Genome-wide surveillance of transcription errors in response to genotoxic stress.

Mutagenic compounds are a potent source of human disease. By inducing genetic instability, they can accelerate the evolution of human cancers or lead to the development of genetically inherited diseases. Here, we show that in addition to genetic mutations, mutagens are also a powerful source of transcription errors. These errors arise in dividing and nondividing cells alike, affect every class of transcripts inside cells, and, in certain cases, greatly exceed the number of mutations that arise in the genome. In addition, we reveal the kinetics of transcription errors in response to mutagen exposure and find that DNA repair is required to mitigate transcriptional mutagenesis after exposure. Together, these observations have far-reaching consequences for our understanding of mutagenesis in human aging and disease, and suggest that the impact of DNA damage on human physiology has been greatly underestimated.

A metagenomic-based study of two sites from the Barbadian reef system.

We study the microbiome of sea water collected from two locations of the Barbadian coral reefs. The two sites differ in several environmental and ecological variables including their endogenous benthic community and their proximity to urban development and runoffs from inland watersheds. The composition of the microbial communities was estimated using whole genome DNA shotgun sequencing with adjuvant measurements of chemical and environmental qualities. Although both sites exhibit a similar degree of richness, the less urbanized site (Maycocks reef at Hangman's Bay) has a strong concentration of phototrophs whereas the more urbanized location (Bellairs reef at Folkstone) is enriched for copiotrophs, macroalgal symbionts and marine-related disease-bearing organisms from taxa scattered across the tree of life. Our results are concordant with previous profiles of warm ocean surface waters, suggesting our approach captures the state of each coral reef site, setting the stage for longitudinal studies of marine microbiome dynamics in Barbados. Supplementary Information: The online version contains supplementary material available at 10.1007/s00338-022-02330-y.

Loneliness in young people: a multilevel exploration of social ecological influences and geographic variation.

BACKGROUND: Loneliness is a growing public health concern, yet little is known about loneliness in young people. The current study aimed to identify social ecological factors related to loneliness and examine the extent to which geographic region may account for differences in loneliness. METHODS: The data come from a cross-sectional sample of 6503 young people living in the UK. Loneliness was measured using the UCLA 3-item scale. Bivariate analyses were used to test associations between each predictor and loneliness. Multilevel models were used to identify key social ecological factors related to loneliness, and the extent to which loneliness may vary across geographic regions (local authority districts). RESULTS: Sociodemographic, social, health and well-being, and community factors were found to be associated with loneliness. Geographic region was associated with 5-8% of the variation in loneliness. The effect of gender, sexual orientation and minority ethnic background on loneliness differed across regions. CONCLUSIONS: This is the first study to highlight modifiable social and community factors related to youth loneliness, and individual vulnerabilities, such as poor mental well-being. Results related to geographic differences suggest that local-level initiatives may be most appropriate in tackling loneliness, rather than wider, less contextualized national efforts.

Costarting sitagliptin with metformin is associated with a lower likelihood of disease progression in newly treated people with type 2 diabetes: a cohort study.

AIM: To examine whether early addition of sitagliptin to metformin is associated with a delay in type 2 diabetes progression. METHODS: Administrative health records from Alberta, Canada, for the period April 2008 to March 2015, were used to conduct a retrospective cohort study in new metformin users. People who started sitagliptin on the same day they initiated metformin therapy were compared with those who added sitagliptin later. Insulin initiation served as a surrogate marker for diabetes progression, and multivariable logistic regression models were used to evaluate the association with sitagliptin addition (costart vs later use). A mixed-effects linear regression model was used to examine the effect of timing of sitagliptin addition on HbA1c change over 1 year. RESULTS: The mean (sd) age of the 8764 people who used sitagliptin was 52.1 (11.1) years, 5665 (64.6%) were men, and 1153 (13.2%) started sitagliptin on the same day as metformin. Insulin was added to the therapy of 173 (15.0%) costarters and 1453 (19.1%) later sitagliptin users. The adjusted odds ratio for adding insulin was 0.76 (95% CI 0.64 to 0.90) in favour of costarting sitagliptin. HbA1c levels decreased in both groups 1 year after starting sitagliptin, with costarters having a significantly greater reduction [absolute between-group difference of 0.5% (95% CI 0.3 to 0.7)] compared with later sitagliptin users. CONCLUSION: Costarting drug therapy with sitagliptin and metformin was associated with a lower likelihood of disease progression in people with type 2 diabetes compared with adding sitagliptin later.

