Cost-effectiveness of AQP4 antibody detection with cell-based assay compared with elisa for devic disease diagnosis in Colombia

Q1Q1A44Objectives Neuromyelitis optica (NMO) or Devic disease is a rare chronic condition characterized by demyelinating lesions in the central nervous system. The aim of this study was to evaluate cost-effectiveness of the detection of antibodies against the protein aquaporin water channel 4 (AQP4) with cell-based assay (CBA), compared with ELISA, for the diagnosis of NMO in Colombia. Methods A decision tree model was constructed to compare costs, correctly diagnosed cases and relapses averted in patients with clinical suspicion of NMO, that were subjected to diagnostic tests for the detection of AQP4 antibodies. The analysis was undertaken from a third-party payer perspective, one year time horizon (first year with the disease) taking all costs for treatment and relapses, in 2014 Colombian pesos, from official published prices (1 USD = 2,033 COP). Since the CBA kit is not available in Colombia (currently samples are processed abroad), the price was obtained from the manufacturer and set in a national laboratory. Clinical variables were from a systematic literature review. Univariate and probabilistic sensitivity analyses (a Monte Carlo simulating a cohort of 1000 patients) were conducted. Results Identification of AQP4 antibodies with CBA is a dominant strategy: more effective (855 correctly diagnosed patients compared with 765 detected by ELISA, and 130 avoided relapses), and less costly, with expected yearly costs per correctly diagnosed Devic patient of USD $14,658 compared with$15,614 for ELISA. Using CBA may represent savings in terms of reduced costs of treating disease and relapse with hospitalization. Conclusions AQP4 antibody identification by the CBA method is a cost-saving diagnostic test, dominant over the ELISA method

Transmitter and receiver equalizers optimization for PCI Express Gen6.0 based on PAM4

The continuously increasing bandwidth demand from new applications has led to the development of the new PCIe Gen6, reaching data rates of 64 GT/s and adopting PAM4 modulation scheme. While PAM4 solves the bandwidth constraint in high-speed interconnects, it brings new challenges for the physical channel analysis. Equalization (EQ) plays an important role even with PAM4 signaling. PCIe specification defines requirements to perform EQ at the transmitter (Tx) and at the receiver (Rx). During the EQ process, one combination of Tx/Rx EQ coefficients must be selected to meet the performance requirements of the system. Testing all possible coefficient combinations is prohibitive. Current industrial practice consists of finding a subset of combinations at post-silicon validation using maps of EQ coefficients. Finding this subset of coefficients is timeconsuming,along with all the new challenges imposed by PAM4. In this paper, we propose an optimization approach for PCIe Gen6 link EQ. Our proposal is based on a suitable objective function formulated over the channel operating margin (COM), which is a new figure of merit (FOM) adopted by standards of communications for signaling speeds beyond 25 Gbps.ITESO, A.C

Adherence to Mediterranean diet associated with health-related quality of life in children and adolescents: a systematic review

Abstract Background: Health-related quality of life (HRQoL) has become a signifcant outcome in assessing interventions in the pediatric population and could be infuenced by diet patterns. The Mediterranean diet (MD) pattern has been related to multiple positive health outcomes, including decreased cardiovascular risk and better mental health. We aimed to evaluate the association between MD adherence and HRQoL in children and adolescents. Methods: The literature search was conducted in PubMed, Cochrane Library, Scopus, Web of Science, Embase, and Ovid-MEDLINE databases from inception to May 2022. Two researchers independently checked titles and abstracts, evaluated full-text studies, extracted data, and appraised the risk of bias using the Newcastle–Ottawa Scale (NOS). Results: Eleven studies (1 longitudinal and 10 cross-sectional), totaling 6,796 subjects, were included. Ten studies assessed MD adherence with KIDMED index, and one assessed MD adherence with Krece Plus test, while all included studies assessed HRQoL with a KIDSCREEN test. All studies analyzed the association between MD adherence and HRQoL with linear regression, and eight used adjusted models. Five studies found a signifcant positive association of MD adherence with HRQoL, with β-values ranging from 0.13 to 0.26. Two found a nonsignifcant positive relationship, while one found a negative association. According to the NOS criteria, the risk of bias assessment showed four studies with a low risk of bias and seven with a high risk of bias. Conclusion: Our fndings suggest a positive correlation of MD adherence with HRQoL in children and adolescents. However, future research is needed to strengthen the evidence of this relationshi

