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Background AZD2811 is a potent, selective Aurora kinase B inhibitor. We report the dose-escalation phase of a first-in-human study assessing nanoparticle-encapsulated AZD2811 in advanced solid tumours. Methods AZD2811 was administered in 12 dose-escalation cohorts (2-h intravenous infusion; 15‒600 mg; 21-/28-day cycles) with granulocyte colony-stimulating factor (G-CSF) at higher doses. The primary objective was determining safety and maximum tolerated/recommended phase 2 dose (RP2D). Results Fifty-one patients received AZD2811. Drug exposure was sustained for several days post-dose. The most common AZD2811-related adverse events (AEs) were fatigue (27.3%) at ≤200 mg/cycle and neutropenia (37.9%) at ≥400 mg/cycle. Five patients had dose-limiting toxicities: grade (G)4 decreased neutrophil count (n = 1, 200 mg; Days 1, 4; 28-day cycle); G4 decreased neutrophil count and G3 stomatitis (n = 1 each, both 400 mg; Day 1; 21-day cycle); G3 febrile neutropenia and G3 fatigue (n = 1 each, both 600 mg; Day 1; 21-day cycle +G-CSF). RP2D was 500 mg; Day 1; 21-day cycle with G-CSF on Day 8. Neutropenia/neutrophil count decrease were on-target AEs. Best overall responses were partial response (n = 1, 2.0%) and stable disease (n = 23, 45.1%). Conclusions At RP2D, AZD2811 was tolerable with G-CSF support. Neutropenia was a pharmacodynamic biomarker. Clinical trial registration NCT02579226.

BackgroundRestorative proctocolectomy with ileal pouch–anal anastomosis (IPAA) is the gold standard procedure for ulcerative colitis refractory to medical treatment, as an alternative to permanent end ileostomy. Gaining experience in pouch surgery is difficult as the procedure is performed infrequently. This study presents an institutional initiative to promote standardisation of multidisciplinary care in IPAA surgery.MethodsA dedicated pathway for patients who had an IPAA or are considering IPAA surgery was developed among colorectal surgeons, gastroenterologists, paediatric colorectal surgeons, inflammatory bowel disease (IBD) nurses, dietitians, stoma nurses, trainees in colorectal surgery. Pathway items were discussed and finalised via emails and videoconferences.The pathway included triaging of patients referred for IPAA surgery, preoperative IBD multidisciplinary team discussion and management plan for surgery, surgical review prior to surgery, peer to peer counselling, surgical technique, postoperative short-term and long-term follow-up, audit, research and training in IPAA surgery.ResultsA multidisciplinary preoperative pathway was developed and a stepwise approach to minimally invasive ileoanal pouch surgery was formalised. A dedicated one-stop ileoanal pouch clinic was established integrating endoscopy and imaging on the same day of the consultation with the surgical and gastroenterology team. The clinic reviewed 72 patients over 24 months, and during the same time 36 patients underwent IPAA surgery at our institution.ConclusionsWe have described our initial experience in establishing a specialist IPAA surgery pathway and have proposed outcome measures that we hope will support a subspecialty IPAA service.

Stroke is a common cause of death and disability in both men and women. Differences in the incidence, presenting features and outcome after stroke have been reported between men and women. The global lifetime risk of stroke of approximately 25% is similar in men and women, although in women, the first cardiovascular event is more likely to be stroke than in men. Concerningly, there are reports of underuse of some treatments in women, although these differences may be diminishing over time. In addition, there are specific clinical challenges that can arise in women with stroke, such as stroke in people taking hormonal therapy, and stroke during pregnancy and stroke in the post-partum period. This review will cover these areas highlighting important differences and areas for future research. We found there are important differences in incidence of stroke, which differ by age. Further, there is concerning evidence that some treatments such as intravenous thrombolysis are underused in women. While there may be some differences in the relative effectiveness of treatments such as antiplatelet therapy and blood pressure reduction between men and women, for most aspects of stroke care, benefit is clear in both men and women and the emphasis must be on more equitable access. There is limited evidence to inform decision making during pregnancy and the post-partum period, but guidelines now exist and further research is needed in these areas.

