The Ethics of Time: Towards Temporal Bioethics.

In this paper I discuss the important yet overlooked role played by time in public health ethics, clinical ethics, and personal ethics, and present an exploratory analysis of temporal inequalities and temporal autonomy.

Association between body mass and hypotension in dogs under general anaesthesia.

OBJECTIVES: To investigate the association between body mass and hypotension during general anaesthesia in dogs undergoing surgical and diagnostic procedures within a referral hospital. MATERIALS AND METHODS: Retrospective evaluation of the anaesthetic records of 1789 dogs was performed. Data on signalment, anaesthetic protocol and physiological variables, including mean arterial pressure, were collected. A multivariable generalised linear model was used to identify associations between explanatory variables, including body mass, and hypotension. RESULTS: In the population studied, increasing body mass (per 10 kg) was significantly associated with decreasing odds of hypotension (odds ratio 0.68; 95% confidence interval: 0.60 to 0.77). Additional variables associated with a decreased odds of hypotension were pre-anaesthetic medication with alpha-2 agonists (odds ratio 0.63; 95% confidence interval 0.48 to 0.82) and increased body temperature (per 1°C) during general anaesthesia (odds ratio 0.77; 95% confidence interval 0.67 to 0.88). Brachycephaly (odds ratio 1.72; 95% confidence interval 1.25 to 2.38), ASA physical status classification >3 (odds ratio 2.03; 95% confidence interval 1.16 to 3.56), undergoing a surgical procedure (versus diagnostic) (odds ratio 1.57; 95% confidence interval 1.10 to 2.23) and bradycardia (odds ratio 1.37; 95% confidence interval 1.05 to 1.80) were independently associated with increased odds of hypotension. CLINICAL SIGNIFICANCE: Dogs of lower body mass and brachycephalic breeds may be at higher risk of hypotension during general anaesthesia or alternatively represent subpopulations in which accurate blood pressure measurement presents a greater challenge. Monitoring blood pressure accurately in these groups requires particular attention and provisions for treating hypotension should be readily accessible.

Genome-wide association study identifies novel risk loci for apical periodontitis.

Apical periodontitis (AP) is a common consequence of root canal infection leading to periapical bone resorption. Microbial and host genetic factors, and their interactions, have been shown to play a role in AP development and progression. Variations in a few genes have been reported in association with AP, however, the lack of genome-wide studies has hindered progress in understanding the mechanisms involved in AP. Here, we report the first genome-wide association study of AP in a well-characterized population. Male and female adults (n=932) presenting with deep caries with AP (cases) or without AP (controls) were included. Genotyping was performed using the Illumina Expanded Multi-Ethnic Genotyping Array. Single-variant association testing was performed adjusting for sex and five principal components. Subphenotype association testing, analyses of genetically regulated gene expression, polygenic risk score and phenome-wide association (PheWAS) analyses were also performed. Eight loci reached near-genome-wide significant association with AP (p < 5 x 10-6); gene-focused analyses replicated three previously reported associations (p < 8.9 x 10-5). Sex-specific and subphenotype analyses revealed additional significant associations with variants genome-wide. Functionally oriented gene-based analyses revealed eight genes significantly associated with AP (p < 5 x 10-5), and PheWAS analysis revealed 33 phecodes associated with AP risk score (p < 3.08 x 10-5). This study identified novel genes/loci contributing to AP and revealed specific contributions to AP risk in males and females. Importantly, we identified additional systemic conditions significantly associated with AP risk. Our findings provide strong evidence for host-mediated effects on AP susceptibility.

The interacting brain: Dynamic functional connectivity among canonical brain networks dissociates cooperative from competitive social interactions.

