Recombinant AAV Serotype and Capsid Mutant Comparison for Pulmonary Gene Transfer of ��-1-Antitrypsin Using Invasive and Noninvasive Delivery

Recombinant adeno-associated viral (rAAV) vectors have been widely used in pulmonary gene therapy research. In this study, we evaluated the transduction and expression efficiencies of several AAV serotypes and AAV2 capsid mutants with specific pulmonary targeting ligands in the mouse lung. The noninvasive intranasal delivery was compared with the traditional intratracheal lung delivery. The rAAV8 was the most efficient serotype at expressing α-1-antitrypsin (AAT) in the lung among all the tested serotypes and mutants. A dose of 1 × 10¹⁰ vg of rAAV8-CB-AAT transduced a high percentage of cells in the lung when delivered intratrachealy. The serum and the broncho-alveolar lavage fluid (BALF) levels of human AAT (hAAT) were about 6- and 2.5-fold higher, respectively, than those of rAAV5 group. Among the rAAV2 capsid mutants, the rAAV2 capsid mutants that display a peptide sequence from hAAT (“long serpin”) indicated a twofold increase in transgene expression. For most vectors, the serum hAAT levels achieved after intranasal delivery were 1/2 to 1/3 of those with the intratracheal method. Overall, rAAV8 was the most promising vector for the future application in gene therapy of pulmonary diseases such as AAT deficiency–related emphysema.     

Biotin supplementation reduces plasma triacylglycerol and VLDL in type 2 diabetic patients and in nondiabetic subjects with hypertriglyceridemia.

Biotin is a water-soluble vitamin that acts as a prosthetic group of carboxylases. Besides its role as carboxylase prosthetic group, biotin regulates gene expression and has a wide repertoire of effects on systemic processes. The vitamin regulates genes that are critical in the regulation of intermediary metabolism. Several studies have reported a relationship between biotin and blood lipids. In the present work we investigated the effect of biotin administration on the concentration of plasma lipids, as well as glucose and insulin in type 2 diabetic and nondiabetic subjects. Eighteen diabetic and 15 nondiabetic subjects aged 30-65 were randomized into two groups and received either 61.4 micromol/day of biotin or placebo for 28 days. Plasma samples obtained at baseline and after treatment were analyzed for total triglyceride, cholesterol, very low density lipoprotein (VLDL), glucose and insulin. We found that the vitamin significantly reduced (P=0.005) plasma triacylglycerol and VLDL concentrations. Biotin produced the following changes (mean of absolute differences between 0 and 28 day treatment+/-S.E.M.): a) triacylglycerol -0.55+/-0.2 in the diabetic group and -0.92+/-0.36 in the nondiabetic group; b) VLDL: -0.11+/-0.04 in the diabetic group and -0.18+/-0.07 in the nondiabetic group. Biotin treatment had no significant effects on cholesterol, glucose and insulin in either the diabetic or nondiabetic subjects. We conclude that pharmacological doses of biotin decrease hypertriglyceridemia. The triglyceride-lowering effect of biotin suggests that biotin could be used in the treatment of hypertriglyceridemia.     

Plasma β-amyloid peptides in canine aging and cognitive dysfunction as a model of Alzheimer's disease

Aging dogs naturally demonstrate cognitive impairment and neuropathology that model early Alzheimer's disease (AD). In particular, there is evidence that canine cognitive dysfunction syndrome (CDS) in aged dogs is accompanied by cortical deposition of Aβ peptides and neurodegeneration. Plasma Aβ levels have been examined in humans as putative biomarkers for AD, but to date, no similar studies have been conducted for canine dementia. The aim of the present study was to assess plasma Aβ1-42 and Aβ1-40 levels in a blind study using pet dogs that were either successfully aging or exhibiting CDS. The severity of cognitive impairment was assessed using an owner-based questionnaire. On average, young dogs presented significantly higher plasma levels of Aβ1-42 and Aβ1-40 than aged, cognitively unimpaired dogs. Notably, among aged dogs, the levels of Aβ1-42 and the Aβ42/40 ratio were significantly higher in those showing mild cognitive impairment than in either cognitively unimpaired or severely affected dogs. These results suggest that increased plasma Aβ1-42 levels and Aβ42/40 ratio could be a biomarker for canine cognitive dysfunction, which is considered an excellent natural model of early AD.     