SARS-CoV-2 diagnostic practices broadly involve either quantitative polymerase chain reaction (qPCR)-based nucleic amplification of viral sequences or antigen-based tests such as lateral flow assays (LFAs). Reverse transcriptase-qPCR can detect viral RNA and is the gold standard for sensitivity. However, the technique is time-consuming and requires expensive laboratory infrastructure and trained staff. LFAs are lower in cost and near real time, and because they are antigen-based, they have the potential to provide a more accurate indication of a disease state. However, LFAs are reported to have low real-world sensitivity and in most cases are only qualitative. Here, an antigen-based electrochemical aptamer sensor is presented, which has the potential to address some of these shortfalls. An aptamer, raised to the SARS-CoV-2 spike protein, was immobilized on a low-cost gold-coated polyester substrate adapted from the blood glucose testing industry. Clinically relevant detection levels for SARS-CoV-2 are achieved in a simple, label-free measurement format using sample incubation times as short as 15 min on nasopharyngeal swab samples. This assay can readily be optimized for mass manufacture and is compatible with a low-cost meter.

An often-overlooked aspect of human missions to Mars is that the optimal path to the Red Planet could include a flyby of Venus. As part of so-called opposition missions, a crewed spacecraft would, after departing Earth, approach Venus en route to Mars. Such Venus flybys would offer unique opportunities to practice deep-space human operations during phases of flight for which a direct return to Earth would be a viable abort option. Indeed, crewed flyby missions to Venus provide a basis for longer-duration human spaceflight activities before committing to longer-duration and lower-launch-cadence missions solely to Mars. During Venus flybys, astronauts bound for Mars could carry out opportunistic “human-in-the-loop” scientific activities, such as controlling an aerial platform or directing in situ sampling by a landed spacecraft for much lower cost than a dedicated crewed mission to Venus. An independent crewed Venus flyby could also serve as a useful systems demonstration mission prior to a first human mission to Mars. With a renewed focus on landing humans on Mars in the 2030s and the formidable challenges still ahead for safe and successful long-duration human spaceflight, the time to consider incorporating Venus on the path to Mars is now.

The inaccessibility of living bone marrow (BM) hampers the study of its pathophysiology under myelotoxic stress induced by drugs, radiation or genetic mutations. Here, we show that a vascularized human BM-on-a-chip (BM chip) supports the differentiation and maturation of multiple blood cell lineages over 4 weeks while improving CD34+ cell maintenance, and that it recapitulates aspects of BM injury, including myeloerythroid toxicity after clinically relevant exposures to chemotherapeutic drugs and ionizing radiation, as well as BM recovery after drug-induced myelosuppression. The chip comprises a fluidic channel filled with a fibrin gel in which CD34+ cells and BM-derived stromal cells are co-cultured, a parallel channel lined by human vascular endothelium and perfused with culture medium, and a porous membrane separating the two channels. We also show that BM chips containing cells from patients with the rare genetic disorder Shwachman–Diamond syndrome reproduced key haematopoietic defects and led to the discovery of a neutrophil maturation abnormality. As an in vitro model of haematopoietic dysfunction, the BM chip may serve as a human-specific alternative to animal testing for the study of BM pathophysiology. A vascularized human bone-marrow-on-a-chip improves the maintenance of patient-derived CD34+ cells, and recapitulates clinically relevant aspects of bone marrow injury as well as key haematopoietic defects of patients with a rare genetic disorder.

This paper presents a survey informing a user-first approach to designing calming affective haptic stimuli by eliciting user preferences in different social scenarios. Prior affective haptics research presented users with stimuli and recorded emotional responses. By contrast this work focuses on the sensations users wish to experience and how these can be simulated using haptics. The survey (n=81) investigated which users preferences in four social situations to reduce social anxiety. Using thematic analysis of responses we created a coding scheme of stimuli derived from real-world experiences to emulate with affective haptics. By cross-referencing these categories with affective haptics research, we provide recommendations to designers about which calming stimuli users wish to experience socially and how they can be implemented.

SARS-CoV-2 diagnostic practices broadly involve either qPCR based nucleic amplification or lateral flow assays (LFAs). qPCR based techniques suffer from the disadvantage of requiring thermal cycling (difficult to implement for low-cost field use) leading to limitation on sample to answer time, the potential to amplify viral RNA sequences after a person is no longer infectious and being reagent intense. LFA performance is restricted by qualitative or semi-quantitative readouts, limits on sensitivity and poor reproducibility. Electrochemical biosensors, and particularly glucose test strips, present an appealing platform for development of biosensing solutions for SARS-CoV-2 as they can be multiplexed and implemented at very low cost at point of use with high sensitivity and quantitative digital readout. This work reports the successful raising of an Opti-mer sequence for the spike protein of SARS-CoV-2 and then development of an impedimetric biosensor which utilises thin film gold sensors on low-cost laminate substrates from home blood glucose monitoring. Clinically relevant detection levels for SARS-CoV-2 are achieved in a simple, label-free measurement format using sample incubation times of 15 minutes. The biosensor developed here is compatible with mass manufacture, is sensitive and low-cost CE marked readout instruments already exist. These findings pave the way to a low cost and mass manufacturable test with the potential to overcome the limitations associated with current technologies.

