An interferon-inducible neutrophil-driven blood transcriptional signature in human tuberculosis

Tuberculosis (TB), caused by infection with Mycobacterium tuberculosis (M. tuberculosis), is a major cause of morbidity and mortality worldwide and efforts to control TB are hampered by difficulties with diagnosis, prevention and treatment 1,2. Most people infected with M. tuberculosis remain asymptomatic, termed latent TB, with a 10% lifetime risk of developing active TB disease, but current tests cannot identify which individuals will develop disease 3. The immune response to M. tuberculosis is complex and incompletely characterized, hindering development of new diagnostics, therapies and vaccines 4,5. We identified a whole blood 393 transcript signature for active TB in intermediate and high burden settings, correlating with radiological extent of disease and reverting to that of healthy controls following treatment. A subset of latent TB patients had signatures similar to those in active TB patients. We also identified a specific 86-transcript signature that discriminated active TB from other inflammatory and infectious diseases. Modular and pathway analysis revealed that the TB signature was dominated by a neutrophil-driven interferon (IFN)-inducible gene profile, consisting of both IFN-γ and Type I IFNαβ signalling. Comparison with transcriptional signatures in purified cells and flow cytometric analysis, suggest that this TB signature reflects both changes in cellular composition and altered gene expression. Although an IFN signature was also observed in whole blood of patients with Systemic Lupus Erythematosus (SLE), their complete modular signature differed from TB with increased abundance of plasma cell transcripts. Our studies demonstrate a hitherto under-appreciated role of Type I IFNαβ signalling in TB pathogenesis, which has implications for vaccine and therapeutic development. Our study also provides a broad range of transcriptional biomarkers with potential as diagnostic and prognostic tools to combat the TB epidemic

Food for pollinators: quantifying the nectar and pollen resources of urban flower meadows

Planted meadows are increasingly used to improve the biodiversity and aesthetic amenity value of urban areas. Although many ‘pollinator-friendly’ seed mixes are available, the floral resources these provide to flower-visiting insects, and how these change through time, are largely unknown. Such data are necessary to compare the resources provided by alternative meadow seed mixes to each other and to other flowering habitats. We used quantitative surveys of over 2 million flowers to estimate the nectar and pollen resources offered by two exemplar commercial seed mixes (one annual, one perennial) and associated weeds grown as 300m2 meadows across four UK cities, sampled at six time points between May and September 2013. Nectar sugar and pollen rewards per flower varied widely across 65 species surveyed, with native British weed species (including dandelion, Taraxacum agg.) contributing the top five nectar producers and two of the top ten pollen producers. Seed mix species yielding the highest rewards per flower included Leontodon hispidus, Centaurea cyanus and C. nigra for nectar, and Papaver rhoeas, Eschscholzia californica and Malva moschata for pollen. Perennial meadows produced up to 20x more nectar and up to 6x more pollen than annual meadows, which in turn produced far more than amenity grassland controls. Perennial meadows produced resources earlier in the year than annual meadows, but both seed mixes delivered very low resource levels early in the year and these were provided almost entirely by native weeds. Pollen volume per flower is well predicted statistically by floral morphology, and nectar sugar mass and pollen volume per unit area are correlated with flower counts, raising the possibility that resource levels can be estimated for species or habitats where they cannot be measured directly. Our approach does not incorporate resource quality information (for example, pollen protein or essential amino acid content), but can easily do so when suitable data exist. Our approach should inform the design of new seed mixes to ensure continuity in floral resource availability throughout the year, and to identify suitable species to fill resource gaps in established mixes

Effective Components of Collaborative Care for Depression in Primary Care An Individual Participant Data Meta-Analysis

