Efectividad y seguridad comparada de inhibidores del cotransportador sodio-glucosa tipo 2 (iSGLT2) en diabetes mellitus tipo 2: revisión rápida de revisiones sistemáticas y metaanálisis

Objetivo: recopilar y evaluar la evidencia disponible respecto a la efectividad y seguridad comparada de inhibidores del cotransportador de sodio glucosa tipo 2 (iSGLT2) en pacientes con diabetes mellitus tipo 2. Metodología: se realizó una revisión sistemática rápida de revisiones sistemáticas de iSGLT2 en las bases de datos Medline y Embase hasta septiembre de 2019. El desenlace primario cardiovascular incluyó eventos adversos cardiovasculares mayores (MACE) que corresponden a muerte por causa cardiovascular, ataque cerebrovascular (ACV) no fatal, infarto agudo de miocardio (IAM) no fatal, además de hospitalización por insuficiencia cardíaca; desenlace renal (definido como progresión de enfermedad renal), disminución de la tasa de filtración glomerular (TFG) y de la relación albuminuria-creatinuria. El desenlace de seguridad agrupó hipoglucemia, fracturas, infecciones urinarias, entre otros. La calidad metodológica de las revisiones se evaluó con el instrumento A measurement Tool to Assess Systematic Review (AMSTAR-2) modificado. Resultados: se incluyeron 5 revisiones sistemáticas de la literatura de calidad media y alta según AMSTAR-2 modificado, entre las cuales se encontró que los iSGLT2 reducen el riesgo de mortalidad cardiovascular en un 23 %, de mortalidad por todas las causas en 20 % y en admisión hospitalaria por insuficiencia cardíaca en un 33 %, en comparación con el cuidado estándar. En cuanto al desenlace renal, los iSGLT2 enlentecen el deterioro de la enfermedad renal y reducen la progresión a albuminuria en pacientes con proteinuria ya documentada. En el desenlace de seguridad se observa una mayor posibilidad de desarrollar infecciones del tracto genitourinario respecto a antidiabéticos orales. Conclusiones: la evidencia sugiere que los iSGLT2 son efectivos en la reducción del riesgo de mortalidad cardiovascular, de mortalidad por todas las causas, de admisión hospitalaria por insuficiencia cardíaca, de progresión de la nefropatía y del desarrollo de enfermedad renal en estadio final. En desenlaces de seguridad, la evidencia sugiere que los iSGLT2 tienen menor riesgo de eventos de hipoglucemia

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

Safety and efficacy of the ChAdOx1 nCoV-19 vaccine (AZD1222) against SARS-CoV-2: an interim analysis of four randomised controlled trials in Brazil, South Africa, and the UK.

BACKGROUND: A safe and efficacious vaccine against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), if deployed with high coverage, could contribute to the control of the COVID-19 pandemic. We evaluated the safety and efficacy of the ChAdOx1 nCoV-19 vaccine in a pooled interim analysis of four trials. METHODS: This analysis includes data from four ongoing blinded, randomised, controlled trials done across the UK, Brazil, and South Africa. Participants aged 18 years and older were randomly assigned (1:1) to ChAdOx1 nCoV-19 vaccine or control (meningococcal group A, C, W, and Y conjugate vaccine or saline). Participants in the ChAdOx1 nCoV-19 group received two doses containing 5 × 1010 viral particles (standard dose; SD/SD cohort); a subset in the UK trial received a half dose as their first dose (low dose) and a standard dose as their second dose (LD/SD cohort). The primary efficacy analysis included symptomatic COVID-19 in seronegative participants with a nucleic acid amplification test-positive swab more than 14 days after a second dose of vaccine. Participants were analysed according to treatment received, with data cutoff on Nov 4, 2020. Vaccine efficacy was calculated as 1 - relative risk derived from a robust Poisson regression model adjusted for age. Studies are registered at ISRCTN89951424 and ClinicalTrials.gov, NCT04324606, NCT04400838, and NCT04444674. FINDINGS: Between April 23 and Nov 4, 2020, 23 848 participants were enrolled and 11 636 participants (7548 in the UK, 4088 in Brazil) were included in the interim primary efficacy analysis. In participants who received two standard doses, vaccine efficacy was 62·1% (95% CI 41·0-75·7; 27 [0·6%] of 4440 in the ChAdOx1 nCoV-19 group vs71 [1·6%] of 4455 in the control group) and in participants who received a low dose followed by a standard dose, efficacy was 90·0% (67·4-97·0; three [0·2%] of 1367 vs 30 [2·2%] of 1374; pinteraction=0·010). Overall vaccine efficacy across both groups was 70·4% (95·8% CI 54·8-80·6; 30 [0·5%] of 5807 vs 101 [1·7%] of 5829). From 21 days after the first dose, there were ten cases hospitalised for COVID-19, all in the control arm; two were classified as severe COVID-19, including one death. There were 74 341 person-months of safety follow-up (median 3·4 months, IQR 1·3-4·8): 175 severe adverse events occurred in 168 participants, 84 events in the ChAdOx1 nCoV-19 group and 91 in the control group. Three events were classified as possibly related to a vaccine: one in the ChAdOx1 nCoV-19 group, one in the control group, and one in a participant who remains masked to group allocation. INTERPRETATION: ChAdOx1 nCoV-19 has an acceptable safety profile and has been found to be efficacious against symptomatic COVID-19 in this interim analysis of ongoing clinical trials. FUNDING: UK Research and Innovation, National Institutes for Health Research (NIHR), Coalition for Epidemic Preparedness Innovations, Bill & Melinda Gates Foundation, Lemann Foundation, Rede D'Or, Brava and Telles Foundation, NIHR Oxford Biomedical Research Centre, Thames Valley and South Midland's NIHR Clinical Research Network, and AstraZeneca

