Strategies to reduce the risk of SARS-CoV-2 importation from international travellers: modelling estimations for the United Kingdom, July 2020.

BackgroundTo mitigate SARS-CoV-2 transmission risks from international air travellers, many countries implemented a combination of up to 14 days of self-quarantine upon arrival plus PCR testing in the early stages of the COVID-19 pandemic in 2020.AimTo assess the effectiveness of quarantine and testing of international travellers to reduce risk of onward SARS-CoV-2 transmission into a destination country in the pre-COVID-19 vaccination era.MethodsWe used a simulation model of air travellers arriving in the United Kingdom from the European Union or the United States, incorporating timing of infection stages while varying quarantine duration and timing and number of PCR tests.ResultsQuarantine upon arrival with a PCR test on day 7 plus a 1-day delay for results can reduce the number of infectious arriving travellers released into the community by a median 94% (95% uncertainty interval (UI): 89-98) compared with a no quarantine/no test scenario. This reduction is similar to that achieved by a 14-day quarantine period (median > 99%; 95% UI: 98-100). Even shorter quarantine periods can prevent a substantial amount of transmission; all strategies in which travellers spend at least 5 days (mean incubation period) in quarantine and have at least one negative test before release are highly effective (median reduction 89%; 95% UI: 83-95)).ConclusionThe effect of different screening strategies impacts asymptomatic and symptomatic individuals differently. The choice of an optimal quarantine and testing strategy for unvaccinated air travellers may vary based on the number of possible imported infections relative to domestic incidence.

Visible red and infrared light alters gene expression in human marrow stromal fibroblast cells.

OBJECTIVES: This study tested whether or not gene expression in human marrow stromal fibroblast (MSF) cells depends on light wavelength and energy density. MATERIALS AND METHODS: Primary cultures of isolated human bone marrow stem cells (hBMSC) were exposed to visible red (VR, 633 nm) and infrared (IR, 830 nm) radiation wavelengths from a light emitting diode (LED) over a range of energy densities (0.5, 1.0, 1.5, and 2.0 Joules/cm2) Cultured cells were assayed for cell proliferation, osteogenic potential, adipogenesis, mRNA and protein content. mRNA was analyzed by microarray and compared among different wavelengths and energy densities. Mesenchymal and epithelial cell responses were compared to determine whether responses were cell type specific. Protein array analysis was used to further analyze key pathways identified by microarrays. RESULT: Different wavelengths and energy densities produced unique sets of genes identified by microarray analysis. Pathway analysis pointed to TGF-beta 1 in the visible red and Akt 1 in the infrared wavelengths as key pathways to study. TGF-beta protein arrays suggested switching from canonical to non-canonical TGF-beta pathways with increases to longer IR wavelengths. Microarrays suggest RANKL and MMP 10 followed IR energy density dose-response curves. Epithelial and mesenchymal cells respond differently to stimulation by light suggesting cell type-specific response is possible. CONCLUSIONS: These studies demonstrate differential gene expression with different wavelengths, energy densities and cell types. These differences in gene expression have the potential to be exploited for therapeutic purposes and can help explain contradictory results in the literature when wavelengths, energy densities and cell types differ.

Visual rating versus volumetry to detect frontotemporal dementia.

BACKGROUND/AIMS: Automated, volumetrically defined atrophy in the left anterior cingulate (LAC) and anterior temporal regions (LAT) on MRI can be used to distinguish most patients with frontotemporal dementia (FTD) from controls. FTD and Alzheimer's disease (AD) can differ in the degree of anterior temporal atrophy. We explored whether clinicians can visually detect this atrophy pattern and whether they can use it to classify the 2 groups of dementia patients with the same accuracy. METHODS: Four neurologists rated atrophy in the LAC and LAT regions on MRI slices from 21 FTD, 21 controls, and 14 AD participants. Inter-rater reliability and diagnostic accuracy were assessed. RESULTS: All 4 raters agreed on the presence of clinically significant atrophy, and their atrophy scoring correlated with the volumes, but without translation into high inter-rater diagnostic agreement. CONCLUSIONS: Volumetric analyses are difficult to translate into routine clinical practice.

Stable interference of EWS-FLI1 in an Ewing sarcoma cell line impairs IGF-1/IGF-1R signalling and reveals TOPK as a new target.

