The first clinical trial of an implantable microchip-based drug delivery device is discussed. Human parathyroid hormone fragment (1-34) hPTH(1-34) was delivered from the device in vivo. hPTH(1-34) is ...the only approved anabolic osteoporosis treatment, but requires daily injections, making patient compliance an obstacle to effective treatment. Furthermore, a net increase in bone mineral density requires intermittent or pulsatile hPTH(1-34) delivery, a challenge for implantable drug delivery products. The microchip-based devices, containing discrete doses of lyophilized hPTH(1-34), were implanted in eight osteoporotic postmenopausal women for 4 months and wirelessly programmed to release doses from the device once daily for up to 20 days. A computer-based programmer, operating in the Medical Implant Communications Service band, established a bidirectional wireless communication link with the implant to program the dosing schedule and receive implant status confirming proper operation. Each woman subsequently received hPTH(1-34) injections in escalating doses. The pharmacokinetics, safety, tolerability, and bioequivalence of hPTH(1-34) were assessed. Device dosing produced similar pharmacokinetics to multiple injections and had lower coefficients of variation. Bone marker evaluation indicated that daily release from the device increased bone formation. There were no toxic or adverse events due to the device or drug, and patients stated that the implant did not affect quality of life.
We characterize the ecological, economic, and community performance of 21 major tuna fisheries, accounting for at least 77% of global tuna production, using the Fishery Performance Indicators. Our ...analysis reveals that the biggest variations in performance among tuna fisheries are driven by the final markets that they target: international sashimi market tuna fisheries considerably outperform a comparison set of 62 non-tuna fisheries in the Fishery Performance Indicator database, international canned tuna market fisheries perform similarly to the comparison set, and tuna fisheries supplying local markets in coastal states considerably underperform the comparison set. Differences among regional fishery management organizations primarily reflect regional species composition and market access, despite stark variation in governance, management, and other enabling conditions. With a legacy of open access, tuna's harvest sector performance is similar across all fisheries, reflecting only a normal return on the capital and skill invested: industrial vessels slightly outperform semi-industrial and artisanal vessels. Differences emerge in the post-harvest sector however, as value chains able to preserve quality and transport fish to high value markets outperform others.
Single photons and entangled photon pairs are a key resource of many quantum secure communication and quantum computation protocols, and non-Poissonian sources emitting in the low-loss wavelength ...region around 1,550 nm are essential for the development of fibre-based quantum network infrastructure. However, reaching this wavelength window has been challenging for semiconductor-based quantum light sources. Here we show that quantum dot devices based on indium phosphide are capable of electrically injected single photon emission in this wavelength region. Using the biexciton cascade mechanism, they also produce entangled photons with a fidelity of 87 ± 4%, sufficient for the application of one-way error correction protocols. The material system further allows for entangled photon generation up to an operating temperature of 93 K. Our quantum photon source can be directly integrated with existing long distance quantum communication and cryptography systems, and provides a promising material platform for developing future quantum network hardware.
Wave attenuation by vegetation is a highly dynamic process and its quantification is important for understanding shore protection potential and modeling coastal hydrodynamics. Data documenting the ...interactions of Spartina alterniflora, represented by polyolefin tubing, and single- and double-peaked irregular waves were collected in a large-scale laboratory flume. The laboratory provided a controlled environment to evaluate wave attenuation, including the parameters of stem density, submergence, wave height, and peak period. Wave attenuation appeared to be most dependent on stem density and the ratio of stem length to water depth. Wave attention increased slightly with wave height while no clear trend with respect to wave period was seen. Treating double-peaked spectra as superimposed wave systems revealed a preferential dissipation of the higher-frequency wave system relative to the lower-frequency wave system under emergent conditions. Wave energy loss occurred at all frequencies of both spectral types, with dissipation increasing with frequency above the spectral peak. Parameterizing the spectral equilibrium range as a function of frequency showed a steepening of the spectral tail compared to the −4 power law under emergent conditions. An empirical relationship defining the bulk drag coefficient for S. alterniflora as a function of the stem Reynolds number is found to serve as a first estimate for engineering applications.