Safety and efficacy of the ChAdOx1 nCoV-19 vaccine (AZD1222) against SARS-CoV-2: an interim analysis of four randomised controlled trials in Brazil, South Africa, and the UK

Background A safe and efficacious vaccine against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), if deployed with high coverage, could contribute to the control of the COVID-19 pandemic. We evaluated the safety and efficacy of the ChAdOx1 nCoV-19 vaccine in a pooled interim analysis of four trials. Methods This analysis includes data from four ongoing blinded, randomised, controlled trials done across the UK, Brazil, and South Africa. Participants aged 18 years and older were randomly assigned (1:1) to ChAdOx1 nCoV-19 vaccine or control (meningococcal group A, C, W, and Y conjugate vaccine or saline). Participants in the ChAdOx1 nCoV-19 group received two doses containing 5 × 1010 viral particles (standard dose; SD/SD cohort); a subset in the UK trial received a half dose as their first dose (low dose) and a standard dose as their second dose (LD/SD cohort). The primary efficacy analysis included symptomatic COVID-19 in seronegative participants with a nucleic acid amplification test-positive swab more than 14 days after a second dose of vaccine. Participants were analysed according to treatment received, with data cutoff on Nov 4, 2020. Vaccine efficacy was calculated as 1 - relative risk derived from a robust Poisson regression model adjusted for age. Studies are registered at ISRCTN89951424 and ClinicalTrials.gov, NCT04324606, NCT04400838, and NCT04444674. Findings Between April 23 and Nov 4, 2020, 23 848 participants were enrolled and 11 636 participants (7548 in the UK, 4088 in Brazil) were included in the interim primary efficacy analysis. In participants who received two standard doses, vaccine efficacy was 62·1% (95% CI 41·0–75·7; 27 [0·6%] of 4440 in the ChAdOx1 nCoV-19 group vs71 [1·6%] of 4455 in the control group) and in participants who received a low dose followed by a standard dose, efficacy was 90·0% (67·4–97·0; three [0·2%] of 1367 vs 30 [2·2%] of 1374; pinteraction=0·010). Overall vaccine efficacy across both groups was 70·4% (95·8% CI 54·8–80·6; 30 [0·5%] of 5807 vs 101 [1·7%] of 5829). From 21 days after the first dose, there were ten cases hospitalised for COVID-19, all in the control arm; two were classified as severe COVID-19, including one death. There were 74 341 person-months of safety follow-up (median 3·4 months, IQR 1·3–4·8): 175 severe adverse events occurred in 168 participants, 84 events in the ChAdOx1 nCoV-19 group and 91 in the control group. Three events were classified as possibly related to a vaccine: one in the ChAdOx1 nCoV-19 group, one in the control group, and one in a participant who remains masked to group allocation. Interpretation ChAdOx1 nCoV-19 has an acceptable safety profile and has been found to be efficacious against symptomatic COVID-19 in this interim analysis of ongoing clinical trials

