Results of the c-TRAK TN trial: a clinical trial utilising ctDNA mutation tracking to detect molecular residual disease and trigger intervention in patients with moderate- and high-risk early-stage triple-negative breast cancer.

BACKGROUND: Post-treatment detection of circulating tumour DNA (ctDNA) in early-stage triple-negative breast cancer (TNBC) patients predicts high risk of relapse. c-TRAK TN assessed the utility of prospective ctDNA surveillance in TNBC and the activity of pembrolizumab in patients with ctDNA detected [ctDNA positive (ctDNA+)]. PATIENTS AND METHODS: c-TRAK TN, a multicentre phase II trial, with integrated prospective ctDNA surveillance by digital PCR, enrolled patients with early-stage TNBC and residual disease following neoadjuvant chemotherapy, or stage II/III with adjuvant chemotherapy. ctDNA surveillance comprised three-monthly blood sampling to 12 months (18 months if samples were missed due to coronavirus disease), and ctDNA+ patients were randomised 2 : 1 to intervention : observation. ctDNA results were blinded unless patients were allocated to intervention, when staging scans were done and those free of recurrence were offered pembrolizumab. A protocol amendment (16 September 2020) closed the observation group; all subsequent ctDNA+ patients were allocated to intervention. Co-primary endpoints were (i) ctDNA detection rate and (ii) sustained ctDNA clearance rate on pembrolizumab (NCT03145961). RESULTS: Two hundred and eight patients registered between 30 January 2018 and 06 December 2019, 185 had tumour sequenced, 171 (92.4%) had trackable mutations, and 161 entered ctDNA surveillance. Rate of ctDNA detection by 12 months was 27.3% (44/161, 95% confidence interval 20.6% to 34.9%). Seven patients relapsed without prior ctDNA detection. Forty-five patients entered the therapeutic component (intervention n = 31; observation n = 14; one observation patient was re-allocated to intervention following protocol amendment). Of patients allocated to intervention, 72% (23/32) had metastases on staging at the time of ctDNA+, and 4 patients declined pembrolizumab. Of the five patients who commenced pembrolizumab, none achieved sustained ctDNA clearance. CONCLUSIONS: c-TRAK TN is the first prospective study to assess whether ctDNA assays have clinical utility in guiding therapy in TNBC. Patients had a high rate of metastatic disease on ctDNA detection. Findings have implications for future trial design, emphasising the importance of commencing ctDNA testing early, with more sensitive and/or frequent ctDNA testing regimes.

Malignant hyperthermia 2020: Guideline from the Association of Anaesthetists.

Malignant hyperthermia is defined in the International Classification of Diseases as a progressive life-threatening hyperthermic reaction occurring during general anaesthesia. Malignant hyperthermia has an underlying genetic basis, and genetically susceptible individuals are at risk of developing malignant hyperthermia if they are exposed to any of the potent inhalational anaesthetics or suxamethonium. It can also be described as a malignant hypermetabolic syndrome. There are no specific clinical features of malignant hyperthermia and the condition may prove fatal unless it is recognised in its early stages and treatment is promptly and aggressively implemented. The Association of Anaesthetists has previously produced crisis management guidelines intended to be displayed in all anaesthetic rooms as an aide memoire should a malignant hyperthermia reaction occur. The last iteration was produced in 2011 and since then there have been some developments requiring an update. In these guidelines we will provide background information that has been used in updating the crisis management recommendations but will also provide more detailed guidance on the clinical diagnosis of malignant hyperthermia. The scope of these guidelines is extended to include practical guidance for anaesthetists dealing with a case of suspected malignant hyperthermia once the acute reaction has been reversed. This includes information on care and monitoring during and after the event; appropriate equipment and resuscitative measures within the operating theatre and ICU; the importance of communication and teamwork; guidance on counselling of the patient and their family; and how to make a referral of the patient for confirmation of the diagnosis. We also review which patients presenting for surgery may be at increased risk of developing malignant hyperthermia under anaesthesia and what precautions should be taken during the peri-operative management of the patients.

Laboratory evaluation of a novel anaesthesia delivery device.