Condition-dependent responses of fish to motorboats.

Anthropogenic noise is a pollutant of global concern that has been shown to have a wide range of detrimental effects on multiple taxa. However, most noise studies to-date consider only overall population means, ignoring the potential for intraspecific variation in responses. Here, we used field experiments on Australia's Great Barrier Reef to assess condition-dependent responses of blue-green damselfish (Chromis viridis) to real motorboats. Despite finding no effect of motorboats on a physiological measure (opercular beat rate; OBR), we found a condition-dependent effect on anti-predator behaviour. In ambient conditions, startle responses to a looming stimulus were equivalent for relatively poor- and good-condition fish, but when motorboats were passing, poorer-condition fish startled at significantly shorter distances to the looming stimulus than better-condition fish. This greater susceptibility to motorboats in poorer-condition fish may be the result of generally more elevated stress levels, as poorer-condition fish had a higher pre-testing OBR than those in better condition. Considering intraspecific variation in responses is important to avoid misrepresenting potential effects of anthropogenic noise and to ensure the best management and mitigation of this pervasive pollutant.

Hall technique: is it superior in success and savings to conventional restorations?

Design A cost-effectiveness analysis of caries management in primary molars using Hall technique (HT) versus conventional restoration (CR) from a pre-existing dataset from a randomised split-mouth trial, within primary care in Scotland, with a five-year follow-up.Case selection Computer-generated block randomisation was used to match asymptomatic primary molars of 3-10-year-old children recruited from primary care, to either HT or CR arms.Economic evaluation A cost-effectiveness analysis was undertaken. A five-year horizon was chosen. A societal perspective was adopted. Estimation of direct, indirect and opportunity costs were presented. Costs were discounted at 1.5%. Molar survival was chosen as the effectiveness measure.Data analysis Statistical significance of primary outcome (survival) was examined using the log-rank test. Bootstrapping produced a sampling distribution of mean cost and effectiveness with a 95% confidence interval around a mean value. An incremental cost-effectiveness ratio (ICER) was provided.Results HT molars had superior survival of 99% (95% CI: 98-100%) compared to CR at 92% (95% CI: 87-97%). Initials costs indicated HT to be more expensive than CR; however, direct costs, including retreatments, were cheaper for HT when using both NHS Scotland and NHS England cost data. Indirect/opportunity costs, including time and travel of parents, were significantly less for HT. Total cumulative costs were significantly lower in HT (32 GBP; 95% CI: 31-34) than CR (49 GBP; 34-69). HT dominated CR, being less costly and more effective with a mean ICER of 2.38 GBP spent additionally while losing 1% of molar survival with CR over HT.Conclusions HT molars are cost-effective, compared to CR, when managing asymptomatic carious primary molars after five years' follow-up.

Patient-reported outcomes are worse for progressive-onset multiple sclerosis than relapse-onset multiple sclerosis, particularly early in the disease process.

BACKGROUND AND PURPOSE: Treatments for progressive-onset multiple sclerosis (MS) are lacking. To improve the disease management for progressive-onset MS, the differences between relapse-onset MS and progressive-onset MS in patient-reported disability, progression and symptoms were examined. METHODS: A total of 1985 participants of the Australian Multiple Sclerosis Longitudinal Study were included. Associations between onset type and outcomes were assessed with negative binomial regression. RESULTS: The severity of 17 of the 19 outcomes was significantly higher for progressive-onset MS patients than relapse-onset MS patients, including perspectives from disability, progression over the last year, fatigue, sensory, walking difficulties, pain, balance, spasticity, sexual dysfunction, bladder, bowel, anxiety, depression and the European quality of life (EQ-5D) (P < 0.05; adjusted mean ratio ranged from 1.11 to 1.52). The differences between the two onset types were most pronounced early in the disease process and reduced with increasing MS duration, and the interaction was significant for disability, progression over the last year, walking difficulties, bladder problems, bowel problems and spasticity. CONCLUSION: Participants with progressive-onset MS were significantly worse off on nearly all patient-reported outcomes than relapse-onset MS participants, and the differences were most pronounced early in the disease course, highlighting the importance of early intervention for those with progressive-onset MS.

