F
is a low-potential redox cofactor that mediates the transformations of a wide range of complex organic compounds. Considered one of the rarest cofactors in biology, F
is best known for its role in ...methanogenesis and has only been chemically identified in two phyla to date, the Euryarchaeota and Actinobacteria. In this work, we show that this cofactor is more widely distributed than previously reported. We detected the genes encoding all five known F
biosynthesis enzymes (cofC, cofD, cofE, cofG and cofH) in at least 653 bacterial and 173 archaeal species, including members of the dominant soil phyla Proteobacteria, Chloroflexi and Firmicutes. Metagenome datamining validated that these genes were disproportionately abundant in aerated soils compared with other ecosystems. We confirmed through high-performance liquid chromatography analysis that aerobically grown stationary-phase cultures of three bacterial species, Paracoccus denitrificans, Oligotropha carboxidovorans and Thermomicrobium roseum, synthesized F
, with oligoglutamate sidechains of different lengths. To understand the evolution of F
biosynthesis, we also analyzed the distribution, phylogeny and genetic organization of the cof genes. Our data suggest that although the F
precursor to F
originated in methanogens, F
itself was first synthesized in an ancestral actinobacterium. F
biosynthesis genes were then disseminated horizontally to archaea and other bacteria. Together, our findings suggest that the cofactor is more significant in aerobic bacterial metabolism and soil ecosystem composition than previously thought. The cofactor may confer several competitive advantages for aerobic soil bacteria by mediating their central metabolic processes and broadening the range of organic compounds they can synthesize, detoxify and mineralize.
To estimate the prevalence of inadequate pain relief (IPR) among patients with symptomatic knee OA prescribed analgesic therapy and to characterize patients with IPR.
Patients ≥50 years old with ...physician-diagnosed knee OA who had taken topical or oral pain medication for at least 14 days were recruited for this prospective non-interventional study in six European countries. Pain and function were assessed using the Brief Pain Inventory (BPI) and the WOMAC; quality of life (QoL) was assessed using the 12-item short form. IPR was defined as an average pain score of >4 out of 10 on BPI question 5.
Of 1187 patients enrolled, 68% were female and the mean age was 68 years (s.d. 9); 639 (54%) met the definition of IPR. Patient responses for the BPI average pain question were well correlated with responses on the WOMAC pain subscale (Spearman r = 0.64, P < 0.001). In multivariate logistic regression, patients with IPR had greater odds of being female adjusted odds ratio (adjOR) 1.90 (95% CI 1.46, 2.48) and having OA in both knees adjOR 1.48 (95% CI 1.15, 1.90), higher BMI, longer OA duration, depression or diabetes. Patients with IPR (vs non-IPR) were more likely to have worse QoL, greater function loss and greater pain interference.
IPR is common among patients with knee OA requiring analgesics and is associated with large functional loss and impaired QoL. Patients at particular risk of IPR, as characterized in this study, may require greater attention towards their analgesic treatment options.
https://clinicaltrials.gov/ (NCT01294696).
We explored the association between liver metastases, tumor CD8
T-cell count, and response in patients with melanoma or lung cancer treated with the anti-PD-1 antibody, pembrolizumab. The melanoma ...discovery cohort was drawn from the phase I Keynote 001 trial, whereas the melanoma validation cohort was drawn from Keynote 002, 006, and EAP trials and the non-small cell lung cancer (NSCLC) cohort from Keynote 001. Liver metastasis was associated with reduced response and shortened progression-free survival PFS; objective response rate (ORR), 30.6%; median PFS, 5.1 months compared with patients without liver metastasis (ORR, 56.3%; median PFS, 20.1 months)
≤ 0.0001, and confirmed in the validation cohort (
= 0.0006). The presence of liver metastasis significantly increased the likelihood of progression (OR, 1.852;
< 0.0001). In a subset of biopsied patients (
= 62), liver metastasis was associated with reduced CD8
T-cell density at the invasive tumor margin (liver metastasis
group,
= 547 ± 164.8; liver metastasis
group,
= 1,441 ± 250.7;
< 0.016). A reduced response rate and shortened PFS was also observed in NSCLC patients with liver metastasis median PFS, 1.8 months; 95% confidence interval (CI), 1.4-2.0, compared with those without liver metastasis (
= 119, median PFS, 4.0 months; 95% CI, 2.1-5.1),
= 0.0094. Thus, liver metastatic patients with melanoma or NSCLC that had been treated with pembrolizumab were associated with reduced responses and PFS, and liver metastases were associated with reduced marginal CD8
T-cell infiltration, providing a potential mechanism for this outcome.
.