Prevalence of drug resistance mutations among ART-naive and -experienced HIV-infected patients in Sierra Leone

Objectives: The aim of this study was to assess the prevalence of HIV drug resistance (HIVDR) in HIV-infected ART-naive and -experienced patients in Sierra Leone. Patients and methods: We conducted a cross-sectional study of HIV-positive adults aged 18 years at Connaught Hospital in Freetown, Sierra Leone in November 2017. Sequencing was performed in the reverse transcriptase, protease and integrase regions, and interpreted using the Stanford HIVDR database andWHO 2009mutation list. Results: Two hundred and fifteen HIV-infected patients were included (64 ART naive and 151 ART experienced). The majority (66%) were female, the median age was 36 years and the median ART exposure was 48months. The majority (83%) were infected with HIV-1 subtype CRF02_AG. In the ART-naive group, the pretreatment drug resistance (PDR) prevalence was 36.7% (14.2% to NRTIs and 22.4% to NNRTIs). The most prevalent PDR mutations were K103N (14.3%), M184V (8.2%) and Y181C (4.1%). In the ART-experienced group, 64.4% harboured resistance-associated mutations (RAMs) and the overall prevalence of RAMs to NRTIs and NNRTIs was 85.2% (52/61) and 96.7% (59/61), respectively. The most prevalent RAMs were K103N (40.7%), M184V (28.8%), D67N (15.3%) and T215I/F/Y (15.3%). Based on the genotypic susceptibility score estimates, 22.4% of ART-naive patients and 56% of ART-experienced patients were not susceptible to first-line ART used in Sierra Leone. Conclusions: A high prevalence of circulating NRTI- and NNRTI-resistant variants was observed in ART-naive and -experienced HIV-1-infected patients in Sierra Leone. This necessitates the implementation of HIVDR surveillance programmes to inform national ART guidelines for the treatment and monitoring of HIV-infected patients in Sierra Leone.Xunta Galicia-Fondo Social Europeo | Ref. IN606A-2016/023Case Western Reserve University | Ref. NIH NIAID T32 AI07024Instituto de Salud Carlos III and Fondo Europeo de Desarrollo Regional-FEDER | Ref. RD16/0025/002

Early Science with the Large Millimeter Telescope: an energy-driven wind revealed by massive molecular and fast X-ray outflows in the Seyfert Galaxy IRAS 17020+4544

We report on the coexistence of powerful gas outflows observed in millimeter and X-ray data of the Radio-Loud Narrow Line Seyfert 1 Galaxy IRAS 17020+4544. Thanks to the large collecting power of the Large Millimeter Telescope, a prominent line arising from the 12CO(1-0) transition was revealed in recent observations of this source. The complex profile is composed by a narrow double-peak line and a broad wing. While the double-peak structure may be arising in a disk of molecular material, the broad wing is interpreted as the signature of a massive outflow of molecular gas with an approximate bulk velocity of -660 km/s. This molecular wind is likely associated to a multi-component X-ray Ultra-Fast Outflow with velocities reaching up to ~0.1c and column densities in the range 10^{21-23.9} cm^-2 that was reported in the source prior to the LMT observations. The momentum load estimated in the two gas phases indicates that within the observational uncertainties the outflow is consistent with being propagating through the galaxy and sweeping up the gas while conserving its energy. This scenario, which has been often postulated as a viable mechanism of how AGN feedback takes place, has so far been observed only in ULIRGs sources. IRAS 17020+4544 with bolometric and infrared luminosity respectively of 5X10^{44} erg/s and 1.05X10^{11} L_sun appears to be an example of AGN feedback in a NLSy1 Galaxy (a low power AGN). New proprietary multi-wavelength data recently obtained on this source will allow us to corroborate the proposed hypothesis.Comment: Accepted for publication on ApJ Letters, 9 pages, 4 figure

Leishmania (Viannia) panamensis expresa una nucleasa molecular y bioquímicamente similar a la Endonucleasa G de eucariotas superiores.

