Interleukin (IL)-10-producing B cells (B10 cells) have emerged as important regulatory elements with immunosuppressive roles. Chronic lymphocytic leukemia (CLL) B cells also secrete IL-10 and share features of B10 cells, suggesting a possible contribution of CLL B cells to immunosuppression in CLL patients. Factors controlling the emergence of B10 cells are not known. B-cell-activating factor of the tumor necrosis factor (TNF) family (BAFF) is critical for B-cell maturation and survival, and is implicated in the development and progression of CLL. We sought to investigate the role of BAFF in the emergence of IL-10-producing regulatory B cells in healthy donors and CLL patients. Here, we report that BAFF signaling promotes IL-10 production by CLL B cells in a mouse model of CLL and in CLL patients. Moreover, BAFF-mediated IL-10 production by normal and CLL B cells is mediated via its receptor transmembrane activator and cyclophilin ligand interactor. Our work uncovered a major targetable pathway important for the generation of regulatory B cells that is detrimental to immunity in CLL.

Subtle gait and balance dysfunction is a precursor to loss of mobility in multiple sclerosis (MS). Biomechanical assessments using advanced gait and balance analysis technologies can identify these subtle changes and could be used to predict mobility loss early in the disease. This update critically evaluates advanced gait and balance analysis technologies and their applicability to identifying early lower limb dysfunction in people with MS. Non-wearable (motion capture systems, force platforms, and sensor-embedded walkways) and wearable (pressure and inertial sensors) biomechanical analysis systems have been developed to provide quantitative gait and balance assessments. Non-wearable systems are highly accurate, reliable and provide detailed outcomes, but require cumbersome and expensive equipment. Wearable systems provide less detail but can be used in community settings and can provide real-time feedback to patients and clinicians. Biomechanical analysis using advanced gait and balance analysis technologies can identify changes in gait and balance in early MS and consequently have the potential to significantly improve monitoring of mobility changes in MS.

Tremor in people with multiple sclerosis (MS) is a frequent and debilitating symptom with a relatively poorly understood pathophysiology. To determine the relationship between clinical tremor severity and structural magnetic resonance imaging parameters. Eleven patients with clinically definite MS and right-sided upper limb tremor were studied. Tremor severity was assessed using the Bain score (overall severity, writing, and Archimedes spiral drawing). Cerebellar dysfunction was assessed using the Scale for the Assessment and Rating of Ataxia. Dystonia was assessed using the Global Dystonia Scale adapted for upper limb. For all subjects, volume was calculated for the thalamus from T1-weighted volumetric scans using Freesurfer. Superior cerebellar peduncle (SCP) cross-sectional areas were measured manually. The presence of lesions was visually determined and the lesion volumes were calculated by the lesion growth algorithm as implemented in the Lesion Segmentation Toolbox. Right thalamic volume negatively correlated with Bain tremor severity score (ρ = - 0.65, p = 0.03). Left thalamic volume negatively correlated with general Bain tremor severity score (ρ = - 0.65, p = 0.03) and the Bain writing score (ρ = - 0.65, p = 0.03). Right SCP area negatively correlated with Bain writing score (ρ = - 0.69, p = 0.02). Finally, Bain Archimedes score was significantly higher in patients with lesions in the contralateral thalamus. Whole brain lesion load showed no relationship with tremor severity. These results implicate degeneration of key structures within the cerebello-thalamic pathway as pathological substrates for tremor in MS patients.

Invasive Brain-Computer Interfaces (BCIs) require surgeries with high health-risks. The risk-to-benefit ratio of the procedure could potentially be improved by pre-surgically identifying the ideal locations for mental strategy classification. We recorded high-spatiotemporal resolution blood-oxygenation-level-dependent (BOLD) signals using functional MRI at 7 Tesla in eleven healthy participants during two motor imagery tasks. BCI diagnostic task isolated the intent to imagine movements, while BCI simulation task simulated the neural states that may be yielded in a real-life BCI-operation scenario. Imagination of movements were classified from the BOLD signals in sub-regions of activation within a single or multiple dorsal motor network regions. Then, the participant's decoding performance during the BCI simulation task was predicted from the BCI diagnostic task. The results revealed that drawing information from multiple regions compared to a single region increased the classification accuracy of imagined movements. Importantly, systematic unimodal and multimodal classification revealed the ideal combination of regions that yielded the best classification accuracy at the individual-level. Lastly, a given participant's decoding performance achieved during the BCI simulation task could be predicted from the BCI diagnostic task. These results show the feasibility of 7T-fMRI with unimodal and multimodal classification being utilized for identifying ideal sites for mental strategy classification.

