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While specialty medications offer hope to the more than 20 million Americans currently taking them for complex health conditions, getting that first prescription filled can cost what these patients can [...]

Nutrition has broad impacts on all physiological processes. However, how nutrition affects human immunity remains largely unknown. Here we explored the impact of a dietary intervention on both immunity and the microbiota by performing a post hoc analysis of a clinical trial in which each of the 20 participants sequentially consumed vegan or ketogenic diets for 2 weeks (NCT03878108). Using a multiomics approach including multidimensional flow cytometry, transcriptomic, proteomic, metabolomic and metagenomic datasets, we assessed the impact of each diet, and dietary switch, on host immunity and the microbiota. Our data revealed that overall, a ketogenic diet was associated with a significant upregulation of pathways and enrichment in cells associated with the adaptive immune system. In contrast, a vegan diet had a significant impact on the innate immune system, including upregulation of pathways associated with antiviral immunity. Both diets significantly and differentially impacted the microbiome and host-associated amino acid metabolism, with a strong downregulation of most microbial pathways following ketogenic diet compared with baseline and vegan diet. Despite the diversity of participants, we also observed a tightly connected network between datasets driven by compounds associated with amino acids, lipids and the immune system. Collectively, this work demonstrates that in diverse participants 2 weeks of controlled dietary intervention is sufficient to significantly and divergently impact host immunity, which could have implications for precision nutritional interventions. ClinicalTrials.gov registration: NCT03878108.

ObjectiveTo explore the effect of left ventricular (LV) diastolic dysfunction (LVDD) in systemic sclerosis (SSc)-associated interstitial lung disease (ILD), and to investigate SSc-specific associations and clinical correlates of LVDD.MethodsThere were 102 Australian Scleroderma Cohort Study participants with definite SSc and radiographic ILD included. Diastolic function was classified as normal, indeterminate, or abnormal according to 2016 American Society of Echocardiography/European Association of Cardiovascular Imaging guidelines for assessment of LV diastolic function. Associations between clinical features and patient- and physician-reported dyspnea were evaluated using logistic regression. Survival analyses were performed using Kaplan-Meier survival estimates and Cox regression modeling.ResultsLVDD was identified in 26% of participants, whereas 19% had indeterminate and 55% had normal diastolic function. Those with ILD and LVDD had increased mortality (hazard ratio 2.4, 95% CI 1.0-5.7; P= 0.05). After adjusting for age and sex, those with ILD and LVDD were more likely to have severe dyspnea on the Borg Dyspnoea Scale (odds ratio [OR] 2.6, 95% CI 1.0-6.6; P= 0.05) and numerically more likely to record World Health Organization Function Class II or higher dyspnea (OR 4.2, 95% CI 0.9-20.0; P= 0.08). Older age (95% CI 1.0-6.4; P= 0.05), hypertension (OR 5.0, 95% CI 1.8-13.8; P< 0.01), and ischemic heart disease (OR 4.8, 95% CI 1.5-15.7; P< 0.01) were all associated with LVDD, as was proximal muscle atrophy (OR 5.0, 95% CI 1.9-13.6; P< 0.01) and multimorbidity (Charlson Comorbidity Index scores ≥ 4, OR 3.0, 95% CI 1.1-8.7; P= 0.04).ConclusionLVDD in SSc-ILD is more strongly associated with traditional LVDD risk factors than SSc-specific factors. LVDD is associated with worse dyspnea and survival in those with SSc-ILD.

There is a point in every patient journey that either leads to healthy outcomes or missed opportunities and unmet needs. While this was true long before the pandemic, COVID-19 has [...]

Higher levels of inflammatory biomarkers are associated with an increased risk of perioperative atrial fibrillation and myocardial injury after non-cardiac surgery (MINS). Colchicine is an anti-inflammatory drug that might reduce the incidence of these complications.