Systemic Autoimmune Diseases in Patients Hospitalized with COVID-19 in Spain: A Nation-Wide Registry Study

We aimed to evaluate the clinical outcome of Systemic Autoimmune Diseases (SADs) patients hospitalized with COVID-19 in Spain, before the introduction of SARS-CoV-2 vaccines. A nationwide, retrospective and observational analysis of the patients admitted during 2020, based on the ICD10 codes in the National Registry of Hospital Discharges, was performed. Among 117,694 patients, only 892 (0.8%) presented any type of SAD before COVID-19-related admission: Sjogren’s Syndrome constituted 25%, Systemic Vasculitides 21%, Systemic Lupus Erythematosus 19%, Sarcoidosis 17%, Systemic Sclerosis 11%, Mixed and Undifferentiated Connective Tissue Disease 4%, Behçet’s Disease 4% and Inflammatory Myopathies 2%. The in-hospital mortality rate was higher in SAD individuals (20% vs. 16%, p < 0.001). After adjustment by baseline conditions, SADs were not associated with a higher mortality risk (OR = 0.93, 95% CI 0.78–1.11). Mortality in the SADs patients was determined by age (OR = 1.05, 95% CI 1.04–1.07), heart failure (OR = 1.67, 95% CI 1.10–2.49), chronic kidney disease (OR = 1.29, 95% CI 1.05–1.59) and liver disease (OR = 1.97, 95% CI 1.13–3.44). In conclusion, the higher COVID-19 mortality rate seen in SADs patients hospitalized in Spain in 2020 was related to the higher burden of comorbidities, secondary to direct organ damage and sequelae of their condition. Whilst further studies should evaluate the impact of baseline immunosuppression on COVID-19 outcomes in this population, efforts should be focused on the optimal management of SAD to minimize the impact of the organ damage that has been shown to determine COVID-19 prognosis.     

Halochromic Inks Applied on Cardboard for Food Spoilage Monitorization

Control of food spoilage is a critical concern in the current world scenario, not only to ensure the quality and safety of food but also to avoid the generation of food waste. This paper evaluates a dual-sensor strategy using six different pH indicators stamped on cardboard for the detection of spoilage in three different foods: beef, salmon, and strawberries. After function validation and formulation optimizations in the laboratory, the halochromic sensors methyl orange and bromocresol purple 2% (w/v) were stamped on cardboard and, in contact with the previously mentioned foods, were able to produce an easily perceptible signal for spoilage by changing color. Additionally, when it comes to mechanical characterization the inks showed high abrasion (>100 cycles) and adhesion resistance (>91%).     

The Role of Systemic Therapy in Resectable Colorectal Liver Metastases: Systematic Review and Network Meta-Analysis

BackgroundDespite multiple randomized trials, the role of perioperative chemotherapy in colorectal cancer liver metastasis (CRLM) is still under debate. In this systematic review and network meta-analysis (NMA), we aim to evaluate the efficacy of perioperative systemic therapies for patients with CRLM.MethodsWe searched various databases for abstracts and full-text articles published from database inception through May 2021.We included randomized controlled trials (RCTs) comparing the addition of perioperative (post, pre, or both) systemic therapies to surgery alone in patients with CRLM. The outcomes were compared according to the chemotherapy regimen using a random effects model. Outcomes of interest included disease-free survival (DFS) and overall survival (OS).ResultsSeven RCTs with a total of 1504 patients with CRLM were included. Six studies included post-operative treatment and one evaluated perioperative (pre- and postoperative) therapy. Fluoropyrimidine-based chemotherapy was the most used systemic therapy. NMA showed benefit of adding perioperative therapy to surgery in terms of DFS (HR 0.73, 95% CI 0.63 to 0.84). However, these findings did not translate into a statistically significant OS benefit (HR 0.88, 95% CI 0.74 to 1.05). NMA did not show any advantage of one regimen over another including oxaliplatin or irinotecan.ConclusionsThis systematic review and NMA of 7 RCTs found that the addition of perioperative systemic treatment for resectable CRLM could improve disease-free survival but not overall survival. Based on the findings, addition of perioperative treatment in resectable CRLM should be individualized weighing the risks and benefits.

The role of perioperative chemotherapy in colorectal cancer liver metastasis is unclear. This review evaluates the efficacy of perioperative systemic therapies for patients with colorectal cancer liver metastasis.

Implications for PracticeThe role of adding systemic therapy to surgery in patients with resectable colorectal liver metastases is unclear. In this network meta-analysis of 7 trials, we found that the addition of systemic therapy improves disease-free survival but not overall survival. Therefore, chemotherapy should not be uniformly recommended in this setting.     

Underreporting of work accidents associated with blood-borne risk factors

Background: Work accidents (WA) due to percutaneous or mucocutaneous injury are frequent among health professionals. Accident notification ensures compliance with legal requirements, enabling health institutions to develop, implement and evaluate prevention strategies. This study aimed to estimate the proportion of underreporting of work accidents caused by percutaneous and mucocutaneous lesions in a hospital setting and its determinants. Methods: A self-administered questionnaire was made available to all hospital employees. The multivariate logistic regression models computed age, gender, professional category, and type of service adjusted odds ratios (OR) and 95% confidence intervals (95% CI). Results: Underreporting of WA associated with biological risk factors was high, particularly in accidents by mucocutaneous injury (80.9%). Physicians were the professional category that least reported this type of work accident (OR=4.64; 95% CI2.20-9.78). The main determinants of underreporting were underestimating the risk of transmission and the excessive bureaucracy. Conclusion: The underreporting of work accidents associated with biological risk factors was considerable, and it contributes to a high degree of uncertainty on accidents'' characterization.     

