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Southern Africa produces almost a third of the Earth's biomass burning (BB) aerosol particles, yet the fate of these particles and their influence on regional and global climate is poorly understood. ORACLES (ObseRvations of Aerosols above CLouds and their intEractionS) is a 5-year NASA EVS-2 (Earth Venture Suborbital-2) investigation with three intensive observation periods designed to study key atmospheric processes that determine the climate impacts of these aerosols. During the Southern Hemisphere winter and spring (June–October), aerosol particles reaching 3–5 km in altitude are transported westward over the southeast Atlantic, where they interact with one of the largest subtropical stratocumulus (Sc) cloud decks in the world. The representation of these interactions in climate models remains highly uncertain in part due to a scarcity of observational constraints on aerosol and cloud properties, as well as due to the parameterized treatment of physical processes. Three ORACLES deployments by the NASA P-3 aircraft in September 2016, August 2017, and October 2018 (totaling ∼350 science flight hours), augmented by the deployment of the NASA ER-2 aircraft for remote sensing in September 2016 (totaling ∼100 science flight hours), were intended to help fill this observational gap. ORACLES focuses on three fundamental science themes centered on the climate effects of African BB aerosols: (a) direct aerosol radiative effects, (b) effects of aerosol absorption on atmospheric circulation and clouds, and (c) aerosol–cloud microphysical interactions. This paper summarizes the ORACLES science objectives, describes the project implementation, provides an overview of the flights and measurements in each deployment, and highlights the integrative modeling efforts from cloud to global scales to address science objectives. Significant new findings on the vertical structure of BB aerosol physical and chemical properties, chemical aging, cloud condensation nuclei, rain and precipitation statistics, and aerosol indirect effects are emphasized, but their detailed descriptions are the subject of separate publications. The main purpose of this paper is to familiarize the broader scientific community with the ORACLES project and the dataset it produced.

Pharmacovigilance is the science of monitoring the effects of medicinal products to identify and evaluate potential adverse reactions and provide necessary and timely risk mitigation measures. Intelligent automation technologies have a strong potential to automate routine work and to balance resource use across safety risk management and other pharmacovigilance activities. While emerging technologies such as artificial intelligence (AI) show great promise for improving pharmacovigilance with their capability to learn based on data inputs, existing validation guidelines should be augmented to verify intelligent automation systems. While the underlying validation requirements largely remain the same, additional activities tailored to intelligent automation are needed to document evidence that the system is fit for purpose. We propose three categories of intelligent automation systems, ranging from rule-based systems to dynamic AI-based systems, and each category needs a unique validation approach. We expand on the existing good automated manufacturing practices, which outline a risk-based approach to artificially intelligent static systems. Our framework provides pharmacovigilance professionals with the knowledge to lead technology implementations within their organizations with considerations given to the building, implementation, validation, and maintenance of assistive technology systems. Successful pharmacovigilance professionals will play an increasingly active role in bridging the gap between business operations and technical advancements to ensure inspection readiness and compliance with global regulatory authorities.

The colocation of clouds and smoke over the southeast Atlantic Ocean during the southern African biomass burning season has numerous radiative implications, including microphysical modulation of the clouds if smoke is entrained into the marine boundary layer. NASA's ObseRvations of Aerosols above CLouds and their intEractionS (ORACLES) campaign is studying this system with aircraft in three field deployments between 2016 and 2018. Results from ORACLES-2016 show that the relationship between cloud droplet number concentration and smoke below cloud is consistent with previously reported values, whereas cloud droplet number concentration is only weakly associated with smoke immediately above cloud at the time of observation. By combining field observations, regional chemistry–climate modeling, and theoretical boundary layer aerosol budget equations, we show that the history of smoke entrainment (which has a characteristic mixing timescale on the order of days) helps explain variations in cloud properties for similar instantaneous above-cloud smoke environments. Precipitation processes can obscure the relationship between above-cloud smoke and cloud properties in parts of the southeast Atlantic, but marine boundary layer carbon monoxide concentrations for two case study flights suggest that smoke entrainment history drove the observed differences in cloud properties for those days. A Lagrangian framework following the clouds and accounting for the history of smoke entrainment and precipitation is likely necessary for quantitatively studying this system; an Eulerian framework (e.g., instantaneous correlation of A-train satellite observations) is unlikely to capture the true extent of smoke–cloud interaction in the southeast Atlantic.