We spend much our lives interacting with others in various social contexts. Although we deal with this myriad of interpersonal exchanges with apparent ease, each one relies upon a broad array of sophisticated cognitive processes. Recent research suggests that the cognitive operations supporting interactive behaviour are themselves underpinned by several canonical functional brain networks (CFNs) that integrate dynamically with one another in response to changing situational demands. Dynamic integrations among these CFNs should therefore play a pivotal role in coordinating interpersonal behaviour. Further, different types of interaction should present different demands on cognitive systems, thereby eliciting distinct patterns of dynamism among these CFNs. To investigate this, the present study performed functional magnetic resonance imaging (fMRI) on 30 individuals while they interacted with one another cooperatively or competitively. By applying a novel combination of analytical techniques to these brain imaging data, we identify six states of dynamic functional connectivity characterised by distinct patterns of integration and segregation among specific CFNs that differ systematically between these opposing types of interaction. Moreover, applying these same states to fMRI data acquired from an independent sample engaged in the same kinds of interaction, we were able to classify interpersonal exchanges as cooperative or competitive. These results provide the first direct evidence for the systematic involvement of CFNs during social interactions, which should guide neurocognitive models of interactive behaviour and investigations into biomarkers for the interpersonal dysfunction characterizing many neurological and psychiatric disorders.

Differential pulse oximetry readings between ethnic groups and delayed transfer to intensive care units.

BACKGROUND: Pulse oximeters are widely used to monitor blood oxygen saturations, although concerns exist that they are less accurate in individuals with pigmented skin. AIMS: This study aimed to determine if patients with pigmented skin were more severely unwell at the period of transfer to intensive care units (ICUs) than individuals with White skin. METHODS: Using data from a large teaching hospital, measures of clinical severity at the time of transfer of patients with COVID-19 infection to ICUs were assessed, and how this varied by ethnic group. RESULTS: Data were available on 748 adults. Median pulse oximetry demonstrated similar oxygen saturations at the time of transfer to ICUs (Kruskal-Wallis test, P = 0.51), although median oxygen saturation measurements from arterial blood gases at this time demonstrated lower oxygen saturations in patients classified as Indian/Pakistani ethnicity (91.6%) and Black/Mixed ethnicity (93.0%), compared to those classified as a White ethnicity (94.4%, Kruskal-Wallis test, P = 0.005). There were significant differences in mean respiratory rates in these patients (P < 0.0001), ranging from 26 breaths/min in individuals with White ethnicity to 30 breaths/min for those classified as Indian/Pakistani ethnicity and 31 for those who were classified as Black/Mixed ethnicity. CONCLUSIONS: These data are consistent with the hypothesis that differential measurement error for pulse oximeter readings negatively impact on the escalation of clinical care in individuals from other than White ethnic groups. This has implications for healthcare in Africa and South-East Asia and may contribute to differences in health outcomes across ethnic groups globally.

Risk of subtrochanteric and femoral shaft fractures due to bisphosphonate therapy in asthma: a population-based nested case-control study.

Concerns have been raised over the association between bisphosphonates and atypical fractures in subtrochanteric and femoral shaft regions, but the potential risk of these fractures due to bisphosphonate use in asthma has not been examined. INTRODUCTION: Bisphosphonates are used as first-line treatment for osteoporosis; however, concerns have been raised over their association with atypical subtrochanteric (ST) and femoral shaft (FS) fractures. The potential risk of atypical ST/FS fractures from bisphosphonate use in asthma has not been examined. METHODS: A nested case-control study was conducted using linked data from the Clinical Practice Research Datalink (CPRD) and Hospital Episode Statistics (HES) databases. Using an asthma cohort, we identified patients with atypical ST/FS fractures and sex, age, and practice-matched controls. Conditional logistic regression was used to determine the association between bisphosphonate exposure and atypical ST/FS fractures. RESULTS: From a cohort of 69,074 people with asthma, 67 patients with atypical ST/FS fractures and 260 matched control subjects were identified. Of the case patients, 40.3% had received bisphosphonates as compared with 14.2% of the controls corresponding to an adjusted odds ratio (aOR) of 4.42 (95%CI, 2.98 to 8.53). The duration of use influenced the risk with long-term users to be at a greater risk (> 5 years vs no exposure; aOR = 7.67; 95%CI, 1.75 to 33.91). Drug withdrawal was associated with diminished odds of atypical ST/FS fractures. CONCLUSION: Regular review of bisphosphonates should occur in patients with asthma. The risks and benefits of bisphosphonate therapy should be carefully considered in consultation with the patient. To improve AFF prevention, early signs which may warrant imaging, such as prodromal thigh pain, should be discussed.

Current production by non-methanotrophic bacteria enriched from an anaerobic methane-oxidizing microbial community.

