Unravelling the mechanisms of antibiotic and heavy metal resistance co-selection in environmental bacteria.

The co-selective pressure of heavy metals is a contributor to the dissemination and persistence of antibiotic resistance genes in environmental reservoirs. The overlapping range of antibiotic and metal contamination and similarities in their resistance mechanisms point to an intertwined evolutionary history. Metal resistance genes are known to be genetically linked to antibiotic resistance genes, with plasmids, transposons, and integrons involved in the assembly and horizontal transfer of the resistance elements. Models of co-selection between metals and antibiotics have been proposed, however, the molecular aspects of these phenomena are in many cases not defined or quantified and the importance of specific metals, environments, bacterial taxa, mobile genetic elements, and other abiotic or biotic conditions are not clear. Co-resistance is often suggested as a dominant mechanism, but interpretations are beset with correlational bias. Proof of principle examples of cross-resistance and co-regulation has been described but more in-depth characterizations are needed, using methodologies that confirm the functional expression of resistance genes and that connect genes with specific bacterial hosts. Here, we comprehensively evaluate the recent evidence for different models of co-selection from pure culture and metagenomic studies in environmental contexts and we highlight outstanding questions.

Estimating the risk of hospitalisation and death in England's remaining unvaccinated population

The roll-out of COVID-19 vaccines in the England has generally been very good - with over 80% of over 12s having received two doses of vaccine by the start of February 2022, and 67% having received a further booster dose. Despite this, there is a small section of the population who remain unvaccinated, either due to lack of access, hesitancy or resistant to vaccination. In this report we estimate that, during 2021, there were approximately 3,500 deaths in unvaccinated people, who could otherwise have reasonably been expected to receive a vaccination. Further, we show that if all of the remaining unvaccinated population in England were to become infected (or reinfected) with the Omicron variant of COVID-19, we would expect to see approximately 11,700 further deaths and 29,600 hospitalisations. These number could fall to 5,300 and 19,600 respectively, if all but the most vaccine resistant individuals become fully vaccinated.

Mitigating isolation: The use of rapid antigen testing to reduce the impact of self-isolation periods

Isolating, either enforced or self-guided, is a well-recognised and used technique in the limitation and reduction of disease spread. This usually balances the societal harm of disease transmission against the individual harm of being isolated and is typically limited to a very small number of individuals. With the widespread transmission of SARS-CoV-2 and requirements to self-isolate when symptomatic or having tested positive, the number of people affected has grown very large causing noticeable individual cost, and disruption to the provision of essential services. With widespread access to reliable rapid antigen tests (also known as LFD or LFTs), in this paper we examine strategies to utilise this testing technology to limit the individual harm whist maintaining the protective effect of isolation. We extend this work to examine how isolation may be improved and mitigate the release of infective individuals into the population caused by fixed time-periods.

The 2013-2016 Ebola epidemic: evaluating communication strategies between two affected countries in West Africa.

BACKGROUND: Ebola is a haemorrhagic disease with high fatality rates between 25 and 90%. The 2013-16 Ebola outbreak in West Africa was the largest to date with >28 000 cases and >11 000 fatalities. This outbreak exposed inadequacies in public health agencies and has spurred health officials to re-evaluate the way Ebola virus disease (EVD) epidemics are co-ordinated and communicated. METHODS: This project compares, using the systematic review method, differences in the communication of EVD in Nigeria and Liberia with data from selected articles analyzed using thematic analysis. RESULTS: The most successful communication strategies were community engagement and targeted health-communication to the most at-risk groups. We also highlight the importance of a multi-modal strategy to effectively communicate prevention and management of EVD to affected communities. Secondary to these findings included the relevance of the media, particularly social media tools in managing such serious outbreak situations. CONCLUSION: This study provides the basis for the development of a theory-based framework to effectively communicate EVD and reduce the negative outcomes observed during the 2013-16 EVD outbreak.

tDCS increases anxiety reactivity to intentional worry.

While considerable experimental research has examined the impact of transcranial direct current stimulation (tDCS) on a range of cognitive processes associated with emotional pathology, the impact of tDCS on worry has been comparatively neglected. Given that anxiety pathology is characterised by motivated engagement in worry, and that frontal tDCS has the capacity to enhance goal-oriented cognition, it is important to examine whether tDCS would increase or ameliorate the cognitive and emotional effects of worry. In the current study we examined how tDCS influenced the anxiety response to worry, and the frequency of negative intrusive thoughts. We additionally examined whether stimulation delivered in isolation, or in combination with a mindful-focus task would augment the effects of tDCS. Ninety-seven (75 female) healthy participants received either active or sham anodal tDCS to the left dorsolateral prefrontal cortex, delivered either in isolation or concurrently with a mindful task (four conditions). The frequency of negative thought intrusions was assessed before and after a period of instructed worry, and state anxiety was assessed across the study. Active tDCS was associated with significantly greater elevation in anxiety in response to the worry induction. No effects were observed on the frequency of negative thought intrusions, and the combined delivery of tDCS with the concurrent mindful task did not alter the pattern of observed effects. While inviting replication in a high anxious sample, the present results highlight the possibility that tDCS may interact with motivated engagement in negative patterns of cognition, such as worry, to produce greater emotional reactivity.

