This study examined whether pioglitazone can reduce the risk of type 2 diabetes mellitus in adults with impaired glucose tolerance. As compared with placebo, pioglitazone reduced the conversion of ...IGT to diabetes by 72% but was associated with significant weight gain and edema.
Type 2 diabetes mellitus affects 21 million Americans,
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and its prevalence is increasing.
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Microvascular and macrovascular complications are common in type 2 diabetes mellitus and are related to both the severity and the duration of hyperglycemia.
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The natural history of type 2 diabetes mellitus has been well defined,
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starting with a genetic predisposition and progression from normal glucose tolerance with insulin resistance to impaired glucose tolerance and eventually type 2 diabetes mellitus with the superimposition of beta-cell failure.
Because hyperglycemia plays a central role in the microvascular and macrovascular complications of diabetes,
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it is possible that interventions that . . .
Atomically precise, δ-doped structures forming electronic devices in Si have been routinely fabricated in recent years by using depassivation lithography in a scanning tunneling microscope (STM). ...While H-based precursor/monatomic resist chemistries for incorporation of donor atoms have dominated these efforts, the use of halogen-based chemistries offers a promising path toward atomic-scale manufacturing of acceptor-based devices. Here, B-doped δ-layers were fabricated in Si(100) by using BCl3 as an acceptor dopant precursor in ultrahigh vacuum. Additionally, we demonstrate compatibility of BCl3 with both H and Cl monatomic resists to achieve area-selective deposition on Si. In comparison to bare Si, BCl3 adsorption selectivity ratios for H- and Cl-passivated Si were determined by secondary ion mass spectrometry depth profiling (SIMS) to be 310(10):1 and 1529(5):1, respectively. STM imaging revealed that BCl3 adsorbed readily on bare Si at room temperature, with SIMS measurements indicating a peak B concentration greater than 1.2(1) × 1021 cm–3 with a total areal dose of 1.85(1) × 1014 cm–2 resulting from a 30 langmuir BCl3 dose at 150 °C. In addition, SIMS showed a δ-layer thickness of ∼0.5 nm. Hall bar measurements of a similar sample were performed at 3.0 K, revealing a sheet resistance of ρ□ = 1.9099(4) kΩ □–1, a hole carrier concentration of p = 1.90(2) × 1014 cm–2, and a hole mobility of μ = 38.0(4) cm2 V–1 s–1 without performing an incorporation anneal. Finally, 15 nm wide B δ-doped nanowires were fabricated from BCl3 and were found to exhibit ohmic conduction. This validates the use of BCl3 as a dopant precursor for atomic-precision fabrication of acceptor-doped devices in Si and enables development of simultaneous n- and p-type doped bipolar devices.
Model–data comparisons of plant physiological processes provide an understanding of mechanisms underlying vegetation responses to climate. We simulated the physiology of a piñon pine–juniper woodland ...(Pinus edulis–Juniperus monosperma) that experienced mortality during a 5 yr precipitation-reduction experiment, allowing a framework with which to examine our knowledge of drought-induced tree mortality. We used six models designed for scales ranging from individual plants to a global level, all containing state-of-the-art representations of the internal hydraulic and carbohydrate dynamics of woody plants. Despite the large range of model structures, tuning, and parameterization employed, all simulations predicted hydraulic failure and carbon starvation processes co-occurring in dying trees of both species, with the time spent with severe hydraulic failure and carbon starvation, rather than absolute thresholds per se, being a better predictor of impending mortality. Model and empirical data suggest that limited carbon and water exchanges at stomatal, phloem, and below-ground interfaces were associated with mortality of both species. The model–data comparison suggests that the introduction of a mechanistic process into physiology-based models provides equal or improved predictive power over traditional process-model or empirical thresholds. Both biophysical and empirical modeling approaches are useful in understanding processes, particularly when the models fail, because they reveal mechanisms that are likely to underlie mortality. We suggest that for some ecosystems, integration of mechanistic pathogen models into current vegetation models, and evaluation against observations, could result in a breakthrough capability to simulate vegetation dynamics.
