Accuracy of intra ocular lens calculation formulae in patients with pseudoexfoliation syndrome.

BACKGROUND: The purpose of this study was to investigate the visual and refractive outcomes in patients with pseudoexfoliation (PXF) undergoing routine cataract surgery and to compare the accuracy of intraocular lens (IOL) power calculation formulae. METHODS: Retrospective case-series study from Shamir medical center, a public hospital, Israel. Medical records of patients who underwent routine cataract surgery between January 2019 and August 2021 were investigated. Postoperative visual acuity and manifest refraction were examined. The error in predicted refraction and IOL power calculation accuracy within a range of ± 0.50 to ± 1.00 diopters were compared between different IOL calculating formulae. RESULTS: 151 eyes of 151 patients ages 73.9 ± 7.1 years were included in this study- 58 eyes in the PXF group and 93 eyes in the control group. The mean absolute error (MAE) for the BUII formula was 0.63D ± 0.87 for the PXF group and 0.36D ± 0.48 for the control group (p < 0.05). The MAE for the Hill-RBF 3.0 formula was 0.61D ± 0.84 for the PXF group and 0.42D ± 0.55 for the control group (p = 0.05). There were significant differences in MAE and MedAE between PXF group and control group measures (p < 0.05). In the PXF group there were no significant differences between the different formulae. CONCLUSIONS: There were significant differences in accuracy of IOL power calculations in all formulae between PXF group and control group measures. PXF patients show hyperopic shift from predicted refraction. Barret universal II formula had the highest proportion of eyes with absolute error in prediction below or equal to 0.50 D in both PXF and control groups.

Validation of a new acoustic telemetry transmitter for the study of predation events in small fishes.

Acoustic telemetry has emerged as an important tool for studying the movement and behavior of aquatic animals. Predation-sensing acoustic transmitters combine the functions of typical acoustic transmitters with the added ability to identify the predation of tagged animals. The objective of this paper was to assess the performance of a newly miniaturized acid-based predation-sensing acoustic transmitter (Innovasea V3D; 0.33 g in air). We conducted staged predation events in the laboratory where acoustically tagged rainbow trout (Oncorhynchus mykiss) were fed to largemouth bass (Micropterus nigricans) at 3.3-7.0, 9.0-10.8, 16.0-20.0, and 22.0-25.8°C. We also conducted false-positive tests where tagged rainbow trout were held at 10.0 and 16.8°C without the risk of predation. Predation events were successfully identified in 92% of the staged predation trials. Signal lag (i.e., the time required for a predation tag to indicate that predation occurred) ranged from 0.11 to 6.29 days and decreased strongly with increasing water temperature and increased with increasing body mass of the tagged prey. Tag retention in the gut of the predator was much more variable than signal lag and was influenced by water temperature and individual predators but not by prey mass. No false positives were detected after 60 days at either temperature (n = 27 individuals). Although the relationships between water temperature, signal lag, and retention time are likely species-specific, the data reported here provide useful information for the use of these transmitters to study predation in wild fishes, especially for temperate, freshwater fish.

How are Conversations via an On-Demand Peer-To-Peer Emotional Well-Being App Associated with Emotional Improvement?

Non-clinical, on-demand peer-to-peer (PtP) support apps have become increasingly popular over the past several years. Although not as pervasive as general self-help apps, these PtP support apps are usually free and instantly connect individuals through live texting with a non-clinical volunteer who has been minimally trained to listen and offer support. To date, there is little empirical work that examines whether and how using an on-demand PtP support app improves emotional well-being. Applying regression and multilevel models to N = 1000+ PtP conversations, this study examined whether individuals experience emotional improvement following a conversation on a PtP support app (HearMe) and whether dyadic characteristics of the conversation - specifically, verbal and emotional synchrony - are associated with individuals' emotional improvement. We found that individuals reported emotional improvement following a conversation on the PtP support app and that verbal (but not emotional) synchrony was associated with the extent of individuals' emotional improvement. Our results suggest that online PtP support apps are a viable source of help. We discuss cautions and considerations when applying our findings to enhance the delivery of support provision on PtP apps.

