flux at the sample is 3.4 × 1012 photons s-1. The beamline endstation allows robotic handling of cryogenic samples via an updated SSRL SAM robot. This beamline is ideal for weakly diffracting hard-to-crystallize proteins, virus particles, protein assemblies and nucleic acids as well as smaller molecules such as inorganic catalysts and organic drug molecules. The beamline is now mature and has enjoyed a full user program for the last nine years. This paper describes the beamline status, plans for its future and some recent scientific highlights.

Cardiovascular disease biomarkers are associated with declining renal function in type 2 diabetes.

AIMS/HYPOTHESIS: We investigated whether biochemical cardiovascular risk factors and/or markers of subclinical cardiovascular disease were associated with the development of reduced renal function in people with type 2 diabetes. METHODS: A cohort of 1066 Scottish men and women aged 60-74 years with type 2 diabetes from the Edinburgh Type 2 Diabetes Study were followed up for a median of 6.7 years. New-onset reduced renal function was defined as two eGFRs <60 ml-1 min-1 (1.73 m)-2 at least 3 months apart with a > 25% decline from baseline eGFR. Ankle brachial pressure index (ABI), N-terminal pro-B-type natriuretic peptide (NT-proBNP) and high-sensitivity troponin T (hsTnT) were measured at baseline. Pulse wave velocity (PWV) and carotid intima media thickness were measured 1 year into follow-up. Data were analysed using Cox proportional hazards models. RESULTS: A total of 119 participants developed reduced renal function during follow-up. ABI, PWV, NT-proBNP and hsTnT were all associated with onset of decline in renal function following adjustment for age and sex. These associations were attenuated after adjustment for additional diabetes renal disease risk factors (systolic BP, baseline eGFR, albumin:creatinine ratio and smoking pack-years), with the exception of hsTnT which remained independently associated (HR 1.51 [95% CI 1.22, 1.87]). Inclusion of hsTnT in a predictive model improved the continuous net reclassification index by 0.165 (0.008, 0.286). CONCLUSIONS/INTERPRETATION: Our findings demonstrate an association between hsTnT, a marker of subclinical cardiac ischaemia, and subsequent renal function decline. Further research is required to establish the predictive value of hsTnT and response to intervention.

Gender Bias in the Measurement of Workaholism.

Past research suggests gender differences in workaholism might be due to differences in how men and women respond to the item content in workaholism measures. Using item response theory differential item functioning, we show women are less likely to report some workaholism items, leading to contamination. Specifically, women are less likely to report spending more time at work than other activities, and staying at work longer than others. We speculate that societal norms and practical restrictions on women's time results in lower endorsement rates for these items compared to men, and thus underestimates their workaholism. Results contradict past findings that men and women are similar in regard to workaholism and suggest women are in fact higher in workaholism than men. Limitations and future directions are discussed.

The Downsides of Extreme Conscientiousness for Psychological Well-being: The Role of Obsessive Compulsive Tendencies.

Although conscientiousness exhibits positive relations with psychological well-being, theoretical and empirical work suggests individuals can be too conscientious, resulting in obsessive-compulsiveness, and therein less positive individual outcomes. However, the potential for curvilinearity between conscientiousness and well-being has been underexplored. We measured 912 subjects on facets of conscientiousness, obsessive-compulsive personality, and well-being variables (life satisfaction, job satisfaction, self-esteem, positive affect, negative affect, work stress). Methods of scoring included traditional sum-scoring, traditional item response theory (IRT), and a relatively new IRT approach. Structural models were estimated to evaluate curvilinearity. Results confirmed the curvilinear relationship between conscientiousness and well-being, and demonstrated that differential facet-level relationships underlie weaker curvilinearity at the general trait level. Consistency was found in the strength of relation between conscientiousness facets with their obsessive-compulsive variants and their contribution to decreased well-being. The most common association was that higher standing on conscientiousness facets was positively related to negative affect. Findings support the idea that extreme standing on facets of conscientiousness more strongly linked to their obsessive-compulsive variants contributed to lower well-being, highlighting the importance of considering alternative functional representations of the relationship between personality and other constructs. Future work should seek to further clarify the link between conscientiousness and negative affect.

S-nitrosylation therapy to improve oxygen delivery of banked blood.