IntroductionNon-cirrhotic treatment-naive hepatitis C patients infected with genotype 1 can be treated with ledipasvir/sofosbuvir (LDV/SOF) for 8 weeks, but in practice this regimen is frequently extended up to 12 weeks at least in part due to insufficient real-world data supporting shortening of treatment. The aim of our study was to compare 8- and 12-week regimens’ efficacy in patients eligible for 8-week therapy in a real-world setting.Material and methodsData of HCV genotype 1 infected patients treated with LDV/SOF between 2015 and 2018 included in the EpiTer-2 database were analyzed with respect to patients’ characteristics and length of treatment.ResultsAmong a total of 1718 patients treated with LDV/SOF, 679 were included in the analysis, 238 (35%) received 8-week regimen, whereas 441 were treated for 12 weeks although they fulfilled the criteria for a shorter course. The majority of patients were infected with genotype 1b (89%) and demonstrated minimal fibrosis (55%). The 12-week regimen was assigned significantly more frequently to patients with comorbidities, concomitant medications and advanced liver fibrosis. The sustained virologic response rate was similar after 8 (98%) and 12 (97%) weeks of therapy according to intent-to-treat analysis and reached 99% in both groups after exclusion of patients lost to follow-up.ConclusionsWe confirmed high effectiveness regardless of treatment duration with LDV/SOF in non-cirrhotics infected with HCV genotype 1 eligible for the 8-week regimen according to the current label. This real-world study also demonstrated no need for addition of ribavirin (RBV) in this population and showed that shortening of treatment significantly improves the safety profile of LDV/SOF medication.

The aim of the study Was to analyze the efficacy achieved with regimens available for chronic hepatitis C (CHC) in Poland between 2013 and 2016. Material and methods Data were collected from 29 centers and included 6786 patients with available sustained virologic response (SVR) data between 1 January 2013 and 31 March 2016. Results The sustained virologic response rate for genotypes (G) 1a, 1b, 2, 3 and 4 was 62%, 56%, 92%, 67% and 56% respectively; 71% patients (n = 4832) were treated with pegylated interferon α (Peg-IFNα) and ribavirin (RBV), with SVR rates of 58%, 49%, 92%, 67% and 55% respectively. The sustained virologic response among 5646 G1 infected patients was the lowest with natural interferon α (7%, n = 70) or PegIFN (50%, n = 3779) with RBV, and improved in those receiving triple regimens of Peg-IFN + RBV combined with boceprevir (47%, n = 485), telaprevir (64%, n = 805), simeprevir (73%, n = 132) or sofosbuvir (70%, n = 23). The sustained virologic response with interferon-free regimens of sofosbuvir and RBV (n = 7), sofosbuvir and simeprevir (n = 53), and ledipasvir and sofosbuvir (n = 64) achieved 86%, 89% and 94% respectively. The highest SVR of 98% was observed with ombitasvir/paritaprevir combined with dasabuvir (n = 227). Patients infected with G3 (n = 896) and G4 (n = 220) received mostly Peg-IFN + RBV with SVR of 67% and 56% respectively. Interferon-free regimens were administered in 18 G3/G4 patients and all achieved an SVR. Sofosbuvir combined with Peg-IFN and RBV was administered to 33 patients with an SVR rate of 94%, and a similar rate was achieved among 13 G2 patients treated with interferon and RBV. Conclusions We observed significant differences in efficacy of HCV regimens available in Poland at the turn of the interferon era. The data will be useful as a comparison for therapeutic options expected in the next few years.

The aim of the EpiTer-2 study was to analyse patient characteristics and their medication for HCV infection in Poland at the beginning of the interferon-free era. Analysis of data of HCV infected patients treated during the initial period of availability of interferon-free regimens in Poland, who started therapy after 1 July 2015 and had available an efficacy evaluation report before 30 June 2017 was undertaken. A total of 2879 patients with chronic hepatitis C were entered, including 46% with liver cirrhosis. The most common was genotype 1b (86.8%). The study population was gender balanced, the majority of patients were overweight or obese and 69% presented comorbidities, with the highest prevalence that for hypertension. More than half of patients were retreated due to failure of previous therapy with pegylated interferon and ribavirin. Almost two-third of patients received current therapy with ombitasvir/paritaprevir/ritonavir±dasabuvir (OPrD) ±ribavirin. Other patients received mostly sofosbuvir-based regimens including combination with ledipasvir and pegylated interferon and ribavirin for genotype 3-infected patients. Efficacy of treatment in the whole study population measured as intent-to-treat analysis was 95%. The most frequent regimen, administered for patients infected with genotype 1b, was 12 weeks of OPrD, resulting in an SVR rate of 98%. At least one adverse event was reported in 38% of patients, and the death rate was 0.8%. In conclusion, data from the EpiTer-2 study confirmed the excellent efficacy and safety profile of the real-world experience with recently introduced therapeutic options for genotype 1 HCV infection, but demonstrated weakness of the current therapeutic programme regarding genotype 3 infections.