Background
In 2021, Canada implemented a pilot plasma program allowing some sexually active men who have sex with men (including but not limited to gay and bisexual men; gbMSM) to donate plasma. ...Changes to plasma donation policy could help address inequities in access to plasma donation and increase Canada's domestically collected plasma supply if more gbMSM donate as a result. We aimed to (1) examine views regarding plasma donation and the pilot program prior to implementation and (2) identify modifiable theory‐informed predictors of gbMSM's intention to donate plasma.
Methods
We developed, piloted, and disseminated a questionnaire informed by the Theoretical Domains Framework (TDF). We recruited gbMSM in London (ON) and Calgary (AB) to an anonymous, online cross‐sectional survey.
Results
A total of 246 gbMSM completed the survey. On scales from 1 (strongly disagree) to 5 (strongly agree), general intention to donate was high (mean = 4.24; SD = 0.94). The pilot program itself was mostly acceptable (mean = 3.71, SD = 1.16), but the intention to donate under the unique requirements of the pilot program was lower than general intention (mean = 3.58; SD = 1.26). Two domains from the theoretical domains framework (TDF) (beliefs about consequences of donating plasma and social influences) were independently associated with general intention to donate.
Discussion
The pilot plasma program as an incremental step toward more inclusive policies was mostly viewed as acceptable by the impacted communities. Historical and ongoing exclusions create unique barriers to donation. There are clear opportunities for developing theory‐informed interventions to support gbMSM to donate plasma as policies continue to become more inclusive and more become eligible to donate.
Catchment urbanization perturbs the water and sediment budgets of streams, degrades stream health and function, and causes a constellation of flow, water quality, and ecological symptoms collectively ...known as the urban stream syndrome. Low-impact development (LID) technologies address the hydrologic symptoms of the urban stream syndrome by mimicking natural flow paths and restoring a natural water balance. Over annual time scales, the volumes of stormwater that should be infiltrated and harvested can be estimated from a catchment-scale water-balance given local climate conditions and preurban land cover. For all but the wettest regions of the world, a much larger volume of stormwater runoff should be harvested than infiltrated to maintain stream hydrology in a preurban state. Efforts to prevent or reverse hydrologic symptoms associated with the urban stream syndrome will therefore require: (1) selecting the right mix of LID technologies that provide regionally tailored ratios of stormwater harvesting and infiltration; (2) integrating these LID technologies into next-generation drainage systems; (3) maximizing potential cobenefits including water supply augmentation, flood protection, improved water quality, and urban amenities; and (4) long-term hydrologic monitoring to evaluate the efficacy of LID interventions.
Diagnostic tools available to support general practitioners diagnose heart failure (HF) are limited.
(i) Determine the feasibility of the novel cardiac output response to stress (CORS) test in ...suspected HF patients, and (ii) Identify differences in the CORS results between (a) confirmed HF patients from non-HF patients, and (b) HF reduced (HFrEF) vs HF preserved (HFpEF) ejection fraction.
Single centre, prospective, observational, feasibility study. Consecutive patients with suspected HF (N = 105; mean age: 72 ± 10 years) were recruited from specialized HF diagnostic clinics in secondary care. The consultant cardiologist confirmed or refuted a HF diagnosis. The patient completed the CORS but the researcher administering the test was blinded from the diagnosis. The CORS assessed cardiac function (stroke volume index, SVI) noninvasively using the bioreactance technology at rest-supine, challenge-standing, and stress-step exercise phases.
A total of 38 patients were newly diagnosed with HF (HFrEF, n = 21) with 79% being able to complete all phases of the CORS (91% of non-HF patients). A 17% lower SVI was found in HF compared with non-HF patients at rest-supine (43 ± 15 vs 51 ± 16 mL/beat/m2, P = 0.02) and stress-step exercise phase (49 ± 16 vs 58 ± 17 mL/beat/m2, P = 0.02). HFrEF patients demonstrated a lower SVI at rest (39 ± 15 vs 48 ± 13 mL/beat/m2, P = 0.02) and challenge-standing phase (34 ± 9 vs 42 ± 12 mL/beat/m2, P = 0.03) than HFpEF patients.
The CORS is feasible and patients with HF responded differently to non-HF, and HFrEF from HFpEF. These findings provide further evidence for the potential use of the CORS to improve HF diagnostic and referral accuracy in primary care.
Mitochondrial disease is maternally inherited and refractory to treatment, but assisted reproduction methods can result in unaffected pregnancies. The authors provide estimates of the number of ...affected pregnancies per year in the United Kingdom and the United States.