Self-reported cognitive function in a large international cohort of people with multiple sclerosis: associations with lifestyle and other factors.

BACKGROUND AND PURPOSE: We aimed to estimate the prevalence of perceived cognitive impairment (PCI) and explore its associations with lifestyle and disease characteristics in a large international cohort of people with multiple sclerosis (MS). METHODS: This study was a cross-sectional analysis. Participants rated their cognitive function over the preceding 4 weeks using four questions in a subscale within the Multiple Sclerosis Quality of Life questionnaire (MSQOL-54). These questions assessed perceived concentration, attention and memory by the patient and family/friends. Four definitions of PCI were derived, ranging from lowest to highest specificity. Associations with PCI were assessed by log-binomial regression. RESULTS: The prevalence of PCI in our sample ranged from 41.0% (95% confidence interval, 39.0-43.0) using the least-specific definition to 11.6% (95% confidence interval, 10.3-12.9) using the most specific definition. A number of factors were associated with PCI, increasing in magnitude as the definition specificity increased, including positive associations for smoking and body mass index, whereas physical activity, dietary quality and use of vitamin D/omega-3 supplements were inversely associated with PCI. CONCLUSIONS: Our study reports associations between healthy lifestyle behaviours and PCI in people with MS. Although reverse causality is a potential explanation for our findings, previous studies have shown comparable associations with healthy lifestyle and MS onset and progression. Subject to external validation, these results suggest benefits realized from a healthy lifestyle in people with MS.

Interactive effects of music tempi and intensities on grip strength and subjective affect.

Pretask music is widely used by athletes albeit there is scant empirical evidence to support its use. The present study extended a line of work into pretask music by examining the interactive effects of music tempo and intensity (volume) on the performance of a simple motor skill and subjective affect. A 2 × 2 within-subjects factorial design was employed with an additional no-music control, the scores from which were used as a covariate. A sample of 52 male athletes (Mage  = 26.1 ± 4.8 years) was exposed to five conditions: fast/loud (126 bpm/80 dBA), fast/quiet (126 bpm/70 dBA), slow/loud (87 bpm/80 dBA), slow/quiet (87 bpm/70 dBA) music, and a no-music control. Dependent variables were grip strength, measured with a handgrip dynamometer, and subjective affect, assessed by use of the Affect Grid. The tempo and intensity components of music had interactive effects for grip strength but only main effects for subjective affect. Fast-tempo music played at a high intensity yielded the highest grip strength, while fast-tempo music played at a low-intensity resulted in much lower grip strength (Mdiff.  = -1.11 Force kg). For affective valence, there were main effects of tempo and intensity, with fast and loud music yielding the highest scores. For affective arousal, there was no difference between tempi although there was between intensities, with the high-intensity condition yielding higher scores. The present findings indicate the utility of fast/loud pretask music in enhancing affective valence and arousal in preparation for a simple or gross motor task.

Fishes in a changing world: learning from the past to promote sustainability of fish populations.

Populations of fishes provide valuable services for billions of people, but face diverse and interacting threats that jeopardize their sustainability. Human population growth and intensifying resource use for food, water, energy and goods are compromising fish populations through a variety of mechanisms, including overfishing, habitat degradation and declines in water quality. The important challenges raised by these issues have been recognized and have led to considerable advances over past decades in managing and mitigating threats to fishes worldwide. In this review, we identify the major threats faced by fish populations alongside recent advances that are helping to address these issues. There are very significant efforts worldwide directed towards ensuring a sustainable future for the world's fishes and fisheries and those who rely on them. Although considerable challenges remain, by drawing attention to successful mitigation of threats to fish and fisheries we hope to provide the encouragement and direction that will allow these challenges to be overcome in the future.

Measuring the benefits of using market based approaches to provide water and sanitation in humanitarian contexts.