Here, we describe proof of concept of a novel method for delivering volatile anaesthetics, where the liquid anaesthetic (sevoflurane or isoflurane) is formulated into an emulsion that is contained in a compact, lightweight device through which carrier gas flows. Release of anaesthetic is achieved by stirring of the formulation, allowing controlled and responsive release of anaesthetic at a variety of fixed flow rates between 0.5 l.min-1 and 5 l.min-1 , with ventilated, non-ventilated and draw-over breathing systems. Anaesthetic release was evaluated using target anaesthetic concentrations ranging from 0.5% v/v to 8% v/v to mimic those typically required for induction and maintenance of anaesthesia, and lower concentrations suitable for sedation. Under all conditions, output could be maintained within 0.1% v/v of the intended setting, and the device could deliver a controlled level of anaesthetic for at least 60 min, with compensation for different ambient temperatures (10-30 °C) and carrier gas flow rates. This device offers a simple, inexpensive method of delivering safe concentrations of volatile anaesthetics for a wide range of applications.

AAGBI: Safer pre-hospital anaesthesia 2017: Association of Anaesthetists of Great Britain and Ireland.

Pre-hospital emergency anaesthesia with oral tracheal intubation is the technique of choice for trauma patients who cannot maintain their airway or achieve adequate ventilation. It should be carried out as soon as safely possible, and performed to the same standards as in-hospital emergency anaesthesia. It should only be conducted within organisations with comprehensive clinical governance arrangements. Techniques should be straightforward, reproducible, as simple as possible and supported by the use of checklists. Monitoring and equipment should meet in-hospital anaesthesia standards. Practitioners need to be competent in the provision of in-hospital emergency anaesthesia and have supervised pre-hospital experience before carrying out pre-hospital emergency anaesthesia. Training programmes allowing the safe delivery of pre-hospital emergency anaesthesia by non-physicians do not currently exist in the UK. Where pre-hospital emergency anaesthesia skills are not available, oxygenation and ventilation should be maintained with the use of second-generation supraglottic airways in patients without airway reflexes, or basic airway manoeuvres and basic airway adjuncts in patients with intact airway reflexes.

The Global Health Security Agenda and the role of the World Organisation for Animal Health.

The World Organisation for Animal Health (OIE) plays an important leadership role in global efforts to prevent, detect and respond to infectious disease threats. Since 1924, the OIE has helped Member Countries to prevent the spread of animal diseases, while facilitating safe agricultural trade. In recent years, the OIE has also increasingly focused on the biosecurity objectives of preventing unauthorised access to and loss, theft, misuse or diversion of dangerous pathogens, including their intentional release. Preventing the intentional introduction of animal disease is critical not only because of the significant economic impact that animal diseases can have on a nation's economy, but also because a number of animal diseases can affect humans. Over 60% of human diseases are of animal origin. Therefore, the OIE, working in conjunction with its partner organisations, the Food and Agriculture Organization of the United Nations and the World Health Organization, has become a leading international organisation for the control of global infectious disease in humans as well as in animals.

L'Organisation mondiale de la santé animale (OIE) joue un rôle de chef de file dans les efforts mobilisés à l'échelle mondiale pour la prévention des menaces liées aux maladies infectieuses, leur détection et la réponse qui y est apportée. Depuis sa création en 1924, l'OIE aide ses Pays membres à prévenir la propagation des maladies animales tout en facilitant l'accès sans risque de leurs productions agricoles aux marchés internationaux. Depuis quelques années, l'OIE porte une attention accrue aux objectifs de biosûreté, c'est-à-dire l'ensemble des mesures prises pour prévenir l'accès sans autorisation, la perte, le vol, l'utilisation abusive ou l'emploi détourné d'agents pathogènes dangereux ainsi que leur libération délibérée. La prévention de l'introduction intentionnelle de maladies animales est un impératif majeur, non seulement parce que ces maladies ont un impact économique important sur l'économie d'un pays, mais aussi parce qu'un certain nombre d'entre elles affectent également l'être humain. En effet, plus de 60 % des maladies humaines sont d'origine animale. L'OIE, qui œuvre sur ces questions aux côtés de ses organisations partenaires (l'Organisation des Nations Unies pour l'alimentation et l'agriculture et l'Organisation mondiale de la santé), est devenue l'organisation phare dans le domaine de la lutte contre les maladies infectieuses dans le monde, tant humaines qu'animales.