•Laboratory studies show the wave attenuation potential of salt marsh vegetation.•Explores the effects of stem density and varied hydrodynamics on wave attenuation.•Considers the attenuation of double-peaked spectra through vegetation.•Explores deviations from the f-4equlibrium range parameterization.•Presents an empirical formula for a bulk drag coefficient for S. alterniflora.
It is unknown if extremely early initiation of antiretroviral therapy (ART) may lead to long-term ART-free HIV remission or cure. As a result, we studied 2 individuals recruited from a pre-exposure ...prophylaxis (PrEP) program who started prophylactic ART an estimated 10 days (Participant A; 54-year-old male) and 12 days (Participant B; 31-year-old male) after infection with peak plasma HIV RNA of 220 copies/mL and 3,343 copies/mL, respectively. Extensive testing of blood and tissue for HIV persistence was performed, and PrEP Participant A underwent analytical treatment interruption (ATI) following 32 weeks of continuous ART.
Colorectal and lymph node tissues, bone marrow, cerebral spinal fluid (CSF), plasma, and very large numbers of peripheral blood mononuclear cells (PBMCs) were obtained longitudinally from both participants and were studied for HIV persistence in several laboratories using molecular and culture-based detection methods, including a murine viral outgrowth assay (mVOA). Both participants initiated PrEP with tenofovir/emtricitabine during very early Fiebig stage I (detectable plasma HIV-1 RNA, antibody negative) followed by 4-drug ART intensification. Following peak viral loads, both participants experienced full suppression of HIV-1 plasma viremia. Over the following 2 years, no further HIV could be detected in blood or tissue from PrEP Participant A despite extensive sampling from ileum, rectum, lymph nodes, bone marrow, CSF, circulating CD4+ T cell subsets, and plasma. No HIV was detected from tissues obtained from PrEP Participant B, but low-level HIV RNA or DNA was intermittently detected from various CD4+ T cell subsets. Over 500 million CD4+ T cells were assayed from both participants in a humanized mouse outgrowth assay. Three of 8 mice infused with CD4+ T cells from PrEP Participant B developed viremia (50 million input cells/surviving mouse), but only 1 of 10 mice infused with CD4+ T cells from PrEP Participant A (53 million input cells/mouse) experienced very low level viremia (201 copies/mL); sequence confirmation was unsuccessful. PrEP Participant A stopped ART and remained aviremic for 7.4 months, rebounding with HIV RNA of 36 copies/mL that rose to 59,805 copies/mL 6 days later. ART was restarted promptly. Rebound plasma HIV sequences were identical to those obtained during acute infection by single-genome sequencing. Mathematical modeling predicted that the latent reservoir size was approximately 200 cells prior to ATI and that only around 1% of individuals with a similar HIV burden may achieve lifelong ART-free remission. Furthermore, we observed that lymphocytes expressing the tumor marker CD30 increased in frequency weeks to months prior to detectable HIV-1 RNA in plasma. This study was limited by the small sample size, which was a result of the rarity of individuals presenting during hyperacute infection.
We report HIV relapse despite initiation of ART at one of the earliest stages of acute HIV infection possible. Near complete or complete loss of detectable HIV in blood and tissues did not lead to indefinite ART-free HIV remission. However, the small numbers of latently infected cells in individuals treated during hyperacute infection may be associated with prolonged ART-free remission.