The first 100 thrombolysis cases in a novel Scottish mesh telestroke system.

Stroke thrombolysis has been a major driver for change within stroke services. However, until recently its widespread application has been limited to tertiary centres. Transfer to tertiary care can lead to significant delays in thrombolysis. We developed a novel mesh telestroke network, which allows stroke specialists to make videoconference-based thrombolysis decisions either from one of three stroke units or from home. We report data on the first 100 patients treated using this model and retrospectively review the first 100 strokes thrombolysed with tissue plasminogen activator across three stroke units. Prospectively collected data were extracted from the Stroke Audit In Lanarkshire database. Case notes were retrieved for clarification when necessary. Outcome measures were timings from symptom onset to infusion, post-thrombolysis symptomatic intracerebral haemorrhage and death. Fifty-one percent of cases were assessed by telestroke link. Median symptom onset to thrombolysis was 160 min (IQR 125-190). There were two symptomatic intracerebral haemorrhages, both in patients assessed face-to-face. Overall mortality was 14%. Our experience of tissue plasminogen activator is comparable to UK data extracted from SITS-MOST in overall timings and complication rates. This model of telemedicine could be replicated to provide safe thrombolysis to areas with challenging infrastructure, geography or insufficient stroke specialist cover.

The influence of calculation method on estimates of cerebral critical closing pressure.

The critical closing pressure (CrCP) of cerebral circulation is normally estimated by extrapolation of instantaneous velocity-pressure curves. Different methods of estimation were analysed to assess their robustness and reproducibility in both static and dynamic applications. In ten healthy subjects (mean ± SD age 37.5 ± 9.2 years) continuous recordings of arterial blood pressure (BP, Finapres) and bilateral cerebral blood flow velocity (transcranial Doppler ultrasound, middle cerebral arteries) were obtained at rest. Each session consisted of three separate 5 min recordings. A total of four recording sessions for each subject took place over a 2 week period. A total of 117 recordings contained 34 014 cardiac cycles. For each cardiac cycle, CrCP and resistance-area product (RAP) were estimated using linear regression (LR), principal component analysis (PCA), first harmonic fitting (H1), 2-point systolic/diastolic values (2Ps) and 2-point mean/diastolic values (2Pm). LR and PCA were also applied using only the diastolic phase (LRd, PCAd). The mean values of CrCP and RAP for the entire 5 min recording ('static' condition) were not significantly different for LRd, PCAd, H1 and 2Pm, as opposed to the other methods. The same four methods provided the best results regarding the absence of negative values of CrCP and the coefficient of variation (CV) of the intra-subject standard error of the mean (SEM). On the other hand, 'dynamic' applications, such as the transfer function between mean BP and RAP (coherence and RAP step response) led to a different ranking of methods, but without significant differences in CV SEM coherence. For the CV of the RAP step response though, LRd and PCAd performed badly. These results suggest that H1 or 2Pm perform better than LR analysis and should be used for the estimation of CrCP and RAP for both static and dynamic applications.

Spontaneous fluctuations in cerebral blood flow regulation: contribution of PaCO2.

To investigate the temporal variability of dynamic cerebral autoregulation (CA), the transient response of cerebral blood flow to rapid changes in arterial blood pressure, a new approach was introduced to improve the temporal resolution of dynamic CA assessment. Continuous bilateral recordings of cerebral blood flow velocity (transcranial Doppler, middle cerebral artery), end-tidal Pco(2) (Pet(CO(2)), infrared capnograph), and blood pressure (Finapres) were obtained at rest and during breath hold in 30 young subjects (25 ± 6 yr old) and 30 older subjects (64 ± 4 yr old). Time-varying estimates of the autoregulation index [ARI(t)] were obtained with an autoregressive-moving average model with coefficients expanded by orthogonal decomposition. The temporal pattern of ARI(t) varied inversely with Pet(CO(2)), decreasing with hypercapnia. At rest, ARI(t) showed spontaneous fluctuations that were significantly different from noise and significantly correlated with spontaneous fluctuations in Pet(CO(2)) in the majority of recordings (young: 72% and old: 65%). No significant differences were found in ARI(t) due to aging. This new approach to improve the temporal resolution of dynamic CA parameters allows the identification of physiologically meaningful fluctuations in dynamic CA efficiency at rest and in response to changes in arterial CO(2).

Continuous estimates of dynamic cerebral autoregulation during transient hypocapnia and hypercapnia.