Thermal performance curves for aerobic scope and specific dynamic action in a sexually dimorphic piscivore: implications for a warming climate.

Digestion can make up a substantial proportion of animal energy budgets, yet our understanding of how it varies with sex, body mass, and ration size is limited. A warming climate may have consequences on animal growth and feeding dynamics that will differentially impact individuals in their ability to efficiently acquire and assimilate meals. Many species, such as walleye (Sander vitreus), exhibit sexual size dimorphism (SSD), whereby one sex is larger than the other, suggesting sex-differences in energy acquisition and/or expenditure. Here we present the first thorough estimates of specific dynamic action (SDA) in adult walleye using intermittent-flow respirometry. We fed male (n=14) and female (n=9) walleye two ration sizes; 2% and 4% of individual body weight, over a range of temperatures from 2 - 20°C. SDA was shorter in duration and reached higher peak rates of oxygen consumption with increasing temperatures. Peak SDA increased with ration size and decreased with body mass. The proportion of digestible energy lost to SDA (i.e., the SDA coefficient) was consistent at 6% and was unrelated to temperature, body mass, sex, or ration size. Our findings suggest that sex has a negligible role in shaping SDA, nor is SDA a contributor to SSD for this species. Standard and maximum metabolic rates were similar between sexes but maximum metabolic rate decreased drastically with body mass. Large fish, which are important for population growth due to reproductive hyperallometry, may therefore face a bioenergetic disadvantage and struggle most to perform optimally in future, warmer waters.

Thermal stressors during embryo incubation have limited ontogenic carryover effects in brook trout.

Winter climate is changing rapidly in northern latitudes, and these temperature events have effects on salmonid thermal biology. Stressors during winter egg incubation could reduce hatching success and physiological performance of fall-spawning fishes. Here we quantified the potential for ontogenic carryover effects from embryonic thermal stress in multiple wild and hatchery-origin populations of brook trout (Salvelinus fontinalis), a temperate ectotherm native to northeastern North America. Fertilized eggs from four populations were incubated over the winter in the laboratory in four differing thermal regimes: ambient stream-fed water, chronic warming (+2 °C), ambient with a mid-winter cold-shock, and short-term warming late during embryogenesis (to stimulate an early spring). We examined body size and upper thermal tolerance at the embryonic, fry (10 weeks post-hatch and 27-30 weeks post-hatch) and gravid adult (age 2+) life stages (overall N = 1482). In a separate experiment, we exposed developing embryos to acute seven-day heat stress events immediately following fertilization and at the eyed-egg stage, and then assessed upper thermal tolerance (CTmax) 37 weeks post-hatch. In all cases, fish were raised in common garden conditions after hatch (i.e., same temperatures). Our thermal treatments during incubation had effects that varied by life stage, with incubation temperature and life stage both affecting body size and thermal tolerance. Embryos incubated in warmer treatment groups had higher thermal tolerance; there was no effect of the mid-winter melt event on embryo CTmax. Ten weeks after hatch, fry from the ambient and cold-shock treatment groups had higher and less variable thermal tolerance than did the warmer treatment groups. At 27-30 post-hatch and beyond, differences in thermal tolerance among treatment groups were negligible. Collectively, our study suggests that brook trout only exhibit short-term carryover effects from thermal stressors during embryo incubation, with no lasting effects on phenotype beyond the first few months after hatch.

Estimation of sensitivity and specificity of bulk tank milk PCR and 2 antibody ELISA tests for herd-level diagnosis of Mycoplasma bovis infection using Bayesian latent class analysis.