Parasitic nematodes are a major threat to global food security, particularly as the world amasses 10 billion people amid limited arable land1–4. Most traditional nematicides have been banned owing to poor nematode selectivity, leaving farmers with inadequate means of pest control4–12. Here we use the model nematode Caenorhabditis elegansto identify a family of selective imidazothiazole nematicides, called selectivins, that undergo cytochrome-p450-mediated bioactivation in nematodes. At low parts-per-million concentrations, selectivins perform comparably well with commercial nematicides to control root infection by Meloidogyne incognita, a highly destructive plant-parasitic nematode. Tests against numerous phylogenetically diverse non-target systems demonstrate that selectivins are more nematode-selective than most marketed nematicides. Selectivins are first-in-class bioactivated nematode controls that provide efficacy and nematode selectivity.

Abstract: Delighting customers is currently being touted as a requirement for survival within today's unpredictable marketplace and the need for product developers to move beyond satisfying their customers to delighting [...]

Abstract:Pandemics do not exist in isolation and COVID-19 is no exception. We argue that existing health crises, notably substance use disorder (SUD), developed syndemic relationships with COVID-19 that produced compounding deleterious effects. Combining Merrill Singer's theory of syndemics and assemblage theory, we analyze the combinatory impact of overdose and COVID-19 within a localized context. We focus on Sandusky, Ohio, where we combine police reports, in-depth interviews with area residents, and ethnographic data to compare conditions before and after the emergence of COVID-19. We find dramatic shifts in relevant local contexts due to COVID-19, inhibiting existing systems of law and public policy aimed at overdose prevention and SUD treatment. Further, our findings provide evidence of complications in the COVID-19 response originating from the overdose epidemic.

Major advances have been made to improve the sensitivity of mass analyzers, spectral quality, and speed of data processing enabling more comprehensive proteome discovery and quantitation. While focus has recently begun shifting toward robust proteomics sample preparation efforts, a high-throughput proteomics sample preparation is still lacking. We report the development of a highly automated universal 384-well plate sample preparation platform with high reproducibility and adaptability for extraction of proteins from cells within a culture plate. Digestion efficiency was excellent in comparison to a commercial digest peptide standard with minimal sample loss while improving sample preparation throughput by 20- to 40-fold (the entire process from plated cells to clean peptides is complete in ∼300 min). Analysis of six human cell types, including two primary cell samples, identified and quantified ∼4,000 proteins for each sample in a single high-performance liquid chromatography (HPLC)–tandem mass spectrometry injection with only 100–10K cells, thus demonstrating universality of the platform. The selected protein was further quantified using a developed HPLC-multiple reaction monitoring method for HeLa digests with two heavy labeled internal standard peptides spiked in. Excellent linearity was achieved across different cell numbers indicating a potential for target protein quantitation in clinical research.

Exercise capacity is frequently reduced in people with diabetes mellitus (DM) and may be due to subclinical cardiac dysfunction. Speckle-tracking echocardiography is now widely available; however, the clinical utility and significance of left ventricular (LV) strain and twist parameters remain uncertain. We hypothesized that LV strain and twist would be reduced in DM subjects during exercise.

The differential diagnosis of peripartum chest pain and cardiogenic shock is broad and includes pulmonary embolism, amniotic fluid embolism, peripartum and Takotsubo cardiomyopathy, myocardial infarction, and anaesthetic complications.

Introduction: Pulmonary arterial hypertension and left ventricular diastolic dysfunction are associated with significant morbidity and mortality in systemic sclerosis. N-terminal pro-brain natriuretic peptide has been proposed as part of composite screening algorithms for pulmonary arterial hypertension. Our aim was to assess the prevalence of pulmonary hypertension and diastolic dysfunction, and evaluate their association with serum N-terminal pro-brain natriuretic peptide in systemic sclerosis patients.Methods: Patients with systemic sclerosis were prospectively enrolled to undergo N-terminal pro-brain natriuretic peptide testing and transthoracic echocardiography at a tertiary Australian centre from January to October 2022. We collected demographic and transthoracic echocardiography variables including pulmonary hypertension estimated by tricuspid regurgitant velocity and diastolic dysfunction assessed by the ASE/EACVI 2016 guidelines. Pearson’s correlation coefficient was used to evaluate association between N-terminal pro-brain natriuretic peptide and echocardiographic parameters.Results: Sixty-one patients were enrolled (median age = 62 years (interquartile range = 55–69 years); 84% female). Two-thirds of patients had limited systemic sclerosis (40/61). Five patients (8%) had high likelihood of pulmonary hypertension by transthoracic echocardiography. Seven patients (11%) had diastolic dysfunction; however, seven patients (11%) had indeterminate diastology. Six patients underwent right heart catheterisation, with five patients diagnosed with pulmonary hypertension. N-terminal pro-brain natriuretic peptide in patients with pulmonary hypertension or diastolic dysfunction was significantly higher (median = 207 and 226 pg/mL, respectively) compared to patients without either condition (median = 69 pg/mL, p = 0.01). N-terminal pro-brain natriuretic peptide showed a statistically significant although limited correlation with estimated pulmonary pressures measured by tricuspid regurgitant velocity (r = 0.44, p = 0.002) and left ventricular filling pressures (r = 0.27, p = 0.04).Conclusion: Pulmonary hypertension and diastolic dysfunction are both observed in systemic sclerosis. N-terminal pro-brain natriuretic peptide is associated with both conditions; however, it cannot distinguish between the two disease processes. Right heart catheterisation may be required to make this distinction.

