Application of pharmacogenomics and bioinformatics to exemplify the utility of human <i>ex vivo</i> organoculture models in the field of precision medicine

Here we describe a collaboration between industry, the National Health Service (NHS) and academia that sought to demonstrate how early understanding of both pharmacology and genomics can improve strategies for the development of precision medicines. Diseased tissue ethically acquired from patients suffering from chronic obstructive pulmonary disease (COPD), was used to investigate inter-patient variability in drug efficacy using ex vivo organocultures of fresh lung tissue as the test system. The reduction in inflammatory cytokines in the presence of various test drugs was used as the measure of drug efficacy and the individual patient responses were then matched against genotype and microRNA profiles in an attempt to identify unique predictors of drug responsiveness. Our findings suggest that genetic variation in CYP2E1 and SMAD3 genes may partly explain the observed variation in drug response

The Asymmetric Merger of Black Holes

We study event horizons of non-axisymmetric black holes and show how features found in axisymmetric studies of colliding black holes and of toroidal black holes are non-generic and how new features emerge. Most of the details of black hole formation and black hole merger are known only in the axisymmetric case, in which numerical evolution has successfully produced dynamical space-times. The work that is presented here uses a new approach to construct the geometry of the event horizon, not by locating it in a given spacetime, but by direct construction. In the axisymmetric case, our method produces the familiar pair-of-pants structure found in previous numerical simulations of black hole mergers, as well as event horizons that go through a toroidal epoch as discovered in the collapse of rotating matter. The main purpose of this paper is to show how new - substantially different - features emerge in the non-axisymmetric case. In particular, we show how black holes generically go through a toroidal phase before they become spherical, and how this fits together with the merger of black holes.Comment: 28 pages, 10 figures, uses REVTEX. Improved quality figures and additional color images are provided at http://www.phyast.pitt.edu/~shusa/EH

Modern Solutions for Ancient Pathogens: Direct Pathogen Sequencing for Diagnosis of Lepromatous Leprosy and Cerebral Coenurosis.

Microbes unculturable in vitro remain diagnostically challenging, dependent historically on clinical findings, histology, or targeted molecular detection. We applied whole-genome sequencing directly from tissue to diagnose infections with mycobacteria (leprosy) and parasites (coenurosis). Direct pathogen DNA sequencing provides flexible solutions to diagnosis of difficult pathogens in diverse contexts

BINGO: A code for the efficient computation of the scalar bi-spectrum

We present a new and accurate Fortran code, the BI-spectra and Non-Gaussianity Operator (BINGO), for the efficient numerical computation of the scalar bi-spectrum and the non-Gaussianity parameter f_{NL} in single field inflationary models involving the canonical scalar field. The code can calculate all the different contributions to the bi-spectrum and the parameter f_{NL} for an arbitrary triangular configuration of the wavevectors. Focusing firstly on the equilateral limit, we illustrate the accuracy of BINGO by comparing the results from the code with the spectral dependence of the bi-spectrum expected in power law inflation. Then, considering an arbitrary triangular configuration, we contrast the numerical results with the analytical expression available in the slow roll limit, for, say, the case of the conventional quadratic potential. Considering a non-trivial scenario involving deviations from slow roll, we compare the results from the code with the analytical results that have recently been obtained in the case of the Starobinsky model in the equilateral limit. As an immediate application, we utilize BINGO to examine of the power of the non-Gaussianity parameter f_{NL} to discriminate between various inflationary models that admit departures from slow roll and lead to similar features in the scalar power spectrum. We close with a summary and discussion on the implications of the results we obtain.Comment: v1: 5 pages, 5 figures; v2: 35 pages, 11 figures, title changed, extensively revised; v3: 36 pages, 11 figures, to appear in JCAP. The BINGO code is available online at http://www.physics.iitm.ac.in/~sriram/bingo/bingo.htm

Distasteful nectar deters floral robbery

Toxic nectar is an ecological paradox[1,2]. Plants divert substantial resources to produce nectar that attracts pollinators [3], but toxins in this reward could disrupt the mutualism and reduce plant fitness [4]. Alternatively, such compounds could protect nectar from robbers [2], provided they do not significantly alter pollinator visitation to the detriment of plant fitness [1,5–8]. Indeed, very few studies have investigated the role of plant toxins in nectar for defence against nectar robbers [4,9,10]. Here, we compared two Aconitum species (A. napellus and A. lycoctonum) that have flowers specialized for long-tongued bumblebee pollinators (Bombus hortorum) but are occasionally robbed by short-tongued bumblebees (B. terrestris) [6,11–13]. Pollinator visits to flowers were much more frequent than by robbers but visits correlated negatively with nectar alkaloid concentration and declined sharply between 200-380ppm. However, alkaloid concentrations of > 20ppm were deterrent to B. terrestris suggesting robbers were less tolerant of nectar alkaloids. Nectar of both plant species contained similar concentrations of carbohydrates and toxic alkaloids, but A. lycoctonum was more likely to secrete nectar in each flower and was also visited more frequently by pollinators and robbers.  We conclude that alkaloids in Aconitum sp. nectar affect rates of both pollinator visitation and robbery but may have co-evolved with nectar availability to maintain the fitness benefits of specialized plant-pollinator relationships. Chemical defence of nectar is, however, ultimately constrained by pollinator gustatory sensitivity