The use of cash transfers and market based programming (CT/MBP) to increase the efficiency and effectiveness of emergency responses is gaining prominence in the humanitarian sector. However, there is a lack of existing indicators and methodologies to monitor activities designed to strengthen water and sanitation (WaSH) markets. Gender and vulnerability markers to measure the impact of such activities on different stakeholders is also missing. This study identifies parameters to monitor, evaluate and determine the added value of utilising CT/MBP to achieve WaSH objectives in humanitarian response. The results of the work revealed that CT/MBP can be used to support household, community and market level interventions to effectively reduce transmission of faeco-oral diseases. Efficiency, effectiveness, sustainability, appropriateness and equity were identified as useful parameters which correlated to widely accepted frameworks against which to evaluate humanitarian action. The parameters were found to be directly applicable to the case of increasing demand and supply of point of use water treatment technology for a) disaster resilience activities, and b) post-crisis response. The need for peer review of the parameters and indicators and pilot measurement in humanitarian contexts was recognised.

Dietary restriction increases variability in longevity.

Nutritional environments, particularly those experienced during early life, are hypothesized to affect longevity. A recent cross-taxa meta-analysis found that, depending upon circumstance, average longevity may be increased or decreased by early-life dietary restriction. Unstudied are the effects of diet during development on among-individual variance in longevity. Here, we address this issue using emerging methods for meta-analysis of variance. We found that, in general, standard deviation (s.d.) in longevity is around 8% higher under early-life dietary restriction than a standard diet. The effects became especially profound when dietary insults were experienced prenatally (s.d. increased by 29%) and/or extended into adulthood (s.d. increased by 36.6%). Early-life dietary restriction may generate variance in longevity as a result of increased variance in resource acquisition or allocation, but the mechanisms underlying these largely overlooked patterns clearly warrant elucidation.

Effect of system of lamb rearing and season on early post-partum fertility of ewes and growth performance of lambs in Katahdin sheep.

The effect of season (S), lamb rearing system (RT) and grain supplementation (GS) on post-partum fertility in Katahdin ewes and growth in Katahdin lambs was evaluated. Katahdin ewes were bred to lamb in fall (n = 36) or spring (n = 56) and at approximately 2.5 months post-partum were randomly assigned to be permanently separated or to continue to suckle their lambs for an additional 3 months. All ewes were joined with rams following treatment to synchronize oestrus. Weaned (W, n = 84) and continuously suckled lambs (CSK, n = 88) were fed forage only (n = 84; hay and pasture for fall- and spring-born lambs respectively) or were supplemented (n = 88; 18% crude protein ration ad libitum) and all weighed biweekly. Ewes rebred in the fall had a shorter ram introduction to lambing interval (p < 0.05), higher prolificacy (p = 0.001) and higher lambing rates (p = 0.02); however, the proportion of ewes lambing was not affected by season. The first service lambing rate was lower in ewes continuously suckling lambs in the spring, but not in the fall breeding season (S × RT, p = 0.03). Lambs that continuously suckled their dams and were supplemented grew quicker and gained more (p < 0.001) than their weaned and unsupplemented counterparts. The effect of CSK on growth rate of lambs was greater in the spring (RT × S; p = 0.05), and the effect of supplementation on growth rate of lambs was greater in the fall (GS × S; p < 0.0001). In conclusion, Katahdin lambs achieved higher weight gains from continuous suckling and grain supplementation. Moreover, Katahdin ewes are capable of early rebreeding post-partum while suckling their lambs, which makes them suited for use in accelerated lambing programmes.

Alternative migratory locust phenotypes are associated with differences in the expression of genes encoding the methylation machinery.

Despite the importance of locust density-dependent polyphenism as a model system for understanding phenotypic plasticity, there is still much to be learnt about its underlying molecular control. Here we describe the first investigation into the expression of genes encoding the DNA methylation machinery in the migratory locust (Locusta migratoria). We show that the alternative solitarious and gregarious phenotypic states induced by different locust rearing densities are associated with significant differences in the expression of the target genes DNA methyltransferase 1, DNA methyltransferase 2 and methyl-CpG-binding domain protein 2/3. This variation was most pronounced in the embryos of solitarious vs. gregarious mothers. We mapped the embryonic methylation profiles of several intragenic regions and a Long Interspersed Nuclear Element (LINE), each of which is known to be differentially expressed between alternative locust phenotypes or has been directly implicated in phase change. LmI and three genes, adenyl cyclase-associated binding protein 2, choline kinase alpha-like and henna, were methylated. Our results set the stage for future studies investigating the specific role of DNA methylation in the maternal transfer of migratory locust phase polyphenism.

