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Structural and metabolic abnormalities in the hippocampus have been associated with the pathophysiological mechanism of central nervous system involvement in primary Sjögren syndrome (pSS). Nevertheless, how hippocampal function is altered in pSS remains unknown. The purpose of our study is to investigate the alterations in hippocampal functional connectivity (FC) in pSS by using resting-state functional magnetic resonance imaging (rs-fMRI). Thirty-eight patients with pSS and 38 age- and education level-matched healthy controls (HCs) underwent magnetic resonance imaging examination. Prior to each MRI examination, neuropsychological tests were performed. Left and right hippocampal FCs were analyzed by using seed-based whole-brain correlation and compared between pSS and HCs. Spearman correlation analysis was performed between the z-value of hippocampal FC in brain regions with significant difference between the two groups and neuropsychological tests/clinical data in pSS. Compared with the controls, the patients with pSS showed decreased hippocampal FC between the left hippocampus and the right inferior occipital gray (IOG)/inferior temporal gray (ITG), as well as between the right hippocampus and right IOG/middle occipital gray (MOG), left MOG, and left middle temporal gray. In addition, increased hippocampal FCs were detected between the left hippocampus and left putamen, as well as between the right hippocampus and right cerebellum posterior lobe. Moreover, the visual reproduction score positively correlated with the FC between right hippocampus and right IOG/MOG. The white matter hyperintensity score negatively correlated with the FC between left hippocampus and right IOG/ITG. In conclusion, patients with pSS suffered decreased hippocampal FC mainly sited in the occipital and temporal cortex with right hippocampal laterality. Altered hippocampal FC might be a potential biomarker in detecting brain function changes and guiding neuroprotection in pSS.

TP53 aberrations [del(17p) or TP53 mutation] predict poor survival with chemoimmunotherapy in patients with chronic lymphocytic leukaemia (CLL). We evaluated long-term efficacy and safety of first-line ibrutinib-based therapy in patients with CLL bearing TP53 aberrations in a pooled analysis across four studies: PCYC-1122e, RESONATE-2 (PCYC-1115/16), iLLUMINATE (PCYC-1130) and ECOG-ACRIN E1912. The pooled analysis included 89 patients with TP53 aberrations receiving first-line treatment with single-agent ibrutinib (n = 45) or ibrutinib in combination with an anti-CD20 antibody (n = 44). All 89 patients had del(17p) (53% of 89 patients) and/or TP53 mutation (91% of 58 patients with TP53 sequencing results available). With a median follow-up of 49 center dot 8 months (range, 0 center dot 1-95 center dot 9), median progression-free survival was not reached. Progression-free survival rate and overall survival rate estimates at four years were 79% and 88%, respectively. Overall response rate was 93%, including complete response in 39% of patients. No new safety signals were identified in this analysis. Forty-six percent of patients remained on ibrutinib treatment at last follow-up. With median follow-up of four years (up to eight years), results from this large, pooled, multi-study data set suggest promising long-term outcomes of first-line ibrutinib-based therapy in patients with TP53 aberrations. Registered at ClinicalTrials.gov (NCT01500733, NCT01722487, NCT02264574 and NCT02048813).

