CYP2E1 VNTR genotyping associated to anti\u2013tuberculosis drug-induced hepatotoxicity

Tuberculosis (TB) remains a major worldwide health problem with an estimated of 9.0 million of new cases and 1.5 million of deaths in 2013. Anti\u2013TB drug-induced hepatotoxicity (ATDH) is considered the most serious and prevalent adverse drug reaction in TB treatment. Isoniazid (INH), one of the first-line drugs against TB, is more commonly associated to ATDH and, it is well known that the enzyme Citochrome P450 2E1 (CYP2E1) is involved in INH metabolism. It has been found that variable number tandem repeat (VNTR) polymorphic sequences in the promoter region regulate negatively CYP2E1 gene transcription: consequently, it could be put in relationship with adverse TB-drugs reactions. In this report we for the first time show advanced investigations regarding the association between CYP2E1- VNTR and ATDH; the study started last year also thank to a small grant by CUIA but was widely extended with other funds. We studied genotypic frequency distributions of the CYP2E1-VNTR (using PCR-RFLP methodology) in a cohort 294 TB patients treated with anti-TB drugs: 167 were Argentines (130 controls without ATDH and 37 cases with ATDH) and 127 were Bolivians (83 controls without ATDH and 44 cases with ATDH). Chi-squared test was used to compare proportions: a value of P<0.05 was considered to be statistically significant. In the Argentine population, we observed that the A2/A4 genotype frequency was significantly higher in cases than in controls (P=0.048). In contrast, no significant differences were observed in Bolivian population between controls and cases regarding to distribution of VNTR genotypes. Our preliminary results showed that the presence of A4 allele of CYP2E1-VNTR could be associated to ATDH, at least in the Argentine population. These results are in agreement with previously reported data which proposed that the transcriptional activity of A4 allele was higher than that of A2 allele since the transcriptional suppression of A4 was weaker than that of A2. It will be necessary to increase the number of cases in both populations to confirm this possible and interesting association. The CYP2E1 VNTR genotype, in fact, promises to be an attractive marker that could be used to predict or prevent ATDH like the acetylator profile

Exploring Multiple‐discreteness in Freight Transport. A Multiple Discrete Extreme Value Model Application for Grain Consolidators in Argentina

There are some examples where freight choices may be of a multiple discrete nature, especially the ones at more tactical levels of planning. Nevertheless, this has not been investigated in the literature, although several discrete-continuous models for mode/vehicle type and shipment size choice have been developed in freight transport. In this work, we propose that the decision of port and mode of the grain consolidators in Argentina is of a discrete-continuous nature, where they can choose more than one alternative and how much of their production to send by each mode. The Multiple Discrete Extreme Value Model (MDCEV) framework was applied to a stated preference data set with a response variable that allowed this multiple-discreteness. To our knowledge, this is the only application of the MDCEV in regional freight context. Free alongside ship price, freight transport cost, lead-time and travel time were included in the utility function and observed and random heterogeneity was captured by the interaction with the consolidator’s characteristics and random coefficients. In addition, different discrete choice models were used to compare the forecasting performance, willingness to pay measures and structure of the utility function against

C3-Cloud personalised care plan development platform for addressing the needs of multi-morbidity and managing poly-pharmacy : protocol for a pilot technology trial

Background: There is an increasing need to organise the care around the patient and not the disease, as well as taking into account the complex realities of multiple physical, psycho-social conditions and polypharmacy. Integrated patient-centred care delivery platforms have been developed for both patients and clinicians. These platforms could provide a promising way to achieve a collaborative environment that improves the provision of integrated care for patients via enhanced ICT solutions. Objective: The C3-Cloud project has developed two collaborative computer platforms for patients and members of the Multi-Disciplinary Team and deployed these in three different European settings. The objective of this study is to pilot test the platforms and evaluate their impact on patients, informal caregivers, healthcare professionals and, in extend, healthcare systems. Methods: This paper describes the protocol for conducting an evaluation of the user-centred design, user experience, acceptability, and usefulness of the platforms. For this, four ‘testing and evaluation’ phases have been defined, involving multiple qualitative methods, and advanced impact modelling. Results: The technology trial in this 4-year funded project (2016-2020) is currently in its execution phase. The testing and evaluation phase 1 and 2 have been completed with satisfying results on system component tests, and promising results on application and usability tests. The pilot technology trial for evaluation phase 3 and 4 was launched in August 2019. Data collection for these phases is underway and results are forthcoming, approximately in April 2020. We believe that the phased, iterative approach taken is useful as it involves relevant stakeholders at crucial stages in the platform development and allows for a sound user acceptance assessment of the final product. Conclusions: Patients with multiple chronic conditions often experience shortcomings in the care they receive. It is hoped that personalised care plan platforms for patients and collaboration platforms for members of Multi-Disciplinary Teams can help to tackle the specific challenges of clinical guideline reconciliation for multimorbid patients and improved the management of poly-pharmacy. The initial evaluative phases have indicated promising results of platform usability. The phased methodology has shown useful results in the first two phases, while results of phase 3 and 4 are pending. Clinical Trial: https://www.clinicaltrials.gov/ct2/show/NCT0383420

