A dual colour dual fusion fluorescence in situ hybridisation study on the genesis of complex variant translocations in chronic myelogenous leukaemia

Complex variant 9;22 translocations occur in a significant minority of chronic myelogenous leukaemia (CML) patients. Different mechanisms of their formation have been described. We report dual colour dual fusion fluorescence in situ hybridisation data in 12 Chinese CML patients with complex translocations. Three previously reported breakpoint hotspots in a third partner chromosome (14q32, 17q25, 1q2l) were observed. In 10/12 (83.3%) patients, the abnormality occurred as a single step 3-break event. Only a single abnormal clone harbouring the complex translocation was seen in this group. The remaining 2 cases in the chronic phase showed a 4-break mechanism (2/12,16.7%). Deletion of 5' ABL at der(9) was not observed in any of the 12 patients, however, the loss of 3' BCR was observed in 1 patient (1/12, 8.3%). Together with previous findings, these data suggest that these variant translocations occur more often as a 3-break single-step process with no reciprocal ABL-BCR fusion. On the other hand, a 4-break event is also regularly seen during the initial stages of leukaemogenesis, which likely predisposes to der(9) deletion. The observed difference in rates of der(9) deletion reported in a series of CML patients with variant translocations may be related to a difference in rates of a 4-break event.published_or_final_versio

Assessment of intervention measures for the 2003 SARS epidemic in Taiwan by use of a back-projection method

OBJECTIVES. To reconstruct the infection curve for the 2003 severe acute respiratory syndrome (SARS) epidemic in Taiwan and to ascertain the temporal changes in the daily number of infections that occurred during the course of the outbreak. METHOD. Back-projection method. RESULTS. The peaks of the epidemic correspond well with the occurrence of major infection clusters in the hospitals. The overall downward trend of the infection curve after early May corresponds well to the date (May 10) when changes in the review and classification procedure were implemented by the SARS Prevention and Extrication Committee. CONCLUSION. The major infection control measures taken by the Taiwanese government over the course of the SARS epidemic, particularly those regarding infection control in hospitals, played a crucial role in containing the outbreak. © 2007 by The Society for Healthcare Epidemiology of America. All rights reserved.published_or_final_versio

Identification and characterization of long-range SOX9 enhancers in limb development

The transcription factor Sox9 is a master regulator of skeletogenesis. Heterozygous mutations of human SOX9 result in Campomelic Dysplasia (CD), in which affected individuals display distinct abnormalities in limbs and other skeletal assemblies. Recently, chromosomal translocations and deletions at >1Mb from SOX9 have been detected in some CD patients, suggesting the requirement of long‐range regulatory elements in mediating both spatiotemporal and dosage of Sox9 during limb development. To this end, we exploited several published ChIP‐Seq data, and identified nine, evolutionarily conserved, putative limb enhancers of SOX9, namely E1Sox9 to E9Sox9. Transgenic mouse embryos carrying E1Sox9‐driven LacZ reporter showed discrete transgene expression at the pre‐scapular domain where endogenous Sox9 is also expressed. Bioinformatic analyses on our candidate enhancers result in the identification of several signaling effector binding motifs, and indeed, we revealed that BMP‐Smad and Shh‐Gli pathways are possible upstream regulatory networks that govern the spatiotemporal and dosage of limb Sox9 expression via our predicted enhancers, respectively. Our results unveil the underlying molecular control in governing the complex patterning of Sox9 expression in the developing limb, and provide new molecular insight to the etiology of CD syndrome.postprin

Characterisation of animal angiotensin-converting enzyme 2 receptors and use of pseudotyped virus to correlate receptor binding with susceptibility of SARS-CoV infection

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Common association of haemolytic uraemic syndrome with invasive Streptococcus pneumoniae infection in five Chinese paediatric patients

