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Throughout history, oral administration has been regarded as the most convenient mode of drug delivery, as it requires minimal expertise and invasiveness. Although oral delivery works well for small-molecule drugs, oral delivery of macromolecules (particularly proteins and peptides) has been limited by acidic conditions in the stomach and low permeability across the intestinal epithelium. Accordingly, the large numbers of biologic drugs that have become available in the past 10 years typically require administration by injection or infusion. As such, a renewed emphasis has been placed on the development of novel materials that overcome the physiological challenges of oral delivery for macromolecular agents. This Review provides an overview of physiological barriers to the oral delivery of biologics and highlights the advances made in materials across various length scales, from small molecules to macroscopic devices. This Review also describes the current status of materials for oral delivery of protein and peptide drugs. New materials, beyond those that have already obtained regulatory approval, are needed to improve the bioavailability of orally administered proteins. In this Review, barriers to the oral delivery of protein-based therapies are discussed, along with the current translational landscape and state of the art of materials for oral protein delivery.

With the rise in diabetes mellitus cases worldwide and lack of patient adherence to glycemia management using injectable insulin, there is an urgent need for the development of efficient oral insulin formulations. However, the gastrointestinal tract presents a formidable barrier to oral delivery of biologics. Here we report the development of a highly effective oral insulin formulation using choline and geranate (CAGE) ionic liquid. CAGE significantly enhanced paracellular transport of insulin, while protecting it from enzymatic degradation and by interacting with the mucus layer resulting in its thinning. In vivo, insulin-CAGE demonstrated exceptional pharmacokinetic and pharmacodynamic outcome after jejunal administration in rats. Low insulin doses (3–10 U/kg) brought about a significant decrease in blood glucose levels, which were sustained for longer periods (up to 12 hours), unlike s.c. injected insulin. When 10 U/kg insulin-CAGE was orally delivered in enterically coated capsules using an oral gavage, a sustained decrease in blood glucose of up to 45% was observed. The formulation exhibited high biocompatibility and was stable for 2 months at room temperature and for at least 4 months under refrigeration. Taken together, the results indicate that CAGE is a promising oral delivery vehicle and should be further explored for oral delivery of insulin and other biologics that are currently marketed as injectables.

Nanoparticle‐based therapeutic formulations are being increasingly explored for the treatment of various ailments. Despite numerous advances, the success of nanoparticle‐based technologies in treating brain diseases has been limited. Translational hurdles of nanoparticle therapies are attributed primarily to their limited ability to cross the blood–brain barrier (BBB), which is one of the body's most exclusive barriers. Several efforts have been focused on developing affinity‐based agents and using them to increase nanoparticle accumulation at the brain endothelium. Very little is known about the role of fundamental physical parameters of nanoparticles such as size, shape, and flexibility in determining their interactions with and penetration across the BBB. Using a three‐dimensional human BBB microfluidic model (μHuB), we investigate the impact of these physical parameters on nanoparticle penetration across the BBB. To gain insights into the dependence of transport on nanoparticle properties, two separate parameters were measured: the number of nanoparticles that fully cross the BBB and the number that remain associated with the endothelium. Association of nanoparticles with the brain endothelium was substantially impacted by their physical characteristics. Hard particles associate more with the endothelium compared to soft particles, as do small particles compared to large particles, and spherical particles compared to rod‐shaped particles. Transport across the BBB also exhibited a dependence on nanoparticle properties. A nonmonotonic dependence on size was observed, where 200 nm particles exhibited higher BBB transport compared to 100 and 500 nm spheres. Rod‐shaped particles exhibited higher BBB transport when normalized by endothelial association and soft particles exhibited comparable transport to hard particles when normalized by endothelial association. Tuning nanoparticles' physical parameters could potentially enhance their ability to cross the BBB for therapeutic applications.

