e-INEBRIA special interest group roadmap to best practices for practice and research on brief digital interventions for problematic alcohol and illicit drug use

Background: There is huge potential for scaling up the delivery of brief interventions for alcohol and illicit drug use, given the increasing coverage and technologies of e-digital interventions, including applications for smartphones and tablets. However, while the quantity of digital interventions is increasing rapidly, the involvement of brief-intervention researchers and the development of good practices has just begun. Roadmap: In 2018, the Special Interest Group on digital interventions from the International Network on Brief Interventions for Alcohol & Other Drugs (e-INEBRIA SIG) initiated a conversation on possible avenues of future research, which subsequently turned into a roadmap for digital interventions during further discussions. This roadmap consists of points considered relevant for future research, ongoing technological developments, and their implementation across a continuum of prevention and care. Moreover, it outlines starting points for the diversification of brief digital interventions, as well as next steps for quality improvement and implementation in public health and clinical practice. Conclusions: The roadmap of the e-INEBRIA SIG on digital interventions is a starting point that indicates relevant next steps and provides orientation for researchers and interested practitioners in the ambiguous literature and complexity of current digital interventions

Limiting distributions for explosive PAR(1) time series with strongly mixing innovation

This work deals with the limiting distribution of the least squares estimators of the coefficients a r of an explosive periodic autoregressive of order 1 (PAR(1)) time series X r = a r X r--1 +u r when the innovation {u k } is strongly mixing. More precisely {a r } is a periodic sequence of real numbers with period P \textgreater{} 0 and such that P r=1 |a r | \textgreater{} 1. The time series {u r } is periodically distributed with the same period P and satisfies the strong mixing property, so the random variables u r can be correlated

Reprogramming human T cell function and specificity with non-viral genome targeting.

Decades of work have aimed to genetically reprogram T cells for therapeutic purposes1,2 using recombinant viral vectors, which do not target transgenes to specific genomic sites3,4. The need for viral vectors has slowed down research and clinical use as their manufacturing and testing is lengthy and expensive. Genome editing brought the promise of specific and efficient insertion of large transgenes into target cells using homology-directed repair5,6. Here we developed a CRISPR-Cas9 genome-targeting system that does not require viral vectors, allowing rapid and efficient insertion of large DNA sequences (greater than one kilobase) at specific sites in the genomes of primary human T cells, while preserving cell viability and function. This permits individual or multiplexed modification of endogenous genes. First, we applied this strategy to correct a pathogenic IL2RA mutation in cells from patients with monogenic autoimmune disease, and demonstrate improved signalling function. Second, we replaced the endogenous T cell receptor (TCR) locus with a new TCR that redirected T cells to a cancer antigen. The resulting TCR-engineered T cells specifically recognized tumour antigens and mounted productive anti-tumour cell responses in vitro and in vivo. Together, these studies provide preclinical evidence that non-viral genome targeting can enable rapid and flexible experimental manipulation and therapeutic engineering of primary human immune cells

Avalanche criticalities and elastic and calorimetric anomalies of the transition from cubic Cu-Al-Ni to a mixture of18Rand2Hstructures

We studied the two-step martensitic transition of a Cu-Al-Ni shape-memory alloy by calorimetry, acoustic emission (AE), and resonant ultrasound spectroscopy (RUS) measurements. The transition occurs under cooling from the cubic (β, Fm3m) parent phase near 242 K to a mixture of orthorhombic 2H and monoclinic 18R phases. Heating leads first to the back transformation of small 18R domains to β and/or 2H near 255 K, and then to the transformation 2H to β near 280 K. The total transformation enthalpy is ΔHT=328±10 J/mol and is observed as one large latent heat peak under cooling. The back-transformation entropy under heating breaks down into a large component 18R to β at 255 K and a smaller, smeared component of the transformation 2H to β near 280 K. The proportions inside the phase mixture depend on the thermal history of the sample. The elastic response of the sample is dominated by large elastic softening during cooling. The weakening of the elastic shear modulus shows a peak at 242 K, which is typical for the formation of complex microstructures. Cooling the sample further leads to additional changes of the microstructure and domain wall freezing, which is seen by gradual elastic hardening and increasing damping of the RUS signal. Heating from 220 K to room temperature leads to elastic anomalies due to the initial transformation, which is now shifted to high temperatures. The transition is smeared over a wider temperature interval and shows strong elastic damping. The shear modulus of the cubic phase is recovered at 280 K. The phase transformation leads to avalanches, which were recorded by AE and by time-resolved calorimetry. The cooling transition shows very extended avalanche signals in calorimetry with power-law distributions. Cooling and heating runs show AE signals over a large temperature interval above 260 K. Splitting the transformation into two martensite phases leads to power-law exponents ɛ∼2 (β↔ 18R) and ɛ∼1.5 (β↔ 2H) while the phase mixture shows an effective AE exponent of 1.7