BACKGROUND: Ewing sarcoma is a paradigm of solid tumour -bearing chromosomal translocations resulting in fusion proteins that act as deregulated transcription factors. Ewing sarcoma translocations fuse the EWS gene with an ETS transcription factor, mainly FLI1. Most of the EWS-FLI1 target genes still remain unknown and many have been identified in heterologous model systems. METHODS: We have developed a stable RNA interference model knocking down EWS-FLI1 in the Ewing sarcoma cell line TC71. Gene expression analyses were performed to study the effect of RNA interference on the genetic signature of EWS-FLI1 and to identify genes that could contribute to tumourigenesis. RESULTS: EWS-FLI1 inhibition induced apoptosis, reduced cell migratory and tumourigenic capacities, and caused reduction in tumour growth. IGF-1 was downregulated and the IGF-1/IGF-1R signalling pathway was impaired. PBK/TOPK (T-LAK cell-originated protein kinase) expression was decreased because of EWS-FLI1 inhibition. We showed that TOPK is a new target gene of EWS-FLI1. TOPK inhibition prompted a decrease in the proliferation rate and a dramatic change in the cell's ability to grow in coalescence. CONCLUSION: This is the first report of TOPK activity in Ewing sarcoma and suggests a significant role of this MAPKK-like protein kinase in the Ewing sarcoma biology.

The ETV6-NTRK3 gene fusion encodes a chimeric protein tyrosine kinase that transforms NIH3T3 cells.

The congenital fibrosarcoma t(12;15)(p13;q25) rearrangement splices the ETV6 (TEL) gene on chromosome 12p13 in frame with the NTRK3 (TRKC) neurotrophin-3 receptor gene on chromosome 15q25. Resultant ETV6-NTRK3 fusion transcripts encode the helix - loop - helix (HLH) dimerization domain of ETV6 fused to the protein tyrosine kinase (PTK) domain of NTRK3. We show here that ETV6-NTRK3 homodimerizes and is capable of forming heterodimers with wild-type ETV6. Moreover, ETV6-NTRK3 has PTK activity and is autophosphorylated on tyrosine residues. To determine if the fusion protein has transforming activity, NIH3T3 cells were infected with recombinant retroviral vectors carrying the full-length ETV6-NTRK3 cDNA. These cells exhibited a transformed phenotype, grew macroscopic colonies in soft agar, and formed tumors in severe combined immunodeficient (SCID) mice. We hypothesize that chimeric proteins mediate transformation by dysregulating NTRK3 signal transduction pathways via ligand-independent dimerization and PTK activation. To test this hypothesis, we expressed a series of ETV6-NTRK3 mutants in NIH3T3 cells and assessed their transformation activities. Deletion of the ETV6 HLH domain abolished dimer formation with either ETV6 or ETV6-NTRK3, and cells expressing this mutant protein were morphologically non-transformed and failed to grow in soft agar. An ATP-binding mutant failed to autophosphorylate and completely lacked transformation activity. Mutants of the three NTRK3 PTK activation-loop tyrosines had variable PTK activity but had limited to absent transformation activity. Of a series of signaling molecules well known to bind to wild-type NTRK3, only phospholipase-Cgamma (PLCgamma) associated with ETV6-NTRK3. However, a PTK active mutant unable to bind PLCgamma did not show defects in transformation activity. Our studies confirm that ETV6-NTRK3 is a transforming protein that requires both an intact dimerization domain and a functional PTK domain for transformation activity. Oncogene (2000) 19, 906 - 915.

Alternative lengthening of telomeres is associated with chromosomal instability in osteosarcomas.

Telomere maintenance is regarded as a key mechanism in overcoming cellular senescence in tumor cells and in most cases is achieved by the activation of telomerase. However there is at least one alternative mechanism of telomere lengthening (ALT) which is characterized by heterogeneous and elongated telomeres in the absence of telomerase activity (TA). We evaluated the prevalence of TA, gene expression of telomerase subunits and ALT in relation to telomere morphology and function in matrix producing bone tumors and in osteosarcoma cell lines and present evidence of a direct association of ALT with telomere dysfunction and chromosomal instability. Telomere fluorescence in situ hybridization (T-FISH) in ALT cells revealed elongated and shortened telomeres, partly in unusual configurations and loci, dicentric marker chromosomes and signal-free chromosome ends. Free ends give rise to end-to-end associations and may induce breakage-fusion-bridge cycles resulting in an increased number of complex chromosomal rearrangements, as detected by multiplex-FISH (M-FISH). We propose that ALT cannot be seen as an equivalent to telomerase activity in telomere maintenance. Its association with telomere dysfunction and chromosomal instability may have major implications for tumor progression.

The effects of major abdominal surgery, enteral and parenteral nutrition on pancreatic function and morphology.