Objective: To characterize the molecular and biochemical features of the Endonuclease G of Leishmania (Viannia) panamensis. Methods: The gene of the putative L. (V.) panamensis Endonuclease G was amplified, cloned, and sequenced. The recombinant protein was produced in a heterologous expression system and biochemical assays were run to determine its ion, temperature, and pH preferences. Results: The L. (V.) panamensis rENDOG has biochemical features similar to those found in other trypanosomatids and higher eukaryotes. In addition, phylogenetic analysis revealed a possible evolutionary relationship with metazoan ENDOG. Conclusions: L. (V.) panamensis has a gene that codifies an ENDOG homologous to those of higher organisms. This enzyme can be produced in Escherichia coli and is able to degrade covalently closed circular double-stranded DNA. It has a magnesium preference, can be inhibited by potassium, and is able to function within a wide temperature and pH range. Objetivo: Caracterizar molecular y bioquímicamente la Endonucleasa G (EndoG) de Leishmania (Viannia) panamensis. Métodos: El gen de la putativa Endonucleasa G de L. (V.) panamensis fue amplificado, clonado y secuenciado. La proteína recombinante se produjo en un sistema de expresión heterólogo y la proteína activa se sometió a pruebas bioquímicas para determinar la preferencia de iones, temperatura y pH. Resultados: La rEndoG de L. (V.) panamensis muestra características bioquímicas similares a aquellas descritas en otros trypanosomatidos y en eucariotas superiores. Además, los análisis filogenéticos muestran una posible relación evolutiva con la Endonucleasa G de metazoos. Conclusiones: Leishmania (V.) panamensis posee un gen que codifica para una endonucleasa homóloga a la EndoG de otros organismos superiores, que se puede producir de forma recombinante en Escherichia coli y que es capaz de degradar ADN circular cerrado de doble cadena. Tiene una preferencia por los iones magnesio y manganeso para usarlos como cofactor y es inhibida por el potasio. Además, funciona en un amplio rango de pH y temperatura

Familial hypercholesterolaemia: A study of 36 cases with a phenotype of homozygous familiar hypercholesterolaemia

La hipercolesterolemia familiar homocigótica (HFHo) se caracteriza por niveles muy elevados de cLDL y por enfermedad aterosclerótica temprana. Aunque la frecuencia es baja (1/300.000), las complicaciones son muy severas y pueden ser evitadas. Encontrar y tratar esta población de manera temprana podría reducir la mortalidad. Se describen 36 casos en Colombia, en donde se calcula que haya entre 160 y 200 casos. Resultados Un total de 36 pacientes con fenotipo sugestivo de HFHo fueron identificados y tratados en un período de observación de cuatro años. La media de edad fue 27 años (24 mujeres). 34 pacientes tuvieron un puntaje según la Red de Clínicas de Lípidos de Holanda (RCLH) mayor de 8 (diagnóstico definitivo) y los restantes 2 tenían puntaje equivalente a diagnóstico probable. Un cuarto de los casos procedían de la costa norte colombiana. En las pruebas genéticas, 14 fueron homocigóticos verdaderos para mutación del gen que codifica para el receptor de LDL (LDLR), 12 heterocigóticos compuestos, 2 heterocigóticos dobles y uno autosómico recesivo (LDLRAP1); 5 pacientes fueron heterocigóticos simples (LDLR) y 2 pacientes no autorizaron la prueba. En los homocigóticos verdaderos, la variante más frecuente encontrada fue la c.11G>A. 14 pacientes cursaron con enfermedad coronaria, 9 con estenosis carotídea, 8 con estenosis aórtica y 2 tuvieron ataques cerebrovasculares (ACV). 34 pacientes recibían estatinas (24 rosuvastatina), 30 recibían ezetimibe, 2 recibían evolocumab y 20 recibían lomitapide (dosis promedio 12,7mg). Ninguno recibió aféresis de cLDL. Los medicamentos, en general, fueron bien tolerados y la reducción promedio de cLDL con la terapia fue de 533,7mg/dl a 245,1mg/dl (54%). Conclusiones Todos los pacientes recibieron tratamiento hipolipemiante y se encontraron alteraciones genéticas diagnósticas en todos aquellos que autorizaron el examen. Los niveles elevados de cLDL conllevan tanto riesgo que el tratamiento debe establecerse aún sin conocer el diagnóstico genético.Homozygous familial hypercholesterolemia (HoFH) is characterized for very high levels of cLDL and early cardiovascular disease. Although incidence is low (1/300 000), complications are very severe and can be avoided. Finding and treating this population promptly could reduce mortality. We describe 36 cases in Colombia, where 160 to 200 cases are expected. Results 36 patients with phenotype of HoHF were identified and treated in a follow-up of 4 years. The mean age was 27 years (24 women). 34 of them had at least 8 points in the FH Dutch Lipid Clinic Criteria (definitive diagnosis) and two had probable diagnosis. A quarter of the cases came from the Colombian North Coast. In molecular tests, 14 were true homozygous for LDLR, 12 were compound heterozygous for LDLR, 2 double heterozygous and one was autosomal recessive; 5 were heterozygous and 2 patients did not authorized genetic test. In true homozygous subjects, the most frequent variant was c.11G>A. 14 patients had coronary disease, 9 carotid stenosis, 8 aortic stenosis and 2 had stroke. 34 patients were on statins (25 rosuvastatin), 30 were receiving ezetimibe, 2 were receiving a PSCK9 inhibitor (evolocumab) and 20 were on lomitapide with mean doses of 12.7mg. None received lipoprotein apheresis. Medications were very well tolerated. Changes in cLDL after therapy was from 533.7 mg/dL to 245 mg/dL, (54%). Conclusions Treatment was started in all patients. We found genetic mutations in all patients with genetic tests. The high levels of cLDL mean such a high risk that treatment must be started promptly, even without a genetic test