Risk of new-onset heart failure in patients using sitagliptin: a population-based cohort study.

AIMS: To examine whether patients using sitagliptin at the time of an acute coronary syndrome event are at increased risk of incident heart failure compared with those not exposed. METHODS: Using US claims data, people with diabetes without a history of heart failure in the 3 years before hospitalization for acute coronary syndrome were identified for the period 2004 to 2010. We used a nested case-control design, whereby cases were patients who developed incident heart failure <30 days after admission to hospital for acute coronary syndrome and were matched by age and sex with up to 10 controls with no heart failure. Subjects exposed or not exposed to sitagliptin in the 90 days before acute coronary syndrome admission were compared using conditional logistic regression after adjustment for clinical and laboratory data, healthcare utilization and propensity scores. RESULTS: In total, 457 cases of heart failure developing de novo after diagnosis of acute coronary syndrome were matched to 4570 controls. The average age of the subjects was 55 years and 65% were male. Overall, 11 of 147 (7%) people exposed to sitagliptin developed heart failure compared with 446 of the 4880 people not exposed (9%, adjusted odds ratio 0.75, 95% CI 0.38-1.46; P=0.40). Sitagliptin exposure before acute coronary syndrome was not associated with an increased risk of death or heart failure combined (7% vs 9%, adjusted odds ratio 0.66, 95% CI 0.34-1.28). CONCLUSIONS: In our sample of patients who are at high risk of heart failure after acute coronary syndrome, sitagliptin exposure was not associated with an increased risk of de novo heart failure.

Anxiety, depression and fatigue at 5-year review following CNS demyelination.

BACKGROUND: Anxiety and depression are common in multiple sclerosis (MS). We evaluated the prevalence and factors associated with anxiety, depression and fatigue at the 5-year review of a longitudinal cohort study following a first clinical diagnosis of CNS demyelination (FCD). METHODS: Cases with a FCD were recruited soon after diagnosis and followed annually thereafter. A variety of environmental, behavioural and clinical covariates were measured at five-year review. Anxiety and depression were measured using the Hospital Anxiety & Depression Scale (HADS), and fatigue by the Fatigue Severity Scale (FSS). RESULTS: Of the 236 cases, 40.2% had clinical anxiety (median HADS-A: 6.0), 16.0% had clinical depression (median HADS-D: 3.0), and 41.3% had clinical fatigue (median FSS: 4.56). The co-occurrence of all three symptoms was 3.76 times greater than expectation. Younger age, higher disability, concussion or other disease diagnosis were independently associated with a higher anxiety score; male sex, higher disability, being unemployed, less physical activity, and antidepressant and/or anxiolytic-sedative medication use were independently associated with a higher depression score. Higher disability, immunomodulatory medication use, other disease diagnosis and anxiolytic-sedative medication use were independently associated with having fatigue, while female sex, higher BMI, having had a concussion, being unemployed and higher disability were associated with a higher fatigue score. CONCLUSION: These results support previous findings of the commonality of anxiety, depression and fatigue in established MS and extend this to post-FCD and early MS cases. The clustering of the three symptoms indicates that they may share common antecedents.

A protocol for management of blood loss in surgical treatment of peritoneal malignancy by cytoreductive surgery and hyperthermic intraperitoneal chemotherapy.

BACKGROUND AND AIMS: The treatment of peritoneal malignancies with cytoreductive surgery (CRS) combined with hyperthermic intraperitoneal chemotherapy (HIPEC) has been shown to be associated with massive surgical blood loss. Maintaining high fibrinogen levels throughout surgery may reduce blood loss in these patients. The primary aim of the study was to see if Tranexamic Acid (TXA) and cryoprecipitate reduced surgical blood loss and hence red cell transfusions. A comparison was made with a cohort of patients treated with fresh frozen plasma (FFP) alone. The secondary aim was to measure the effect of both protocols on coagulation parameters and the incidence of arterial or venous thrombosis. METHOD: We used prospectively collected data from 201 patients who had complete CRS with HIPEC for peritoneal malignancy using different protocols during two discrete 12-month time periods. RESULTS: The new transfusion protocol led to a higher average fibrinogen level intra-operatively and post-operatively, with a significant reduction in average RBC, FFP and platelet transfusion intra-operatively per patient from 4·2 to 1·8 units, 6·2 to 0·2 units and 0·1 to 0 units, respectively. No significant difference in PT or APTT was seen between patients treated with the standard and new protocols. Venous thrombosis occurred in seven patients treated with the standard protocol and five with the new protocol. A single case of arterial thrombosis was seen in both groups. CONCLUSION: Patients treated with upfront TXA and cryoprecipitate during CRS required less RBC transfusion than those treated with the standard protocol of early FFP.