The current study proposes an extension of theory and research on the effect of status threat specific to heterosexual men’s anti-gay slurs usage. Drawing on both the Precarious Manhood Thesis and the Coalitional Value Theory, the current study investigates whether masculine personality traits moderate the association between status threat and men’s readiness to use anti-gay slurs. A sample of heterosexual male university students ( N  = 139) was recruited from two English-speaking universities in Montreal, Quebec, and Houston, Texas. Participants completed questionnaires and randomly received either status threatening or status confirming feedback. Next, after reading vignettes describing heterosexual men behaving in ways that might jeopardize their status, participants reported their estimated probability of calling the target character a “fag” or “faggot.” Findings revealed a significant interaction effect. That is, only among participants high in masculine personality traits, those in the threat condition indicated significantly greater readiness to use anti-gay slurs relative to those in the status affirmation group. These findings contribute to a more comprehensive understanding of men’s anti-gay slur usage grounded in a status striving motive paired with distinct personality features. Future research directions are discussed.

This study from South Africa showed that extensively drug-resistant tuberculosis, an emerging global public health threat, is largely associated with transmission of drug-resistant strains rather than new emergence of drug resistance. Drug-resistant tuberculosis is a major global epidemic, with a half million cases occurring each year. 1 Extensively drug-resistant (XDR) tuberculosis — the most severe form of drug resistance — has been reported worldwide and involves resistance to at least four first-line and second-line drugs for tuberculosis. This high degree of resistance severely limits treatment options, necessitating the use of complex, toxic, and costly regimens. Rates of treatment success are less than 40% in most patient populations, and rates of death are 50 to 80%. 2 – 6 Drug-resistant tuberculosis has traditionally been thought to develop as a result of selection pressure that occurs . . .

Measuring gene flow between malaria parasite populations in different geographic locations can provide strategic information for malaria control interventions. Multiple important questions pertaining to the design of such studies remain unanswered, limiting efforts to operationalize genomic surveillance tools for routine public health use. This report examines the use of population-level summaries of genetic divergence ( F ST ) and relatedness (identity-by-descent) to distinguish levels of gene flow between malaria populations, focused on field-relevant questions about data size, sampling, and interpretability of observations from genomic surveillance studies. To do this, we use P. falciparum whole genome sequence data and simulated sequence data approximating malaria populations evolving under different current and historical epidemiological conditions. We employ mobile-phone associated mobility data to estimate parasite migration rates over different spatial scales and use this to inform our analysis. This analysis underscores the complementary nature of divergence- and relatedness-based metrics for distinguishing gene flow over different temporal and spatial scales and characterizes the data requirements for using these metrics in different contexts. Our results have implications for the design and implementation of malaria genomic surveillance studies.

The rate of rocket launches is accelerating, driven by the rapid global development of the space industry. Rocket launches emit gases and particulates into the stratosphere, where they impact the ozone layer via radiative and chemical processes. We create a three‐dimensional per‐vehicle inventory of stratospheric emissions, accounting for flight profiles and all major fuel types in active use (solid, kerosene, cryogenic and hypergolic). In 2019, stratospheric (15–50 km) rocket launch emissions were 5.82 Gg CO2${\\mathrm{C}\\mathrm{O}}_{2}$ , 6.38 Gg H2${\\mathrm{H}}_{2}$ O, 0.28 Gg black carbon, 0.22 Gg nitrogen oxides, 0.50 Gg reactive chlorine and 0.91 Gg particulate alumina. The geographic locations of launch sites are preserved in the inventory, which covers all active launch sites in 2019. We also report the emissions data from contemporary vehicles that were not launched in 2019, so that users have freedom to construct their own launch activity scenarios. A subset of the inventory—stratospheric emissions for successful launches in 2019—is freely available and formatted for direct use in global chemistry‐climate or Earth system models. Plain Language Summary Many governments and companies have expressed bold ambitions to grow their presence in space. However, rocket launches throw out a stream of air pollutants from their burnt fuel as they pass through the stratosphere, which is where the protective ozone layer resides. Currently, launch operators do not have to measure the impacts of their activities on the ozone layer. We gather together all the publicly available information on rocket launches in 2019, from 18 active spaceports worldwide, and make some careful assumptions to convert each rocket's fuel to its burnt fuel products left in the atmosphere. We encourage modeling groups to use our inventory for studies on how rocket launches may impact the ozone layer. Key Points We compile a comprehensive emissions inventory of all rocket launches in 2019 at 18 active spaceports It itemizes chemically and radiatively active species that are produced by the main rocket fuels (kerosene, cryogenic, solid and hypergolic) We discuss the inventory's uncertainties and its usage in global models to study the impacts of rocket launches on the ozone layer