Mycoplasmosis (due to infection with Mycoplasma bovis) is a serious disease of beef and dairy cattle that can adversely impact health, welfare and productivity (Maunsell et al. (2011)). Mycoplasmosis can lead to a range of often severe, clinical presentations. Mycoplasma bovis (M. bovis) infection can present either clinically or subclinically, with the potential for recrudescence of shedding in association with stressful periods. Infection can be maintained within herds because of intermittent shedding (Calcutt et al., 2018, Hazelton et al., 2018). M. bovis is recognized as poorly responsive to treatment which represents a major challenge for control in infected herds. Given this, particular focus is needed on biosecurity measures to prevent introduction into uninfected herds in the first place. A robust and reliable laboratory test for surveillance is important both for herd-level prevention and control. The objective of this study was to estimate the sensitivity and specificity of 3 diagnostic tests (one PCR and 2 ELISA tests) on bulk tank milk, for the herd-level detection of M. bovis using Bayesian latent class analysis. In autumn 2018, bulk tank milk samples from 11,807 herds, covering the majority of the main dairy regions in Ireland had been submitted to the Department of Agriculture testing laboratory for routine surveillance were made available. A stratified random sample approach was used to select a cohort of herds for testing from this larger sample set. A final study population of 728 herds had bulk tank milk samples analyzed using a Bio-X ELISA (ELISA 1), an IDvet ELISA (ELISA 2) and a PCR test. A Bayesian latent class analysis (BLCA) was conducted to estimate the sensitivity (Se) and specificity (Sp) of the 3 diagnostic tests applied to bulk tank milk (BTM) for the detection of the herd-level infection. An overall LCA was conducted on all herds within a single population (a 3-test, 1-population model). The herds were also split into 2 populations based on herd size (small herds had < 82 cattle) (a 3-test, 2-population model) and separately into 3 regions in Ireland (Leinster, Munster and Connacht/Ulster) (a 3-test, 3-population model). The latent variable of interest was the herd-level M. bovis infection status. In total, 363/728 (50%) were large herds, 7 (1.0%) were positive on PCR, 88 (12%) positive on ELISA 1, and 406 (56%) positive on ELISA 2. Based on the 2-population model, the sensitivity (95% Bayesian credible interval (BCI) was 0.03 (0.02, 0.05), 0.22 (0.18, 0.27), 0.94 (0.88, 0.98) for PCR, ELISA 1 and ELISA 2 respectively. The specificity (95% BCI) was 0.99 (0.99, 1.0), 0.97 (0.95, 0.99), and 0.92 (0.86, 0.97) for PCR, ELISA 1 and ELISA 2 respectively. The herd-level true prevalence was estimated at 0.43 (BCI 0.35, 0.5) for smaller herds. The true prevalence was estimated at 0.62 (BCI 0.55, 0.69) for larger herds. The true prevalence was estimated at 0.56 (BCI 0.49, 0.463) in the 1-population model. For the 3-population model, the sensitivity (95% BCI) was 0.03 (0.02, 0.05), 0.24 (0.18, 0.29), 0.95 (0.9, 0.98) for PCR, ELISA 1 and ELISA 2 respectively. The specificity (95% BCI) was 0.99 (0.99, 1.0), 0.98 (0.96, 0.99), and 0.88 (0.79, 0.95) for PCR, ELISA 1 and ELISA 2 respectively. The herd-level true prevalence (95% BCI) was estimated at 0.65 (0.56, 0.73), 0.38 (0.28, 0.46) and 0.53 (0.4, 0.65) for population 1, 2, 3 respectively. Across all 3 models, the range in true prevalence was 38% to 65% of Irish dairy herds infected with M. bovis. The operating characteristics vary substantially between tests. The IDvet ELISA had a relatively high Se (the highest Se of the 3 tests studied) but it was estimated at 0.95 at its highest in 3-test, 3-population model. This test may be an appropriate test for herd-level screening or prevalence estimation within the context of the endemically infected Irish dairy cattle population. Further work is required to optimize this test and its interpretation when applied at herd-level to offset concerns related to the lower than optimal test Sp.

Unsaturation in the air spaces of leaves and its implications.