Large birthweight, or macrosomia, is one of the commonest complications for pregnancies affected by diabetes. As macrosomia is associated with an increased risk of a number of adverse outcomes for both the mother and offspring, accurate antenatal prediction of fetal macrosomia could be beneficial in guiding appropriate models of care and interventions that may avoid or reduce these associated risks. However, current prediction strategies which include physical examination and ultrasound assessment, are imprecise. Biomarkers are proving useful in various specialties and may offer a new avenue for improved prediction of macrosomia. Prime biomarker candidates in pregnancies with diabetes include maternal glycaemic markers (glucose, 1,5-anhydroglucitol, glycosylated haemoglobin) and hormones proposed implicated in placental nutrient transfer (adiponectin and insulin-like growth factor-1). There is some support for an association of these biomarkers with birthweight and/or macrosomia, although current evidence in this emerging field is area is still limited. Thus, although biomarkers hold promise, further investigation is needed to elucidate the potential clinical utility of biomarkers for macrosomia prediction for pregnancies affected by diabetes.

Background: The phase-II modafinil in debilitating fatigue after stroke trial demonstrated that modafinil improves fatigue and quality of life in severely fatigued stroke survivors. For this study, we sought to examine the interaction between fatigue and quality of life after stroke and determine whether reducing fatigue resulted in improved quality of life. In addition, we followed up a subset of patients 12-months after the trial to assess the long-term outcomes of modafinil therapy. Methods: We used linear regression to analyze interaction between baseline fatigue, as measured by the multidimensional fatigue inventory (MFI), and quality of life, as measured by the stroke-specific quality of life scale (SSQoL); and between changes in MFI and SSQoL during treatment. Patients also took part in semi-structured interviews and study assessments 12-months after trial completion to assess long-term patterns of modafinil use, safety and efficacy. Results: MFI and SSQoL were significantly correlated at baseline (β = -1.975 95% CI -3.082, -0.869, p < 0.001), as were changes in MFI and SSQoL during treatment (β = -1.054 95% CI -1.556, -0.553, p < 0.001). 18 patients agreed to 12-month follow-up, of whom 5 had continued to use modafinil. Patients taking modafinil daily demonstrated sustained improvement of 33-38 points in MFI compared to baseline. Two adverse events were reported and there was no evidence of drug tolerance. Conclusion: Modafinil appears to be safe and, for at least some patients, effective long-term in fatigued stroke survivors. Alleviating fatigue has a significant relationship with improved quality of life. Clinical trial registration: https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=368268, unique-identifier: ACTRN12615000350527.

Background: Successful engraftment and reconstitution of the innate and adaptive immune system are associated with improved outcomes in recipients of allogeneic hematopoietic stem cell transplantation (HSCT). A clinically meaningful and simple biomarker of immunosuppression could potentially assist clinicians in their decision-making. We aimed to determine the relationship between T-cell production of interferon gamma (IFN-γ) in response to phytohemagglutinin (PHA) to clinical outcomes in HSCT recipients. Methods: A prospective observational multicenter study of 73 adult allogeneic HSCT recipients was conducted in Melbourne, Australia. Eligible participants were >18 years and at risk of cytomegalovirus disease. T-cell responses to PHA were assessed at 3, 6, 9, and 12 months post-HSCT using the commercial quantiferon-cytomegalovirus assay, which quantifies IFN-γ production by ELISA following stimulation with PHA. A low response was defined as IFN-γ <0.5 IU/ml following stimulation with PHA. Results: At 3 months post-HSCT, high responses to PHA (median IFN-γ 7.68 IU/ml) were seen in 63% of participants and low responses to PHA (median IFN-γ 0.06 IU/ml) in 37%. IFN-γ responses to PHA were significantly associated with the severity of acute graft versus host disease (AGVHD) (spearman r = -0.53, p < 0.001) and correlated with blood lymphocyte count (spearman r = 0.52, p < 0.001). Twelve month overall survival was greater in individuals with high compared to low IFN-γ response to PHA at 3 months [92 vs. 62%, respectively, Cox proportional hazard ratio (HR): 4.12 95% CI: 1.2-13.7, p = 0.02]. Non-relapse mortality (NRM) was higher in individuals with low IFN-γ response to PHA (competing risk regression HR 11.6 p = 0.02). In individuals with no AGVHD compared to AGVHD and high IFN-γ response to PHA compared to AGVHD and low IFN-γ response to PHA, 12-month survival was 100 vs. 80 vs. 52%, respectively (log rank test p < 0.0001). Conclusion: Low IFN-γ response to PHA at the 3-month time-point following allogeneic HSCT was predictive of reduced 12-month overall survival, increased NRM, and reduced survival in recipients with AGVHD. Assessing IFN-γ response to PHA post-HSCT may be a clinically useful immune biomarker.

Development of a neural interface that can be implanted without risky, open brain surgery will increase the safety and viability of chronic neural recording arrays. We have developed a minimally invasive surgical procedure and an endovascular electrode-array that can be delivered to overlie the cortex through blood vessels. Here, we describe feasibility of the endovascular interface through electrode viability, recording potential and safety. Electrochemical impedance spectroscopy demonstrated that electrode impedance was stable over 91 days and low frequency phase could be used to infer electrode incorporation into the vessel wall. Baseline neural recording were used to identify the maximum bandwidth of the neural interface, which remained stable around 193 Hz for six months. Cross-sectional areas of the implanted vessels were non-destructively measured using the Australian Synchrotron. There was no case of occlusion observed in any of the implanted animals. This work demonstrates the feasibility of an endovascular neural interface to safely and efficaciously record neural information over a chronic time course.