COVID-19 mRNA vaccine effectiveness (second and first booster dose) against hospitalisation and death during Omicron BA.5 circulation: cohort study based on electronic health records,Portugal, May to July 2022

We measured vaccine effectiveness (VE) against COVID-19-related severe outcomes in elderly people in Portugal between May and July 2022. In ≥ 80 year-olds, the second booster dose VE was 81% (95% CI: 75–85) and 82% (95% CI: 77–85), respectively, against COVID-19-related hospitalisation and death. The first booster dose VE was 63% (95% CI: 55–70) in ≥ 80 year-olds and 74% (95% CI: 66–80) in 60–79 year-olds against hospitalisation, and 63% (95% CI: 57–69) and 65% (95% CI: 54–74) against death.     

Capacity factors for electrical power generation from renewable and nonrenewable sources

Given the dire consequences of climate change and the war in Ukraine, decarbonization of electrical power systems around the world must be accomplished, while avoiding recurring blackouts. A good understanding of performance and reliability of different power sources underpins this endeavor. As an energy transition involves different societal sectors, we must adopt a simple and efficient way of communicating the transition’s key indicators. Capacity factor (CF) is a direct measure of the efficacy of a power generation system and of the costs of power produced. Since the year 2000, the explosive expansion of solar PV and wind power made their CFs more reliable. Knowing the long-time average CFs of different electricity sources allows one to calculate directly the nominal capacity required to replace the current fossil fuel mix for electricity generation or expansion to meet future demand. CFs are straightforwardly calculated, but they are rooted in real performance, not in modeling or wishful thinking. Based on the current average CFs, replacing 1 W of fossil electricity generation capacity requires installation of 4 W solar PV or 2 W of wind power. An expansion of the current energy mix requires installing 8.8 W of solar PV or 4.3 W of wind power.

Greenhouse gas emissions are the driving force behind climate change (1), which threatens biodiversity (2), food security (3), and cultural diversity (4). The main source of carbon emissions in electricity generation is the current mixture of inputs (5). The current state of affairs demands an energy transition, but numerous challenges emerge (6–8). Such a transition implicates different societies in different ways (9–11), but even the conservative United States wants a decarbonized future (12). Actions toward a sustainable future have been taken at different scales from city (13) to country level (14).The current energy system in place has a rigid structure with a modus operandi of “winner takes all” that hampers the establishment of alternatives (15). Policies can be implemented to overcome the status quo. However, unintended consequences can arise, e.g., carbon pricing policies tend to incentivize optimization of the current energy system instead of the required transformations to achieve a decarbonized one (16). This conclusion is not universally accepted (17–19). It seems, however, that renewables will lead the energy transition and solar photovoltaics will play a key role (20–22).Engaging different players in a society for the energy transition is essential. However, the diversity of stakeholders creates communication barriers, particularly when technical details are transmitted to a broad audience. The war in Ukraine and insufficient natural gas supply in Europe have added painful urgency to clear and truthful communication of the potential pitfalls of any energy transition that boil down to the clear understanding of what the different components of electricity generation systems can and cannot do. Regarding power-generation efficiencies of different sources, the use of CF is an excellent tool to connect with a broad set of audiences.CF is a measure of a power plant efficacy (23). In short, it is an indicator of how fully the power plant is used, relative to its thermodynamic and technological constraints and required spare capacity (24). For all technologies, CFs have typical values for a set time interval and input (a fuel, light, water, or wind).An electrical power plant’s CF gives this plant’s average output relative to its maximum capacity. This could be quite misleading for renewables. If a plant works at 50% of nominal capacity, its CF is 0.5. This does not mean that the plant worked 12 h at full capacity and was off over the remaining 12 h. This plant could be down for different reasons such as repairs, maintenance, refueling, or intermittency for renewables. Despite its limitations, CF is a straightforward indicator that can be easily calculated and predict the amount of electricity that will be obtained on average from a specific nominal capacity installed.Comparing CFs across different technologies can be tricky, mainly when some are well established and mature, while others are at pilot-scale or not fully deployed. In the last two decades, solar PV and wind have been growing exponentially. This explosive growth allows one to obtain reliably their CFs. When a technology is more established, the effects of pilot plants, learning curves (25–28), or optimal sites no longer dominate, giving reliable estimates about that technology’s performance. Field tests are the ultimate answer. Theoretical estimates can differ significantly from the measured ones. Such discrepancies have been presented for wind (29) and concentrated solar power plants (30) (SI Appendix, section 10). Knowing the real value of CFs is fundamental to estimating costs, power production, and the future roles of specific technologies.In this work, we analyze the average CFs of different electricity sources (i.e., biomass, fossil fuels, geothermal heat, water, uranium, solar light, and wind) over the period 2000–2017. Global and regional values are estimated to highlight the differences in the performance of different technologies. These average CF values are then used to calculate the required nominal capacity to be installed in the future for our unavoidable energy transition.