A Comparative Study of Biomechanical Simulators in Deformable Registration of Brain Tumor Images

Simulating the brain tissue deformation caused by tumor growth has been found to aid the deformable registration of brain tumor images. In this paper, we evaluate the impact that different biomechanical simulators have on the accuracy of deformable registration. We use two alternative frameworks for biomechanical simulations of mass effect in 3-D magnetic resonance (MR) brain images. The first one is based on a finite-element model of nonlinear elasticity and unstructured meshes using the commercial software package ABAQUS. The second one employs incremental linear elasticity and regular grids in a fictitious domain method. In practice, biomechanical simulations via the second approach may be at least ten times faster. Landmarks error and visual examination of the coregistered images indicate that the two alternative frameworks for biomechanical simulations lead to comparable results of deformable registration. Thus, the computationally less expensive biomechanical simulator offers a practical alternative for registration purposes

SMN1 dosage analysis in spinal muscular atrophy from India

BACKGROUND: Spinal muscular atrophy (SMA) represents the second most common fatal autosomal recessive disorder after cystic fibrosis. Due to the high carrier frequency, the burden of this genetic disorder is very heavy in developing countries like India. As there is no cure or effective treatment, genetic counseling becomes very important in disease management. SMN1 dosage analysis results can be utilized for identifying carriers before offering prenatal diagnosis in the context of genetic counseling. METHODS: In the present study we analyzed the carrier status of parents and sibs of proven SMA patients. In addition, SMN1 copy number was determined in suspected SMA patients and parents of children with a clinical diagnosis of SMA. RESULTS: wenty nine DNA samples were analyzed by quantitative PCR to determine the number of SMN1 gene copies present, and 17 of these were found to have one SMN1 gene copy. The parents of confirmed SMA patients were found to be obligate carriers of the disease. Dosage analysis was useful in ruling out clinical suspicion of SMA in four patients. In a family with history of a deceased floppy infant and two abortions, both parents were found to be carriers of SMA and prenatal diagnosis could be offered in future pregnancies. CONCLUSION: SMN1 copy number analysis is an important parameter for identification of couples at risk for having a child affected with SMA and reduces unwarranted prenatal diagnosis for SMA. The dosage analysis is also useful for the counseling of clinically suspected SMA with a negative diagnostic SMA test

Informed consent for clinical trials in acute coronary syndromes and stroke following the European Clinical Trials Directive: investigators' experiences and attitudes

<p>Abstract</p> <p>Background</p> <p>During clinical trials in emergency medicine, providing appropriate oral and written information to a patient is usually a challenge. There is little published information regarding patients' opinions and competence to provide informed consent, nor on physicians' attitudes towards the process. We have investigated the problem of obtaining consent from patients in emergency-setting clinical trials (such as acute coronary syndromes (ACS) and stroke) from a physicians' perspective.</p> <p>Methods</p> <p>A standardised anonymous 14-item questionnaire was distributed to Polish cardiac and stroke centres.</p> <p>Results</p> <p>Two hundred and fourteen informative investigator responses were received. Of these investigators, 73.8% had experience with ACS and 25.2% had experience with acute stroke trials (and 1% with both fields). The complete model of informed consent (embracing all aspects required by Good Clinical Practice (GCP) and law) was used in 53.3% of cases in emergency settings, whereas the legal option of proxy consent was not used at all. While less than 15% of respondents considered written information to have been fully read by patients, 80.4% thought that the amount of information being given to emergency patients is too lengthy. Although there is no legal obligation, more than half of the investigators sought parallel consent (assent) from patients' relatives. Most investigators confirmed that they would adopt the model proposed by the GCP guidelines: abbreviated verbal and written consent in emergency conditions with obligatory "all-embracing" deferred consent to continue the trial once the patient is able to provide it. However, this model would not follow current Polish and European legislation.</p> <p>Conclusion</p> <p>An update of national and European regulations is required to enable implementation of the emergency trial consent model referred to in GCP guidelines.</p

Association of patient characteristics with clinical outcomes in a cohort of hospitalised patients with SARS-CoV-2 infection in a Greek referral centre for COVID-19