Summary Background Neonatal mortality accounts for a high proportion of deaths in children under the age of 5 years in Bangladesh. Therefore the project for advancing the health of newborns and ...mothers (Projahnmo) implemented a community-based intervention package through government and non-government organisation infrastructures to reduce neonatal mortality. Methods In Sylhet district, 24 clusters (with a population of about 20 000 each) were randomly assigned in equal numbers to one of two intervention arms or to the comparison arm. Because of the study design, masking was not feasible. All married women of reproductive age (15–49 years) were eligible to participate. In the home-care arm, female community health workers (one per 4000 population) identified pregnant women, made two antenatal home visits to promote birth and newborn-care preparedness, made postnatal home visits to assess newborns on the first, third, and seventh days of birth, and referred or treated sick neonates. In the community-care arm, birth and newborn-care preparedness and careseeking from qualified providers were promoted solely through group sessions held by female and male community mobilisers. The primary outcome was reduction in neonatal mortality. Analysis was by intention to treat. The study is registered with ClinicalTrials.gov , number 00198705. Findings The number of clusters per arm was eight. The number of participants was 36059, 40159, and 37598 in the home-care, community-care, and comparison arms, respectively, with 14 769, 16 325, and 15 350 livebirths, respectively. In the last 6 months of the 30-month intervention, neonatal mortality rates were 29·2 per 1000, 45·2 per 1000, and 43·5 per 1000 in the home-care, community-care, and comparison arms, respectively. Neonatal mortality was reduced in the home-care arm by 34% (adjusted relative risk 0·66; 95% CI 0·47–0·93) during the last 6 months versus that in the comparison arm. No mortality reduction was noted in the community-care arm (0·95; 0·69–1·31). Interpretation A home-care strategy to promote an integrated package of preventive and curative newborn care is effective in reducing neonatal mortality in communities with a weak health system, low health-care use, and high neonatal mortality. Funding United States Agency for International Development and saving newborn lives programme by Save the Children (US) with a grant from Bill and Melinda Gates Foundation.
The beneficial effects of physical activity (PA) are well documented, yet the mechanisms by which PA prevents disease and improves health outcomes are poorly understood. To identify major gaps in ...knowledge and potential strategies for catalyzing progress in the field, the NIH convened a workshop in late October 2014 entitled “Understanding the Cellular and Molecular Mechanisms of Physical Activity-Induced Health Benefits.” Presentations and discussions emphasized the challenges imposed by the integrative and intermittent nature of PA, the tremendous discovery potential of applying “-omics” technologies to understand interorgan crosstalk and biological networking systems during PA, and the need to establish an infrastructure of clinical trial sites with sufficient expertise to incorporate mechanistic outcome measures into adequately sized human PA trials. Identification of the mechanisms that underlie the link between PA and improved health holds extraordinary promise for discovery of novel therapeutic targets and development of personalized exercise medicine.
This Perspective reports on the NIH October 2014 workshop “Understanding the Cellular and Molecular Mechanisms of Physical Activity-Induced Health Benefits,” where major gaps in knowledge, as well as potential strategies for catalyzing progress in the field of physical activity, were discussed and the outcome consensus points reached.
Surface water is a vital component of the Earth’s water cycle and characterizing its dynamics is essential for understanding and managing our water resources. Satellite-based remote sensing has been ...used to monitor surface water dynamics, but cloud cover can obscure surface observations, particularly during flood events, hindering water identification. The fusion of optical and synthetic aperture radar (SAR) data leverages the advantages of both sensors to provide accurate surface water maps while increasing the temporal density of unobstructed observations for monitoring surface water spatial dynamics. This paper presents a method for generating dense time series of surface water observations using optical–SAR sensor fusion and gap filling. We applied this method to data from the Copernicus Sentinel-1 and Landsat 8 satellite data from 2019 over six regions spanning different ecological and climatological conditions. We validated the resulting surface water maps using an independent, hand-labeled dataset and found an overall accuracy of 0.9025, with an accuracy range of 0.8656–0.9212 between the different regions. The validation showed an overall false alarm ratio (FAR) of 0.0631, a probability of detection (POD) of 0.8394, and a critical success index (CSI) of 0.8073, indicating that the method generally performs well at identifying water areas. However, it slightly underpredicts water areas with more false negatives. We found that fusing optical and SAR data for surface water mapping increased, on average, the number of observations for the regions and months validated in 2019 from 11.46 for optical and 55.35 for SAR to 64.90 using both, a 466% and 17% increase, respectively. The results show that the method can effectively fill in gaps in optical data caused by cloud cover and produce a dense time series of surface water maps. The method has the potential to improve the monitoring of surface water dynamics and support sustainable water management.
The objectives of this study were to characterize noise and light levels for extremely low birth weight newborns throughout their stay in the NICU, evaluate factors influencing noise and light ...levels, and determine whether exposures meet recommendations from the American Academy of Pediatrics.
Sound and light were measured inside the beds of extremely low birth weight newborns (n = 22) from birth to discharge. Measurements were recorded for 20 consecutive hours weekly from birth until 36 weeks' postmenstrual age, biweekly until 40 weeks, and every 4 weeks thereafter. Clinical variables including bed type and method of respiratory support were recorded at each session.
Age-related changes in respiratory support and bed type explained the weekly increase of 0.22 dB in sound level and 3.67 lux in light level. Old incubators were the noisiest bed types, and new incubators were the quietest. Light levels were significantly higher in open beds than in incubators. The variations in noise and light levels over time were greatest for open beds. Noise and light levels were much less affected by respiratory support in incubators compared with open beds. A typical extremely low birth weight neonate was exposed to noise levels averaging 56.44 dB(A) and light levels averaging 70.56 lux during their stay from 26 to 42 weeks' postmenstrual age in the NICU. Noise levels were rarely within American Academy of Pediatrics recommendations (5.51% of the time), whereas light levels almost always met recommendations (99.37% of the time).