Treatment challenges in and outside a specialist network setting: Pancreatic neuroendocrine tumours

Pancreatic Neuroendocrine Neoplasms comprise a group of rare tumours with special biology, an often indolent behaviour and particular diagnostic and therapeutic requirements. The specialized biochemical tests and radiological investigations, the complexity of surgical options and the variety of medical treatments that require individual tailoring, mandate a multidisciplinary approach that can be optimally achieved through an organized network. The present study describes currents concepts in the management of these tumours as well as an insight into the challenges of delivering the pathway in and outside a Network

Perturbative instabilities in Horava gravity

We investigate the scalar and tensor perturbations in Horava gravity, with and without detailed balance, around a flat background. Once both types of perturbations are taken into account, it is revealed that the theory is plagued by ghost-like scalar instabilities in the range of parameters which would render it power-counting renormalizable, that cannot be overcome by simple tricks such as analytic continuation. Implementing a consistent flow between the UV and IR limits seems thus more challenging than initially presumed, regardless of whether the theory approaches General Relativity at low energies or not. Even in the phenomenologically viable parameter space, the tensor sector leads to additional potential problems, such as fine-tunings and super-luminal propagation.Comment: 21 pages, version published at Class. Quant. Gra

Testicular germ-cell tumours and penile squamous cell carcinoma: Appropriate management makes the difference

Germ-cell tumours (GCT) of the testis and penile squamous cell carcinoma (PeSCC) are a rare and a very rare uro-genital cancers, respectively. Both tumours are well defined entities in terms of management, where specific recommendations - in the form of continuously up-to-dated guide lines-are provided. Impact of these tumour is relevant. Testicular GCT affects young, healthy men at the beginning of their adult life. PeSCC affects older men, but a proportion of these patients are young and the personal consequences of the disease may be devastating. Deviation from recommended management may be a reason of a significant prognostic worsening, as proper treatment favourably impacts on these tumours, dramatically on GCT and significantly on PeSCC. RARECAREnet data may permit to analyse how survivals may vary according to geographical areas, histology and age, leading to assume that non-homogeneous health-care resources may impact the cure and definitive outcomes. In support of this hypothesis, some epidemiologic datasets and clinical findings would indicate that survival may improve when appropriate treatments are delivered, linked to a different accessibility to the best health institutions, as a consequence of geographical, cultural and economic barriers. Finally, strong clues based on epidemiological and clinical data support the hypothesis that treatment delivered at reference centres or under the aegis of a qualified multi-institutional network is associated with a better prognosis of patients with these malignancies. The ERN EURACAN represents the best current European effort to answer this clinical need

Treatment challenges in and outside a network setting: Head and neck cancers

Head and neck cancer (HNC) is a rare disease that can affect different sites and is characterized by variable incidence and 5-year survival rates across Europe. Multiple factors need to be considered when choosing the most appropriate treatment for HNC patients, such as age, comorbidities, social issues, and especially whether to prefer surgery or radiation-based protocols. Given the complexity of this scenario, the creation of a highly specialized multidisciplinary team is recommended to guarantee the best oncological outcome and prevent or adequately treat any adverse effect. Data from literature suggest that the multidisciplinary team-based approach is beneficial for HNC patients and lead to improved survival rates. This result is likely due to improved diagnostic and staging accuracy, a more efficacious therapeutic approach and enhanced communication across disciplines. Despite the benefit of MTD, it must be noted that this approach requires considerable time, effort and financial resources and is usually more frequent in highly organized and high-volume centers. Literature data on clinical research suggest that patients treated in high-accrual centers report better treatment outcomes compared to patients treated in low-volume centers, where a lower radiotherapy-compliance and worst overall survival have been reported. There is general agreement that treatment of rare cancers such as HNC should be concentrated in high volume, specialized and multidisciplinary centers. In order to achieve this goal, the creation of international collaboration network is fundamental. The European Reference Networks for example aim to create an international virtual advisory board, whose objectives are the exchange of expertise, training, clinical collaboration and the reduction of disparities and enhancement of rationalize migration across Europe. The purpose of our work is to review all aspects and challenges in and outside this network setting planned for the management of HNC patients