Haemolytic uraemic syndrome is an important cause of acute renal impairment in childhood. We review the incidence, and clinical and laboratory features of haemolytic uraemic syndrome in a Chinese population. Five patients were identified from 2006 to 2008. All patients were young children with associated invasive Streptococcus pneumoniae pulmonary infection. Serotypes 3, 14, and 19A were confirmed in four patients. The classical post-diarrhoeal form associated with Escherichia coli (O157:H7) infection was not seen. One patient died of acute respiratory failure. Streptococcus pneumoniae infection, as an associated condition in haemolytic uraemic syndrome, is important and relatively common in Chinese patients, especially among children. The acute clinical picture is similar to that reported in the western literature, except for an uncommon association with meningitis. The medium-term renal outcome of the Chinese population appears to be more favourable than the Caucasians. Widespread vaccination against Streptococcus pneumoniae may have resulted in changes in bacterial epidemiology and clinicians should be continuously aware of this severe disease. The use of washed blood components for transfusion in the acute stage requires further study.published_or_final_versio

Help-seeking and antibiotic prescribing for acute cough in a Chinese primary care population: a prospective multicentre observational study

Acute cough is a common reason to prescribe antibiotics in primary care. This study aimed to explore help-seeking and antibiotic prescribing for acute cough in Chinese primary care population. This is a prospective multicentre observational study that included adults presenting with acute cough. Clinicians recorded patients’ presenting symptoms, examination findings and medication prescription. Patients completed symptom diaries for up to 28 days by charting their symptom severity and recovery. Adjusted binary logistic regression models identified factors independently associated with antibiotic prescription. Primary care clinicians (n=19) recruited 455 patients. A total of 321 patients (70.5%) returned their completed symptom diaries. Concern about illness severity (41.6%) and obtaining a prescription for symptomatic medications (45.9%), rather than obtaining a prescription for antibiotics, were the main reasons for consulting. Antibiotics were prescribed for 6.8% (n=31) of patients, of which amoxicillin was the most common antimicrobial prescribed (61.3%), as it was associated with clinicians’ perception of benefit from antibiotic treatment (odds ratio (OR): 25.9, 95% confidence interval (CI): 6.7–101.1), patients’ expectation for antibiotics (OR: 5.1, 95% CI: 1.7–11.6), anticipation (OR: 5.1, 95% CI: 1.6–15.0) and request for antibiotics (OR 15.7, 95% CI: 5.0–49.4), as well as the severity of respiratory symptoms (cough, sputum, short of breath and wheeze OR: 2.7–3.7, all P<0.05). There was a significant difference in antibiotic prescription rates between private primary care clinicians and public primary care clinicians (17.4 vs 1.6%, P=0.00). Symptomatic medication was prescribed in 98.0% of patients. Mean recovery was 9 days for cough and 10 days for all symptoms, which was not significantly associated with antibiotic treatment. Although overall antibiotic-prescribing rates were low, there was a higher rate of antibiotic prescribing among private primary care clinicians, which warrants further exploration and scope for education and intervention.published_or_final_versio

Phylogenetic evidence for homologous recombination within the family Birnaviridae

Birnaviruses are bi-segmented double-stranded RNA (dsRNA) viruses infecting insects, avian species and a wide range of aquatic species. Although homologous recombination is a common phenomenon in positive-sense RNA viruses, recombination in dsRNA viruses is rarely reported. Here we performed a comprehensive survey on homologous recombination in all available sequences (>1800) of the family Birnaviridae based on phylogenetic incongruence. Although inter-species recombination was not evident, potential intra-species recombination events were detected in aquabirnaviruses and infectious bursal disease virus (IBDV). Eight potential recombination events were identified and the possibility that these events were non-naturally occurring was assessed case by case. Five of the eight events were identified in IBDVs and all of these five events involved live attenuated vaccine strains. This finding suggests that homologous recombination between vaccine and wild-type IBDV strains may have occurred; the potential risk of mass vaccination using live vaccines is discussed. This is the first report of evidence for homologous recombination within the family Birnaviridae. © 2008 SGM.published_or_final_versio

The association between attention-deficit/hyperactivity disorder and retinal nerve fiber/ganglion cell layer thickness measured by optical coherence tomography: a systematic review and meta-analysis