Strategies to design clinical studies to identify predictive biomarkers in cancer research

The discovery of reliable biomarkers to predict efficacy and toxicity of anticancer drugs remains one of the key challenges in cancer research. Despite its relevance, no efficient study designs to identify promising candidate biomarkers have been established. This has led to the proliferation of a myriad of exploratory studies using dissimilar strategies, most of which fail to identify any promising targets and are seldom validated. The lack of a proper methodology also determines that many anti-cancer drugs are developed below their potential, due to failure to identify predictive biomarkers. While some drugs will be systematically administered to many patients who will not benefit from them, leading to unnecessary toxicities and costs, others will never reach registration due to our inability to identify the specific patient population in which they are active. Despite these drawbacks, a limited number of outstanding predictive biomarkers have been successfully identified and validated, and have changed the standard practice of oncology. In this manuscript, a multidisciplinary panel reviews how those key biomarkers were identified and, based on those experiences, proposes a methodological framework—the DESIGN guidelines—to standardize the clinical design of biomarker identification studies and to develop future research in this pivotal field

Genomic characterization of individuals presenting extreme phenotypes of high and low risk to develop tobacco-induced lung cancer

Single nucleotide polymorphisms (SNPs) may modulate individual susceptibility to carcinogens. We designed a genome-wide association study to characterize individuals presenting extreme phenotypes of high and low risk to develop tobacco-induced non-small cell lung cancer (NSCLC), and we validated our results. We hypothesized that this strategy would enrich the frequencies of the alleles that contribute to the observed traits. We genotyped 2.37 million SNPs in 95 extreme phenotype individuals, that is: heavy smokers that either developed NSCLC at an early age (extreme cases); or did not present NSCLC at an advanced age (extreme controls), selected from a discovery set (n=3631). We validated significant SNPs in 133 additional subjects with extreme phenotypes selected from databases including >39,000 individuals. Two SNPs were validated: rs12660420 (p(combined)=5.66x10(-5); ORcombined=2.80), mapping to a noncoding transcript exon of PDE10A; and rs6835978 (p(combined)=1.02x10(-4); ORcombined=2.57), an intronic variant in ATP10D. We assessed the relevance of both proteins in early-stage NSCLC. PDE10A and ATP10D mRNA expressions correlated with survival in 821 stage I-II NSCLC patients (p=0.01 and p<0.0001). PDE10A protein expression correlated with survival in 149 patients with stage I-II NSCLC (p=0.002). In conclusion, we validated two variants associated with extreme phenotypes of high and low risk of developing tobacco-induced NSCLC. Our findings may allow to identify individuals presenting high and low risk to develop tobacco-induced NSCLC and to characterize molecular mechanisms of carcinogenesis and resistance to develop NSCLC