Bed type and respiratory support explained differences in noise and light levels that extremely low birth weight newborns experience during their hospital stay. Noise levels exceeded recommendations, although evidence supporting those recommendations is lacking. Well-designed intervention studies are needed to determine the effects of noise reduction on the development of extremely low birth weight newborns.
Body mass results from a complex interplay between genetics and environment. Previous studies of the genetic contribution to body mass have excluded repetitive regions due to the technical ...limitations of platforms used for population scale studies. Here we apply genome-wide approaches, identifying an association between adult body mass and the copy number (CN) of 47S-ribosomal DNA (rDNA). rDNA codes for the 18 S, 5.8 S and 28 S ribosomal RNA (rRNA) components of the ribosome. In mammals, there are hundreds of copies of these genes. Inter-individual variation in the rDNA CN has not previously been associated with a mammalian phenotype. Here, we show that rDNA CN variation associates with post-pubertal growth rate in rats and body mass index in adult humans. rDNA CN is not associated with rRNA transcription rates in adult tissues, suggesting the mechanistic link occurs earlier in development. This aligns with the observation that the association emerges by early adulthood.Many genetic variants have been associated with body size, but the contribution of copy number of rDNA is unknown. Here, the authors explore the association between rDNA copy number and body size in both rats and humans, finding that lower rDNA CN is associated with higher weight and BMI.
There is a critical need for more-effective treatments to combat multidrug-resistant Gram-negative infections. Combination therapies are a promising strategy, especially when these enable existing ...clinical drugs to be repurposed as antibiotics. We examined the mechanisms of action and basis of innate Gram-negative resistance for the anthelmintic drug niclosamide and subsequently exploited this information to demonstrate that niclosamide and analogs kill Gram-negative bacteria when combined with antibiotics that inhibit drug efflux or permeabilize membranes. We confirm the synergistic potential of niclosamide
in vitro
against a diverse range of recalcitrant Gram-negative clinical isolates and
in vivo
in a mouse abscess model. We also demonstrate that nitroreductases can confer resistance to niclosamide but show that evolution of these enzymes for enhanced niclosamide resistance confers a collateral sensitivity to other clinical antibiotics. Our results highlight how detailed mechanistic understanding can accelerate the evaluation and implementation of new combination therapies.
ABSTRACT
One avenue to combat multidrug-resistant Gram-negative bacteria is the coadministration of multiple drugs (combination therapy), which can be particularly promising if drugs synergize. The identification of synergistic drug combinations, however, is challenging. Detailed understanding of antibiotic mechanisms can address this issue by facilitating the rational design of improved combination therapies. Here, using diverse biochemical and genetic assays, we examine the molecular mechanisms of niclosamide, a clinically approved salicylanilide compound, and demonstrate its potential for Gram-negative combination therapies. We discovered that Gram-negative bacteria possess two innate resistance mechanisms that reduce their niclosamide susceptibility: a primary mechanism mediated by multidrug efflux pumps and a secondary mechanism of nitroreduction. When efflux was compromised, niclosamide became a potent antibiotic, dissipating the proton motive force (PMF), increasing oxidative stress, and reducing ATP production to cause cell death. These insights guided the identification of diverse compounds that synergized with salicylanilides when coadministered (efflux inhibitors, membrane permeabilizers, and antibiotics that are expelled by PMF-dependent efflux), thus suggesting that salicylanilide compounds may have broad utility in combination therapies. We validate these findings
in vivo
using a murine abscess model, where we show that niclosamide synergizes with the membrane permeabilizing antibiotic colistin against high-density infections of multidrug-resistant Gram-negative clinical isolates. We further demonstrate that enhanced nitroreductase activity is a potential route to adaptive niclosamide resistance but show that this causes collateral susceptibility to clinical nitro-prodrug antibiotics. Thus, we highlight how mechanistic understanding of mode of action, innate/adaptive resistance, and synergy can rationally guide the discovery, development, and stewardship of novel combination therapies.
IMPORTANCE
There is a critical need for more-effective treatments to combat multidrug-resistant Gram-negative infections. Combination therapies are a promising strategy, especially when these enable existing clinical drugs to be repurposed as antibiotics. We examined the mechanisms of action and basis of innate Gram-negative resistance for the anthelmintic drug niclosamide and subsequently exploited this information to demonstrate that niclosamide and analogs kill Gram-negative bacteria when combined with antibiotics that inhibit drug efflux or permeabilize membranes. We confirm the synergistic potential of niclosamide
in vitro
against a diverse range of recalcitrant Gram-negative clinical isolates and
in vivo
in a mouse abscess model. We also demonstrate that nitroreductases can confer resistance to niclosamide but show that evolution of these enzymes for enhanced niclosamide resistance confers a collateral sensitivity to other clinical antibiotics. Our results highlight how detailed mechanistic understanding can accelerate the evaluation and implementation of new combination therapies.
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