31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016) : part two

Background The immunological escape of tumors represents one of the main ob- stacles to the treatment of malignancies. The blockade of PD-1 or CTLA-4 receptors represented a milestone in the history of immunotherapy. However, immune checkpoint inhibitors seem to be effective in specific cohorts of patients. It has been proposed that their efficacy relies on the presence of an immunological response. Thus, we hypothesized that disruption of the PD-L1/PD-1 axis would synergize with our oncolytic vaccine platform PeptiCRAd. Methods We used murine B16OVA in vivo tumor models and flow cytometry analysis to investigate the immunological background. Results First, we found that high-burden B16OVA tumors were refractory to combination immunotherapy. However, with a more aggressive schedule, tumors with a lower burden were more susceptible to the combination of PeptiCRAd and PD-L1 blockade. The therapy signifi- cantly increased the median survival of mice (Fig. 7). Interestingly, the reduced growth of contralaterally injected B16F10 cells sug- gested the presence of a long lasting immunological memory also against non-targeted antigens. Concerning the functional state of tumor infiltrating lymphocytes (TILs), we found that all the immune therapies would enhance the percentage of activated (PD-1pos TIM- 3neg) T lymphocytes and reduce the amount of exhausted (PD-1pos TIM-3pos) cells compared to placebo. As expected, we found that PeptiCRAd monotherapy could increase the number of antigen spe- cific CD8+ T cells compared to other treatments. However, only the combination with PD-L1 blockade could significantly increase the ra- tio between activated and exhausted pentamer positive cells (p= 0.0058), suggesting that by disrupting the PD-1/PD-L1 axis we could decrease the amount of dysfunctional antigen specific T cells. We ob- served that the anatomical location deeply influenced the state of CD4+ and CD8+ T lymphocytes. In fact, TIM-3 expression was in- creased by 2 fold on TILs compared to splenic and lymphoid T cells. In the CD8+ compartment, the expression of PD-1 on the surface seemed to be restricted to the tumor micro-environment, while CD4 + T cells had a high expression of PD-1 also in lymphoid organs. Interestingly, we found that the levels of PD-1 were significantly higher on CD8+ T cells than on CD4+ T cells into the tumor micro- environment (p < 0.0001). Conclusions In conclusion, we demonstrated that the efficacy of immune check- point inhibitors might be strongly enhanced by their combination with cancer vaccines. PeptiCRAd was able to increase the number of antigen-specific T cells and PD-L1 blockade prevented their exhaus- tion, resulting in long-lasting immunological memory and increased median survival

Decreasing Estimated Glomerular Filtration Rate Is Associated With Increased Risk of Hospitalization After Kidney Transplantation

After renal transplantation, decreased renal function is associated with increased risk of cardiovascular disease, graft loss, and mortality. We investigated whether declining renal function was associated with hospitalization after transplantation. Methods: Adult, first-time, kidney transplant recipients between 2004 and 2006 from the United Network for Organ Sharing database and hospitalizations 1 year after the 6-month posttransplant follow-up visit were examined. Generalized linear models explored the relationship between estimated glomerular filtration rate (eGFR) measured at 6 months and the number of hospitalizations in the following year. Results: Of 15,778 kidney transplant recipients, 19.1% were admitted in the year after the 6-month follow-up visit. Among those hospitalized, the mean number of hospitalizations was 1.71, which increased with decreasing eGFR. In multivariable models, a decrease in eGFR was significantly associated with increased hospitalizations: for every 10 ml/min per 1.73 m2 decrease in eGFR, there was an 11% increase in hospitalization rate (P < 0.001). Lower eGFR after the first 6 months after transplantation was associated with an increase in late hospitalizations among adult kidney transplant recipients. Discussion: Identifying patients with declining eGFR and other risk factors may help prevent morbidity and mortality associated with hospitalization after transplantation

Children born prematurely have atypical Sensory Profiles

OBJECTIVE: To determine if children born prematurely exhibit atypical responses to normally occurring sensory stimuli, as measured by the Sensory Profile. STUDY DESIGN: This is a cross-sectional study of children born at ≤32 weeks gestation, followed at 1 to 8 years of age. The Sensory Profile questionnaire was completed by each child’s primary caregiver. The overall Sensory Profile was considered atypical if any quadrant or section score was >2 s.d. from the mean of the Sensory Profile validation group. Bivariate analyses were performed to determine associations between risk factors for adverse neurodevelopment and overall atypical Sensory Profiles. A section or quadrant was considered atypical if its score was >2 s.d. from the mean. A test of proportions was used to compute observed versus expected scores for each section and quadrant (Sensory Profile scores were based on a normal distribution so one would expect approximately 95% of participants to score within 2 s.d. of the mean). RESULT: Of our 107 participants, 39% had an atypical score in at least one section or quadrant. No specific perinatal or neonatal risk factors were associated with atypical overall Sensory Profiles (P≥0.05 for all). Children born prematurely were at risk of having atypical scores in the auditory, tactile and vestibular processing sections, and in the four Sensory Profile quadrants (P<0.05). CONCLUSION: Children born prematurely exhibit atypical sensory behaviors on the Sensory Profile. Further investigation to understand the underlying neural mechanisms and to develop effective interventions are critical to support neurodevelopment for these children