Physiologic and behavioral changes during pregnancy may alter HIV-1 susceptibility and infectiousness. Prospective studies exploring pregnancy and HIV-1 acquisition risk in women have found ...inconsistent results. No study has explored the effect of pregnancy on HIV-1 transmission risk from HIV-1-infected women to male partners.
In a prospective study of African HIV-1-serodiscordant couples, we evaluated the relationship between pregnancy and the risk of HIV-1 acquisition among women and HIV-1 transmission from women to men.
Three thousand three hundred and twenty-one HIV-1-serodiscordant couples were enrolled, 1085 (32.7%) with HIV-1 susceptible female partners and 2236 (67.3%) with susceptible male partners. HIV-1 incidence in women was 7.35 versus 3.01 per 100 person-years during pregnant and nonpregnant periods hazard ratio 2.34, 95% confidence interval (CI) 1.33-4.09. This effect was attenuated and not statistically significant after adjusting for sexual behavior and other confounding factors (adjusted hazard ratio 1.71, 95% CI 0.93-3.12). HIV-1 incidence in male partners of infected women was 3.46 versus 1.58 per 100 person-years when their partners were pregnant versus not pregnant (hazard ratio 2.31, 95% CI 1.22-4.39). This effect was not attenuated in adjusted analysis (adjusted hazard ratio 2.47, 95% CI 1.26-4.85).
HIV-1 risk increased two-fold during pregnancy. Elevated risk of HIV-1 acquisition in pregnant women appeared in part to be explained by behavioral and other factors. This is the first study to show that pregnancy increased the risk of female-to-male HIV-1 transmission, which may reflect biological changes of pregnancy that could increase HIV-1 infectiousness.
Plastid and mitochondrial RNAs in vascular plants are subjected to cytidine‐to‐uridine editing. The model plant species Arabidopsis thaliana (Arabidopsis) has two nuclear‐encoded plastid‐targeted ...organelle RNA recognition motif (ORRM) proteins: ORRM1 and ORRM6. In the orrm1 mutant, 21 plastid RNA editing sites were affected but none are essential to photosynthesis. In the orrm6 mutants, two plastid RNA editing sites were affected: psbF‐C77 and accD‐C794. Because psbF encodes the β subunit of cytochrome b559 in photosystem II, which is essential to photosynthesis, the orrm6 mutants were much smaller than the wild type. In addition, the orrm6 mutants had pale green leaves and reduced photosynthetic efficiency. To investigate the functional relationship between ORRM1 and ORRM6, we generated orrm1 orrm6 double homozygous mutants. Morphological and physiological analyses showed that the orrm1 orrm6 double mutants had a smaller plant size, reduced chlorophyll contents, and decreased photosynthetic efficiency, similar to the orrm6 single mutants. Although the orrm1 orrm6 double mutants adopted the phenotype of the orrm6 single mutants, the total number of plastid RNA editing sites affected in the orrm1 orrm6 double mutants was the sum of the sites affected in the orrm1 and orrm6 single mutants. These data suggest that ORRM1 and ORRM6 are in charge of distinct sets of plastid RNA editing sites and that simultaneous mutations in ORRM1 and ORRM6 genes do not cause additional reduction in editing extent at other plastid RNA editing sites.
Multiple pathogenic mechanisms may be involved in generating the migraine symptom complex, and multimechanism-targeted therapy may confer advantages over monotherapy.
To evaluate the efficacy and ...safety of a fixed-dose tablet containing sumatriptan succinate and naproxen sodium relative to efficacy and safety of each monotherapy and placebo for the acute treatment of migraine.
Two replicate, randomized, double-blind, single-attack, parallel-group studies conducted among 1461 (study 1) and 1495 (study 2) patients at 118 US clinical centers who were diagnosed as having migraine and received study treatment for a moderate or severe migraine attack.
Patients were randomized in a 1:1:1:1 ratio to receive a single tablet containing sumatriptan, 85 mg, and naproxen sodium, 500 mg; sumatriptan, 85 mg (monotherapy); naproxen sodium, 500 mg (monotherapy); or placebo, to be used after onset of a migraine with moderate to severe pain.