Background In the era of widespread rituximab use for Waldenstrm's macro globulinaemia, new treatment options for patients with rituximab-refractory disease are an important clinical need. Ibrutinib has induced durable responses in previously treated patients with Waldenstrm's macro globulinaemia. We assessed the effi cacy and safety of ibrutinib in a population with rituximab-refractory disease. Methods This multicentre, open-label substudy was done at 19 sites in seven countries in adults aged 18 years and older with confi rmed Waldenstrm's macro globulinaemia, refractory to rituximab and requiring treatment. Disease refractory to the last rituximab-containing therapy was defi ned as either relapse less than 12 months since last dose of rituximab or failure to achieve at least a minor response. Key exclusion criteria included: CNS involvement, a stroke or intracranial haemorrhage less than 12 months before enrolment, clinically signifi cant cardiovascular disease, hepatitis B or hepatitis C viral infection, and a known bleeding disorder. Patients received oral ibrutinib 420 mg once daily until progression or unacceptable toxicity. The substudy was not prospectively powered for statistical comparisons, and as such, all the analyses are descriptive in nature. This study objectives were the proportion of patients with an overall response, progression-free survival, overall survival, haematological improvement measured by haemoglobin, time to next treatment, and patient-reported outcomes according to the Functional Assessment of Cancer TherapyAnemia (FACT-An) and the Euro Qol 5 Dimension Questionnaire (EQ-5D-5L). All analyses were per protocol. The study is registered at ClinicalTrials. gov, number NCT02165397, and follow-up is ongoing but enrolment is complete. Findings Between Aug 18, 2014, and Feb 18, 2015, 31 patients were enrolled. Median age was 67 years (IQR 58-74); 13 (42%) of 31 patients had high-risk disease per the International Prognostic Scoring System Waldenstrm Macroglobulinaemia, median number of previous therapies was four (IQR 2-6), and all were rituximab-refractory. At a median follow-up of 18.1 months (IQR 17.5-18.9), the proportion of patients with an overall response was 28 [90%] of 31 (22 [71%] of patients had a major response), the estimated 18 month progression-free survival rate was 86% (95% CI 66-94), and the estimated 18 month overall survival rate was 97% (95% CI 79-100). Baseline median haemoglobin of 10.3 g/dL (IQR 9.3-11.7) increased to 114 mu g/dL (10.9-12.4) after 4 weeks of ibrutinib treatment and reached 127 g/dL (11.8-13.4) at week 49. A clinically meaningful improvement from baseline in FACT-An score, anaemia subscale score, and the EQ-5D-5L were reported at all post-baseline visits. Time to next treatment will be presented at a later date. Common grade 3 or worse adverse events included neutropenia in four patients (13%), hypertension in three patients (10%), and anaemia, thrombocytopenia, and diarrhoea in two patients each (6%). Serious adverse events occurred in ten patients (32%) and were most often infections. Five (16%) patients discontinued ibrutinib: three due to progression and two due to adverse events, while the remaining 26 [84%] of patients are continuing ibrutinib at the time of this report. Interpretation The sustained responses and median progression-free survival time, combined with a manageable toxicity profi le observed with single-agent ibrutinib indicate that this chemotherapy-free approach is a potential new treatment choice for patients who had heavily pretreated, rituximab-refractory Waldenstrm's macro globulinaemia.

Ammopiptanthus mongolicus, an evergreen broadleaf legume shrub, can survive under conditions of high and low temperature, extreme salinity, and drought. This attribute makes it an ideal model for studying mechanisms of stress tolerance in plants. However, simple sequence repeat (SSR) resources for this species are insufficient in public databases. In this study, a total of 44,959 unigenes identified from the A. mongolicus transcriptome were used for SSR analysis by MIcroSAtellite (MISA). A total of 13,859 SSRs were found to be distributed within 10,409 unigenes, with an average length of 15 bp and an average density of one SSR per 4.4 kb. There were 222 different motif types in the A. mongolicus transcriptome, and mononucleotide repeats represented the main type, accounting for 44.2% of all SSRs. The (A/T)n repeat was the most frequent motif, accounting for 42.37% of all SSRs. We also performed Gene Ontology functional analysis, Kyoto Encyclopedia of Genes and Genomes database pathway analysis, and eggNOG analysis, and identified 6157, 2301, and 9845 unigenes containing SSRs in these three databases, respectively. The functional categorization of A. mongolicus unigenes containing SSRs revealed that these unigenes represent many transcribed genes with different functions. These data provide sequence information that may be used to improve molecular-assisted markers for the study A. mongolicus genetic diversity.