BACKGROUND: Decision support tools may facilitate shared decision-making and improve quality of care. AIM: To assess the effectiveness of a decision support tool on improving quality of care in ulcerative colitis. METHODS: A prospective quality of care intervention was conducted at two Australian hospitals comparing out-patient-based ulcerative colitis care with, and without, a tablet-based decision support tool. This included questions on disease activity management; psychological well-being; and preventive care, with 13 process indicators relevant to each domain. Participants included adult out-patients with mild-to-moderate ulcerative colitis and their clinicians who were divided into two cohorts. The first cohort were followed up immediately after their clinical review to check whether their clinician had discussed the 13 process indicators during the consultation. The second cohort of patients used the decision support tool immediately prior to their consultation which then generated a suggested management plan for the patient and clinician to discuss during the consultation. Management between the 2 cohorts was compared to assess the effectiveness of the decision support tool in improving the primary outcome, defined as the proportion of quality process indicators used for ulcerative colitis care, with and without the decision support tool. RESULTS: Thirteen physicians and 100 patients participated. Fifty patients were managed without the decision support tool using standard care (median age 40; 44% male), and 50 patients used the decision support tool (median age 40; 46% male) over a 20-week period. Increase in the median use of process indicators overall was observed following use of the decision support tool (27% vs 100%; P < 0.001). Improvements were seen in psychological well-being management (30% vs 100%; P < 0.001), preventive care (16% vs 100%; P < 0.001) and process indicators related to disease activity management (50% vs 100%; P < 0.001). The decision support tool was found to be usable and acceptable. Shared decision-making was greater in the post-intervention group (mean decision conflict score of 18.0 vs 33.5; P = 0.002). CONCLUSIONS: The decision support tool substantially improved the quality of the delivery of care. Decision support tools have the potential to minimise errors of omission via a standardised approach to care.

Advances in genomic sequencing have enormous potential to revolutionize personalized medicine, however distinguishing disease-causing from benign variants remains a challenge. The increasing number of human genome and exome sequences available has revealed areas where unfavourable variation is removed through purifying selection. Here, we present the MTR-Viewer, a web-server enabling easy visualization at the gene or variant level of the Missense Tolerance Ratio (MTR), a measure of regional intolerance to missense variation calculated using variation from 240 000 exome and genome sequences. The MTR-Viewer enables exploration of MTR calculations, using different sliding windows, for over 18 000 human protein-coding genes and 85 000 alternative transcripts. Users can also view MTR scores calculated for specific ethnicities, to enable easy exploration of regions that may be under different selective pressure. The spatial distribution of population and known disease variants is also displayed on the protein's domain structure. Intolerant regions were found to be highly enriched for ClinVar pathogenic and COSMIC somatic missense variants (Mann-Whitney U test P < 2.2 × 10-16). As the MTR is not biased by known domains and protein features, it can highlight functionally important regions within genes overlooked or inaccessible by traditional methods. MTR-Viewer is freely available via a user friendly web-server at http://biosig.unimelb.edu.au/mtr-viewer/.

BACKGROUND: The introduction of highly effective direct-acting antiviral (DAA) therapy for hepatitis C has led to calls to eliminate it as a public health threat through treatment-as-prevention. Recent studies suggest it is possible to develop a vaccine to prevent hepatitis C. Using a mathematical model, we examined the potential impact of a hepatitis C vaccine on the feasibility and cost of achieving the global WHO elimination target of an 80% reduction in incidence by 2030 in the era of DAA treatment. METHODS: The model was calibrated to 167 countries and included two population groups (people who inject drugs (PWID) and the general community), features of the care cascade, and the coverage of health systems to deliver services. Projections were made for 2018-2030. RESULTS: The optimal incidence reduction strategy was to implement test and treat programmes among PWID, and in settings with high levels of community transmission undertake screening and treatment of the general population. With a vaccine available, the optimal strategy was to include vaccination within test and treat programmes, in addition to vaccinating adolescents in settings with high levels of community transmission. Of the 167 countries modelled, between 0 and 48 could achieve an 80% reduction in incidence without a vaccine. This increased to 15-113 countries if a 75% efficacious vaccine with a 10-year duration of protection were available. If a vaccination course cost US$200, vaccine use reduced the cost of elimination for 66 countries (40%) by an aggregate of US$7.4 (US$6.6-8.2) billion. For a US$50 per course vaccine, this increased to a US$9.8 (US$8.7-10.8) billion cost reduction across 78 countries (47%). CONCLUSIONS: These findings strongly support the case for hepatitis C vaccine development as an urgent public health need, to ensure hepatitis C elimination is achievable and at substantially reduced costs for a majority of countries.