Abstract Many analyses of observational data are attempts to emulate a target trial. The emulation of the target trial may fail when researchers deviate from simple principles that guide the design ...and analysis of randomized experiments. We review a framework to describe and prevent biases, including immortal time bias, that result from a failure to align start of follow-up, specification of eligibility, and treatment assignment. We review some analytic approaches to avoid these problem in comparative effectiveness or safety research.
Cytochrome c (Cc) is a protein that functions as an electron carrier in the mitochondrial respiratory chain. However, Cc has moonlighting roles outside mitochondria driving the transition of ...apoptotic cells from life to death. When living cells are damaged, Cc escapes its natural mitochondrial environment and, once in the cytosol, it binds other proteins to form a complex named the apoptosome—a platform that triggers caspase activation and further leads to controlled cell dismantlement. Early released Cc also binds to inositol 1,4,5‐triphosphate receptors on the ER membrane, which stimulates further massive Cc release from mitochondria. Besides the well‐characterized binding proteins contributing to the proapoptotic functions of Cc, many novel protein targets have been recently described. Among them, histone chaperones were identified as key partners of Cc following DNA breaks, indicating that Cc might modulate chromatin dynamics through competitive binding to histone chaperones. In this article, we review the ample set of recently discovered antiapoptotic proteins—involved in DNA damage, transcription, and energetic metabolism—reported to interact with Cc in the cytoplasm and even the nucleus upon DNA breaks.
Perovskites (ABO3) with transition metals in active B sites are considered alternative catalysts for the water oxidation to oxygen through the oxygen evolution reaction (OER) and for ...the oxygen reduction through the oxygen reduction reaction (ORR) back to water. We have synthesized a double perovskite (A2BB′O6) with different cations in A, B, and B′ sites, namely, (La1.5Sr0.5)A(Ni0.5Mn0.5)B(Ni0.5Ru0.5)B′O6 (LSNMR), which displays an outstanding OER/ORR bifunctional performance. The composition and structure of the oxide has been determined by powder X-ray diffraction, powder neutron diffraction, and transmission electron microscopy to be monoclinic with the space group P21/n and with cationic ordering between the ions in the B and B′ sites. X-ray absorption near-edge spectroscopy suggests that LSNMR presents a configuration of ∼Ni2+, ∼Mn4+, and ∼Ru5+. This bifunctional catalyst is endowed with high ORR and OER activities in alkaline media, with a remarkable bifunctional index value of ∼0.83 V (the difference between the potentials measured at −1 mA cm–2 for the ORR and +10 mA cm–2 for the OER). The ORR onset potential (E onset) of 0.94 V is among the best reported to date in alkaline media for ORR-active perovskites. The ORR mass activity of LSNMR is 1.1 A g–1 at 0.9 V and 7.3 A g–1 at 0.8 V. Furthermore, LSNMR is stable in a wide potential window down to 0.05 V. The OER potential to achieve a current density of 10 mA cm–2 is 1.66 V. Density functional theory calculations demonstrate that the high ORR/OER activity of LSNMR is related to the presence of active Mn sites for the ORR- and Ru-active sites for the OER by virtue of the high symmetry of the respective reaction steps on those sites. In addition, the material is stable to ORR cycling and also considerably stable to OER cycling.
We report the international experience in outcomes after related and unrelated hematopoietic transplantation for infantile osteopetrosis in 193 patients. Thirty-four percent of transplants used ...grafts from HLA-matched siblings, 13% from HLA-mismatched relatives, 12% from HLA-matched, and 41% from HLA-mismatched unrelated donors. The median age at transplantation was 12 months. Busulfan and cyclophosphamide was the most common conditioning regimen. Long-term survival was higher after HLA-matched sibling compared to alternative donor transplantation. There were no differences in survival after HLA-mismatched related, HLA-matched unrelated, or mismatched unrelated donor transplantation. The 5- and 10-year probabilities of survival were 62% and 62% after HLA-matched sibling and 42% and 39% after alternative donor transplantation (P = .01 and P = .002, respectively). Graft failure was the most common cause of death, accounting for 50% of deaths after HLA-matched sibling and 43% of deaths after alternative donor transplantation. The day-28 incidence of neutrophil recovery was 66% after HLA-matched sibling and 61% after alternative donor transplantation (P = .49). The median age of surviving patients is 7 years. Of evaluable surviving patients, 70% are visually impaired; 10% have impaired hearing and gross motor delay. Nevertheless, 65% reported performance scores of 90 or 100, and in 17%, a score of 80 at last contact. Most survivors >5 years are attending mainstream or specialized schools. Rates of veno-occlusive disease and interstitial pneumonitis were high at 20%. Though allogeneic transplantation results in long-term survival with acceptable social function, strategies to lower graft failure and hepatic and pulmonary toxicity are urgently needed.
•Hematopoietic cell transplantation results in long-term survival.•Primary graft failure is very high and the predominant cause of death.
Glioblastoma is the most common primary central nervous system malignancy and has a poor prognosis. Standard first-line treatment, which includes surgery followed by adjuvant radio-chemotherapy, ...produces only modest benefits to survival
. Here, to explore the feasibility, safety and immunobiological effects of PD-1 blockade in patients undergoing surgery for glioblastoma, we conducted a single-arm phase II clinical trial (NCT02550249) in which we tested a presurgical dose of nivolumab followed by postsurgical nivolumab until disease progression or unacceptable toxicity in 30 patients (27 salvage surgeries for recurrent cases and 3 cases of primary surgery for newly diagnosed patients). Availability of tumor tissue pre- and post-nivolumab dosing and from additional patients who did not receive nivolumab allowed the evaluation of changes in the tumor immune microenvironment using multiple molecular and cellular analyses. Neoadjuvant nivolumab resulted in enhanced expression of chemokine transcripts, higher immune cell infiltration and augmented TCR clonal diversity among tumor-infiltrating T lymphocytes, supporting a local immunomodulatory effect of treatment. Although no obvious clinical benefit was substantiated following salvage surgery, two of the three patients treated with nivolumab before and after primary surgery remain alive 33 and 28 months later.