In recent years, the externalization of electrons as part of respiratory metabolic processes has been discovered in many different bacteria and some archaea. Microbial extracellular electron transfer (EET) plays an important role in many anoxic natural or engineered ecosystems. In this study, an anaerobic methane-converting microbial community was investigated with regard to its potential to perform EET. At this point, it is not well-known if or how EET confers a competitive advantage to certain species in methane-converting communities. EET was investigated in a two-chamber electrochemical system, sparged with methane and with an applied potential of +400 mV versus standard hydrogen electrode. A biofilm developed on the working electrode and stable low-density current was produced, confirming that EET indeed did occur. The appearance and presence of redox centers at -140 to -160 mV and at -230 mV in the biofilm was confirmed by cyclic voltammetry scans. Metagenomic analysis and fluorescence in situ hybridization of the biofilm showed that the anaerobic methanotroph 'Candidatus Methanoperedens BLZ2' was a significant member of the biofilm community, but its relative abundance did not increase compared to the inoculum. On the contrary, the relative abundance of other members of the microbial community significantly increased (up to 720-fold, 7.2% of mapped reads), placing these microorganisms among the dominant species in the bioanode community. This group included Zoogloea sp., Dechloromonas sp., two members of the Bacteroidetes phylum, and the spirochete Leptonema sp. Genes encoding proteins putatively involved in EET were identified in Zoogloea sp., Dechloromonas sp. and one member of the Bacteroidetes phylum. We suggest that instead of methane, alternative carbon sources such as acetate were the substrate for EET. Hence, EET in a methane-driven chemolithoautotrophic microbial community seems a complex process in which interactions within the microbial community are driving extracellular electron transfer to the electrode.

Precision worm control in grazing lambs by targeting group treatment based on performance of sentinels.

Given the economic impact of gastrointestinal nematode infection on livestock farming worldwide, and increasing anthelmintic resistance, it is imperative to develop practical, efficient and sustainable control strategies. Targeted selective treatment (TST), whereby anthelmintic treatments are administered to animals individually, based on selection criteria such as weight gain, has been shown to successfully maintain animal productivity whilst reducing the selection pressure for anthelmintic resistance and the economic cost of treatment in experimental and commercial settings. Despite the benefits of the TST approach, the equipment and time required to monitor animals individually make this strategy unsuitable for some farming enterprises. The sentinel group approach aims to maintain the benefits observed using TST whilst reducing these requirements. The study involved two experiments, each following a group of 80 lambs through their first grazing season. Anthelmintic treatment of the whole group was determined by monitoring the weight gain of identified sentinel lambs within it every 2 weeks: when 40% of the sentinel lambs failed to reach their weight gain targets, the whole group was treated. The sentinel lambs consisted of 45% of the group (n = 36) in experiment one and 20% (n = 16) in experiment two. A control group of 20 lambs was co-grazed with the main group during both experiments; in experiment one, the sentinel approach was compared with a TST approach, in which control lambs were treated on an individual basis in response to weight gain. In experiment two, the sentinel approach was compared with conventional prophylaxis, where all lambs in the control group were treated at strategic time points throughout the season (= strategic prophylactic treatment). The sentinel lambs were found to be representative of overall group performance regardless of the proportion of sentinels within the group: they recorded similar growth rates and reached weight gain targets simultaneously at each time point and overall. Live-weight gain was also similar between sentinel and control animals in both experiments. The findings of the current study suggest that monitoring sentinel lambs comprising 20% of a group of grazing lambs is sufficient to determine the need for anthelmintic treatment within the whole group, and that this approach maintains production in line with conventional or TST treatment regimes.

You took the words right out of my mouth: Dual-fMRI reveals intra- and inter-personal neural processes supporting verbal interaction.