Byline: Andrew Burns lmost six months on from the summer riots in London, and other major UK cities, the impact on the nation and the insurance industry is still being [...]

Unlike biologically available nitrogen and phosphorus, which are often at limiting concentrations in surface seawater, sulfur in the form of sulfate is plentiful and not considered to constrain marine microbial activity. Nonetheless, in a model system in which a marine bacterium obtains all of its carbon from co-cultured phytoplankton, bacterial gene expression suggests that at least seven dissolved organic sulfur (DOS) metabolites support bacterial heterotrophy. These labile exometabolites of marine dinoflagellates and diatoms include taurine, N-acetyltaurine, isethionate, choline-O-sulfate, cysteate, 2,3-dihydroxypropane-1-sulfonate (DHPS), and dimethylsulfoniopropionate (DMSP). Leveraging from the compounds identified in this model system, we assessed the role of sulfur metabolites in the ocean carbon cycle by mining the Tara Oceans dataset for diagnostic genes. In the 1.4 million bacterial genome equivalents surveyed, estimates of the frequency of genomes harboring the capability for DOS metabolite utilization ranged broadly, from only 1 out of every 190 genomes (for the C2 sulfonate isethionate) to 1 out of every 5 (for the sulfonium compound DMSP). Bacteria able to participate in DOS transformations are dominated by Alphaproteobacteria in the surface ocean, but by SAR324, Acidimicrobiia, and Gammaproteobacteria at mesopelagic depths, where the capability for utilization occurs in higher frequency than in surface bacteria for more than half the sulfur metabolites. The discovery of an abundant and diverse suite of marine bacteria with the genetic capacity for DOS transformation argues for an important role for sulfur metabolites in the pelagic ocean carbon cycle.

A novel natural cellulose material (“biofibre”) suspension in water has potential both for enhanced oil recovery and proppant placement during fracturing in tight reservoirs. We analyse the different carrying mechanisms of biofibre against those of a cross-linked guar benchmark. Three viscosity determination methods have been applied that are relevant to the different applications. Non-Newtonian, shear-thinning effects with viscoelastic enhancement have been observed. These results are compared to the viscosity in a falling ball rheometer as well as in pressure-driven flow through capillaries and conduits. The results indicate that viscosity can be tuned to automatically adjust to the desired flow conditions in the reservoir to provide optimal behaviour for each application.

TECHNOLOGICAL progress--improvements in the ways that goods and services are produced, marketed, and brought to market--is at the very heart of human advancement and development. It has helped reduce the [...]

In their role as primary producers, marine phytoplankton modulate heterotrophic bacterial activities through differences in the types and amounts of organic matter they release. This study investigates the transcriptional response of bacterium Ruegeria pomeroyi, a member of the Roseobacter clade known to affiliate with diverse phytoplankton groups in the ocean, during a shift in phytoplankton taxonomy. The bacterium was initially introduced into a culture of the dinoflagellate Alexandrium tamarense, and then experienced a change in phytoplankton community composition as the diatom Thalassiosira pseudonanagradually outcompeted the dinoflagellate. Samples were taken throughout the 30-day experiment to track shifts in bacterial gene expression informative of metabolic and ecological interactions. Transcriptome data indicate fundamental differences in the exometabolites released by the two phytoplankton. During growth with the dinoflagellate, gene expression patterns indicated that the main sources of carbon and energy for R. pomeroyiwere dimethysulfoniopropionate (DMSP), taurine, methylated amines, and polyamines. During growth with the diatom, dihydroxypropanesulfonate (DHPS), xylose, ectoine, and glycolate instead appeared to fuel the bulk of bacterial metabolism. Expression patterns of genes for quorum sensing, gene transfer agent, and motility suggest that bacterial processes related to cell communication and signaling differed depending on which phytoplankton species dominated the co-culture. A remodeling of the R. pomeroyitranscriptome implicating more than a quarter of the genome occurred through the change in phytoplankton regime.