Patient-important outcomes related to coronavirus disease 2019 (COVID-19) continue to drive the pandemic response across the globe. Various prognostic factors for COVID-19 severity have emerged and their replication across different clinical settings providing health services is ongoing. We aimed to describe the clinical characteristics and their association with outcomes in patients hospitalised with COVID-19 in the University Hospital of Ioannina. We assessed a cohort of 681 consecutively hospitalised patients with COVID-19 from January 2020 to December 2021. Demographic data, underlying comorbidities, clinical presentation, biochemical markers, radiologic findings, COVID-19 treatment and outcome data were collected at the first day of hospitalisation and up to 90 days. Multivariable Cox regression analyses were performed to investigate the associations between clinical characteristics (hazard ratios (HRs) per standard deviation (S.D.)) with intubation and/or mortality status. The participants' mean age was 62.8 (S.D., 16.9) years and 57% were males. The most common comorbidities were hypertension (45%), cardiovascular disease (19%) and diabetes mellitus (21%). Patients usually presented with fever (81%), cough (50%) and dyspnoea (27%), while lymphopenia and increased inflammatory markers were the most common laboratory abnormalities. Overall, 55 patients (8%) were intubated, and 86 patients (13%) died. There were statistically significant positive associations between intubation or death with age (HR: 2.59; 95% CI 1.52–4.40), lactate dehydrogenase (HR: 1.44; 95% CI 1.04–1.98), pO2/FiO2 ratio < 100 mmHg (HR: 3.52; 95% CI 1.14–10.84), and inverse association with absolute lymphocyte count (HR: 0.54; 95% CI 0.33–0.87). These data might help to identify points for improvement in the management of COVID-19 patients

Ethical considerations in prehospital ambulance based research : qualitative interview study of expert informants

Abstract: Background: Prehospital ambulance based research has unique ethical considerations due to urgency, time limitations and the locations involved. We sought to explore these issues through interviews with experts in this research field. Methods: We undertook semi-structured interviews with expert informants, primarily based in the UK, seeking their views and experiences of ethics in ambulance based clinical research. Participants were questioned regarding their experiences of ambulance based research, their opinions on current regulations and guidelines, and views about their general ethical considerations. Participants were chosen because they were actively involved in, or in their expert capacity (e.g. law) expressed an interest in, ambulance based research. Results: Fourteen participants were interviewed including principal investigators, researchers, ethicists and medical lawyers. Five major themes were identified: Capacity, Consent, Clinical Considerations, Consultation and Regulation. Questions regarding consent and capacity were foremost in the discussions as all participants highlighted these as areas for concern. The challenges and use of multiple consent models reflected the complexity of research in this environment. The clinical theme referred to the role of paramedics in research and how research involving ambulance services is increasingly informing improvements to patient care and outcomes and reducing the burden on hospital services. Most felt that, although current regulations were fit for purpose, more specific guidance on implementing these in the ambulance setting would be beneficial. This related closely to the theme of consultation, which examined the key role of ethics committees and other regulatory bodies, as well as public engagement. Conclusions: By interviewing experts in research or ethics in this setting we were able to identify key concerns and highlight areas for future development such as improved guidance

Genetic and expression studies of SMN2 gene in Russian patients with spinal muscular atrophy type II and III

<p>Abstract</p> <p>Background</p> <p>Spinal muscular atrophy (SMA type I, II and III) is an autosomal recessive neuromuscular disorder caused by mutations in the survival motor neuron gene (<it>SMN1</it>). <it>SMN2 </it>is a centromeric copy gene that has been characterized as a major modifier of SMA severity. SMA type I patients have one or two <it>SMN2 </it>copies while most SMA type II patients carry three <it>SMN2 </it>copies and SMA III patients have three or four <it>SMN2 </it>copies. The <it>SMN1 </it>gene produces a full-length transcript (FL-SMN) while <it>SMN2 </it>is only able to produce a small portion of the FL-SMN because of a splice mutation which results in the production of abnormal SMNΔ7 mRNA.</p> <p>Methods</p> <p>In this study we performed quantification of the <it>SMN2 </it>gene copy number in Russian patients affected by SMA type II and III (42 and 19 patients, respectively) by means of real-time PCR. Moreover, we present two families consisting of asymptomatic carriers of a homozygous absence of the <it>SMN1 </it>gene. We also developed a novel RT-qPCR-based assay to determine the FL-SMN/SMNΔ7 mRNA ratio as SMA biomarker.</p> <p>Results</p> <p>Comparison of the <it>SMN2 </it>copy number and clinical features revealed a significant correlation between mild clinical phenotype (SMA type III) and presence of four copies of the <it>SMN2 </it>gene. In both asymptomatic cases we found an increased number of <it>SMN2 </it>copies in the healthy carriers and a biallelic <it>SMN1 </it>absence. Furthermore, the novel assay revealed a difference between SMA patients and healthy controls.</p> <p>Conclusions</p> <p>We suggest that the <it>SMN2 </it>gene copy quantification in SMA patients could be used as a prognostic tool for discrimination between the SMA type II and SMA type III diagnoses, whereas the FL-SMN/SMNΔ7 mRNA ratio could be a useful biomarker for detecting changes during SMA pharmacotherapy.</p