Verbal communication relies heavily upon mutual understanding, or common ground. Inferring the intentional states of our interaction partners is crucial in achieving this, and social neuroscience has begun elucidating the intra- and inter-personal neural processes supporting such inferences. Typically, however, neuroscientific paradigms lack the reciprocal to-and-fro characteristic of social communication, offering little insight into the way these processes operate online during real-world interaction. In the present study, we overcame this by developing a "hyperscanning" paradigm in which pairs of interactants could communicate verbally with one another in a joint-action task whilst both undergoing functional magnetic resonance imaging simultaneously. Successful performance on this task required both interlocutors to predict their partner's upcoming utterance in order to converge on the same word as each other over recursive exchanges, based only on one another's prior verbal expressions. By applying various levels of analysis to behavioural and neuroimaging data acquired from 20 dyads, three principal findings emerged: First, interlocutors converged frequently within the same semantic space, suggesting that mutual understanding had been established. Second, assessing the brain responses of each interlocutor as they planned their upcoming utterances on the basis of their co-player's previous word revealed the engagement of the temporo-parietal junctional (TPJ), precuneus and dorso-lateral pre-frontal cortex. Moreover, responses in the precuneus were modulated positively by the degree of semantic convergence achieved on each round. Second, effective connectivity among these regions indicates the crucial role of the right TPJ in this process, consistent with the Nexus model. Third, neural signals within certain nodes of this network became aligned between interacting interlocutors. We suggest this reflects an interpersonal neural process through which interactants infer and align to one another's intentional states whilst they establish a common ground.

Disentangling nature from nurture in examining the interplay between parent-child relationships, ADHD, and early academic attainment.

BACKGROUND: Attention deficit hyperactivity disorder (ADHD) is highly heritable and is associated with lower educational attainment. ADHD is linked to family adversity, including hostile parenting. Questions remain regarding the role of genetic and environmental factors underlying processes through which ADHD symptoms develop and influence academic attainment. METHOD: This study employed a parent-offspring adoption design (N = 345) to examine the interplay between genetic susceptibility to child attention problems (birth mother ADHD symptoms) and adoptive parent (mother and father) hostility on child lower academic outcomes, via child ADHD symptoms. Questionnaires assessed birth mother ADHD symptoms, adoptive parent (mother and father) hostility to child, early child impulsivity/activation, and child ADHD symptoms. The Woodcock-Johnson test was used to examine child reading and math aptitude. RESULTS: Building on a previous study (Harold et al., 2013, Journal of Child Psychology and Psychiatry, 54(10), 1038-1046), heritable influences were found: birth mother ADHD symptoms predicted child impulsivity/activation. In turn, child impulsivity/activation (4.5 years) evoked maternal and paternal hostility, which was associated with children's ADHD continuity (6 years). Both maternal and paternal hostility (4.5 years) contributed to impairments in math but not reading (7 years), via impacts on ADHD symptoms (6 years). CONCLUSION: Findings highlight the importance of early child behavior dysregulation evoking parent hostility in both mothers and fathers, with maternal and paternal hostility contributing to the continuation of ADHD symptoms and lower levels of later math ability. Early interventions may be important for the promotion of child math skills in those with ADHD symptoms, especially where children have high levels of early behavior dysregulation.

Clinical predictors of donor antibody titre and correlation with recipient antibody response in a COVID-19 convalescent plasma clinical trial.

BACKGROUND: Convalescent plasma therapy for COVID-19 relies on transfer of anti-viral antibody from donors to recipients via plasma transfusion. The relationship between clinical characteristics and antibody response to COVID-19 is not well defined. We investigated predictors of convalescent antibody production and quantified recipient antibody response in a convalescent plasma therapy clinical trial. METHODS: Multivariable analysis of clinical and serological parameters in 103 confirmed COVID-19 convalescent plasma donors 28 days or more following symptom resolution was performed. Mixed-effects regression models with piecewise linear trends were used to characterize serial antibody responses in 10 convalescent plasma recipients with severe COVID-19. RESULTS: Donor antibody titres ranged from 0 to 1 : 3892 (anti-receptor binding domain (RBD)) and 0 to 1 : 3289 (anti-spike). Higher anti-RBD and anti-spike titres were associated with increased age, hospitalization for COVID-19, fever and absence of myalgia (all P < 0.05). Fatigue was significantly associated with anti-RBD (P = 0.03). In pairwise comparison amongst ABO blood types, AB donors had higher anti-RBD and anti-spike than O donors (P < 0.05). No toxicity was associated with plasma transfusion. Non-ECMO recipient anti-RBD antibody titre increased on average 31% per day during the first three days post-transfusion (P = 0.01) and anti-spike antibody titre by 40.3% (P = 0.02). CONCLUSION: Advanced age, fever, absence of myalgia, fatigue, blood type and hospitalization were associated with higher convalescent antibody titre to COVID-19. Despite variability in donor titre, 80% of convalescent plasma recipients showed significant increase in antibody levels post-transfusion. A more complete understanding of the dose-response effect of plasma transfusion amongst COVID-19-infected patients is needed.