The effects of major abdominal surgery and nutritional support upon pancreatic function and morphology were studied in similar groups of patients who underwent major abdominal surgery (n = 18), received parenteral nutritional support (n = 18) or received enteral nutritional support (n = 16). The exocrine function of the pancreas was measured by means of an oral pancreatic function test (using 1 g of N-benzoyl-L-tyrosyl para-aminobenzoic acid) with measurement of serum para-aminobenzoic acid at 3 h and the Pancreatic Excretion Index. Pancreatic morphology was assessed by real time ultrasound and a pancreatic size index was calculated (maximum diameter of head x body). Serial measurements of function and morphology were carried out in each patient at entry into the study and at 7 and 14 days after operation or start of nutritional support. Serum PABA levels were similar in the 3 groups at the start of the study. Although the levels remained unchanged in the enteral and parenteral groups, a significant and progressive decrease was observed in the surgical group (serum PABA = 27.5 nmol/l (24.0-30.6) before operation, 10.5 nmol/l (5.5-13.4) 14 days after operation, P < 0.01). No significant changes in pancreatic size were seen. Parenteral and enteral nutrition preserves pancreatic exocrine function. A dramatic reduction in pancreatic exocrine function is seen after major abdominal surgery.

Genetic imbalances in benign bone tumors revealed by comparative genomic hybridization.

There have been no reports on choromosomal aberrations of benign bone tumors revealed by comparative genomic hybridization (CGH). CGH analysis of benign tumors may be useful in understanding the mechanism of tumorigenesis with comparisons to malignant tumors. There were 4 tumors (2 enchondromas, one chondromyxoid fibroma, and one osteoid osteoma) and 8 tumor-like conditions (4 aneurysmal bone cysts (ABCs), one eosinophilic granuloma, one fibrous dysplasia, one solitary bone cyst, and one Rosai-Dorfman disease) available for analysis. One of 2 enchondromas and one of 4 ABCs exhibited rapid growth. Six lesions showed chromosomal aberrations, while 6 others did not. The most frequent aberrations were the loss of a whole chromosome-19 in 6 cases, the loss of chromosome-arm 22q in 4 cases, and the loss of chromosome-arm 17p in 3 cases. Gains were seen in 13q21 in 2 cartilaginous tumors and at 12q15-q21 in eosinophilic granulomas. Therefore, in benign bone tumors or tumor-like lesions, chromosomal aberrations are not frequent; however, some clear tendencies of clustering of aberrations can be observed.

Diagnosis of abdominal masses with percutaneous biopsy guided by ultrasound.

OBJECTIVE: To assess the accuracy and safety of percutaneous biopsy of abdominal masses guided by ultrasound. DESIGN: Prospective study. SETTING: Combined gastroenterology service, Scarborough Hospital. PATIENTS: 108 Consecutive patients identified as having a discrete mass on diagnostic ultrasound examination of the abdomen. INTERVENTION: A sample of tissue was obtained with an aseptic technique under local anaesthesia: an 18 steel wire gauge needle (Tru-Cut) was mounted in a spring loaded firing device (Biopty gun) that was advanced under simultaneous ultrasound scanning, permitting precise localisation of the target organ. MAIN OUTCOME MEASURE: Results of histological examination of tissue specimens. RESULTS: Biopsy failed in four patients. Adequate histological specimens were obtained in 104 patients with masses in the liver (31), pancreas (37), kidney (10), and adrenal glands (six) and in 20 undiagnosed abdominal and retroperitoneal masses. Follow up was until death or confirmation of the diagnosis. Three complications but no deaths occurred. Malignancy was suspected in 84 patients before biopsy. This was confirmed in 70 patients, in 26 of whom confirmation of dissemination obviated the need for further investigation. In 10 patients biopsy indicated a previously unsuspected primary tumour, and in 12 it showed only a benign lesion. Among 24 patients considered to have benign disease biopsy showed an unsuspected neoplasm in seven. Use of biopsy thus had a major effect on clinical management in 55 patients. Four false negative but no false positive diagnoses resulted from the procedure. CONCLUSION: Percutaneous biopsy of abdominal and retroperitoneal masses under ultrasound guidance is a safe and accurate method of obtaining a histological diagnosis. The results obtained have a considerable effect on clinical management.

Have the most recent Pap smear guidelines affected GP practices?