Modern plant physiological theory stipulates that the resistance to water movement from plants to the atmosphere is overwhelmingly dominated by stomata. This conception necessitates a corollary assumption-that the air spaces in leaves must be nearly saturated with water vapour; that is, with a relative humidity that does not decline materially below unity. As this idea became progressively engrained in scientific discourse and textbooks over the last century, observations inconsistent with this corollary assumption were occasionally reported. Yet, evidence of unsaturation gained little traction, with acceptance of the prevailing framework motivated by three considerations: (1) leaf water potentials measured by either thermocouple psychrometry or the Scholander pressure chamber are largely consistent with the framework; (2) being able to assume near saturation of intercellular air spaces was transformational to leaf gas exchange analysis; and (3) there has been no obvious mechanism to explain a variable, liquid-phase resistance in the leaf mesophyll. Here, we review the evidence that refutes the assumption of universal, near saturation of air spaces in leaves. Refining the prevailing paradigm with respect to this assumption provides opportunities for identifying and developing mechanisms for increased plant productivity in the face of increasing evaporative demand imposed by global climate change.

Udder health outcomes in Irish herds participating in cellcheck dry cow consults.

The CellCheck Dry Cow Consult (DCC) was developed by the CellCheck Technical Working Group to enable farmers to engage with their nominated vet to develop farm-specific selective dry cow therapy (SDCT) plans, where appropriate. This study evaluated the effect of the DCC on farmer decision-making around dry cow therapy, and the udder health impact of implementing SDCT, in study herds over the 2019 and 2020 dry periods. The DCC was a 3-h consult, delivered and funded as part of the Targeted Advisory Service on Animal Health (TASAH). Herds that completed a DCC were invited to register for a Dry Cow Review the following year. The combined data set for analysis across both years comprised of 439 herds and 25,357 cows. Available herd size ranged from 25 to 800. The median SCC of cows dried off with teat sealant only was 47,000 cells/ml before drying off in 2019 and 48,000 cells/ml at first milk recording in 2020, and 43,000 cells/ml before drying off in 2020 and 39,000 cells/ml at first milking recording in 2021. Following both the 2019 and 2020 dry periods, cows tended to converge toward a similar median SCC early in the following lactation, irrespective of prior dry cow treatment strategy. The uptake of SDCT was greater in Review herds, with 21% of cows receiving teat sealant only in 2020, compared with 16.3% of cows in herds participating in a Consult for the first time in 2020. At an individual cow level, in both years dry period new infection rate (NIR) was approximately 2.7% higher for cows treated with teat sealant only, than for those treated with both dry cow antibiotic tubes and teat sealant, and 1.2% higher than cows treated with antibiotic only. Regardless of treatment, there was a significant association between increasing parity and the risk of a dry period new infection. Increasing herd size had a statistically significant effect on the risk of dry period new infection rates. At a herd level, there was no statistically significant increase in NIR when SDCT was used compared with herds where blanket dry cow therapy was used. While not without risk, SDCT can be successfully implemented in Irish herds; however, constant attention to hygiene and management is essential. Though there are challenges to face, facilitating continued farmer education and engagement with professional guidance will be important.

Social determinants of health inequalities in early phase clinical trials in Northern England.

BACKGROUND: Early phase clinical trials in Oncology represent a subspecialised area where UK patient selection is influenced by access to Experimental Cancer Medicine Centres (ECMCs). Equity of access with respect to social determinants of health (SDoH) were explored for two major ECMCs. METHODS: A retrospective cohort study including all referrals to Newcastle and Manchester ECMCs in 2021 was completed. Consent to screening or pre-screening was stratified against SDoH characteristics, including: Index of Multiple Deprivation (IMD) decile, ethnicity and distance to centre. RESULTS: 1243 patients were referred for trials. IMD quintile 1 (most deprived) patients had reduced likelihood of referral compared to expected population models (OR, 0.67; 95% CI: 0.55 to 0.80, p = <0.0001). IMD quintile 5 (least deprived) had increased likelihood of referral (OR, 1.46; 95% CI: 1.17 to 1.82, p = 0.0007). Living beyond median distance from Manchester reduced the likelihood of consenting to trials (OR, 0.72; 95% CI: 0.55 to 0.94, p = 0.015). Ethnicity data represented a White British propensity. CONCLUSIONS: Inequalities in socioeconomic and geographic factors influence referral and enrolment to early phase clinical trials in Northern England. This has implications for equity of access and generalisability of trial results internationally and warrants further study.