Pelizaeus-Merzbacher disease (PMD) is a rare X-linked recessive disorder characterized by nystagmus, impaired motor development, ataxia, and progressive spasticity. Genetically defective or altered levels of proteolipid protein (PLP1) or gap-junction alpha protein 12 gene have been found to be a common cause. Here we report on two large Han Chinese families affected with this disease. The probands of both families had produced sons featuring cerebral palsy that had never been correctly diagnosed. PMD was suspected after careful analysis of family history and clinical features. Three rounds of molecular testing, including RT-PCR, genetics linkage and SRY sequence analyses, in combination with fetal ultrasound and magnetic resonance imaging, confirmed the diagnosis. In Family 1, in addition to two patients, three carriers were identified, including one who was not yet married. Genetic testing indicated that a fetus did not have the disease. A healthy girl was born later. In Family 2, two patients and two carriers were identified, while a fetus was genetically normal. A healthy girl was born later. We concluded that by combining genetic testing and imaging, awareness of the symptoms of PMD and understanding of its molecular biology, there is great benefit for families that are at risk for producing offspring affected with this severe disease.

One of the critical missions for bridge structural health monitoring (SHM) is to provide a reliable assessment technique to potential hazards caused by structural damage or other structural defects using continuously monitored vibration data. Recognising the needs and shortcomings of SHM, a project was established by NICTA, the University of Technology Sydney and The University of Sydney to develop reliable damage detection methods to provide robust and accurate assessment techniques for critical bridge infrastructure in Australia. This paper presents the progress of research and development of a vibration-based damage detection technique and its experimental validation in the laboratory. The proposed technique uses residual frequency response functions (FRFs) combined with principal component analysis (PCA) to form damage specific features (DSFs) that are incorporated in pattern recognition using artificial neural networks (ANNs). In the method, FRFs are obtained using modal analysis techniques and damage is identified using ANNs that innovatively map the DSF to damage characteristics, such as damage location and severity. The results of the experimental validation show that the proposed technique can successfully locate and quantify damage induced to a concrete arch beam simulating a real life structural component of the Sydney Harbour Bridge.

Timber utility poles represent a significant part of Australia’s infrastructure for power distribution and communication networks. Due to their advanced age, significant efforts are undertaken to prevent utility lines from failure. However, the lack of reliable tools for assessing the condition of in-service poles seriously jeopardizes the maintenance and asset management. Non-destructive testing (NDT) methods based on stress wave propagation can potentially offer simple and cost-effective tools for the condition assessment of in-service timber poles. Based on the impact direction and location, mainly two wave types can be excited in a pole, i.e. longitudinal and bending waves. A conventional stresswave- based method that analyses longitudinal waves is the Sonic Echo (SE) method; and a typical signal processing method for the analysis of bending waves (BW) is the Short Kernel Method (SKM). In this paper, firstly, the application of the conventional SE method and the BW method with SKM data analysis is investigated for the condition assessment of timber poles from a signal processing perspective. Secondly, to improve limitations of the current methods, the application of a multisensors array is proposed for more reliable and accurate results. The new method is validated on numerical data of a timber pole modelled with both isotropic and orthotropic material properties.

Timber utility poles represent a significant part of Australia’s infrastructure for power distribution and communication networks. Due to the advanced age of Australia’s timber pole infrastructure, significant efforts are undertaken by state authorities on maintenance and asset management to prevent utility lines from failure. However, the lack of reliable tools for assessing the condition of in-service poles seriously jeopardizes the maintenance and asset management. For example, each year approximately 300,000 poles are replaced in the Eastern States of Australia with up to 80% of them still being in a very good serviceable condition, resulting in significant waste of natural resources and money.

Huntington disease (HD) is caused by the expansion of a CAG repeat within the coding region of a novel gene on 4p16.3. Although the variation in age at onset is partly explained by the size of the expanded repeat, the unexplained variation in age at onset is strongly heritable (h2=0.56), which suggests that other genes modify the age at onset of HD. To identify these modifier loci, we performed a 10-cM density genomewide scan in 629 affected sibling pairs (295 pedigrees and 695 individuals), using ages at onset adjusted for the expanded and normal CAG repeat sizes. Because all those studied were HD affected, estimates of allele sharing identical by descent at and around the HD locus were adjusted by a positionally weighted method to correct for the increased allele sharing at 4p. Suggestive evidence for linkage was found at 4p16 (LOD=1.93), 6p21-23 (LOD=2.29), and 6q24-26 (LOD=2.28), which may be useful for investigation of genes that modify age at onset of HD.