Changes in the incidence of invasive disease due to Streptococcus pneumoniae, Haemophilus influenzae, and Neisseria meningitidis during the COVID-19 pandemic in 26 countries and territories in the Invasive Respiratory Infection Surveillance Initiative: a prospective analysis of surveillance data

Streptococcus pneumoniae, Haemophilus influenzae, and Neisseria meningitidis, which are typically transmitted via respiratory droplets, are leading causes of invasive diseases, including bacteraemic pneumonia and meningitis, and of secondary infections subsequent to post-viral respiratory disease. The aim of this study was to investigate the incidence of invasive disease due to these pathogens during the early months of the COVID-19 pandemic. Methods In this prospective analysis of surveillance data, laboratories in 26 countries and territories across six continents submitted data on cases of invasive disease due to S pneumoniae, H influenzae, and N meningitidis from Jan 1, 2018, to May, 31, 2020, as part of the Invasive Respiratory Infection Surveillance (IRIS) Initiative. Numbers of weekly cases in 2020 were compared with corresponding data for 2018 and 2019. Data for invasive disease due to Streptococcus agalactiae, a non-respiratory pathogen, were collected from nine laboratories for comparison. The stringency of COVID-19 containment measures was quantified using the Oxford COVID-19 Government Response Tracker. Changes in population movements were assessed using Google COVID-19 Community Mobility Reports. Interrupted time-series modelling quantified changes in the incidence of invasive disease due to S pneumoniae, H influenzae, and N meningitidis in 2020 relative to when containment measures were imposed. Findings 27 laboratories from 26 countries and territories submitted data to the IRIS Initiative for S pneumoniae (62 434 total cases), 24 laboratories from 24 countries submitted data for H influenzae (7796 total cases), and 21 laboratories from 21 countries submitted data for N meningitidis (5877 total cases). All countries and territories had experienced a significant and sustained reduction in invasive diseases due to S pneumoniae, H influenzae, and N meningitidis in early 2020 (Jan 1 to May 31, 2020), coinciding with the introduction of COVID-19 containment measures in each country. By contrast, no significant changes in the incidence of invasive S agalactiae infections were observed. Similar trends were observed across most countries and territories despite differing stringency in COVID-19 control policies. The incidence of reported S pneumoniae infections decreased by 68% at 4 weeks (incidence rate ratio 0·32 [95% CI 0·27­0·37]) and 82% at 8 weeks (0·18 [0·14­0·23]) following the week in which significant changes in population movements were recorded. Interpretation The introduction of COVID-19 containment policies and public information campaigns likely reduced transmission of S pneumoniae, H influenzae, and N meningitidis, leading to a significant reduction in life-threatening invasive diseases in many countries worldwide. Funding Wellcome Trust (UK), Robert Koch Institute (Germany), Federal Ministry of Health (Germany), Pfizer, Merck, Health Protection Surveillance Centre (Ireland), SpID-Net project (Ireland), European Centre for Disease Prevention and Control (European Union), Horizon 2020 (European Commission), Ministry of Health (Poland), National Programme of Antibiotic Protection (Poland), Ministry of Science and Higher Education (Poland), Agencia de Salut Pública de Catalunya (Spain), Sant Joan de Deu Foundation (Spain), Knut and Alice Wallenberg Foundation (Sweden), Swedish Research Council (Sweden), Region Stockholm (Sweden), Federal Office of Public Health of Switzerland (Switzerland), and French Public Health Agency (France).

The behavior of dairy cattle in the transition period: Effects of blood calcium status.