N-of-1 Trial of Angina Verification Before Percutaneous Coronary Intervention.

BACKGROUND: In stable coronary artery disease, 30% to 60% of patients remain symptomatic despite successful revascularization. Perhaps not all symptoms reported by a patient with myocardial ischemia are, in fact, angina. OBJECTIVES: This study sought to determine whether independent symptom verification using a placebo-controlled ischemic stimulus could distinguish which patients achieve greatest symptom relief from percutaneous coronary intervention (PCI). METHODS: ORBITA-STAR was a multicenter, n-of-1, placebo-controlled study in patients undergoing single-vessel PCI for stable symptoms. Participants underwent 4 episodes (60 seconds each) of low-pressure balloon occlusion across their coronary stenosis, randomly paired with 4 episodes of placebo inflation. Following each episode, patients reported the similarity of the induced symptom in comparison with their usual symptom. The similarity score ranged from -10 (placebo replicated the symptom more than balloon occlusion) to +10 (balloon occlusion exactly replicated the symptom). The primary endpoint was the ability of the similarity score to predict symptom relief with PCI. RESULTS: Fifty-one patients were recruited, aged 62.9 ± 8.6 years. The median fractional flow reserve was 0.68 (Q1-Q3: 0.57-0.79), and the instantaneous wave-free ratio was 0.80 (Q1-Q3: 0.48-0.89). The median similarity score was 3 (Q1-Q3: 0.875-5.25). The similarity score was a strong predictor of symptom improvement following PCI: a patient with an upper quartile similarity score of 5.25 was significantly more likely to have lower angina frequency at follow-up (OR: 8.01; 95% credible interval: 2.39-15.86) than a patient with a lower quartile similarity score of 0.875 (OR: 1.31; 95% credible interval: 0.71-1.99), Pr(difference) >99.9%. CONCLUSIONS: Similarity score powerfully predicted symptom improvement from PCI. These data lay the foundation for independent symptom mapping to target PCI to those patients most likely to benefit. (Systematic Trial of Angina Assessment Before Revascularization [ORBITA-STAR]; NCT04280575).

Strong habitat and seasonal phenology effects on the evolution of self-compatibility, clonality and pollinator shifts in Lachenalia (Asparagaceae: Scilloideae).

Plants employ a diversity of reproductive safeguarding strategies to circumvent the challenge of pollen limitation. Focusing on southern African Lachenalia (Asparagaceae: Scilloideae), we test the hypothesis that the evolution of reproductive safeguarding traits (self-compatibility, autonomous selfing, bird pollination and clonal propagation) is favoured in species occupying conditions of low insect abundance imposed by critically infertile fynbos heathland vegetation and by flowering outside the austral spring insect abundance peak. We trace the evolution of these traits and selective regimes on a dated, multi-locus phylogeny of Lachenalia and assess their evolutionary associations using ordinary and phylogenetic regression. Ancestral state reconstructions identify an association with non-fynbos vegetation and spring flowering as ancestral in Lachenalia, the transition to fynbos vegetation and non-spring flowering taking place multiple times. They also show that self-compatibility, autofertility, bird pollination and production of multiple clonal offsets have evolved repeatedly. Regression models suggest that bird pollination and self-compatibility are selected for in fynbos and in non-spring flowering lineages, with autofertility being positively associated with non-spring flowering. These patterns support the interpretation of these traits as reproductive safeguarding adaptations under reduced insect pollinator abundance. We find no evidence to support the interpretation of clonal propagation as a reproductive safeguarding strategy.

Interplay between Mg2+ and Ca2+ at multiple sites of the ryanodine receptor.