Primary outcome measures included the percentages of patients with headache relief 2 hours after dosing, absence of photophobia, absence of phonophobia, and absence of nausea for the comparison between sumatriptan-naproxen sodium and placebo, and the percentages of patients with sustained pain-free response for the comparison between sumatriptan-naproxen sodium and each monotherapy.
Sumatriptan-naproxen sodium was more effective than placebo for headache relief at 2 hours after dosing (study 1, 65% vs 28%; P<.001 and study 2, 57% vs 29%; P<.001), absence of photophobia at 2 hours (58% vs 26%; P<.001 and 50% vs 32%; P<.001), and absence of phonophobia at 2 hours (61% vs 38%; P<.001 and 56% vs 34%; P<.001). The absence of nausea 2 hours after dosing was higher with sumatriptan-naproxen sodium than placebo in study 1 (71% vs 65%; P = .007), but in study 2 rates of absence of nausea did not differ between sumatriptan-naproxen sodium and placebo (65% vs 64%; P = .71). For 2- to 24-hour sustained pain-free response, sumatriptan-naproxen sodium was superior at P<.01 (25% and 23% in studies 1 and 2, respectively) to sumatriptan monotherapy (16% and 14% in studies 1 and 2), naproxen sodium monotherapy (10% and 10% in studies 1 and 2), and placebo (8% and 7% in studies 1 and 2). The incidence of adverse events was similar between sumatriptan-naproxen sodium and sumatriptan monotherapy.
Sumatriptan, 85 mg, plus naproxen sodium, 500 mg, as a single tablet for acute treatment of migraine resulted in more favorable clinical benefits compared with either monotherapy, with an acceptable and well-tolerated adverse effect profile.
clinicaltrials.gov Identifiers: NCT00434083 (study 1); NCT00433732 (study 2).
Control applications that facilitate Demand Flexibility (DF) are difficult to deploy at scale in existing buildings. The heterogeneity of systems and non-standard naming conventions for metadata ...describing data points in building automation systems often lead to ad-hoc and building-specific applications. In recent years, several researchers investigated semantic models to describe the meaning of building data. They suggest that these models can enhance the deployment of building applications, enabling data exchanges among heterogeneous sources and their portability across different buildings. However, the studies in question fail to explore these capabilities in the context of controls. This paper proposes a novel semantics-driven framework for developing and deploying portable DF control applications. The design of the framework leverages an iterative design science research methodology, evolving from evidence gathered through simulation and field demonstrations. The framework aims to decouple control applications from specific buildings and control platforms, enabling these control applications to be configured semi-automatically. This allows application developers and researchers to streamline the onboarding of new applications that could otherwise be time-consuming and resource-intensive. The framework has been validated for its capability to facilitate the deployment of control applications sharing the same codebase across diverse virtual and real buildings. The demonstration successfully tested two controls for load shifting and shedding in four virtual buildings using the Building Optimization Testing Framework (BOPTEST) and in one real building using the control platform VOLTTRON. Insights into the current limitations, benefits, and challenges of generalizable controls and semantic models are derived from the deployment efforts and outcomes to guide future research in this field.
•Introduces a semantics-driven framework for portable demand flexibility controls.•Proposes requirements for developing generalizable control applications.•Framework tested with virtual and real buildings using BOPTEST and VOLTTRON.•Successful demonstration of portability across heterogeneous building configurations.•Insights into limitations, benefits, and challenges are derived from the deployment.
Bedaquiline (BDQ) has not been extensively studied among patients co-infected with HIV drug-resistant tuberculosis (DR-TB). We compared treatment outcomes in DR-TB patients treated with BDQ- and ...linezolid (LZD) containing regimens to historic controls treated with second-line injectable-containing regimens.
Retrospective cohort study of consecutive DR-TB patients initiated on BDQ- and LZD-containing regimens at a TB referral hospital in KwaZulu-Natal, South Africa. Participants were prospectively followed through 24 months for treatment outcome and adverse events. Outcomes were compared to a historic control cohort of DR-TB HIV patients enrolled at the same facility prior to BDQ introduction.