Aim: The skeletal muscle Cl− channels, the ClC-1 channels, stabilize the resting membrane potential and dampen muscle fibre excitability. This study explored whether ClC-1 inhibition can recover nerve-stimulated force in isolated muscle under conditions of compromised neuromuscular transmission akin to disorders of myasthenia gravis and Lambert–Eaton syndrome. Methods: Nerve-muscle preparations were isolated from rats. Preparations were exposed to pre-or post-synaptic inhibitors (ω-agatoxin, elevated extracellular Mg2+, α-bungarotoxin or tubocurarine). The potential of ClC-1 inhibition (9-AC or reduced extracellular Cl−) to recover nerve-stimulated force under these conditions was assessed. Results: ClC-1 inhibition recovered force in both slow-twitch soleus and fast-twitch EDL muscles exposed to 0.2 µmol/L tubocurarine or 3.5 mmol/L Mg2+. Similarly, ClC-1 inhibition recovered force in soleus muscles exposed to α-bungarotoxin or ω-agatoxin. Moreover, the concentrations of tubocurarine and Mg2+ required for reducing force to 50% rose from 0.14 ± 0.02 µmol/L and 4.2 ± 0.2 mmol/L in control muscles to 0.45 ± 0.03 µmol/L and 4.7 ± 0.3 mmol/L in muscles with 9-AC respectively (P + channels (4-AP) relieve symptoms in myasthenia gravis and Lambert–Eaton syndrome, respectively. Neostigmine and 9-AC additively increased the tubocurarine concentration required to reduce nerve-stimulated force to 50% (0.56 ± 0.05 µmol/L with 9-AC and neostigmine) and, similarly, 4-AP and 9-AC additively increased the Mg2+ concentration required to reduce nerve-stimulated force to 50% (6.5 ± 0.2 mmol/L with 9-AC and 4-AP). Conclusion: This study shows that ClC-1 inhibition can improve neuromuscular function in pharmacological models of compromised neuromuscular transmission.

In a phase 1b study of acalabrutinib (a covalent Bruton tyrosine kinase (BTK) inhibitor) in combination with vistusertib (a dual mTORC1/2 inhibitor) in patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL), multiple ascending doses of the combination as intermittent or continuous schedules of vistusertib were evaluated. The overall response rate was 12% (3/25). The pharmacodynamic (PD) profile for acalabrutinib showed that BTK occupancy in all patients was >95%. In contrast, PD analysis for vistusertib showed variable inhibition of phosphorylated 4EBP1 (p4EBP1) without modulation of AKT phosphorylation (pAKT). The pharmacokinetic (PK)/PD relationship of vistusertib was direct for TORC1 inhibition (p4EBP1) but did not correlate with TORC2 inhibition (pAKT). Cell-of-origin subtyping or next-generation sequencing did not identify a subset of DLBCL patients with clinical benefit; however, circulating tumor DNA dynamics correlated with radiographic response. These data suggest that vistusertib does not modulate targets sufficiently to add to the clinical activity of acalabrutinib monotherapy. Clinicaltrials.gov identifier: NCT03205046.

We note that intussusception was likely associated with severe acute respiratory syndrome coronavirus-2 infection in 2 infants in Wuhan and London. The intussusception was reduced by enemas in Wuhan; the outcome was fatal. The intussusception was not reduced by enemas in London and required surgery; the outcome was favorable.