Matching Schur complement approximations for certain saddle-point systems

The solution of many practical problems described by mathematical models requires approximation methods that give rise to linear(ized) systems of equations, solving which will determine the desired approximation. This short contribution describes a particularly effective solution approach for a certain class of so-called saddle-point linear systems which arises in different contexts

Characterization of Novel and Uncharacterized p53 SNPs in the Chinese Population – Intron 2 SNP Co-Segregates with the Common Codon 72 Polymorphism

Multiple single nucleotide polymorphisms (SNPs) have been identified in the tumor suppressor gene p53, though the relevance of many of them is unclear. Some of them are also differentially distributed in various ethnic populations, suggesting selective functionality. We have therefore sequenced all exons and flanking regions of p53 from the Singaporean Chinese population and report here the characterization of some novel and uncharacterized SNPs - four in intron 1 (nucleotide positions 8759/10361/10506/11130), three in intron 3 (11968/11969/11974) and two in the 3′UTR (19168/19514). Allelic frequencies were determined for all these and some known SNPs, and were compared in a limited scale to leukemia and lung cancer patient samples. Intron 2 (11827) and 7 (14181/14201) SNPs were found to have a high minor allele frequency of between 26–47%, in contrast to the lower frequencies found in the US population, but similar in trend to the codon 72 polymorphism (SNP12139) that shows a distribution pattern correlative with latitude. Several of the SNPs were linked, such as those in introns 1, 3 and 7. Most interestingly, we noticed the co-segregation of the intron 2 and the codon 72 SNPs, the latter which has been shown to be expressed in an allele-specific manner, suggesting possible regulatory cross-talk. Association analysis indicated that the T/G alleles in both the co-segregating intron 7 SNPs and a 4tagSNP haplotype was strongly associated increased susceptibility to lung cancer in non-smoker females [OR: 1.97 (1.32, 3.394)]. These data together demonstrate high SNP diversity in p53 gene between different populations, highlighting ethnicity-based differences, and their association with cancer risk

Do genetic factors protect for early onset lung cancer? A case control study before the age of 50 years

<p>Abstract</p> <p>Background</p> <p>Early onset lung cancer shows some familial aggregation, pointing to a genetic predisposition. This study was set up to investigate the role of candidate genes in the susceptibility to lung cancer patients younger than 51 years at diagnosis.</p> <p>Methods</p> <p>246 patients with a primary, histologically or cytologically confirmed neoplasm, recruited from 2000 to 2003 in major lung clinics across Germany, were matched to 223 unrelated healthy controls. 11 single nucleotide polymorphisms of genes with reported associations to lung cancer have been genotyped.</p> <p>Results</p> <p>Genetic associations or gene-smoking interactions was found for <it>GPX1(Pro200Leu) </it>and <it>EPHX1(His113Tyr)</it>. Carriers of the Leu-allele of <it>GPX1(Pro200Leu) </it>showed a significant risk reduction of OR = 0.6 (95% CI: 0.4–0.8, p = 0.002) in general and of OR = 0.3 (95% CI:0.1–0.8, p = 0.012) within heavy smokers. We could also find a risk decreasing genetic effect for His-carriers of <it>EPHX1(His113Tyr) </it>for moderate smokers (OR = 0.2, 95% CI:0.1–0.7, p = 0.012). Considered both variants together, a monotone decrease of the OR was found for smokers (OR of 0.20; 95% CI: 0.07–0.60) for each protective allele.</p> <p>Conclusion</p> <p>Smoking is the most important risk factor for young lung cancer patients. However, this study provides some support for the T-Allel of <it>GPX1(Pro200Leu) </it>and the C-Allele of <it>EPHX1(His113Tyr) </it>to play a protective role in early onset lung cancer susceptibility.</p