Purpose: Retinal nerve fiber/ganglion cell layer (RNFL/GCL) thickness measured using optical coherence tomography has been proposed as an ocular biomarker for children with attention-deficit/hyperactivity disorder (ADHD), but findings varied in different studies. This study aims to determine the association between RNFL/GCL thickness and ADHD in children by systematic review and meta-analysis. / Methods: We performed a literature search in Embase, PubMed, Medline, Web of Science, and PsycINFO for relevant articles published up to February 29, 2020. All studies with original data comparing RNFL/GCL thickness in ADHD and healthy children were included. The Newcastle Ottawa Scale was used to assess bias risk and quality of evidence. Pooled estimates of the differences in thickness of RNFL or GCL between ADHD and healthy subjects were generated using meta-analysis with a random-effect model due to significant inter-study heterogeneity. Sensitivity analysis was also performed. / Results: We identified four eligible studies involving a total of 164 ADHD and 150 control subjects. Meta-analysis revealed that ADHD in children was associated with a reduction in global RNFL thickness (SMD, − 0.23; 95% CI − 0.46, − 0.01; p = 0.04). The global GCL thickness was examined in two studies with 89 ADHD and 75 control subjects, but the pooled difference in global GCL thickness between ADHD children and controls was not statistically significant (SMD, − 0.34; 95% CI − 1.25, 0.58; p = 0.47). / Conclusion: Existing evidence suggests a possible association between ADHD and RNFL thinning in children. In view of the limited number of reports, further studies in large cohorts should be warranted

Development and Validation of a Composite Programmatic Assessment Tool for HIV Therapy

Background We developed and validated a new and simple metric, the Programmatic Compliance Score (PCS), based on the IAS-USA antiretroviral therapy management guidelines for HIV-infected adults, as a predictor of all-cause mortality, at a program-wide level. We hypothesized that non-compliance would be associated with the highest probability of mortality. Methods and Findings 3543 antiretroviral-naive HIV-infected patients aged ≥19 years who initiated antiretroviral therapy between January 1, 2000 and August 31, 2009 in British Columbia (BC), Canada, were followed until August 31, 2010. The PCS is composed by six non-performance indicators based on the IAS-USA guidelines: (1) having &lt;3 CD4 count tests in the first year after starting antiretroviral therapy; (2) having &lt;3 plasma viral load tests in the first year after starting antiretroviral therapy; (3) not having drug resistance testing done prior to starting antiretroviral therapy; (4) starting on a non-recommended antiretroviral therapy regimen; (5) starting therapy with CD4 &lt;200 cells/mm3; and (6) not achieving viral suppression within 6 months since antiretroviral therapy initiation. The sum of these six indicators was used to develop the PCS score - higher score indicates poorer performance. The main outcome was all-cause mortality. Each PCS component was independently associated with mortality. In the mortality analysis, the odds ratio (OR) for PCS ≥4 versus 0 was 22.37 (95% CI 10.46–47.84). Conclusions PCS was strongly associated with all-cause mortality. These results lend independent validation to the IAS-USA treatment guidelines for HIV-infected adults. Further efforts are warranted to enhance the PCS as a means to further improve clinical outcomes. These should be specifically evaluated and targeted at healthcare providers and patients

Hedgehog/notch-induced premature gliogenesis represents a new disease mechanism for Hirschsprung disease in mice and humans

Hirschsprung (HSCR) disease is a complex genetic disorder attributed to a failure of the enteric neural crest cells (ENCCs) to form ganglia in the hindgut. Hedgehog and Notch are implicated in mediating proliferation and differentiation of ENCCs. Nevertheless, how these signaling molecules may interact to mediate gut colonization by ENCCs and contribute to a primary etiology for HSCR are not known. Here, we report our pathway- based epistasis analysis of data generated by a genome-wide association study on HSCR disease, which indicates that specific genotype constellations of Patched (PTCH1) (which encodes a receptor for Hedgehog) and delta-like 3 (DLL3) (which encodes a receptor for Notch) SNPs confer higher risk to HSCR. Importantly, deletion of Ptch1 in mouse ENCCs induced robust Dll1 expression and activation of the Notch pathway, leading to premature gliogenesis and reduction of ENCC progenitors in mutant bowels. Dll1 integrated Hedgehog and Notch pathways to coordinate neuronal and glial cell differentiation during enteric nervous system development. In addition, Hedgehog-mediated gliogenesis was found to be highly conserved, such that Hedgehog was consistently able to promote gliogenesis of human neural crest-related precursors. Collectively, we defined PTCH1 and DLL3 as HSCR susceptibility genes and suggest that Hedgehog/Notch-induced premature gliogenesis may represent a new disease mechanism for HSCR.published_or_final_versio