Intraperitoneal drain placement and outcomes after elective colorectal surgery: international matched, prospective, cohort study

Despite current guidelines, intraperitoneal drain placement after elective colorectal surgery remains widespread. Drains were not associated with earlier detection of intraperitoneal collections, but were associated with prolonged hospital stay and increased risk of surgical-site infections.Background Many surgeons routinely place intraperitoneal drains after elective colorectal surgery. However, enhanced recovery after surgery guidelines recommend against their routine use owing to a lack of clear clinical benefit. This study aimed to describe international variation in intraperitoneal drain placement and the safety of this practice. Methods COMPASS (COMPlicAted intra-abdominal collectionS after colorectal Surgery) was a prospective, international, cohort study which enrolled consecutive adults undergoing elective colorectal surgery (February to March 2020). The primary outcome was the rate of intraperitoneal drain placement. Secondary outcomes included: rate and time to diagnosis of postoperative intraperitoneal collections; rate of surgical site infections (SSIs); time to discharge; and 30-day major postoperative complications (Clavien-Dindo grade at least III). After propensity score matching, multivariable logistic regression and Cox proportional hazards regression were used to estimate the independent association of the secondary outcomes with drain placement. Results Overall, 1805 patients from 22 countries were included (798 women, 44.2 per cent; median age 67.0 years). The drain insertion rate was 51.9 per cent (937 patients). After matching, drains were not associated with reduced rates (odds ratio (OR) 1.33, 95 per cent c.i. 0.79 to 2.23; P = 0.287) or earlier detection (hazard ratio (HR) 0.87, 0.33 to 2.31; P = 0.780) of collections. Although not associated with worse major postoperative complications (OR 1.09, 0.68 to 1.75; P = 0.709), drains were associated with delayed hospital discharge (HR 0.58, 0.52 to 0.66; P &lt; 0.001) and an increased risk of SSIs (OR 2.47, 1.50 to 4.05; P &lt; 0.001). Conclusion Intraperitoneal drain placement after elective colorectal surgery is not associated with earlier detection of postoperative collections, but prolongs hospital stay and increases SSI risk

Convalescent plasma in patients admitted to hospital with COVID-19 (RECOVERY): a randomised controlled, open-label, platform trial

Background: Many patients with COVID-19 have been treated with plasma containing anti-SARS-CoV-2 antibodies. We aimed to evaluate the safety and efficacy of convalescent plasma therapy in patients admitted to hospital with COVID-19. Methods: This randomised, controlled, open-label, platform trial (Randomised Evaluation of COVID-19 Therapy [RECOVERY]) is assessing several possible treatments in patients hospitalised with COVID-19 in the UK. The trial is underway at 177 NHS hospitals from across the UK. Eligible and consenting patients were randomly assigned (1:1) to receive either usual care alone (usual care group) or usual care plus high-titre convalescent plasma (convalescent plasma group). The primary outcome was 28-day mortality, analysed on an intention-to-treat basis. The trial is registered with ISRCTN, 50189673, and ClinicalTrials.gov, NCT04381936. Findings: Between May 28, 2020, and Jan 15, 2021, 11558 (71%) of 16287 patients enrolled in RECOVERY were eligible to receive convalescent plasma and were assigned to either the convalescent plasma group or the usual care group. There was no significant difference in 28-day mortality between the two groups: 1399 (24%) of 5795 patients in the convalescent plasma group and 1408 (24%) of 5763 patients in the usual care group died within 28 days (rate ratio 1·00, 95% CI 0·93–1·07; p=0·95). The 28-day mortality rate ratio was similar in all prespecified subgroups of patients, including in those patients without detectable SARS-CoV-2 antibodies at randomisation. Allocation to convalescent plasma had no significant effect on the proportion of patients discharged from hospital within 28 days (3832 [66%] patients in the convalescent plasma group vs 3822 [66%] patients in the usual care group; rate ratio 0·99, 95% CI 0·94–1·03; p=0·57). Among those not on invasive mechanical ventilation at randomisation, there was no significant difference in the proportion of patients meeting the composite endpoint of progression to invasive mechanical ventilation or death (1568 [29%] of 5493 patients in the convalescent plasma group vs 1568 [29%] of 5448 patients in the usual care group; rate ratio 0·99, 95% CI 0·93–1·05; p=0·79). Interpretation: In patients hospitalised with COVID-19, high-titre convalescent plasma did not improve survival or other prespecified clinical outcomes. Funding: UK Research and Innovation (Medical Research Council) and National Institute of Health Research