From the perspectives of disease transmission and sterility maintenance, the world's blood supplies are generally safe. However, in multiple clinical settings, red blood cell (RBC) transfusions are associated with adverse cardiovascular events and multiorgan injury. Because ∼85 million units of blood are administered worldwide each year, transfusion-related morbidity and mortality is a major public health concern. Blood undergoes multiple biochemical changes during storage, but the relevance of these changes to unfavorable outcomes is unclear. Banked blood shows reduced levels of S-nitrosohemoglobin (SNO-Hb), which in turn impairs the ability of stored RBCs to effect hypoxic vasodilation. We therefore reasoned that transfusion of SNO-Hb-deficient blood may exacerbate, rather than correct, impairments in tissue oxygenation, and that restoration of SNO-Hb levels would improve transfusion efficacy. Notably in mice, administration of banked RBCs decreased skeletal muscle pO2, but infusion of renitrosylated cells maintained tissue oxygenation. In rats, hemorrhage-induced reductions in muscle pO2 were corrected by SNO-Hb-repleted RBCs, but not by control, stored RBCs. In anemic awake sheep, stored renitrosylated, but not control RBCs, produced sustained improvements in O2 delivery; in anesthetized sheep, decrements in hemodynamic status, renal blood flow, and kidney function incurred following transfusion of banked blood were also prevented by renitrosylation. Collectively, our findings lend support to the idea that transfusions may be causally linked to ischemic events and suggest a simple approach to prevention (i.e., SNO-Hb repletion). If these data are replicated in clinical trials, renitrosylation therapy could have significant therapeutic impact on the care of millions of patients.

γ-Glutamyltransferase, but not markers of hepatic fibrosis, is associated with cardiovascular disease in older people with type 2 diabetes mellitus: the Edinburgh Type 2 Diabetes Study.

AIMS/HYPOTHESIS: We examined the association of prevalent and incident cardiovascular disease (CVD) with chronic liver disease in a cohort of community-based people with type 2 diabetes, in order to clarify the relationship between these two important conditions. METHODS: 1,066 participants with type 2 diabetes aged 60-75 years underwent assessment of a range of liver injury markers (non-specific injury, steatosis, steatohepatitis, fibrosis, portal hypertension). Individuals were followed up for incident cardiovascular events. RESULTS: At baseline there were 370/1,033 patients with prevalent CVD, including 317/1,033 with coronary artery disease (CAD). After a mean follow-up of 4.4 years there were 44/663 incident CVD events, including 27/663 CAD events. There were 30/82 CVD-related deaths. Risk of dying from or developing CVD was no higher in participants with steatosis than in those without (HR 0.90; 95% CI 0.40, 2.00; p > 0.05). The only notable relationship was with γ-glutamyltransferase (GGT) (incident CVD: adjusted HR for doubling GGT 1.24 [95% CI 0.97, 1.59] p = 0.086; incident CAD: adjusted HR 1.33 [95% CI 1.00, 1.78] p = 0.053), suggesting that in our study population, chronic liver disease may have little effect on the development of, or mortality from, CVD. CONCLUSIONS/INTERPRETATION: An independent association between GGT and CVD warrants further exploration as a potentially useful addition to current cardiovascular risk prediction models in diabetes. However, overall findings failed to suggest that there is a clinical or pathophysiological association between chronic liver disease and CVD in elderly people with type 2 diabetes.

MX1: a bending-magnet crystallography beamline serving both chemical and macromolecular crystallography communities at the Australian Synchrotron.

MX1 is a bending-magnet crystallography beamline at the 3 GeV Australian Synchrotron. The beamline delivers hard X-rays in the energy range from 8 to 18 keV to a focal spot at the sample position of 120 µm FWHM. The beamline endstation and ancillary equipment facilitate local and remote access for both chemical and biological macromolecular crystallography. Here, the design of the beamline and endstation are discussed. The beamline has enjoyed a full user program for the last seven years and scientific highlights from the user program are also presented.

Activin signalling and pre-eclampsia: from genetic risk to pre-symptomatic biomarker.

Pre-eclampsia is a multi-system condition in pregnancy that is characterised by the onset of hypertension and proteinuria in women after the 20th week and it remains a leading cause of maternal and fetal mortality. Despite this the causative molecular basis of pre-eclampsia remains poorly understood. As a result, an intensive research effort has focused on understanding the molecular mechanisms involved in pre-eclampsia and using this information to identify new pre-symptomatic bio-markers of the condition. Activin A and its receptor, ACVR2A, have been extensively studied in this regard. Activin A is a member of the transforming growth factor (TGF)-ß superfamily that has a wide range of biological functions depending on the cellular context. Recent work has shown that polymorphisms in ACVR2A may be a genetic risk factor for pre-eclampsia. Furthermore, both placenta and serum levels of Activin A are significantly increased in pre-eclampsia suggesting that Activin A may be a possible biomarker for the condition. Here we review the latest advances in this field and link these with new molecular data that suggest that the oxidative stress and pro-inflammatory cytokine production seen in pre-eclampsia may result in increased placental Activin A secretion in an attempt to maintain placental function.