OBJECTIVE: To assess the attitudes and knowledge of a sample of NSW general practitioners on issues concerning Papanicolaou (Pap) smear tests after the 1991 National Guidelines were established. DESIGN: During January-March 1994, a sample of Sydney general practitioners obtained from a list from the Department of General Practice, Royal North Shore Hospital, were asked to complete a questionnaire based on Pap smear screening. Issues explored included the perceived value of Pap smears, views on recommended screening intervals and the type of patients believed to be at highest risk of developing cervical cancer. SETTING: Northern Sydney metropolitan area. RESULTS: Seventy of 104 general practitioners from the Department of General Practice, Royal North Shore Hospital, returned completed questionnaires. Ninety-five per cent of respondents rated the Pap-smear as an extremely valuable screening test for cervical cancer prevention. The majority of GPs surveyed tended to overscreen younger patients and underscreen both older women and those at highest risk of developing cervical cancer. Seventy-seven per cent of doctors indicated the use of a patient reminder system, in most cases provided by a pathology laboratory but 43% were unaware of the NSW Cancer Council's reminder service. CONCLUSION: Our study suggests that Pap smears are viewed as an important means of cervical cancer prevention. Unfortunately the majority of respondents did not adhere to the recommended guidelines of 2-yearly screening. Possible changes to the current system include improved awareness of the 1991 National Guidelines, greater public awareness of the NSW Cancer Council reminder service, and the establishment of a state cytology registry.

Visceral adipose tissue, but not waist circumference is a better measure of metabolic risk in Singaporean Chinese and Indian men.

OBJECTIVES: Visceral adipose tissue (VAT) is an independent risk factor in cardiometabolic diseases and is commonly measured by computed tomography (CT). It is measured clinically by waist circumference (WC). The L4/5 intervertebral space VAT (L4/5 VAT) is traditionally used to represent total VAT volume. We set out to determine (1) the level of intervertebral space on CT that best approximates the total VAT volume; (2) compare the association between WC and VAT in Singaporean Chinese and Indian; and (3) examine the correlation between VAT and cardiometabolic risk factors. SUBJECTS: A total of 60 Chinese and 60 Asian Indian men older than 60 years were recruited. Their medical history was taken and anthropometry was measured. Fasting glucose, insulin, lipids, adipokines and inflammatory markers were measured. Insulin resistance was evaluated by homeostasis model assessment-insulin resistance. VAT was determined by CT. Total VAT volume was calculated in 22 patients from VAT areas at seven intervertebral levels. The optimal VAT area most representative of total VAT volume was determined and used for all patients to approximate total VAT volume. RESULTS: The VAT area at L2/3 intervertebral space (L2/3 VAT) correlated almost perfectly with VAT volume (R(2)=0.974 and 0.946 for Chinese and Indians, respectively). SUBJECTS from the two races had similar height, weight, body mass index (BMI), WC and L2/3 VAT but more Indian men had hypertension, hyperlipidemia and type 2 diabetes mellitus. WC was correlated with the L2/3 VAT area in both Chinese (r=0.484, P<0.001) and Indian subjects (r=0.366, P=0.004) without racial difference (P=0.2 for interaction term). L2/3 VAT also correlated better with cardiometabolic risk factors, adipokines and C-reactive protein than WC, BMI or L4/5 VAT. CONCLUSION: The L2-L3 intervertebral space was the best anatomic level for a single-slice CT cross-sectional area measurement of VAT to approximate total body visceral adipose volume in this population of Chinese and Asian Indian men older than 60 years. L2/3 VAT was better correlated with multiple cardiovascular risk factors, adipokines and inflammatory marker than either L4/5 VAT, WC or BMI.

Roles of Education and IQ in Cognitive Reserve in Parkinson's Disease-Mild Cognitive Impairment.

BACKGROUND/AIMS: The role of cognitive reserve in Parkinson's disease (PD)-mild cognitive impairment (MCI) is incompletely understood. METHODS: The relationships between PD-MCI, years of education, and estimated premorbid IQ were examined in 119 consecutive non-demented PD patients using logistic regression models. RESULTS: Higher education and IQ were associated with reduced odds of PD-MCI in univariate analysis. In multivariable analysis, a higher IQ was associated with a significantly decreased odds of PD-MCI, but education was not. CONCLUSION: The association of higher IQ and decreased odds of PD-MCI supports a role for cognitive reserve in PD, but further studies are needed to clarify the interaction of IQ and education and the impact of other contributors such as employment and hobbies.

Biochip analysis: status quo.