La Organización Mundial de Sanidad Animal (OIE) cumple una importante función a la cabeza de las actividades mundiales para prevenir y detectar amenazas infecciosas y responder a ellas. Desde 1924, la OIE viene ayudando a sus Países Miembros a prevenir la propagación de enfermedades animales, facilitando al mismo tiempo un comercio agrícola seguro. De unos años a esta parte, también presta cada vez más atención a los objetivos de seguridad biológica consistentes en impedir el acceso no autorizado a patógenos peligrosos, así como su pérdida, robo, utilización indebida o sustracción, y en particular su liberación intencionada. La prevención de la introducción deliberada de enfermedades animales es fundamental no solo porque las enfermedades animales pueden perjudicar sustancialmente la economía de una nación, sino además porque muchas de esas patologías también pueden afectar al ser humano. Más del 60% de las enfermedades humanas son de origen animal. De ahí que a día de hoy la OIE, trabajando junto con otras organizaciones colaboradoras, a saber, la Organización de las Naciones Unidas para la Alimentación y la Agricultura y la Organización Mundial de la Salud, sea una de las principales instancias que obran por el control de las enfermedades infecciosas de personas y animales a escala planetaria.

Genome-wide differentiation in closely related populations: the roles of selection and geographic isolation.

Population divergence in geographic isolation is due to a combination of factors. Natural and sexual selection may be important in shaping patterns of population differentiation, a pattern referred to as 'isolation by adaptation' (IBA). IBA can be complementary to the well-known pattern of 'isolation by distance' (IBD), in which the divergence of closely related populations (via any evolutionary process) is associated with geographic isolation. The barn swallow Hirundo rustica complex comprises six closely related subspecies, where divergent sexual selection is associated with phenotypic differentiation among allopatric populations. To investigate the relative contributions of selection and geographic distance to genome-wide differentiation, we compared genotypic and phenotypic variation from 350 barn swallows sampled across eight populations (28 pairwise comparisons) from four different subspecies. We report a draft whole-genome sequence for H. rustica, to which we aligned a set of 9493 single nucleotide polymorphisms (SNPs). Using statistical approaches to control for spatial autocorrelation of phenotypic variables and geographic distance, we find that divergence in traits related to migratory behaviour and sexual signalling, as well as geographic distance, together explain over 70% of genome-wide divergence among populations. Controlling for IBD, we find 42% of genomewide divergence is attributable to IBA through pairwise differences in traits related to migratory behaviour and sexual signalling alone. By (i) combining these results with prior studies of how selection shapes morphological differentiation and (ii) accounting for spatial autocorrelation, we infer that morphological adaptation plays a large role in shaping population-level differentiation in this group of closely related populations.

Profiling gene expression to distinguish the likely active diazotrophs from a sea of genetic potential in marine sediments.

Nitrogen (N) cycling microbial communities in marine sediments are extremely diverse, and it is unknown whether this diversity reflects extensive functional redundancy. Sedimentary denitrifiers remove significant amounts of N from the coastal ocean and diazotrophs are typically regarded as inconsequential. Recently, N fixation has been shown to be a potentially important source of N in estuarine and continental shelf sediments. Analysis of expressed genes for nitrite reductase (nirS) and a nitrogenase subunit (nifH) was used to identify the likely active denitrifiers and nitrogen fixers in surface sediments from different seasons in Narragansett Bay (Rhode Island, USA). The overall diversity of diazotrophs expressing nifH decreased along the estuarine gradient from the estuarine head to an offshore continental shelf site. Two groups of sequences related to anaerobic sulphur/iron reducers and sulphate reducers dominated libraries of expressed nifH genes. Quantitative polymerase chain reaction (qPCR) and quantitative reverse transcription polymerase chain reaction (qRT-PCR) data shows the highest abundance of both groups at a mid bay site, and the highest nifH expression at the head of the estuary, regardless of season. Several potential environmental factors, including water temperature, oxygen concentration and metal contamination, may influence the abundance and nifH expression of these two bacterial groups.

Exacerbated inflammatory arthritis in response to hyperactive gp130 signalling is independent of IL-17A.