Using non-invasive biomarkers to identify hepatic fibrosis in people with type 2 diabetes mellitus: the Edinburgh type 2 diabetes study.

BACKGROUND & AIMS: It is difficult to determine the different stages of non-alcoholic fatty liver disease without the use of invasive liver biopsy. In this study we investigated five non-invasive biomarkers used previously to detect hepatic fibrosis and determined the level of agreement between them in order to inform future research. METHODS: In the Edinburgh Type 2 Diabetes Study, a population-based cohort aged 60-74 years with type 2 diabetes, 831 participants underwent ultrasound assessment for fatty liver and had serum aspartate aminotransferase to alanine aminotransferase ratio (AST/ALT), aspartate to platelet ratio index (APRI), European Liver Fibrosis panel (ELF), Fibrosis-4 Score (FIB4) and liver stiffness measurement (LSM) measured. RESULTS: Literature based cut-offs yielded marked differences in the proportions of the cohort with probable liver fibrosis in the full cohort. Agreement between the top 5% of the distribution for each biomarker pair was poor. APRI and FIB4 had the best positive agreement at 76.4%, but agreement for all of the other serum biomarker pairs was between 18% and 34%. Agreement with LSM was poor (9-16%). CONCLUSIONS: We found poor correlation between the five biomarkers of liver fibrosis studied. Using the top 5% of each biomarker resulted in good agreement on the absence of advanced liver disease but poor agreement on the presence of advanced disease. Further work is required to validate these markers against liver biopsy and to determine their predictive value for clinical liver-related endpoints, in a range of different low and high risk population groups.

Non-invasive hepatic biomarkers (ELF and CK18) in people with type 2 diabetes: the Edinburgh type 2 diabetes study.

BACKGROUND & AIMS: Type 2 diabetes is an established risk factor for the presence and progression of fatty liver. Little is known about the distributions and correlates of hepatic non-invasive biomarkers in community-based populations with diabetes, unselected for liver disease. We aimed to identify the distribution of, and metabolic risk factors associated with serum cytokeratin-18 (CK18) and the Enhanced Liver Fibrosis score (ELF), in a large, representative cohort of people with type 2 diabetes (the Edinburgh Type 2 Diabetes Study, ET2DS). METHODS: Nine hundred and thirty-nine ET2DS participants, aged 60-74 years underwent physical examination including ultrasound for assessment of liver fat. Representative subgroups were assessed for markers of chronic liver disease (CK18 and ELF). RESULTS: CK18 values ranged from 29-993 U/L (median 102, IQR 76-137 U/L) and ELF scores ranged from 6.9-11.6 (mean 8.9, SD 0.8). Statistically significant associations were found between both biomarkers and a number of metabolic risk factors. Neither CK18 nor ELF was consistently or strongly associated with established hepatic risk factors (alcohol excess, hepatotoxic medication use and positive immunology titres). CONCLUSIONS: We identified the distribution of CK18 and ELF in a large cohort of older people with type 2 diabetes and showed that these markers are associated with an adverse metabolic risk factor profile, although much of the variation in biomarkers remained unexplained. Prospective studies are required to determine the extent to which CK18 and/or ELF predict the development of symptomatic liver disease and to identify additional risk factors which may influence the development of advanced liver disease in people with type 2 diabetes.

Sarm1 is not necessary for activation of neuron-intrinsic growth programs yet required for the Schwann cell repair response and peripheral nerve regeneration.

Upon peripheral nervous system (PNS) injury, severed axons undergo rapid SARM1-dependent Wallerian degeneration (WD). In mammals, the role of SARM1 in PNS regeneration, however, is unknown. Here we demonstrate that Sarm1 is not required for axotomy induced activation of neuron-intrinsic growth programs and axonal growth into a nerve crush site. However, in the distal nerve, Sarm1 is necessary for the timely induction of the Schwann cell (SC) repair response, nerve inflammation, myelin clearance, and regeneration of sensory and motor axons. In Sarm1-/- mice, regenerated fibers exhibit reduced axon caliber, defective nerve conduction, and recovery of motor function is delayed. The growth hostile environment of Sarm1-/- distal nerve tissue was demonstrated by grafting of Sarm1-/- nerve into WT recipients. SC lineage tracing in injured WT and Sarm1-/- mice revealed morphological differences. In the Sarm1-/- distal nerve, the appearance of p75NTR+, c-Jun+ SCs is significantly delayed. Ex vivo, p75NTR and c-Jun upregulation in Sarm1-/- nerves can be rescued by pharmacological inhibition of ErbB kinase. Together, our studies show that Sarm1 is not necessary for the activation of neuron intrinsic growth programs but in the distal nerve is required for the orchestration of cellular programs that underlie rapid axon extension.