Vistusertib is an orally bioavailable dual target of rapamycin complex (TORC) 1/2 kinase inhibitor currently under clinical investigation in various solid tumour and haematological malignancy settings. The pharmacokinetic, metabolic and excretion profiles of 14Carbon-isotope (14C)-labelled vistusertib were characterised in this open-label phase I patient study. Four patients with advanced solid malignancies received a single oral solution dose of 14C-labelled vistusertib. Blood, urine, faeces, and saliva samples were collected at various time points during the 8-day in-patient period of the study. Safety and preliminary efficacy were also assessed. 14C-labelled vistusertib was rapidly absorbed following administration (time to maximum concentration (Tmax) 90% of radioactivity was recovered with the majority recovered as metabolites in faeces (on average 80% vs. 12% recovered in urine). The majority of circulating radioactivity (~ 78%) is unchanged vistusertib. Various morpholine-ring oxidation metabolites and an N-methylamide circulate at low concentrations [each

Aims This paper describes the pharmacological findings from a study where otelixizumab, an anti-CD3ɛ mAb, was dosed in new onset Type 1 diabetes mellitus (NOT1DM) patients. This is the first time that the full dose-response of an anti-CD3ɛ mAb has been investigated in the clinic. The data have been validated using a previously developed pharmacokinetic/pharmacodynamic (PK/PD) model of otelixizumab to simulate the interplay between drug administration, CD3ɛ target engagement and downmodulation. Methods Patients were randomized to control or active treatment with otelixizumab (1:4), administered via infusion over 6 days, in a dose-ascending study consisted of three cohorts (n = 10 per cohort) at doses of 9, 18 or 27 mg respectively. The study allowed quantification of otelixizumab PK, CD3ɛ target engagement and its pharmacodynamic effect (CD3e/TCR modulation on circulating T lymphocytes). Results Otelixizumab concentrations increased and averaged to 364.09 (54.3), 1625.55 (72.5) and 2781.35 (28.0) ng ml-1 (Geom.mean, %CV) at the 9, 18 and 27 mg dose respectively. CD3ɛ target engagement was found to be rapid (within the first 30 min), leading to a receptor occupancy of ~60% within 6 h of dosing in all three doses. A dose-response relationship was observed with the two highest doses achieving a ~90% target engagement and consequential CD3ɛ/TCR downmodulation by Day 6. Conclusions Data from this study revealed maximum target engagement and CD3ɛ/TCR modulation is achieved at doses of 18, 27 mg of otelixizumab. These findings can be useful in guiding dose selection in clinical trials with anti-CD3ɛ mAbs.

COVID-19’s impact on society and our daily habits has been unprecedented. With a decrease in vehicular traffic and industrial production, a decrease in local emissions was expected to occur. In ord...

Accurate and rapid diagnostic tests are critical to reducing the impact of SARS-CoV-2. This study presents early, but promising measurements of SARS-CoV-2 using the ACE2 enzyme as the recognition element to achieve clinically relevant detection. The test provides a scalable route to sensitive, specific, rapid and low cost mass testing.

In recent decades, Congress has steadily ceded power to the federal judiciary. The judiciary, not Congress, is often left to make important choices about federal policy, in part because Congress leaves it with too little guidance about its policy objectives. The problem has been exacerbated by textualism, which disregards extra-textual clues about Congress's intent. This paper argues that Congress can ameliorate the problem by adopting a Legislative History Act. The Act would direct judges to interpret statutes according to Congress's intent, as expressed in specified legislative-history materials. That direction would give textualist judges a textual hook to consider a much broader range of materials than they consider today. They would have more context for interpreting statutes, and would thus more often adopt interpretations in line with Congress's policy goals.

Emerging in late 2019, the SARS-CoV-2 virus has had a devastating health and economic effects around the world forcing governments to enact restrictions on day to day life, resulting in severe economic and social disruption. The virus has stimulated new research in the fields of drug development, vaccinology and diagnostic testing. Here we present the basis for a simple, mass manufacturable saliva based electrochemical assay for the SARS-CoV-2 virus acheived through adsorption of the Angiotsnsin Converting Enzyme 2 (ACE2) into thiolated amphiphobic prefluoro monolayer assemled on a gold sensor surface. Following sensor preparation, it is possible to measure specific binding of recombinant spike protein and discriminate positive and negative samples of inactivated SARS-CoV-2 following 30 minutes incubation under ambient conditions. Representative calculations of limits of detection are made for recombinant spike protein (1.68 ng/ml) and inactivated virus (37.8 dC/mL). The assay as presented ultimately shows discrimination between positive and negative inactivated SARS-CoV-2 samples originating from clinical molecular standards kit intended for clinical and biomedical assay validation, and which is designed to mimic clinical samples through presence of cells and proteins in the sample medium. The simple design of the label free measurement and the selection of reagents involved means the assay has clear potential for transfer onto mass producible units such as screen-printed electrodes similar to glucose-format test strips, to enable widespread, low cost and rapid testing for SARS-CoV-2 in the general population