OBJECTIVE: Interleukin (IL)-17A producing CD4 T-cells (TH-17 cells) are implicated in rheumatoid arthritis (RA). IL-6/STAT3 signalling drives TH-17 cell differentiation, and hyperactive gp130/STAT3 signalling in the gp130F/F mouse promotes exacerbated pathology. Conversely, STAT1-activating cytokines (eg, IL-27, IFN-γ) inhibit TH-17 commitment. Here, we evaluate the impact of STAT1 ablation on TH-17 cells during experimental arthritis and relate this to IL-17A-associated pathology. METHODS: Antigen-induced arthritis (AIA) was established in wild type (WT), gp130F/F mice displaying hyperactive gp130-mediated STAT signalling and the compound mutants gp130F/F:Stat1-/- and gp130F/F:Il17a-/- mice. Joint pathology and associated peripheral TH-17 responses were compared. RESULTS: Augmented gp130/STAT3 signalling enhanced TH-17 commitment in vitro and exacerbated joint pathology. Ablation of STAT1 in gp130F/F mice (gp130F/F:Stat1-/-) promoted the hyperexpansion of TH-17 cells in vitro and in vivo during AIA. Despite this heightened peripheral TH-17 cell response, disease severity and the number of joint-infiltrating T-cells were comparable with that of WT mice. Thus, gp130-mediated STAT1 activity within the inflamed synovium controls T-cell trafficking and retention. To determine the contribution of IL-17A, we generated gp130F/F:IL-17a-/- mice. Here, loss of IL-17A had no impact on arthritis severity. CONCLUSIONS: Exacerbated gp130/STAT-driven disease in AIA is associated with an increase in joint infiltrating T-cells but synovial pathology is IL-17A independent.

Heat stress effects on the cumulus cells surrounding the bovine oocyte during maturation: altered matrix metallopeptidase 9 and progesterone production.

When the effects of heat stress are detrimental during maturation, cumulus cells are intimately associated with the oocyte. To determine the extent to which heat stress affects these cells, in this study, transcriptome profiles of the cumulus that surrounded control and heat-stressed oocytes (41 °C during the first 12 h only and then shifted back to 38.5 °C) during in vitro maturation (IVM) were compared using Affymetrix bovine microarrays. The comparison of cumulus-derived profiles revealed a number of transcripts whose levels were increased (n=11) or decreased (n=13) ≥ twofold after heat stress exposure (P<0.01), sufficient to reduce the development of blastocysts by 46.4%. In a separate study, quantitative PCR (qPCR) was used to confirm heat-induced differences in the relative abundances of the transcripts of five different genes (caveolin 1, matrix metallopeptidase 9, FSH receptor, Indian hedgehog homolog, and inducible nitric oxide synthase). Heat stress exposure resulted in >1.7-fold decrease in the protein levels of latent matrix metallopeptidase 9 (proMMP9). Heat-induced reductions in transcript levels were noted at 6 h IVM with reductions in proMMP9 protein levels at 18 h IVM (P=0.0002). Independent of temperature, proMMP9 levels at 24 h IVM were positively correlated with the development rate of blastocysts (R²=0.36; P=0.002). The production of progesterone increased during maturation; heat-induced increases were evident by 12 h IVM (P=0.002). Both MMP9 and progesterone are associated with the developmental competence of the oocyte; thus, it seems plausible for some of the negative consequences of heat stress on the cumulus-oocyte complex to be mediated through heat-induced perturbations occurring in the surrounding cumulus.

Cascaded diffractive optical elements for improved multiplane image reconstruction.

Computer-generated phase-only diffractive optical elements in a cascaded setup are designed by one deterministic and one stochastic algorithm for multiplane image formation. It is hypothesized that increasing the number of elements as wavefront modulators in the longitudinal dimension would enlarge the available solution space, thus enabling enhanced image reconstruction. Numerical results show that increasing the number of holograms improves quality at the output. Design principles, computational methods, and specific conditions are discussed.

Combined PET/MRS brain studies show dynamic and long-term physiological changes in a primate model of Parkinson disease.

We used brain imaging to study long-term neurodegenerative and bioadaptive neurochemical changes in a primate model of Parkinson disease. We gradually induced a selective loss of nigrostriatal dopamine neurons, similar to that of Parkinson disease, by creating oxidative stress through infusion of the mitochondrial complex 1 inhibitor MPTP for 14+/-5 months. Repeated evaluations over 3 years by positron emission tomography (PET) demonstrated progressive and persistent loss of neuronal dopamine pre-synaptic re-uptake sites; repeated magnetic resonance spectroscopy (MRS) studies indicated a 23-fold increase in lactate and macromolecules in the striatum region of the brain for up to 10 months after the last administration of MPTP. By 2 years after the MPTP infusions, these MRS striatal lactate and macromolecule values had returned to normal levels. In contrast, there were persistent increases in striatal choline and decreases in N-acetylaspartate. Thus, these combined PET/MRS studies demonstrate patterns of neurochemical changes that are both dynamic and persistent long after selective dopaminergic degeneration.

Paracetamol and selective and non-selective non-steroidal anti-inflammatory drugs for the reduction in morphine-related side-effects after major surgery: a systematic review.