Adenovirus type 7 associated with severe and fatal acute lower respiratory infections in Argentine children

BACKGROUND: Adenoviruses are the second most prevalent cause of acute lower respiratory infection of viral origin in children under four years of age in Buenos Aires, Argentina. The purpose of this study was to analyze the clinical features and outcome of acute lower respiratory infection associated with different adenovirus genotypes in children. METHODS: Twenty-four cases of acute lower respiratory infection and adenovirus diagnosis reported in a pediatric unit during a two-year period were retrospectively reviewed. Adenovirus was detected by antigen detection and isolation in HEp-2 cells. Adenovirus DNA from 17 isolates was studied by restriction enzyme analysis with Bam HI and Sma I. RESULTS: Subgenus b was found in 82.3% of the cases, and subgenus c in 17.7%. Within subgenus b, only genotype 7 was detected, with genomic variant 7h in 85.7% (12/14) and genomic variant 7i in 14.3% (2/14). Mean age was 8.8 ±; 6 months, and male to female ratio was 3.8: 1. At admission, pneumonia was observed in 71% of the cases and bronchiolitis in 29%. Malnutrition occurred in 37% of the cases; tachypnea in 79%; chest indrawing in 66%; wheezing in 58%; apneas in 16%; and conjunctivitis in 29%. Blood cultures for bacteria and antigen detection of other respiratory viruses were negative. During hospitalization, fatality rate was 16.7% (4 /24). Of the patients who died, three had Ad 7h and one Ad 7i. Thus, fatality rate for adenovirus type 7 reached 28.6% (4/14). CONCLUSIONS: These results show the predominance of adenovirus 7 and high lethality associated with the genomic variants 7h and 7i in children hospitalized with acute lower respiratory infection

Insulin-like growth factor I and risk of epithelial invasive ovarian cancer by tumour characteristics: results from the EPIC cohort

Background: Prospective studies on insulin-like growth factor I (IGF-I) and epithelial ovarian cancer (EOC) risk are inconclusive. Data suggest risk associations vary by tumour characteristics. Methods: We conducted a nested case-control study in the European Prospective Investigation into Cancer and Nutrition (EPIC) to evaluate IGF-I concentrations and EOC risk by tumour characteristics (n=565 cases). Multivariable conditional logistic regression models were used to estimate associations. Results: We observed no association between IGF-I and EOC overall or by tumour characteristics. Conclusions: In the largest prospective study to date was no association between IGF-I and EOC risk. Pre-diagnostic serum IGF-I concentrations may not influence EOC risk

Reproductive and hormone-related risk factors for epithelial ovarian cancer by histologic pathways, invasiveness and histologic subtypes: results from the EPIC cohort

Whether risk factors for epithelial ovarian cancer (EOC) differ by subtype (i.e., dualistic pathway of carcinogenesis, histologic subtype) is not well understood; however, data to date suggest risk factor differences. We examined associations between reproductive and hormone-related risk factors for EOC by subtype in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. Among 334,126 women with data on reproductive and hormone-related risk factors (follow-up: 1992–2010), 1,245 incident cases of EOC with known histology and invasiveness were identified. Data on tumor histology, grade, and invasiveness, were available from cancer registries and pathology record review. We observed significant heterogeneity by the dualistic model (i.e., type I [low grade serous or endometrioid, mucinous, clear cell, malignant Brenner] vs. type II [high grade serous or endometrioid]) for full-term pregnancy (phet = 0.02). Full-term pregnancy was more strongly inversely associated with type I than type II tumors (ever vs. never: type I: relative risk (RR) 0.47 [95% confidence interval (CI): 0.33–0.69]; type II, RR: 0.81 [0.61–1.06]). We observed no significant differences in risk in analyses by major histologic subtypes of invasive EOC (serous, mucinous, endometrioid, clear cell). None of the investigated factors were associated with borderline tumors. Established protective factors, including duration of oral contraceptive use and full term pregnancy, were consistently inversely associated with risk across histologic subtypes (e.g., ever full-term pregnancy: serous, RR: 0.73 [0.58–0.92]; mucinous, RR: 0.53 [0.30–0.95]; endometrioid, RR: 0.65 [0.40–1.06]; clear cell, RR: 0.34 [0.18–0.64]; phet = 0.16). These results suggest limited heterogeneity between reproductive and hormone-related risk factors and EOC subtypes