RyR1 is an intracellular Ca2+ channel important in excitable cells such as neurons and muscle fibers. Ca2+ activates it at low concentrations and inhibits it at high concentrations. Mg2+ is the main physiological RyR1 inhibitor, an effect that is overridden upon activation. Despite the significance of Mg2+-mediated inhibition, the molecular-level mechanisms remain unclear. In this work we determined two cryo-EM structures of RyR1 with Mg2+ up to 2.8 Å resolution, identifying multiple Mg2+ binding sites. Mg2+ inhibits at the known Ca2+ activating site and we propose that the EF hand domain is an inhibitory divalent cation sensor. Both divalent cations bind to ATP within a crevice, contributing to the precise transmission of allosteric changes within the enormous channel protein. Notably, Mg2+ inhibits RyR1 by interacting with the gating helices as validated by molecular dynamics. This structural insight enhances our understanding of how Mg2+ inhibition is overcome during excitation.

Estimating maximum oxygen uptake of fishes during swimming and following exhaustive chase - different results, biological bases and applications.

The maximum rate at which animals take up oxygen from their environment (MO2,max) is a crucial aspect of their physiology and ecology. In fishes, MO2,max is commonly quantified by measuring oxygen uptake either during incremental swimming tests or during recovery from an exhaustive chase. In this Commentary, we compile recent studies that apply both techniques to the same fish and show that the two methods typically yield different mean estimates of MO2,max for a group of individuals. Furthermore, within a group of fish, estimates of MO2,max determined during swimming are poorly correlated with estimates determined during recovery from chasing (i.e. an individual's MO2,max is not repeatable across methods). One explanation for the lack of agreement is that these methods measure different physiological states, each with their own behavioural, anatomical and biochemical determinants. We propose that these methods are not directly interchangeable but, rather, each is suited to address different questions in fish biology. We suggest that researchers select the method that reflects the biological contexts of their study, and we advocate for the use of accurate terminology that acknowledges the technique used to elevate MO2 (e.g. peak MO2,swim or peak MO2,recovery). If the study's objective is to estimate the 'true' MO2,max of an individual or species, we recommend that pilot studies compare methods, preferably using repeated-measures designs. We hope that these recommendations contribute new insights into the causes and consequences of variation in MO2,max within and among fish species.

Recognising the importance and impact of Imaging Scientists: Global guidelines for establishing career paths within core facilities.

In the dynamic landscape of scientific research, imaging core facilities are vital hubs propelling collaboration and innovation at the technology development and dissemination frontier. Here, we present a collaborative effort led by Global BioImaging (GBI), introducing international recommendations geared towards elevating the careers of Imaging Scientists in core facilities. Despite the critical role of Imaging Scientists in modern research ecosystems, challenges persist in recognising their value, aligning performance metrics and providing avenues for career progression and job security. The challenges encompass a mismatch between classic academic career paths and service-oriented roles, resulting in a lack of understanding regarding the value and impact of Imaging Scientists and core facilities and how to evaluate them properly. They further include challenges around sustainability, dedicated training opportunities and the recruitment and retention of talent. Structured across these interrelated sections, the recommendations within this publication aim to propose globally applicable solutions to navigate these challenges. These recommendations apply equally to colleagues working in other core facilities and research institutions through which access to technologies is facilitated and supported. This publication emphasises the pivotal role of Imaging Scientists in advancing research programs and presents a blueprint for fostering their career progression within institutions all around the world.

Coronary sinus reducer for the treatment of refractory angina (ORBITA-COSMIC): a randomised, placebo-controlled trial.

