Adeno-associated virus (AAV) vector-based gene therapy is currently the only
gene therapy approved in the US and Europe. The recent tragic death of three children in a clinical trial to treat ...X-Linked Myotubular Myopathy by delivering myotubularin with an AAV8 vector notwithstanding, AAV remains a highly promising therapeutic gene delivery platform. But the successful use of AAV vectors to treat an increasing number of diseases also makes establishing protocols to determine therapeutically relevant titers of pre-existing anti-AAV antibodies and approaches to deplete those antibodies more urgent than ever. In this mini review, I will briefly discuss (i) our knowledge regarding the prevalence of anti-AAV antibodies, (ii) the challenges to measure those antibodies by methods that are most predictive of their influence on therapeutic efficacy of AAV gene transfer, and (iii) approaches to overcome the formidable hurdle that anti-AAV antibodies pose to the successful clinical use of AAV gene therapy.
A key impediment to sharing is a lender's concern about damage to a lent item due to unobservable actions by a renter, usually resulting in moral hazard. This paper shows how an intermediary can ...eliminate the moral hazard problem by providing optimal insurance to the lender and first-best incentives to the renter to exert care, as long as market participants are risk neutral. The solution is illustrated for the collaborative housing market but applies in principle to any sharing market with vertically differentiated goods. A population of renters, heterogeneous both in their preferences for housing quality and with respect to the amount of care they exert in a rental situation, face a choice between collaborative housing and staying at a local hotel. The private hosts choose their prices strategically, and the intermediary sets commission rates on both sides of the market as well as insurance terms for the rental agreement. The latter are set to eliminate moral hazard. The intermediary is able to extract the gains the hosts would earn if transacting directly. Finally, even if hotels set their prices at the outset so as to maximize collusive profits, collaborative housing persists at substantial market shares, regardless of the difference between the efficiencies of hosts and hotels to reduce renters' cost of effort. The aggregate of hosts, intermediary, and hotels benefits from (a variety in) these effort costs, which indicates that the intermediated sharing of goods is an economically viable, robust phenomenon.
The emergence of a collaborative economy has been driven by advances in information technology that allow consumers to borrow and rent goods among peers on a secondary sharing market. In a dynamic ...setting, consumers make intertemporal decisions about purchases and their participation in the sharing market. This study introduces an overlapping-generations model to analyze product pricing and consumer choice with and without a sharing market. The model quantifies the impacts of a peer-to-peer economy on the demand for ownership, the product price, and all participants' payoffs, including consumer surplus, profits, and social welfare. Given consumers that are heterogeneous with respect to their consumption needs and valuations, it illustrates which of them are prone to participate in a sharing economy and whether a retailer (or manufacturer) can benefit from the presence of a secondary exchange. A sharing market tends to increase the price of new products by a "sharing premium," which positively depends on the retailer's commitment ability. The price increment becomes relatively smaller for higher-cost products. Low-cost products and sufficiently impatient consumers together make a peer-to-peer economy unattractive for retailers. For high-cost products, however, the latter stand to gain from the existence of a sharing market. Most important, the introduction of a peer-to-peer economy increases both consumer surplus and social welfare, thus creating an implicit imperative for a social planner to help promote collaborative consumption, for instance, by providing incentives for retailers and manufacturers that tend to offset possible expected negative payoff effects from consumer sharing.
Early-onset colorectal cancer (CRC) is increasing in the USA despite rapid declines in older ages. Similar patterns are reported in Australia and Canada, but a comprehensive global analysis of ...contemporary data is lacking.
We extracted long-term data from Cancer Incidence in Five Continents and supplemental sources to report on worldwide CRC incidence rates and trends by age (20-49 years and ≥50 years) through diagnosis year 2012 or beyond (Australia, Finland, New Zealand, Norway, Sweden, USA).
During 2008-2012, age-standardised CRC incidence rates in adults <50 ranged from 3.5 per 100 000 (95% CI 3.2 to 3.9) in India (Chennai) to 12.9 (95% CI 12.6 to 13.3) in Korea. During the most recent decade of available data, incidence in adults <50 was stable in 14 of 36 countries; declined in Austria, Italy and Lithuania; and increased in 19 countries, nine of which had stable or declining trends in older adults (Australia, Canada, Denmark, Germany, New Zealand, Slovenia, Sweden, UK and USA). In Cyprus, Netherlands and Norway, inclines in incidence in young adults were twice as rapid as those in older adults (eg, Norway average annual per cent change (AAPC), 1.9 (95% CI 1.4 to 2.5) vs 0.5 (95% CI 0.3 to 0.7)). Among most high-income countries with long-term data, the uptick in early-onset disease began in the mid-1990s. The steepest increases in young adults were in Korea (AAPC, 4.2 (95% CI 3.4 to 5.0)) and New Zealand (AAPC, 4.0 (95% CI 2.1 to 6.0)).
CRC incidence increased exclusively in young adults in nine high-income countries spanning three continents, potentially signalling changes in early-life exposures that influence large bowel carcinogenesis.