Adult DR-TB patients initiating BDQ between January 2014 and November 2015 were enrolled (
= 151). The majority of patients were female (52%), HIV co-infected (77%) and on antiretroviral therapy (100%). End of treatment outcomes included cure (63%), TB culture conversion (83%), completion (0.7%), loss to follow-up (15%), treatment failure (5%), and death (17%). Compared to historic controls (
= 105), patients treated with BDQ experienced significantly higher TB culture conversion and cure, with significantly lower mortality. Adverse effects were common (92%), and most frequently attributed to LZD (24.1%). QT segment prolongation was common but without clinical sequelae.
Treatment with BDQ- and LZD-containing regimens was associated with improved treatment outcomes and survival in DR-TB HIV patients.
Multiple candidate vaccines to prevent COVID-19 have entered large-scale phase 3 placebo-controlled randomized clinical trials, and several have demonstrated substantial short-term efficacy. At some ...point after demonstration of substantial efficacy, placebo recipients should be offered the efficacious vaccine from their trial, which will occur before longer-term efficacy and safety are known. The absence of a placebo group could compromise assessment of longer-term vaccine effects. However, by continuing follow-up after vaccination of the placebo group, this study shows that placebo-controlled vaccine efficacy can be mathematically derived by assuming that the benefit of vaccination over time has the same profile for the original vaccine recipients and the original placebo recipients after their vaccination. Although this derivation provides less precise estimates than would be obtained by a standard trial where the placebo group remains unvaccinated, this proposed approach allows estimation of longer-term effect, including durability of vaccine efficacy and whether the vaccine eventually becomes harmful for some. Deferred vaccination, if done open-label, may lead to riskier behavior in the unblinded original vaccine group, confounding estimates of long-term vaccine efficacy. Hence, deferred vaccination via blinded crossover, where the vaccine group receives placebo and vice versa, would be the preferred way to assess vaccine durability and potential delayed harm. Deferred vaccination allows placebo recipients timely access to the vaccine when it would no longer be proper to maintain them on placebo, yet still allows important insights about immunologic and clinical effectiveness over time.
Deficiency of the neutrophil protease inhibitor serpinB1 leads to a reduced pool of mobilizable neutrophils through decreased neutrophil survival in the bone marrow.
SerpinB1 is among the most ...efficient inhibitors of neutrophil serine proteases—NE, CG, and PR‐3—and we investigated here its role in neutrophil development and homeostasis. We found that serpinB1 is expressed in all human bone marrow leukocytes, including stem and progenitor cells. Expression levels were highest in the neutrophil lineage and peaked at the promyelocyte stage, coincident with the production and packaging of the target proteases. Neutrophil numbers were decreased substantially in the bone marrow of serpinB1−/− mice. This cellular deficit was associated with an increase in serum G‐CSF levels. On induction of acute pulmonary injury, neutrophils were recruited to the lungs, causing the bone marrow reserve pool to be completely exhausted in serpinB1−/− mice. Numbers of myeloid progenitors were normal in serpinB1−/− bone marrow, coincident with the absence of target protease expression at these developmental stages. Maturation arrest of serpinB1−/− neutrophils was excluded by the normal CFU‐G growth in vitro and the normal expression in mature neutrophils of early and late differentiation markers. Normal absolute numbers of proliferating neutrophils and pulse‐chase kinetic studies in vivo showed that the bone marrow deficit in serpinB1−/− mice was largely restricted to mature, postmitotic neutrophils. Finally, upon overnight culture, apoptosis and necrosis were greater in purified bone marrow neutrophils from serpinB1−/− compared with WT mice. Collectively, these findings demonstrate that serpinB1 sustains a healthy neutrophil reserve that is required in acute immune responses.
The bioavailability of a development candidate active pharmaceutical ingredient (API) was very low after oral dosing in dogs. In order to improve bioavailability, we sought to increase the ...dissolution rate of the solid form of the API. When traditional methods of forming salts and amorphous material failed to produce a viable solid form for continued development, we turned to the non-traditional approach of cocrystallization.
A crystal engineering approach was used to design and execute a cocrystal screen of the API. Hydrogen bonding between the API and pharmaceutically acceptable carboxylic acids was identified as a viable synthon for associating multiple components in the solid state. A number of carboxylic acid guest molecules were tested for cocrystal formation with the API.