BACKGROUND: The coronary sinus reducer (CSR) is proposed to reduce angina in patients with stable coronary artery disease by improving myocardial perfusion. We aimed to measure its efficacy, compared with placebo, on myocardial ischaemia reduction and symptom improvement. METHODS: ORBITA-COSMIC was a double-blind, randomised, placebo-controlled trial conducted at six UK hospitals. Patients aged 18 years or older with angina, stable coronary artery disease, ischaemia, and no further options for treatment were eligible. All patients completed a quantitative adenosine-stress perfusion cardiac magnetic resonance scan, symptom and quality-of-life questionnaires, and a treadmill exercise test before entering a 2-week symptom assessment phase, in which patients reported their angina symptoms using a smartphone application (ORBITA-app). Patients were randomly assigned (1:1) to receive either CSR or placebo. Both participants and investigators were masked to study assignment. After the CSR implantation or placebo procedure, patients entered a 6-month blinded follow-up phase in which they reported their daily symptoms in the ORBITA-app. At 6 months, all assessments were repeated. The primary outcome was myocardial blood flow in segments designated ischaemic at enrolment during the adenosine-stress perfusion cardiac magnetic resonance scan. The primary symptom outcome was the number of daily angina episodes. Analysis was done by intention-to-treat and followed Bayesian methodology. The study is registered with ClinicalTrials.gov, NCT04892537, and completed. FINDINGS: Between May 26, 2021, and June 28, 2023, 61 patients were enrolled, of whom 51 (44 [86%] male; seven [14%] female) were randomly assigned to either the CSR group (n=25) or the placebo group (n=26). Of these, 50 patients were included in the intention-to-treat analysis (24 in the CSR group and 26 in the placebo group). 454 (57%) of 800 imaged cardiac segments were ischaemic at enrolment, with a median stress myocardial blood flow of 1·08 mL/min per g (IQR 0·77-1·41). Myocardial blood flow in ischaemic segments did not improve with CSR compared with placebo (difference 0·06 mL/min per g [95% CrI -0·09 to 0·20]; Pr(Benefit)=78·8%). The number of daily angina episodes was reduced with CSR compared with placebo (OR 1·40 [95% CrI 1·08 to 1·83]; Pr(Benefit)=99·4%). There were two CSR embolisation events in the CSR group, and no acute coronary syndrome events or deaths in either group. INTERPRETATION: ORBITA-COSMIC found no evidence that the CSR improved transmural myocardial perfusion, but the CSR did improve angina compared with placebo. These findings provide evidence for the use of CSR as a further antianginal option for patients with stable coronary artery disease. FUNDING: Medical Research Council, Imperial College Healthcare Charity, National Institute for Health and Care Research Imperial Biomedical Research Centre, St Mary's Coronary Flow Trust, British Heart Foundation.

Using Carbon Stable Isotopes to Study C3 and C4 Photosynthesis: Models and Calculations.

Stable carbon isotopes are a powerful tool to study photosynthesis. Initial applications consisted of determining isotope ratios of plant biomass using mass spectrometry. Subsequently, theoretical models relating C isotope values to gas exchange characteristics were introduced and tested against instantaneous online measurements of 13C photosynthetic discrimination. Beginning in the twenty-first century, laser absorption spectroscopes with sufficient precision for determining isotope mixing ratios became commercially available. This has allowed collection of large data sets at lower cost and with unprecedented temporal resolution. More data and accompanying knowledge have permitted refinement of 13C discrimination model equations, but often at the expense of increased model complexity and difficult parametrization. This chapter describes instantaneous online measurements of 13C photosynthetic discrimination, provides recommendations for experimental setup, and presents a thorough compilation of equations available to researchers. We update our previous 2018 version of this chapter by including recently improved descriptions of (photo)respiratory processes and associated fractionations. We discuss the capabilities and limitations of the diverse 13C discrimination model equations and provide guidance for selecting the model complexity needed for different applications.

Learning algorithms for identification of whisky using portable Raman spectroscopy.

Reliable identification of high-value products such as whisky is vital due to rising issues of brand substitution and quality control in the industry. We have developed a novel framework that can perform whisky analysis directly from raw spectral data with no human intervention by integrating machine learning models with a portable Raman device. We demonstrate that machine learning models can achieve over 99% accuracy in brand or product identification across twenty-eight commercial samples. To demonstrate the flexibility of this approach, we utilized the same algorithms to quantify ethanol concentrations, as well as measuring methanol levels in spiked whisky samples. To demonstrate the potential use of these algorithms in a real-world environment we tested our algorithms on spectral measurements performed through the original whisky bottle. Through the bottle measurements are facilitated by a beam geometry hitherto not applied to whisky brand identification in conjunction with machine learning. Removing the need for decanting greatly enhances the practicality and commercial potential of this technique, enabling its use in detecting counterfeit or adulterated spirits and other high-value liquids. The techniques established in this paper aim to function as a rapid and non-destructive initial screening mechanism for detecting falsified and tampered spirits, complementing more comprehensive and stringent analytical methods.