Handwritten signatures are biometric traits at the center of debate in the scientific community. Over the last 40 years, the interest in signature studies has grown steadily, having as its main ...reference the application of automatic signature verification, as previously published reviews in 1989, 2000, and 2008 bear witness. Ever since, and over the last 10 years, the application of handwritten signature technology has strongly evolved and much research has focused on the possibility of applying systems based on handwritten signature analysis and processing to a multitude of new fields. After several years of haphazard growth of this research area, it is time to assess its current developments for their applicability in order to draw a structured way forward. This perspective reports a systematic review of the last 10 years of the literature on handwritten signatures with respect to the new scenario, focusing on the most promising domains of research and trying to elicit possible future research directions in this subject.
Combination treatment with BRAF (BRAFi) plus MEK inhibitors (MEKi) has demonstrated survival benefit in patients with advanced melanoma harboring activating BRAF mutations. Previous preclinical ...studies suggested that an intermittent dosing of these drugs could delay the emergence of resistance. Contrary to expectations, the first published phase 2 randomized study comparing continuous versus intermittent schedule of dabrafenib (BRAFi) plus trametinib (MEKi) demonstrated a detrimental effect of the "on-off" schedule. Here we report confirmatory data from the Phase II randomized open-label clinical trial comparing the antitumoral activity of the standard schedule versus an intermittent combination of vemurafenib (BRAFi) plus cobimetinib (MEKi) in advanced BRAF mutant melanoma patients (NCT02583516). The trial did not meet its primary endpoint of progression free survival (PFS) improvement. Our results show that the antitumor activity of the experimental intermittent schedule of vemurafenib plus cobimetinib is not superior to the standard continuous schedule. Detection of BRAF mutation in cell free tumor DNA has prognostic value for survival and its dynamics has an excellent correlation with clinical response, but not with progression. NGS analysis demonstrated de novo mutations in resistant cases.
The design of active and durable catalysts for the H
O/O
interconversion is one of the major challenges of electrocatalysis for renewable energy. The oxygen evolution reaction (OER) is catalyzed by ...SrRuO
with low potentials (ca. 1.35 V
), but the catalyst's durability is insufficient. Here we show that Na doping enhances both activity and durability in acid media. DFT reveals that whereas SrRuO
binds reaction intermediates too strongly, Na doping of ~0.125 leads to nearly optimal OER activity. Na doping increases the oxidation state of Ru, thereby displacing positively O p-band and Ru d-band centers, weakening Ru-adsorbate bonds. The enhanced durability of Na-doped perovskites is concomitant with the stabilization of Ru centers with slightly higher oxidation states, higher dissolution potentials, lower surface energy and less distorted RuO
octahedra. These results illustrate how high OER activity and durability can be simultaneously engineered by chemical doping of perovskites.
The incidence and severity of coronavirus disease 2019 (COVID-19) among HIV-positive persons receiving antiretroviral therapy (ART) have not been characterized in large populations.
To describe the ...incidence and severity of COVID-19 by nucleos(t)ide reverse transcriptase inhibitor (NRTI) use among HIV-positive persons receiving ART.
Cohort study.
HIV clinics in 60 Spanish hospitals between 1 February and 15 April 2020.
77 590 HIV-positive persons receiving ART.
Estimated risks (cumulative incidences) per 10 000 persons and 95% CIs for polymerase chain reaction-confirmed COVID-19 diagnosis, hospitalization, intensive care unit (ICU) admission, and death. Risk and 95% CIs for COVID-19 diagnosis and hospital admission by use of the NRTIs tenofovir disoproxil fumarate (TDF)/emtricitabine (FTC), tenofovir alafenamide (TAF)/FTC, abacavir (ABC)/lamivudine (3TC), and others were estimated through Poisson regression models.
Of 77 590 HIV-positive persons receiving ART, 236 were diagnosed with COVID-19, 151 were hospitalized, 15 were admitted to the ICU, and 20 died. The risks for COVID-19 diagnosis and hospitalization were greater in men and persons older than 70 years. The risk for COVID-19 hospitalization was 20.3 (95% CI, 15.2 to 26.7) among patients receiving TAF/FTC, 10.5 (CI, 5.6 to 17.9) among those receiving TDF/FTC, 23.4 (CI, 17.2 to 31.1) among those receiving ABC/3TC, and 20.0 (CI, 14.2 to 27.3) for those receiving other regimens. The corresponding risks for COVID-19 diagnosis were 39.1 (CI, 31.8 to 47.6), 16.9 (CI, 10.5 to 25.9), 28.3 (CI, 21.5 to 36.7), and 29.7 (CI, 22.6 to 38.4), respectively. No patient receiving TDF/FTC was admitted to the ICU or died.
Residual confounding by comorbid conditions cannot be completely excluded.
HIV-positive patients receiving TDF/FTC have a lower risk for COVID-19 and related hospitalization than those receiving other therapies. These findings warrant further investigation in HIV preexposure prophylaxis studies and randomized trials in persons without HIV.
Instituto de Salud Carlos III and National Institutes of Health.
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