A cocrystal containing the API and glutaric acid in a 1:1 molecular ratio was identified and the single crystal structure is reported. Physical characterization of the cocrystal showed that it is unique regarding thermal, spectroscopic, X-ray, and dissolution properties. The cocrystal solid is nonhygroscopic, and chemically and physically stable to thermal stress. Use of the cocrystal increased the aqueous dissolution rate by 18 times as compared to the homomeric crystalline form of the drug. Single dose dog exposure studies confirmed that the cocrystal increased plasma AUC values by three times at two different dose levels.
APIs that are non-ionizable or demonstrate poor salt forming ability traditionally present few opportunities for creating crystalline solid forms with desired physical properties. Cocrystals are an additional class of crystalline solid that can provide options for improved properties. In this case, a crystalline molecular complex of glutaric acid and an API was identified and used to demonstrate an improvement in the oral bioavailability of the API in dogs.
Organic certification provides an opportunity for crop farmers to improve their viability and reduce the environmental impacts of commodity grain production, yet farmers have only transitioned to ...organic certification on less than five percent of US farmland. We focus on land tenure as a barrier to wider adoption of organic certification in the Midwest state of Indiana, where 50 % of farmland is rented. Addressing the lack of research on the relationship between tenant farmers and their non-operating landowners, we show how these relationships affect the adoption of conservation practices. Presenting findings from a survey and 30 in-depth interviews with conventional, transitioning, and organic farmers in Indiana, we show significant differences in land tenure arrangements for farmers certified and transitioning to organic compared to farmers only using conventional practices. We contextualize tenant-landlord relationship dynamics across the spectrum of practice adoption, illustrating how land tenure arrangements shape conservation management decision making. Our findings illustrate the barriers and opportunities to adoption of organic certification, given the variability in landowners’ interest in organic certification. While conventional tenant farmers described long-term rental relationships characterized by a sense of trust, the high level of competition for access to rented farmland exerted pressure on them to conform to perceived norms about farming practices and avoid consideration of more risky and less socially acceptable or familiar conservation practices, for fear of losing their landlord’s confidence and trust.
•Land tenure constrains adoption of organic certification on rented land in Midwest.•Relationship between tenant farmers and non-operating landowners affects conservation.•Dynamics of land tenure shape conservation management decision making.•Competition for rented land constrains conservation adoption.•Norms about the appearance of crops constrains conservation adoption.
Context. Strong lenses are extremely useful probes of the distribution of matter on galaxy and cluster scales at cosmological distances, however, they are rare and difficult to find. The number of ...currently known lenses is on the order of 1000. Aims. The aim of this study is to use crowdsourcing to carry out a lens search targeting massive galaxies selected from over 442 square degrees of photometric data from the Hyper Suprime-Cam (HSC) survey. Methods. Based on the S16A internal data release of the HSC survey, we chose a sample of ∼300 000 galaxies with photometric redshifts in the range of 0.2 < zphot < 1.2 and photometrically inferred stellar masses of log M* > 11.2. We crowdsourced lens finding on this sample of galaxies on the Zooniverse platform as part of the Space Warps project. The sample was complemented by a large set of simulated lenses and visually selected non-lenses for training purposes. Nearly 6000 citizen volunteers participated in the experiment. In parallel, we used YATTALENS, an automated lens-finding algorithm, to look for lenses in the same sample of galaxies. Results. Based on a statistical analysis of classification data from the volunteers, we selected a sample of the most promising ∼1500 candidates, which we then visually inspected: half of them turned out to be possible (grade C) lenses or better. By including lenses found by YATTALENS or serendipitously noticed in the discussion section of the Space Warps website, we were able to find 14 definite lenses (grade A), 129 probable lenses (grade B), and 581 possible lenses. YATTALENS found half the number of lenses that were discovered via crowdsourcing. Conclusions. Crowdsourcing is able to produce samples of lens candidates with high completeness, when multiple images are clearly detected, and with higher purity compared to the currently available automated algorithms. A hybrid approach, in which the visual inspection of samples of lens candidates pre-selected by discovery algorithms or coupled to machine learning is crowdsourced, will be a viable option for lens finding in the 2020s, with forthcoming wide-area surveys such as LSST, Euclid, and WFIRST.
PDF