Irgm proteins attenuate inflammatory disease in mouse models of genital Chlamydia infection.

Chlamydiae are obligate intracellular bacterial pathogens that may cause genital pathology via induction of destructive host immune responses. Human-adapted Chlamydia trachomatis causes inflammatory disease in human hosts but is easily cleared in mice, and mouse-adapted Chlamydia muridarum establishes a productive and pathogenic infection in murine hosts. While numerous anti-chlamydial host resistance factors have been discovered in mice and humans alike, little is known about host factors promoting host fitness independent of host resistance. Here, we show that interferon-inducible immunity-related GTPase M (Irgm) proteins function as such host factors ameliorating infection-associated sequalae in the murine female genital tract, thus characterizing Irgm proteins as mediators of disease tolerance. Specifically, we demonstrate that mice deficient for all three murine Irgm paralogs (pan-Irgm-/-) are defective for cell-autonomous immunity to C. trachomatis, which correlates with an early and transient increase in bacterial burden and sustained hyperinflammation in vivo. In contrast, upon infection of pan-Irgm-/- mice with C. muridarum, bacterial burden is unaffected, yet genital inflammation and scarring pathology are nonetheless increased, demonstrating that Irgm proteins can promote host fitness without altering bacterial burden. Additionally, pan-Irgm-/- mice display increased granulomatous inflammation in genital Chlamydia infection, implicating Irgm proteins in the regulation of granuloma formation and maintenance. These findings demonstrate that Irgm proteins regulate pathogenic immune responses to Chlamydia infection in vivo, establishing an effective infection model to examine the immunoregulatory functions and mechanisms of Irgm proteins. IMPORTANCE: In response to genital Chlamydia infection, the immune system mounts a proinflammatory response to resist the pathogen, yet inflammation must be tightly controlled to avoid collateral damage and scarring to host genital tissue. Variation in the human IRGM gene is associated with susceptibility to autoinflammatory diseases but its role in ameliorating inflammatory diseases caused by infections is poorly defined. Here, we use mice deficient for all three murine Irgm paralogs to demonstrate that Irgm proteins not only provide host resistance to Chlamydia infections but also limit associated inflammation in the female genital tract. In particular, we find that murine Irgm expression prevents granulomatous inflammation, which parallels inflammatory diseases associated with variants in human IRGM. Our findings therefore establish genital Chlamydia infection as a useful model to study the roles for Irgm proteins in both promoting protective immunity and limiting pathogenic inflammation.

Intratumoral T-cell receptor repertoire composition predicts overall survival in patients with pancreatic ductal adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy that is refractory to immune checkpoint inhibitor therapy. However, intratumoral T-cell infiltration correlates with improved overall survival (OS). Herein, we characterized the diversity and antigen specificity of the PDAC T-cell receptor (TCR) repertoire to identify novel immune-relevant biomarkers. Demographic, clinical, and TCR-beta sequencing data were collated from 353 patients across three cohorts that underwent surgical resection for PDAC. TCR diversity was calculated using Shannon Wiener index, Inverse Simpson index, and "True entropy." Patients were clustered by shared repertoire specificity. TCRs predictive of OS were identified and their associated transcriptional states were characterized by single-cell RNAseq. In multivariate Cox regression models controlling for relevant covariates, high intratumoral TCR diversity predicted OS across multiple cohorts. Conversely, in peripheral blood, high abundance of T-cells, but not high diversity, predicted OS. Clustering patients based on TCR specificity revealed a subset of TCRs that predicts OS. Interestingly, these TCR sequences were more likely to encode CD8+ effector memory and CD4+ T-regulatory (Tregs) T-cells, all with the capacity to recognize beta islet-derived autoantigens. As opposed to T-cell abundance, intratumoral TCR diversity was predictive of OS in multiple PDAC cohorts, and a subset of TCRs enriched in high-diversity patients independently correlated with OS. These findings emphasize the importance of evaluating peripheral and intratumoral TCR repertoires as distinct and relevant biomarkers in PDAC.