IMPORTANCE Collaborative care is a multicomponent intervention for patients with chronic disease in primary care. Previous meta-analyses have proven the effectiveness of collaborative care for depression; however, individual participant data (IPD) are needed to identify which components of the intervention are the principal drivers of this effect. OBJECTIVE To assess which components of collaborative care are the biggest drivers of its effectiveness in reducing symptoms of depression in primary care. DATA SOURCES Data were obtained from MEDLINE, Embase, Cochrane Library, PubMed, and PsycInfo as well as references of relevant systematic reviews. Searches were conducted in December 2023, and eligible data were collected until March 14, 2024. STUDY SELECTION Two reviewers assessed for eligibility. Randomized clinical trials comparing the effect of collaborative care and usual care among adult patients with depression in primary care were included. DATA EXTRACTION AND SYNTHESIS The study was conducted according to the IPD guidance of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses reporting guideline. IPD were collected for demographic characteristics and depression outcomes measured at baseline and follow-ups from the authors of all eligible trials. Using IPD, linear mixed models with random nested effects were calculated. MAIN OUTCOMES AND MEASURES Continuous measure of depression severity was assessed via validated self-report instruments at 4 to 6 months and was standardized using the instrument's cutoff value for mild depression. RESULTS A total of 35 datasets with 38 comparisons were analyzed (N = 20 046 participants [57.3% of all eligible, with minimal differences in baseline characteristics compared with nonretrieved data]; 13 709 [68.4%] female; mean [SD] age, 50.8 [16.5] years). A significant interaction effect with the largest effect size was found between the depression outcome and the collaborative care component therapeutic treatment strategy (−0.07; P < .001). This indicates that this component, including its key elements manual-based psychotherapy and family involvement, was the most effective component of the intervention. Significant interactions were found for all other components, but with smaller effect sizes. CONCLUSIONS AND RELEVANCE Components of collaborative care most associated with improved effectiveness in reducing depressive symptoms were identified. To optimize treatment effectiveness and resource allocation, a therapeutic treatment strategy, such as manual-based psychotherapy or family integration, may be prioritized when implementing a collaborative care intervention

A New Crocodylian from the Late Maastrichtian of Spain: Implications for the Initial Radiation of Crocodyloids

The earliest crocodylians are known primarily from the Late Cretaceous of North America and Europe. The representatives of Gavialoidea and Alligatoroidea are known in the Late Cretaceous of both continents, yet the biogeographic origins of Crocodyloidea are poorly understood. Up to now, only one representative of this clade has been known from the Late Cretaceous, the basal crocodyloid Prodiplocynodon from the Maastrichtian of North America.The fossil studied is a skull collected from sandstones in the lower part of the Tremp Formation, in Chron C30n, dated at -67.6 to 65.5 Ma (late Maastrichtian), in Arén (Huesca, Spain). It is located in a continuous section that contains the K/P boundary, in which the dinosaur faunas closest to the K/P boundary in Europe have been described, including Arenysaurus ardevoli and Blasisaurus canudoi. Phylogenetic analysis places the new taxon, Arenysuchus gascabadiolorum, at the base of Crocodyloidea.The new taxon is the oldest crocodyloid representative in Eurasia. Crocodyloidea had previously only been known from the Palaeogene onwards in this part of Laurasia. Phylogenetically, Arenysuchus gascabadiolorum is situated at the base of the first radiation of crocodyloids that occurred in the late Maastrichtian, shedding light on this part of the cladogram. The presence of basal crocodyloids at the end of the Cretaceous both in North America and Europe provides new evidence of the faunal exchange via the Thulean Land Bridge during the Maastrichtian

Transcutaneous electrical nerve stimulation reduces exercise-induced perceived pain and improves endurance exercise performance