Background According to the EASL and AASLD guidelines, the recommended treatment for patients who failed to achieve a sustained virologic response (SVR) on prior interferon-based triple therapy with protease inhibitors (PI), is a combination of sofosbuvir and NS5A inhibitors. Polish national recommendations also allow the use of paritaprevir/ritonavir/ombitasvir+dasasbuvir±ribavirin (PrODR) in this group of patients. The aim of the study was to evaluate the efficacy and safety of PrODR vs. ledipasvir/sofosbuvir±RBV (LSR) in PI-experienced patients in real-life setting. Methods Our analysis included patients registered in the nationwide, investigators initiated, multicentre EpiTer-2 database. Among 4530 patients registered, 335 with genotype 1 (93% 1b) were previously treated with IFN-based regimens with PIs: 127 with boceprevir (BOC), 208 with telaprevir (TVR). Patients with advanced fibrosis (F3/F4) were significantly predominant (BOC 28.4%/61.4%, TVR 18.8%/64.4%, respectively). Subjects were assigned to IFN-free retreatment as follows: BOC - 64 (50.4%) PrODR and 63 (49.6%) LSR; TVR- 103 (49.5%) PrODR and 105 (50.5%) LSR. Results SVR rates were comparable for particular groups: BOC → PrODR- 100%; BOC → LSR - 98%; TVR → PrODR - 97%; TVR → LSR - 96% (intent-to treat analysis-ITT) and BOC → PrODR→100%; BOC → LSR - 99%; TVR → PrODR - 99%; TVR → LSR - 98% (modified intent-to treat analysis-mITT). Both treatment regimens had a favourable safety profile. Adverse events (AEs) were generally mild or moderate in severity. Three deaths were reported. The treatment was stopped due to AEs in five patients (three treated with PrODR and two with LSR). Conclusion Efficacy and safety of treatment with PrODR and LSR is comparable in BOC or TVR-experienced patients.

We investigated the safety, efficacy, and impact of ribavirin and peginterferon dose reduction on complete early virologic response and sustained virologic response (SVR) to triple therapy with telaprevir in treatment-experienced patients with advanced liver fibrosis. Treatment was initiated for 211 patients who failed treatment with peginterferon and ribavirin, with bridging fibrosis (F3, n = 68) or cirrhosis (F4, n = 143), including 103 (49%) null-responders (NR), 30 (14%) partial responders (PR), and 78 (37%) relapsers (REL). Impaired liver function (ILF) platelets 60% of the total ribavirin dose (23% vs 44%, respectively) or 80% of the total ribavirin dose (33% vs 48%, respectively). A significant SVR24 decrease was noted subsequent to a total peginterferon dose reduction, both when comparing patients who received 60% of the total dose (NR: 0% vs 44%; REL: 33% vs 68%) and patients who received 80% of the total dose (NR: 17% vs 50%; REL: 46% vs 71%). Serious adverse events were observed in 31 patients (15%). Deaths occurred in 4 patients. All of the deceased subjects were cirrhotic members of the ILF (baseline serum albumin level

To report a unique case of a patient with multiple head and neck tumors following treatment for craniopharyngioma. Retrospective review of the medical record. There is an association between radiation treatment for primary intracranial malignancies and the subsequent development of other intracranial tumors. At the same time, reports regarding the association between thyroid cancer and radiation exposure are abundant within the literature. We present a unique case of a young female who underwent resection and radiation treatment for a craniopharyngioma in 1988. With the exception of bitemporal visual loss and panhypopituitarism requiring hormone replacement therapy, the patient had a relatively uneventful course until 2005. At that time, she developed hearing loss and incapacitating vertigo, which was ultimately attributed to a temporal bone Langerhans histiocytosis. A year and a half later, she was noted to have a thyroid nodule, the pathology of which revealed papillary carcinoma. Seven months after that, she developed new auditory and vestibular symptoms attributable to an acoustic neuroma. This case is remarkable because neither Langerhans histiocytosis following radiation of a craniopharyngioma nor this distinctive combination of head and neck tumors in general have ever been previously reported.