I seem to remember a request for car-themed album covers a few years ago (Top ten, May 2009), but I ran across a couple of interesting ones in a rummage-sale [...]

In the chicken-and-egg tug-of-war over which launches first, print or the web, MaMaMedia Inc. is writing a new chapter. The upstart company debuted June 5 with the simultaneous launches of [...]

This paper presents estimates of potential output growth for a sample of 26 Asian economies and projects potential output growth through 2040 under several scenarios. Results suggest that in the absence of further capital deepening, and assuming continued total factor productivity growth at recent rates, potential output growth across economies could slow from a median of 4.6% during 2010–2015 to 2.7% between 2035 and 2040. Demographic trends and an assumed stabilization in capital–output ratios account for most of the slowing. Much better outcomes are possible if trends are supported by policy. Better total factor productivity growth could raise potential output by between 11% and 24% by 2040, while lower unemployment and higher participation rates could boost potential output by 10% or more in some South Asian economies. An improved investment climate could add between 6% and 10% to potential output in most economies, while accelerating structural convergence (moving labor from lower to higher productivity sectors) could raise potential output by 10% or more in half of the examined countries.

Bacteria of the SAR11 clade constitute up to one half of all microbial cells in the oxygen-rich surface ocean. SAR11 bacteria are also abundant in oxygen minimum zones (OMZs), where oxygen falls below detection and anaerobic microbes have vital roles in converting bioavailable nitrogen to N2gas. Anaerobic metabolism has not yet been observed in SAR11, and it remains unknown how these bacteria contribute to OMZ biogeochemical cycling. Here, genomic analysis of single cells from the world’s largest OMZ revealed previously uncharacterized SAR11 lineages with adaptations for life without oxygen, including genes for respiratory nitrate reductases (Nar). SAR11 nar genes were experimentally verified to encode proteins catalysing the nitrite-producing first step of denitrification and constituted ~40% of OMZ nar transcripts, with transcription peaking in the anoxic zone of maximum nitrate reduction activity. These results link SAR11 to pathways of ocean nitrogen loss, redefining the ecological niche of Earth’s most abundant organismal group.

The article offers a personal view of the author on how a smaller, developing Multi-Academy Trust (MAT) is meeting the challenges of participating in the self-improving system in Great Britain. The author pointed out topics such as the concerns of Local Authority about the performance of one of its special schools, the purpose of Redhill Academy Trust and other academies to raise student achievement, and the strategic workshops involving Directors, Chairs of Governors, and Headteachers.