Cutaneous Wound Healing Through Paradoxical Mapk Activation By Braf Inhibitors

BRAF inhibitors are highly effective therapies for the treatment of BRAF(V600)-mutated melanoma, with the main toxicity being a variety of hyperproliferative skin conditions due to paradoxical activation of the mitogen-activated protein kinase (MAPK) pathway in BRAF wild-type cells. Most of these hyperproliferative skin changes improve when a MEK inhibitor is co-administered, as it blocks paradoxical MAPK activation. Here we show how the BRAF inhibitor vemurafenib accelerates skin wound healing by inducing the proliferation and migration of human keratinocytes through extracellular signal-regulated kinase (ERK) phosphorylation and cell cycle progression. Topical treatment with vemurafenib in two wound-healing mice models accelerates cutaneous wound healing through paradoxical MAPK activation; addition of a mitogen-activated protein kinase kinase (MEK) inhibitor reverses the benefit of vemurafenib-accelerated wound healing. The same dosing regimen of topical BRAF inhibitor does not increase the incidence of cutaneous squamous cell carcinomas in mice. Therefore, topical BRAF inhibitors may have clinical applications in accelerating the healing of skin wounds.7NIH [P01 CA168585, R35 CA197633, CA-16042, AI-28697]Ressler Family FoundationGrimaldi Family FundGarcia-Corsini Family FundJames B. Pendleton Charitable TrustUCLA CFAR [5P30 AI028697]UCLA AIDS InstituteJohnson Comprehensive Cancer Center (JCCC)David Geffen School of Medicin

Safety profile and pharmacokinetic analyses of the anti-CTLA4 antibody tremelimumab administered as a one hour infusion

BACKGROUND: CTLA4 blocking monoclonal antibodies provide a low frequency but durable tumor responses in patients with metastatic melanoma, which led to the regulatory approval of ipilimumab based on two randomized clinical trials with overall survival advantage. The similarly fully human anti-CTLA4 antibody tremelimumab had been developed in the clinic at a fixed rate infusion, resulting in very prolonged infusion times. A new formulation of tremelimumab allowed testing a shorter infusion time. METHODS: A phase 1 multi-center study to establish the safety and tolerability of administering tremelimumab as a 1-hour infusion to patients with metastatic melanoma. Secondary endpoints included pharmacokinetic and clinical effects of tremelimumab. RESULTS: No grade 3 or greater infusion-related adverse events or other adverse events preventing the administration of the full tremelimumab dose were noted in 44 treated patients. The overall side effect profile was consistent with prior experiences with anti-CTLA4 antibodies. Objective tumor responses were noted in 11% of evaluable patients with metastatic melanoma, which is also consistent with the prior experience with CTLA4 antagonistic antibodies. CONCLUSIONS: This study did not identify any safety concerns when tremelimumab was administered as a 1-hour infusion. These data support further clinical testing of the 1-hour infusion of tremelimumab. (Clinical trial registration number NCT00585000)

Diagnosis of ventilator-associated pneumonia in critically ill adult patients-a systematic review and meta-analysis.