Over 36 million adults over 65 years of age experience accidental falls each year. The underlying neuromechanics (whole-body function) and driving forces behind accidental falls, as well as the effects of aging on the ability of the musculoskeletal system to adapt, are poorly understood. We evaluated differences in kinematics (lower extremity joint angles and range of motion), kinetics (ground reaction force), and electromyography (muscle co-contraction), due to changes in surface conditions during gait in 14 older adults with a history of falling and 14 young adults. We investigated the impact of challenging surfaces on musculoskeletal adaptation and compared the mechanisms of adaptation between age-groups. Older adults displayed greater hip and knee flexion and range of motion during gait, reduced initial vertical loading, and 13 % greater knee muscle co-contraction during early stance compared to young adults. Across age groups, the presence of an uneven challenging surface increased lower-limb flexion compared to an even surface. On a slick surface, older adults displayed 30 % greater ankle muscle co-contraction during early stance as compared to young adults. Older adults respond to challenging surfaces differently than their younger counterparts, employing greater flexion during early stance. This study underscores the need for determining lower-limb musculoskeletal adaptation strategies during gait and assessing how these strategies change with age, risk of accidental falls, and environmental surfaces to reduce the risk of accidental falls.

Background. The emergence of artemisinin-resistant Plasmodium falciparum in Southeast Asia threatens malaria treatment efficacy. Mutations in a kelch protein encoded on P. falciparum chromosome 13 (K13) have been associated with resistance in vitro and in field samples from Cambodia. Methods. P. falciparum infections from artesunate efficacy trials in Bangladesh, Cambodia, Laos, Myanmar, and Vietnam were genotyped at 33 716 genome-wide single-nucleotide polymorphisms (SNPs). Linear mixed models were used to test associations between parasite genotypes and parasite clearance half-lives following artesunate treatment. K13 mutations were tested for association with artemisinin resistance, and extended haplotypes on chromosome 13 were examined to determine whether mutations arose focally and spread or whether they emerged independently. Results. The presence of nonreference K13 alleles was associated with prolonged parasite clearance half-life (P= 1.97 × 10⁻¹²). Parasites with a mutation in any of the K13 kelch domains displayed longer parasite clearance half-lives than parasites with wild-type alleles. Haplotype analysis revealed both population-specific emergence of mutations and independent emergence of the same mutation in different geographic areas. Conclusions. K13 appears to be a major determinant of artemisinin resistance throughout Southeast Asia. While we found some evidence of spreading resistance, there was no evidence of resistance moving westward from Cambodia into Myanmar.

This study determined if sustained walking with body borne load increases tibial compression, and whether increases in tibial compression are related to vertical GRFs. Thirteen participants had tibial compression and vertical GRF measures quantified while walking at 1.3 m/s for 60 min with body borne load. Each tibial compression (maximum and impulse) and GRF measure (peak, impulse, impact peak and loading rate) were submitted to a RM ANOVA to test the main effect and interaction between load (0, 15, and 30 kg) and time (minute 0, 30 and 60), and correlation analyses determined the relation between tibial compression and vertical GRF measures for each load and time. Each tibial compression and GRF measure increased with the addition of body borne load (all: p < 0.001). Time impacted impact peak (p = 0.034) and loading rate (p = 0.017), but no other GRF or tibial compression measure (p > 0.05). Although both tibial compression and vertical GRFs increased with load, vertical GRF measures exhibited negligible to weak (r: −0.37 to 0.35), and weak to moderate (r: −0.62 to 0.59) relation with maximum and impulse of tibial compression with each body borne load. At each time point, GRF measures exhibited negligible to weak (r: −0.39 to 0.27), and weak to moderate (r: −0.53 to 0.65) relation with maximum and impulse of tibial compression, respectively. Walking with body borne load increased tibial compression, and may place compressive forces on the tibia that lead to stress fracture. But, increases in tibial compression may not stem from concurrent increases in vertical GRFs.