Background: Skeletal muscle can be directly affected by systemic sclerosis (SSc); however, a significant burden of SSc-associated myopathy is undetected because clinical parameters such as weakness and creatine kinase (CK) are unreliable biomarkers of muscle involvement. This study presents qualitative and quantitative magnetic resonance imaging (MRI) findings that quantify the prevalence of myopathy and evaluate any association between skeletal and cardiac muscle involvement in SSc. Methods: Thirty-two patients with SSc who fulfilled the 2013 American College of Rheumatology/European League Against Rheumatism classification criteria underwent skeletal muscle MRI in addition to cardiac MRI. Skeletal muscles were independently assessed by two musculoskeletal radiologists for evidence of oedema, fatty infiltration and atrophy. Skeletal muscle T2 mapping times and percentage fat fraction were calculated. Linear regression analysis was used to evaluate the clinical and myocardial associations with skeletal muscle oedema and fatty infiltration. Cardiac MRI was performed using post gadolinium contrast imaging and parametric mapping techniques to assess focal and diffuse myocardial fibrosis. Results: Thirteen participants (40.6%) had MRI evidence of skeletal muscle oedema. Five (15.6%) participants had fatty infiltration. There was no association between skeletal muscle oedema and muscle strength, creatine kinase, inflammatory markers or fibroinflammatory myocardial disease. Patients with skeletal muscle oedema had higher T2-mapping times; there was a significant association between subjective assessments of muscle oedema and T2-mapping time (coef 2.46, p= 0.02) and percentage fat fraction (coef 3.41, p= 0.02). Diffuse myocardial fibrosis was a near-universal finding, and one third of patients had focal myocardial fibrosis. There was no association between skeletal myopathy detected by MRI and burden of myocardial disease. Conclusions: MRI is a sensitive measure of muscle oedema and systematic assessment of SSc patients using MRI shows that myopathy is highly prevalent, even in patients without symptoms or other signs of muscle involvement. Similarly, cardiac fibrosis is highly prevalent but occurs independently of skeletal muscle changes. These results indicate that novel quantitative MRI techniques may be useful for assessing sub-clinical skeletal muscle disease in SSc.

The hepatitis C virus (HCV) infects more than 200 million people globally, with increasing incidence, especially in developing countries. HCV infection frequently progresses to chronic liver disease, creating a heavy economic burden on resource-poor countries and lowering patient quality of life. Effective HCV diagnosis, treatment selection, and treatment monitoring are important in stopping disease progression. Serological assays, which detect anti-HCV antibodies in the patient after seroconversion, are used for initial HCV diagnosis. Qualitative and quantitative molecular assays are used to confirm initial diagnosis, determine viral load, and genotype the dominant strain. Viral load and genotype information are used to guide appropriate treatment. Various other biomarker assays are performed to assess liver function and enable disease staging. Most of these diagnostic methods are mature and routinely used in high-resource countries with well-developed laboratory infrastructure. Few technologies, however, are available that address the needs of low-resource areas with high HCV prevalence, such as Africa and Southeast Asia.

Left ventricular diastolic dysfunction is a well-described complication of systemic hypertension. However, less is known regarding the effect of chronic pressure overload on right ventricular (RV) diastolic function. We hypothesized that pulmonary hypertension (PHT) is associated with abnormal RV early relaxation and that this would be best shown by invasive pressure measurement. Twenty-five patients undergoing right heart catheterization for investigation of breathlessness and/or suspected PHT were studied. In addition to standard measurements, RV pressure was sampled with a high-fidelity micromanometer, and RV pressure/time curves were analyzed. Patients were divided into a PHT group and a non-PHT group on the basis of a derived mean pulmonary artery systolic pressure of 25 mmHg. Eleven patients were classified to the PHT group. This group had significantly higher RV minimum diastolic pressure (5.1 ± 6.6 vs. −0.1 ± 3.3 mmHg, P= 0.03) and RV end-diastolic pressure (RVEDP; 11.0 ± 6.3 vs. 3.8 ± 3.7 mmHg, P= 0.004), and RV τ was significantly prolonged (53 ± 32 vs. 31 ± 13 ms, P= 0.04). There were strong correlations between RV τ and RV minimum diastolic pressure (r= 0.93, P< 0.0001) and between RV τ and RVEDP (r= 0.87, P< 0.0001). There was a trend toward increased RV contractility (end-systolic elastance) in the PHT group (0.73 ± 0.21 vs. 0.52 ± 0.21 mmHg/mL, P= 0.07) and a correlation between RV systolic pressure and first derivative of maximum pressure change (r= 0.58, P= 0.003). Stroke volumes were similar. Invasive measures of RV early relaxation are abnormal in patients with PHT, whereas measured contractility is static or increasing, which suggests that diastolic dysfunction may precede systolic dysfunction. Furthermore, there is a strong association between measures of RV relaxation and RV filling pressures.

Martin O'Shea's unconfirmed murmurings about the numbers of Jewish architects in our profession were intolerable. To suggest that these architects should club together and speak out about a situation, which [...]

I was very interested to read Anthony Thistledton's negative comments on quality assurance that appeared in the article on Ojeu questionnaires (News analysis November 18). As quality director for a [...]