Dynamic cerebral autoregulation (CA) is the transient response of cerebral blood flow (CBF) to rapid blood pressure changes: it improves in hypocapnia and becomes impaired during hypercapnia. Batch-processing techniques have mostly been used to measure CA, providing a single estimate for an entire recording. A new approach to increase the temporal resolution of dynamic CA parameters was applied to transient hypercapnia and hypocapnia to describe the time-varying properties of dynamic CA during these conditions. Thirty healthy subjects (mean +/- SD: 25 +/- 6 yr, 9 men) were recruited. CBF velocity was recorded in both middle cerebral arteries (MCAs) with transcranial Doppler ultrasound. Arterial blood pressure (Finapres), end-tidal CO(2) (ET(CO(2)); infrared capnograph), and a three-lead ECG were also measured at rest and during repeated breath hold and hyperventilation. A moving window autoregressive moving average model provided continuous values of the dynamic CA index [autoregulation index (ARI)] and unconstrained gain. Breath hold led to significant increase in ET(CO(2)) (+5.4 +/- 6.1 mmHg), with concomitant increase in CBF velocity in both MCAs. Continuous dynamic CA parameters showed highly significant changes (P < 0.001), with a temporal pattern reflecting a delayed dynamic response of CA to changes in arterial Pco(2) and a maximal reduction in ARI of -5.1 +/- 2.4 and -5.1 +/- 2.3 for the right and left MCA, respectively. Hyperventilation led to a marked decrease in ET(CO(2)) (-7.2 +/- 4.1 mmHg, P < 0.001). Unexpectedly, CA efficiency dropped significantly with the inception of the metronome-controlled hyperventilation, but, after approximately 30 s, the ARI increased gradually to show a maximum change of 5.7 +/- 2.9 and 5.3 +/- 3.0 for the right and left MCA, respectively (P < 0.001). These results confirm the potential of continuous estimates of dynamic CA to improve our understanding of human cerebrovascular physiology and represent a promising new approach to improve the sensitivity of clinical applications of dynamic CA modeling.

Controlling hypertension and hypotension immediately post stroke (CHHIPS)--a randomised controlled trial.

OBJECTIVES: To assess the effects of acute pressor and depressor blood pressure (BP) manipulation on 2-week death and dependency following acute stroke and investigate the safety and efficacy of such treatments. DESIGN: A multicentre, prospective, randomised, double-blind, placebo-controlled titrated-dose trial. SETTING: Five hospitals in England. PARTICIPANTS: Patients over 18 years admitted to hospital with a clinical diagnosis of suspected stroke and either (1) symptom onset < 36 hours and hypertension, defined as systolic BP (SBP) < 160 mmHg (depressor arm), or (2) symptom onset < 12 hours and hypotension, defined as SBP < or = 140 mmHg (pressor arm). INTERVENTIONS: Patients were allocated to either the pressor or the depressor arm depending on blood pressure at randomisation. The ratio of allocation to active intervention versus matched placebo was 2:1 for the depressor arm and 1:1 for the pressor arm. MAIN OUTCOME MEASURES: The primary end point was death and dependency at 2 weeks, with dependency defined as a modified Rankin score < 3. Secondary end points were the safety of acute pressor (0-12 hours post stroke) and depressor (0-36 hours post stroke) BP manipulation in stroke patients; whether effects of BP reduction are influenced by stroke type (ischaemic versus haemorrhagic); whether alternative routes for administration of antihypertensive therapy (including sublingual and intravenous) are effective in dysphagic stroke patients; whether effects of BP manipulation are influenced by the time to treatment; and the short- and medium-term cost-effectiveness of such therapy in the acute post-stroke period on subsequent disability or death. RESULTS: 180 patients were recruited over the 36-month trial period, 179 in the depressor arm and one in the pressor arm (who received placebo). No significant difference was found in death or dependency at 2 weeks between those receiving active depressor treatment with lisinopril or labetalol and those receiving placebo, although numbers recruited to the trial were lower than projected. Active treatment was not associated with an increase in early neurological deterioration despite significantly greater reductions in BP at 24 hours and 2 weeks with active therapy compared with placebo. Active treatment was generally well tolerated and treatment discontinuation rates were similar in active and placebo groups. Survival analysis showed that the active treatment group had a lower mortality at 3 months than the placebo group (p = 0.05). The pressor arm was closed early because of problems with recruitment, so no conclusions can be drawn regarding this therapy. CONCLUSIONS: Oral and sublingual lisinopril and oral and intravenous labetalol are effective BP-lowering agents in acute cerebral infarction and haemorrhage and do not increase the likelihood of early neurological deterioration. The study was not sufficiently powered to detect a difference in disability or death at 2 weeks. However, the 3-month difference in mortality in favour of active treatment is of interest, although care must be taken in interpretation of the results. Further work is needed to confirm this and to assess whether there are differences in the effectiveness of labetalol compared with lisinopril in terms of reducing death or dependency after acute stroke, and whether the introduction of treatment post stroke earlier than was achieved here would be of greater benefit.