Non-opioid analgesics, paracetamol, non-steroidal anti-inflammatory drugs (NSAIDs), or cyclo-oxygenase 2 (COX-2) inhibitors are often given along with morphine as part of multimodal analgesia after major surgery. We have undertaken a systematic review and a mixed treatment comparison (MTC) analysis in order to determine explicitly which class of non-opioid analgesic, paracetamol, NSAIDs, or COX-2 inhibitors is the most effective in reducing morphine consumption and morphine-related adverse effects. Sixty relevant studies were identified. The MTC found that when paracetamol, NSAIDs, or COX-2 inhibitors were added to patient-controlled analgesia (PCA) morphine, there was a statistically significant reduction in morphine consumption: paracetamol [mean difference (MD) -6.34 mg; 95% credibility interval (CrI) -9.02, -3.65], NSAIDs (MD -10.18; 95% CrI -11.65, -8.72), and COX-2 inhibitors (MD -10.92; 95% CrI -12.77, -9.08). There was a significant reduction in nausea and postoperative nausea and vomiting with NSAIDs compared with placebo (odds ratio 0.70; 95% CrI 0.53, 0.88) but not for paracetamol or COX-2 inhibitors, nor for NSAIDs compared with paracetamol or COX-2 inhibitors. There was no statistically significant difference in sedation between any intervention and comparator. On the basis of six trials (n=695), 2.4% of participants receiving an NSAID experienced surgical-related bleeding compared with 0.4% with placebo. The MTC found that there is a decrease in 24 h morphine consumption when paracetamol, NSAID, or COX-2 inhibitors are given in addition to PCA morphine after surgery, with no clear difference between them. Similarly, the benefits in terms of reduction in morphine-related adverse effects do not strongly favour one of the three non-opioid analgesics.

Wavelet-based CNN for Predicting PAP Adherence Using Overnight Polysomnography Recordings: a Pilot Study.

Obstructive sleep apnea (OSA) is a common sleep disorder. Positive airway pressure (PAP) therapy is the first-line treatment, while its effectiveness is significantly limited by incomplete adherence in many patients. This work aims to find a predictive association between data from in-laboratory sleep studies during treatment (PAP titration polysomnogram, or PSG) and PAP adherence. Based on a PAP titration PSG database, we present a pipeline to develop a wavelet-based deep learning model and address two challenges. First, to tackle the problem of extremely long overnight PSG signals, it randomly draws segments and extracts features locally. The global representation for the entire signal is achieved by local feature P-norm pooling. Second, to tackle the problem of limited dataset size, the pre-trained EfficienNet-B7 is used as an unsupervised feature extractor to transfer ImageNet knowledge to PSG signals in the wavelet domain. The trained pipeline achieves 78% balanced accuracy and 83% AUC on the test set using airflow and frontal EEG signals, which, we believe, is a compelling result as a pilot study.

Suboptimal sleep and incident cardiovascular disease among African Americans in the Jackson Heart Study (JHS).

BACKGROUND: Suboptimal sleep, including insufficient/long sleep duration and poor sleep quality, is a risk factor for cardiovascular disease (CVD) common but there is little information among African Americans, a group with a disproportionate CVD burden. The current study examined the association between suboptimal sleep and incident CVD among African Americans. METHODS: This study included 4,522 African Americans without CVD at baseline (2000-2004) of the Jackson Heart Study (JHS). Self-reported sleep duration was defined as very short (<6 h/night), short (6 h/night), recommended (7-8 h/night), and long (≥9 h/night). Participants' self-reported sleep quality was defined as "high" and "low" quality. Suboptimal sleep was defined by low quality sleep and/or insufficient/long sleep duration. Incident CVD was a composite of incident coronary heart disease and stroke. Associations between suboptimal sleep and incident CVD were examined using Cox proportional hazards models over 15 follow-up years with adjustment for predictors of CVD risk and obstructive sleep apnea. RESULTS: Sample mean age was 54 years (SD = 13), 64% female and 66% reported suboptimal sleep. Suboptimal sleep was not associated with incident CVD after covariate adjustment [HR(95% CI) = 1.18(0.97-1.46)]. Long [HR(95%CI) = 1.32(1.02-1.70)] and very short [HR(95% CI) = 1.56(1.06-2.30)] sleep duration were associated with incident CVD relative to recommended sleep duration. Low quality sleep was not associated with incident CVD (p = 0.413). CONCLUSIONS: Long and very short self-reported sleep duration but not self-reported sleep quality were associated with increased hazard of incident CVD.