Biochips are collections of miniaturized test sites (microarrays) arranged on a solid substrate onto which a large number of biomolecules are attached with high density. Like a computer chip performing millions of mathematical operations in a few split seconds, a biochip allows for simultaneous analyses of thousands of biological reactions, such as decoding genes, in a few seconds. Biochip technologies can be applied to numerous fields including genomic, proteomic, and glycomic research, as well as pharmacology and toxicology. However, one of the most common applications is in the determination of gene expression in human cells and tissues. Global gene expression analysis has helped to identify important genes and signalling pathways in human malignant tumors. And there is hope that microarrays will make the step from "the (laboratory) bench to the bedside (of the patient)". Recent studies have indeed revealed that analysis of differential gene expression by microarrays may help to identify subtypes of malignant tumors, that allow a risk stratification of the patients. However, there are several issues that need to be addressed before microarrays may become a tool for routine diagnostics, such as problems with bioinformatic analysis, construction of disease or tissue specific microarrays with only limited numbers of genes of interest, standard operation procedures for tissue preparation to prevent RNA degradation, etc.. In this article, an overview over of the multifarious biochip applications and technologies, its limitations, challenges and future developments is provided.

Rate of progression differs in frontotemporal dementia and Alzheimer disease.

OBJECTIVE: To compare survival and rates of cognitive and functional decline in patients with autopsy-confirmed frontotemporal dementia (FTD) and Alzheimer disease (AD) in a large multicenter study. BACKGROUND: Despite advances in the clinical characterization of FTD, little is known about its rate of progression. Characterizing survival and rate of decline in FTD is important because it can provide prognostic guidelines and benchmarks to use in the evaluation of disease-modifying drugs. METHODS: Seventy patients with FTD and 70 patients with AD who were followed by seven Alzheimer disease research centers until confirmation of diagnosis at autopsy were matched for overall age, education, and Mini-Mental State Examination (MMSE) score at initial evaluation. Survival and rates of cognitive and functional decline were compared. RESULTS: Patients with FTD had significantly shorter survival from initial evaluation to death than patients with AD (FTD = 4.2 years, AD = 6.0 years; log-rank test = 5.17, p < 0.05), and they declined significantly faster over one year on the MMSE (mean annual rate of change: -6.7 points for FTD vs -2.3 points for AD). A significantly greater proportion of patients with FTD were impaired in basic activities of daily living (ADLs) at initial evaluation, and lost the capacity for independent or minimally-assisted ADLs over the subsequent year. CONCLUSIONS: The results are consistent with shorter survival and faster rates of cognitive and functional decline in patients with frontotemporal dementia (FTD) compared to those with Alzheimer disease (AD). This suggests that FTD follows a more malignant disease course than AD once dementia is clinically recognized.

Latex allergy and the healthcare worker.

The purpose of this article is to describe the clinical manifestations and treatment of latex allergy. A discussion of the identification of latex-sensitized staff and available diagnostic tests is presented. Emphasis is placed on the healthcare worker's role in preventing future latex allergy cases from developing.

A guide to caring for your latex allergic patient.

The purpose of this article is to assist the health care provider with an understanding of how to care for latex-allergic patients. Ways to ensure patient safety in a health care facility are discussed, including important aspects of patient education.

Corneal scarring and irregular astigmatism following refractive surgery in a corneal transplant.

BACKGROUND: Scarring may follow refractive surgery, causing irregular astigmatism and loss of visual acuity. METHODS: A case report of scarring and irregular astigmatism occurring in a corneal transplant following photorefractive keratectomy and arcuate incisions is presented. RESULTS: Following surgical excision of the scar, unaided visual acuity improved from 1/60 to 6/12. Histopathology of the excised scar was obtained. CONCLUSIONS: Refractive surgery following corneal transplantation may produce scarring. The origin of the scar in the present case has not been established.

Traditional and emerging molecular markers in neuroblastoma prognosis: the good, the bad and the ugly.

BACKGROUND: Neuroblastomas (NB) are a heterogeneous group of childhood tumours with a wide range of likelihood for tumour progression. As traditional parameters do not ensure completely accurate prognostic grouping, new molecular markers are needed for assessing the individual patient's prognosis more precisely. PATIENTS AND METHODS: 133 NB of all stages were analysed in blind-trial fashion for telomerase activity (TA), expression of surviving, and MYCN status. These data were correlated with other traditional prognostic indicators and disease outcome. RESULTS AND CONCLUSIONS: TA is a powerful independent prognostic marker for all stages and is capable of differentiating between good and poor outcome in putative "favourable" clinical or biological subgroups of NB patients. High surviving expression is associated with an adverse outcome, but is more difficult to interprete than TA because survivin expression needs to be accurately quantified to be of predictive value. We propose an extended progression model for NB including emerging prognostic markers, with emphasis on telomerase activity.