'Lissajous-like' trajectories in optical tweezers.

When a microscopic particle moves through a low Reynolds number fluid, it creates a flow-field which exerts hydrodynamic forces on surrounding particles. In this work we study the 'Lissajous-like' trajectories of an optically trapped 'probe' microsphere as it is subjected to time-varying oscillatory hydrodynamic flow-fields created by a nearby moving particle (the 'actuator'). We show a breaking of time-reversal symmetry in the motion of the probe when the driving motion of the actuator is itself time-reversal symmetric. This symmetry breaking results in a fluid-pumping effect, which arises due to the action of both a time-dependent hydrodynamic flow and a position-dependent optical restoring force, which together determine the trajectory of the probe particle. We study this situation experimentally, and show that the form of the trajectories observed is in good agreement with Stokesian dynamics simulations. Our results are related to the techniques of active micro-rheology and flow measurement, and also highlight how the mere presence of an optical trap can perturb the environment it is in place to measure.

Cost-effectiveness analysis of adding pharmacists to primary care teams to reduce cardiovascular risk in patients with Type 2 diabetes: results from a randomized controlled trial.

BACKGROUND: Adding pharmacists to primary care teams significantly improved blood pressure control and reduced predicted 10-year cardiovascular risk in patients with Type 2 diabetes. This pre-specified sub-study evaluated the economic implications of this cardiovascular risk reduction strategy. METHODS: One-year outcomes and healthcare utilization data from the trial were used to determine cost-effectiveness from the public payer perspective. Costs were expressed in 2014 Canadian dollars and effectiveness was based on annualized risk of cardiovascular events derived from the UKPDS Risk Engine. RESULTS: The 123 evaluable trial patients included in this analysis had a mean age of 62 ( ± 11) years, 38% were men, and mean diabetes duration was 6 ( ± 7) years. Pharmacists provided 3.0 ( ± 1.9) hours of additional service to each intervention patient, which cost $226 ( ± $1143) per patient. The overall one-year per-patient costs for healthcare utilization were $190 lower in the intervention group compared with usual care [95% confidence interval (CI): -$1040, $668). Intervention patients had a significant 0.3% greater reduction in the annualized risk of a cardiovascular event (95% CI: 0.08%, 0.6%) compared with usual care. In the cost-effectiveness analysis, the intervention dominated usual care in 66% of 10,000 bootstrap replications. At a societal willingness-to-pay of $4000 per 1% reduction in annual cardiovascular risk, the probability that the intervention was cost-effective compared with usual care reached 95%. A sensitivity analysis using multiple imputation to replace missing data produced similar results. CONCLUSIONS: Within a randomized trial, adding pharmacists to primary care teams was a cost-effective strategy for reducing cardiovascular risk in patients with Type 2 diabetes. In most circumstances, this intervention may also be cost saving.

Body condition constrains immune function in field populations of female Australian plague locust Chortoicetes terminifera.

The insect innate immune system comprises both humoral and cellular defence responses. In the laboratory, the insect immune system is well characterized. In the field, however, little is known about the role of constitutive insect immune function and how it varies within and between populations. Laboratory studies suggest that host nutrition has significant impact upon insect immune function. Thus, the rationale for this study was to sample natural populations of the Australian Plague Locust Chortoicetes terminifera to establish whether locust body condition (as determined by protein and lipid content) impacted their constitutive immune system and, as a result, has the potential to impact on their capacity to respond to a pathogenic challenge. We found that body condition varied greatly between individual female locusts within sites and that haemolymph protein levels, but not body lipid content, varied between sites. Moreover, our measures of immune function were correlated with the haemolymph levels of protein (in the case of haemocyte density), lipid (prophenoloxidase activity) or both (lysozyme-like antimicrobial activity). We discuss the implications of these findings for the role of biological pesticides in the control of locust populations.