There is strong evidence of brain-related abnormalities in COVID-19
. However, it remains unknown whether the impact of SARS-CoV-2 infection can be detected in milder cases, and whether this can ...reveal possible mechanisms contributing to brain pathology. Here we investigated brain changes in 785 participants of UK Biobank (aged 51-81 years) who were imaged twice using magnetic resonance imaging, including 401 cases who tested positive for infection with SARS-CoV-2 between their two scans-with 141 days on average separating their diagnosis and the second scan-as well as 384 controls. The availability of pre-infection imaging data reduces the likelihood of pre-existing risk factors being misinterpreted as disease effects. We identified significant longitudinal effects when comparing the two groups, including (1) a greater reduction in grey matter thickness and tissue contrast in the orbitofrontal cortex and parahippocampal gyrus; (2) greater changes in markers of tissue damage in regions that are functionally connected to the primary olfactory cortex; and (3) a greater reduction in global brain size in the SARS-CoV-2 cases. The participants who were infected with SARS-CoV-2 also showed on average a greater cognitive decline between the two time points. Importantly, these imaging and cognitive longitudinal effects were still observed after excluding the 15 patients who had been hospitalised. These mainly limbic brain imaging results may be the in vivo hallmarks of a degenerative spread of the disease through olfactory pathways, of neuroinflammatory events, or of the loss of sensory input due to anosmia. Whether this deleterious effect can be partially reversed, or whether these effects will persist in the long term, remains to be investigated with additional follow-up.
Introduction: In 2010, the Ottawa Conference produced a set of consensus criteria for good assessment. These were well received and since then the working group monitored their use. As part of the ...2010 report, it was recommended that consideration be given in the future to preparing similar criteria for systems of assessment. Recent developments in the field suggest that it would be timely to undertake that task and so the working group was reconvened, with changes in membership to reflect broad global representation.Methods: Consideration was given to whether the initially proposed criteria continued to be appropriate for single assessments and the group believed that they were. Consequently, we reiterate the criteria that apply to individual assessments and duplicate relevant portions of the 2010 report.Results and discussion: This paper also presents a new set of criteria that apply to systems of assessment and, recognizing the challenges of implementation, offers several issues for further consideration. Among these issues are the increasing diversity of candidates and programs, the importance of legal defensibility in high stakes assessments, globalization and the interest in portable recognition of medical training, and the interest among employers and patients in how medical education is delivered and how progression decisions are made.
Long noncoding RNAs (LncRNAs) have emerged as a diverse class of functional molecules that contribute to nearly every facet of mammalian cardiac development and disease. Recent examples show that ...lncRNAs can be important co-regulators of cardiac patterning and morphogenesis and modulators of the pathogenic signaling that drives heart disease. The flexibility and chemical nature of RNA allows lncRNAs to utilize diverse mechanisms, mediating their effects through their sequence, structure, and molecular interactions with DNA, protein, and other RNAs. In vivo, i.e., animal, studies of individual lncRNAs highlight their ability to balance conserved cardiac gene expression networks, serve as specific and early biomarkers, and indicate their promise as useful therapeutic targets to treat human heart disease. Here, we review recent functionally characterized lncRNAs in cardiac biology and pathology and provide a perspective on emerging approaches to decipher the role of lncRNAs in the heart.
•Uncertainty in market prices drives financial outcomes.•Monte Carlo simulation allows uncertainty to be quantified.•Biochar-only production offers a potentially profitable venture.•Biofuel-biochar ...coproduction requires RINs to achieve financial success.
A comparative techno-economic analysis of two different thermochemical biomass conversion pathways was conducted to examine the effects of fuel price and other variables on project financial performance. Monte Carlo simulation was used to quantify the effects of uncertainty and volatility of ten critical variables: biofuel, biochar and feedstock prices, discount rate, capital investment, labor cost, loan terms, feedstock drying, and biofuel and biochar conversion rates. Market prices for biofuel and biochar have the largest impact on net present value (NPV) of any variable considered, due in part to the high levels of uncertainty associated with future prices of both. Across the ranges of input values for these variables in simulation analysis, hearth-based pyrolysis biochar production had the highest likelihood of profitability with a mean NPV of $41.5 million and only 20% of outcomes resulting in a net loss, while 68% of outcomes for auger-based biochar-biofuel coproduction represented a financial loss, including a mean NPV of -$24.2 million. However, when additional revenue from Renewable Identification Numbers (RINs) credits generated by biofuel production is considered, financial outcomes of biochar-biofuel coproduction improve to 50% likelihood of experiencing a net loss. Findings of the very strong impact of market prices on financial outcomes, relative to other important technical and economic variables, can inform effective targeting of future renewable energy policy, as well as the design of future techno-economic analyses, which do not currently focus on the effect of market prices on profitability.
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