The aim of this study was to use an automated behavior-monitoring system to objectively assess the association between lying and activity behavior in the precalving, calving, and postcalving periods between multiparous and primiparous cows with (1) normocalcemia, (2) subclinical hypocalcemia, or (3) clinical hypocalcemia at calving. Behavioral data and blood serum samples were collected from 51 multiparous and 21 primiparous Holstein dairy cattle. Blood samples from the coccygeal vein were taken within 24 h of calving, and serum was analyzed to measure total calcium concentration. Cows were classified into one of 3 categories: normocalcemia (serum calcium concentration ≥ 2.0 mmol/L), subclinical hypocalcemia (serum calcium concentration < 2.0 mmol/L, absence of clinical signs), and clinical hypocalcemia (clinical signs and successful treatment). An activity sensor was fitted to the right hind leg of cows 3 wk before their expected calving date. Data for lying time, standing time, number of steps, and the total number of standing and lying bouts (postural transitions) were automatically collected and summed into 15-min blocks. Behavioral variables were summarized into 2-h and 24-h periods before analyses. Mixed effect models were used to analyze cow behavior in the entire 14 d before calving (d -14 to -1), on the day of calving, and the entire 21 d postcalving (d 1 to 21). In the precalving period, multiparous cows with normocalcemia had fewer postural transitions (18.5 ± 6.9 no./d) compared with cows with subclinical hypocalcemia (23.5 ± 8.0 no./d) and clinical hypocalcemia (23.5 ± 8.6 no./d). However, there was no association between blood calcium status on lying time (min/d) or step count (no./d) for multiparous cows. For primiparous cows, the step count of cows with subclinical hypocalcemia remained constant across the period, and the step count of cows with normocalcemia decreased from 842.8 steps/d on d -14 to 427.5 steps/d on d -1. Postpartum cows with clinical hypocalcemia were less active (fewer steps) and spent 88 min/d (1.5 h) and 125 min/d (2.1 h) more time lying down compared with cows with subclinical hypocalcemia and normocalcemia, respectively. This shows that clinical hypocalcemia is associated with significant long-lasting behavioral effects on cows during the critical postpartum period.

Invisible Enemies: Coronavirus and Other Hidden Threats.

To say that coronavirus is highly visible is a massive understatement in terms of its omnipresence in our lives and media coverage concerning it, yet also clearly untrue in terms of the virus itself. COVID-19 is our invisible enemy, changing our lives radically without ever revealing itself directly. In this paper I explore its invisibility and how it relates to and exposes other invisible enemies we are and have been fighting, in many cases without even realizing. First, I analyse the virus itself and how its stealthy nature has transformed our lives. Second, I describe how the invisible epidemic of social media sharing of fake news about the virus worsens the situation further. Third, I explore how the virus has revealed to us what really matters in our lives and has forced us to re-evaluate our priorities. Fourth, I go on to explore the underlying structural weaknesses and disparities in society that have been exposed by the virus but previously remained unconsidered for so long that they too have become camouflaged, even if their effects are all too apparent; like the virus, neoliberal capitalism is an invisible enemy that has made prisoners of us all. I conclude by suggesting that the coronavirus pandemic represents a hidden opportunity to overcome perhaps the biggest invisible enemy of all: the moral distance that separates us from others. Only by rendering the rest of humanity morally visible to ourselves can we overcome capitalism and stop treating other people as invisible enemies.

Patients' attitudes towards cost feedback to doctors to prevent unnecessary testing: a qualitative focus group study.

OBJECTIVES: There is a need to improve efficiency in healthcare delivery without compromising quality of care. One approach is the development and evaluation of behavioural strategies to reduce unnecessary use of common tests. However, there is an absence of evidence on patient attitudes to the use of such approaches in the delivery of care. Our objective was to explore patient acceptability of a nudge-type intervention that aimed to modify blood test requests by hospital doctors. STUDY DESIGN: Single-centre qualitative study. METHODS: The financial costs of common blood tests were presented to hospital doctors on results reports for 1 year at a hospital. Focus group discussions were conducted with recent inpatients at the hospital using a semi-structured question schedule. Discussions were transcribed and analysed using qualitative content analysis to identify and prioritise common themes explaining attitudes to the intervention approach. RESULTS: Three focus groups involving 17 participants were conducted. Patients were generally apprehensive about the provision of blood test cost feedback to doctors. Attitudes were organised around themes representing beliefs about blood tests, the impact on doctors and their autonomy, and beliefs about unnecessary testing. Patients thought that blood tests were important, powerful and inexpensive, and cost information could place doctors under additional pressure. CONCLUSION: The findings identify predominantly positive beliefs about testing and negative attitudes to the use of financial costs in the decision-making of hospital doctors. Public discussion and education about the possible overuse of common tests may allow more resources to be allocated to evidence-based healthcare, by reducing the perception that such strategies to improve healthcare efficiency negatively impact on quality of care.