Oceanic emissions represent a highly uncertain term in the natural atmospheric methane (CH
) budget, due to the sparse sampling of dissolved CH
in the marine environment. Here we overcome this ...limitation by training machine-learning models to map the surface distribution of methane disequilibrium (∆CH
). Our approach yields a global diffusive CH
flux of 2-6TgCH
yr
from the ocean to the atmosphere, after propagating uncertainties in ∆CH
and gas transfer velocity. Combined with constraints on bubble-driven ebullitive fluxes, we place total oceanic CH
emissions between 6-12TgCH
yr
, narrowing the range adopted by recent atmospheric budgets (5-25TgCH
yr
) by a factor of three. The global flux is dominated by shallow near-shore environments, where CH
released from the seafloor can escape to the atmosphere before oxidation. In the open ocean, our models reveal a significant relationship between ∆CH
and primary production that is consistent with hypothesized pathways of in situ methane production during organic matter cycling.
Excessive heat exposure reduces intestinal integrity and post-absorptive energetics that can inhibit wellbeing and be fatal. Therefore, our objectives were to examine how acute heat stress (HS) ...alters intestinal integrity and metabolism in growing pigs. Animals were exposed to either thermal neutral (TN, 21°C; 35-50% humidity; n=8) or HS conditions (35°C; 24-43% humidity; n=8) for 24 h. Compared to TN, rectal temperatures in HS pigs increased by 1.6°C and respiration rates by 2-fold (P<0.05). As expected, HS decreased feed intake by 53% (P<0.05) and body weight (P<0.05) compared to TN pigs. Ileum heat shock protein 70 expression increased (P<0.05), while intestinal integrity was compromised in the HS pigs (ileum and colon TER decreased; P<0.05). Furthermore, HS increased serum endotoxin concentrations (P=0.05). Intestinal permeability was accompanied by an increase in protein expression of myosin light chain kinase (P<0.05) and casein kinase II-α (P=0.06). Protein expression of tight junction (TJ) proteins in the ileum revealed claudin 3 and occludin expression to be increased overall due to HS (P<0.05), while there were no differences in claudin 1 expression. Intestinal glucose transport and blood glucose were elevated due to HS (P<0.05). This was supported by increased ileum Na(+)/K(+) ATPase activity in HS pigs. SGLT-1 protein expression was unaltered; however, HS increased ileal GLUT-2 protein expression (P=0.06). Altogether, these data indicate that HS reduce intestinal integrity and increase intestinal stress and glucose transport.
Due to the cyclic function of the human heart, pressure and flow in the circulation are pulsatile rather than continuous. Addressing pulsatile haemodynamics starts with the most convenient ...measurement, brachial pulse pressure, which is widely available, related to development and treatment of heart failure (HF), but often confounded in patients with established HF. The next level of analysis consists of central (rather than brachial) pressures and, more importantly, of wave reflections. The latter are closely related to left ventricular late systolic afterload, ventricular remodelling, diastolic dysfunction, exercise capacity, and, in the long-term, the risk of new-onset HF. Wave reflection may also represent a suitable therapeutic target. Treatments for HF with preserved and reduced ejection fraction, based on a reduction of wave reflection, are emerging. A full understanding of ventricular-arterial coupling, however, requires dedicated analysis of time-resolved pressure and flow signals, which can be readily accomplished with contemporary non-invasive imaging and modelling techniques. This review provides a summary of our current understanding of pulsatile haemodynamics in HF.
The major nutrients nitrate and phosphate have one of the strongest correlations in the sea, with a slope similar to the average nitrogen (N) to phosphorus (P) content of plankton biomass (N/P = ...16:1). The processes through which this global relationship emerges despite the wide range of N/P ratios at the organism level are not known. Here we use an ocean circulation model and observed nutrient distributions to show that the N/P ratio of biological nutrient removal varies across latitude in Southern Ocean surface waters, from 12:1 in the polar ocean to 20:1 in the sub-Antarctic zone. These variations are governed by regional differences in the species composition of the plankton community. The covariation of dissolved nitrate and phosphate is maintained by ocean circulation, which mixes the shallow subsurface nutrients between distinct biogeographic provinces. Climate-driven shifts in these marine biomes may alter the mean N/P ratio and the associated carbon export by Southern Ocean ecosystems.
A cell-averaged constant false alarm rate (CFAR) detector is described and applied to data collected with a multibeam echo sounder (MBES). The CFAR detector is designed specifically for transient ...targets observed with MBES, and operates under the assumption that background noise, including volume and seafloor reverberation, is locally stationary in time. This assumption, and the CFAR detector performance in general, was examined for data collected by a 30-kHz MBES operating in the Gulf of Mexico where the targets of interest were methane gas bubble plumes rising up from the seabed. Results with example data suggest that the CFAR detector was able to remove 99.1% of the MBES raw data while preserving the targets of interest. False detections appear randomly distributed throughout a single MBES ping, unlike the targets, and a within-ping target clustering algorithm was able to remove many of the false detections. In a single ping, an example is shown where the combined CFAR detector and a target cluster-size rule was able to reduce the number of false detections to 99.8% of the original data. The detector and cluster-size rules were applied to a sequence of approximately 400 pings, and two additional morphological rules based on the size and aspect ratio of the resulting target clusters were then applied to the detections to isolate the MBES backscatter intensity associated with gas bubbles. This combination of CFAR detector and simple morphological classification rules provides a useful way to detect gas bubble seeps or other transient targets.
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