The accuracy of the signs and tests that clinicians use to diagnose ventilator-associated pneumonia (VAP) and initiate antibiotic treatment has not been well characterized. We sought to characterize and compare the accuracy of physical examination, chest radiography, endotracheal aspirate (ETA), bronchoscopic sampling cultures (protected specimen brush [PSB] and bronchoalveolar lavage [BAL]), and CPIS > 6 to diagnose VAP. We searched six databases from inception through September 2019 and selected English-language studies investigating accuracy of any of the above tests for VAP diagnosis. Reference standard was histopathological analysis. Two reviewers independently extracted data and assessed study quality. We included 25 studies (1639 patients). The pooled sensitivity and specificity of physical examination findings for VAP were poor: fever (66.4% [95% confidence interval [CI]: 40.7–85.0], 53.9% [95% CI 34.5–72.2]) and purulent secretions (77.0% [95% CI 64.7–85.9], 39.0% [95% CI 25.8–54.0]). Any infiltrate on chest radiography had a sensitivity of 88.9% (95% CI 73.9–95.8) and specificity of 26.1% (95% CI 15.1–41.4). ETA had a sensitivity of 75.7% (95% CI 51.5–90.1) and specificity of 67.9% (95% CI 40.5–86.8). Among bronchoscopic sampling methods, PSB had a sensitivity of 61.4% [95% CI 43.7–76.5] and specificity of 76.5% [95% CI 64.2–85.6]; while BAL had a sensitivity of 71.1% [95% CI 49.9–85.9] and specificity of 79.6% [95% CI 66.2–85.9]. CPIS > 6 had a sensitivity of 73.8% (95% CI 50.6–88.5) and specificity of 66.4% (95% CI 43.9–83.3). Classic clinical indicators had poor accuracy for diagnosis of VAP. Reliance upon these indicators in isolation may result in misdiagnosis and potentially unnecessary antimicrobial use

Differences in mortality in critically ill elderly patients during the second COVID-19 surge in Europe

The primary aim of this study was to assess the outcome of elderly intensive care unit (ICU) patients treated during the spring and autumn COVID-19 surges in Europe. This was a prospective European observational study (the COVIP study) in ICU patients aged 70 years and older admitted with COVID-19 disease from March to December 2020 to 159 ICUs in 14 European countries. An electronic database was used to register a number of parameters including: SOFA score, Clinical Frailty Scale, co-morbidities, usual ICU procedures and survival at 90 days. The study was registered at ClinicalTrials.gov (NCT04321265). In total, 2625 patients were included, 1327 from the first and 1298 from the second surge. Median age was 74 and 75 years in surge 1 and 2, respectively. SOFA score was higher in the first surge (median 6 versus 5, p < 0.0001). The PaO/FiO ratio at admission was higher during surge 1, and more patients received invasive mechanical ventilation (78% versus 68%, p < 0.0001). During the first 15 days of treatment, survival was similar during the first and the second surge. Survival was lower in the second surge after day 15 and differed after 30 days (57% vs 50%) as well as after 90 days (51% vs 40%). An unexpected, but significant, decrease in 30-day and 90-day survival was observed during the second surge in our cohort of elderly ICU patients. The reason for this is unclear. Our main concern is whether the widespread changes in practice and treatment of COVID-19 between the two surges have contributed to this increased mortality in elderly patients. Further studies are urgently warranted to provide more evidence for current practice in elderly patients. , registered March 19th, 2020. The online version contains supplementary material available at 10.1186/s13054-021-03739-7

The primary cosmic ray composition between 10**15 and 10**16 eV from Extensive Air Showers electromagnetic and TeV muon data

The cosmic ray primary composition in the energy range between 10**15 and 10**16 eV, i.e., around the "knee" of the primary spectrum, has been studied through the combined measurements of the EAS-TOP air shower array (2005 m a.s.l., 10**5 m**2 collecting area) and the MACRO underground detector (963 m a.s.l., 3100 m w.e. of minimum rock overburden, 920 m**2 effective area) at the National Gran Sasso Laboratories. The used observables are the air shower size (Ne) measured by EAS-TOP and the muon number (Nmu) recorded by MACRO. The two detectors are separated on average by 1200 m of rock, and located at a respective zenith angle of about 30 degrees. The energy threshold at the surface for muons reaching the MACRO depth is approximately 1.3 TeV. Such muons are produced in the early stages of the shower development and in a kinematic region quite different from the one relevant for the usual Nmu-Ne studies. The measurement leads to a primary composition becoming heavier at the knee of the primary spectrum, the knee itself resulting from the steepening of the spectrum of a primary light component (p, He). The result confirms the ones reported from the observation of the low energy muons at the surface (typically in the GeV energy range), showing that the conclusions do not depend on the production region kinematics. Thus, the hadronic interaction model used (CORSIKA/QGSJET) provides consistent composition results from data related to secondaries produced in a rapidity region exceeding the central one. Such an evolution of the composition in the knee region supports the "standard" galactic acceleration/propagation models that imply rigidity dependent breaks of the different components, and therefore breaks occurring at lower energies in the spectra of the light nuclei.Comment: Submitted to Astroparticle Physic