Variance-component methods that estimate the aggregate contribution of large sets of variants to the heritability of complex traits have yielded important insights into the genetic architecture of ...common diseases. Here, we introduce methods that estimate the total trait variance explained by the typed variants at a single locus in the genome (local SNP heritability) from genome-wide association study (GWAS) summary data while accounting for linkage disequilibrium among variants. We applied our estimator to ultra-large-scale GWAS summary data of 30 common traits and diseases to gain insights into their local genetic architecture. First, we found that common SNPs have a high contribution to the heritability of all studied traits. Second, we identified traits for which the majority of the SNP heritability can be confined to a small percentage of the genome. Third, we identified GWAS risk loci where the entire locus explains significantly more variance in the trait than the GWAS reported variants. Finally, we identified loci that explain a significant amount of heritability across multiple traits.
Gene fusions represent an important class of somatic alterations in cancer. We systematically investigated fusions in 9,624 tumors across 33 cancer types using multiple fusion calling tools. We ...identified a total of 25,664 fusions, with a 63% validation rate. Integration of gene expression, copy number, and fusion annotation data revealed that fusions involving oncogenes tend to exhibit increased expression, whereas fusions involving tumor suppressors have the opposite effect. For fusions involving kinases, we found 1,275 with an intact kinase domain, the proportion of which varied significantly across cancer types. Our study suggests that fusions drive the development of 16.5% of cancer cases and function as the sole driver in more than 1% of them. Finally, we identified druggable fusions involving genes such as TMPRSS2, RET, FGFR3, ALK, and ESR1 in 6.0% of cases, and we predicted immunogenic peptides, suggesting that fusions may provide leads for targeted drug and immune therapy.
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•Highly recurrent fusions were found in prostate, bladder, breast, and lung cancers•Expression increased in oncogene fusions but decreased in tumor suppressor genes•Thyroid carcinoma showed significantly higher rates of kinase fusions•Tumors with fusion events tend to have lower mutational burden
Gao et al. analyze a 9,624 sample TCGA cohort with 33 cancer types to detect gene fusion events. They provide a landscape of fusion events detected, relate fusions to gene expression, focus on kinase fusion structures, examine mutually exclusive mutation and fusion patterns, and highlight fusion druggability.
Chronic limb-threatening ischemia (CLTI) is associated with mortality, amputation, and impaired quality of life. These Global Vascular Guidelines (GVG) are focused on definition, evaluation, and ...management of CLTI with the goals of improving evidence-based care and highlighting critical research needs. The term CLTI is preferred over critical limb ischemia, as the latter implies threshold values of impaired perfusion rather than a continuum. CLTI is a clinical syndrome defined by the presence of peripheral artery disease (PAD) in combination with rest pain, gangrene, or a lower limb ulceration >2 weeks duration. Venous, traumatic, embolic, and nonatherosclerotic etiologies are excluded. All patients with suspected CLTI should be referred urgently to a vascular specialist. Accurately staging the severity of limb threat is fundamental, and the Society for Vascular Surgery Threatened Limb Classification system, based on grading of Wounds, Ischemia, and foot Infection (WIfI) is endorsed. Objective hemodynamic testing, including toe pressures as the preferred measure, is required to assess CLTI. Evidence-based revascularization (EBR) hinges on three independent axes: Patient risk, Limb severity, and ANatomic complexity (PLAN). Average-risk and high-risk patients are defined by estimated procedural and 2-year all-cause mortality. The GVG proposes a new Global Anatomic Staging System (GLASS), which involves defining a preferred target artery path (TAP) and then estimating limb-based patency (LBP), resulting in three stages of complexity for intervention. The optimal revascularization strategy is also influenced by the availability of autogenous vein for open bypass surgery. Recommendations for EBR are based on best available data, pending level 1 evidence from ongoing trials. Vein bypass may be preferred for average-risk patients with advanced limb threat and high complexity disease, while those with less complex anatomy, intermediate severity limb threat, or high patient risk may be favored for endovascular intervention. All patients with CLTI should be afforded best medical therapy including the use of antithrombotic, lipid-lowering, antihypertensive, and glycemic control agents, as well as counseling on smoking cessation, diet, exercise, and preventive foot care. Following EBR, long-term limb surveillance is advised. The effectiveness of nonrevascularization therapies (eg, spinal stimulation, pneumatic compression, prostanoids, and hyperbaric oxygen) has not been established. Regenerative medicine approaches (eg, cell, gene therapies) for CLTI should be restricted to rigorously conducted randomizsed clinical trials. The GVG promotes standardization of study designs and end points for clinical trials in CLTI. The importance of multidisciplinary teams and centers of excellence for amputation prevention is stressed as a key health system initiative.
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