Purpose. Muscle pain is a natural consequence of intense and prolonged exercise and has been suggested to be a limiter of performance. Transcutaneous electrical nerve stimulation (TENS) and interferential current (IFC) have been shown to reduce both chronic and acute pain in a variety of conditions. This study sought to ascertain whether TENS and IFC could reduce exercise-induced pain (EIP) and whether this would affect exercise performance. It was hypothesised that TENS and IFC would reduce EIP and result in an improved exercise performance. Methods. In two parts, 18 (Part I) and 22 (Part II) healthy male and female participants completed an isometric contraction of the dominant bicep until exhaustion (Part I) and a 16.1 km cycling time trial as quickly as they could (Part II) whilst receiving TENS, IFC and a SHAM placebo in a repeated measures, randomized cross-over, and placebo controlled design. Perceived EIP was recorded in both tasks using a validated subjective scale. Results. In Part I, TENS significantly reduced perceived EIP (mean reduction of 12%) during the isometric contraction (P = 0.006) and significantly improved participants’ time to exhaustion by a mean of 38% (P = 0.02). In Part II, TENS significantly improved (P = 0.003) participants’ time trial completion time (~2% improvement) through an increased mean power output. Conclusion. These findings demonstrate that TENS can attenuate perceived EIP in a healthy population and that doing so significantly improves endurance performance in both submaximal isometric single limb exercise and whole-body dynamic exercise

Workshops of the Sixth International Brain–Computer Interface Meeting: brain–computer interfaces past, present, and future

Brain–computer interfaces (BCI) (also referred to as brain–machine interfaces; BMI) are, by definition, an interface between the human brain and a technological application. Brain activity for interpretation by the BCI can be acquired with either invasive or non-invasive methods. The key point is that the signals that are interpreted come directly from the brain, bypassing sensorimotor output channels that may or may not have impaired function. This paper provides a concise glimpse of the breadth of BCI research and development topics covered by the workshops of the 6th International Brain–Computer Interface Meeting

Multimorbidity and survival for patients with acute myocardial infarction in England and Wales: Latent class analysis of a nationwide population-based cohort

Background: There is limited knowledge of the scale and impact of multimorbidity for patients who have had an acute myocardial infarction (AMI). Therefore, this study aimed to determine the extent to which multimorbidity is associated with long-term survival following AMI. Methods and findings: This national observational study included 693,388 patients (median age 70.7 years, 452,896 [65.5%] male) from the Myocardial Ischaemia National Audit Project (England and Wales) who were admitted with AMI between 1 January 2003 and 30 June 2013. There were 412,809 (59.5%) patients with multimorbidity at the time of admission with AMI, i.e., having at least 1 of the following long-term health conditions: diabetes, chronic obstructive pulmonary disease or asthma, heart failure, renal failure, cerebrovascular disease, peripheral vascular disease, or hypertension. Those with heart failure, renal failure, or cerebrovascular disease had the worst outcomes (39.5 [95% CI 39.0–40.0], 38.2 [27.7–26.8], and 26.6 [25.2–26.4] deaths per 100 person-years, respectively). Latent class analysis revealed 3 multimorbidity phenotype clusters: (1) a high multimorbidity class, with concomitant heart failure, peripheral vascular disease, and hypertension, (2) a medium multimorbidity class, with peripheral vascular disease and hypertension, and (3) a low multimorbidity class. Patients in class 1 were less likely to receive pharmacological therapies compared with class 2 and 3 patients (including aspirin, 83.8% versus 87.3% and 87.2%, respectively; β-blockers, 74.0% versus 80.9% and 81.4%; and statins, 80.6% versus 85.9% and 85.2%). Flexible parametric survival modelling indicated that patients in class 1 and class 2 had a 2.4-fold (95% CI 2.3–2.5) and 1.5-fold (95% CI 1.4–1.5) increased risk of death and a loss in life expectancy of 2.89 and 1.52 years, respectively, compared with those in class 3 over the 8.4-year follow-up period. The study was limited to all-cause mortality due to the lack of available cause-specific mortality data. However, we isolated the disease-specific association with mortality by providing the loss in life expectancy following AMI according to multimorbidity phenotype cluster compared with the general age-, sex-, and year-matched population. Conclusions: Multimorbidity among patients with AMI was common, and conferred an accumulative increased risk of death. Three multimorbidity phenotype clusters that were significantly associated with loss in life expectancy were identified and should be a concomitant treatment target to improve cardiovascular outcomes