Mutation burden and other molecular markers of prognosis in colorectal cancer treated with curative intent: results from the QUASAR 2 clinical trial and an Australian community-based series.

Background: Molecular indicators of colorectal cancer prognosis have been assessed in several studies, but most analyses have been restricted to a handful of markers. We aimed to identify prognostic biomarkers for colorectal cancer by sequencing panels of multiple driver genes.

Methods: In stage II or III colorectal cancers from the QUASAR 2 open-label randomised phase 3 clinical trial and an Australian community-based series, we used targeted next-generation sequencing of 82 and 113 genes, respectively, including the main colorectal cancer drivers.

Value of External Data in the Extrapolation of Survival Data: A Study Using the NJR Data Set.

Background: Extrapolation of time-to-event data can be a critical component of cost-effectiveness analysis.

Objectives: To contrast the value of external data on treatment effects as a selection aid in model fitting to the clinical data or for the direct extrapolation of survival.

Methods: We assume the existence of external summary data on both treatment and control and consider two scenarios: availability of external individual patient data (IPD) on the control only and an absence of external IPD.

Variability in Non-Vitamin K Antagonist Oral Anticoagulants Dose Adjustment in Atrial Fibrillation Patients With Renal Dysfunction: The Influence of Renal Function Estimation Formulae.

Background: Non-vitamin K antagonist oral anticoagulants (NOACs) require renal dose adjustment. The most common estimates of renal function in clinical practice are derived from estimated glomerular filtration rate (eGFR; Modified Diet in Renal Disease [MDRD] or the Chronic Kidney Disease Epidemiology Collaboration [CKD-EPI]). However, the landmark stroke prevention trials and product monographs recommend the use of the Cockcroft-Gault creatinine clearance equation (eCrCl) for drug eligibility and dose adjustment.

The evolutionary origins of pesticide resistance.

Durable crop protection is an essential component of current and future food security. However, the effectiveness of pesticides is threatened by the evolution of resistant pathogens, weeds and insect pests. Pesticides are mostly novel synthetic compounds, and yet target species are often able to evolve resistance soon after a new compound is introduced.

Fitness Penalties in the Evolution of Fungicide Resistance.

The evolution of resistance poses an ongoing threat to crop protection. Fungicide resistance provides a selective advantage under fungicide selection, but resistance-conferring mutations may also result in fitness penalties, resulting in an evolutionary trade-off. These penalties may result from the functional constraints of an evolving target site or from the resource allocation costs of overexpression or active transport.

Eligibility for cardiac resynchronization therapy in patients hospitalized with heart failure.

Aims: Recent guidelines recommend cardiac resynchronization therapy (CRT) in mildly symptomatic heart failure (HF) but favour left bundle branch block (LBBB) morphology in patients with moderate QRS prolongation (120-150 ms). We defined how many patients hospitalized with HF fulfil these criteria.

Methods And Results: A single-centre retrospective cohort study of 363 consecutive patients hospitalized with HF (438 admissions) was performed.

Haploinsufficiency Impairs Catalytic Activity of PARP1 and Promotes Chromosome Instability and Growth of Intestinal Tumors.

ADP-ribosylation is an important posttranslational protein modification that regulates diverse biological processes, controlled by dedicated transferases and hydrolases. Here, we show that frequent deletions (∼30%) of the mono-ADP-ribosylhydrolase locus in human colorectal cancer cause impaired PARP1 transferase activity in a gene dosage-dependent manner. haploinsufficiency alters DNA repair and sensitivity to DNA damage and results in chromosome instability.

The novel sodium channel modulator GS-458967 (GS967) is an effective treatment in a mouse model of SCN8A encephalopathy.

Objective: De novo mutations of SCN8A, encoding the voltage-gated sodium channel Na 1.6, have been associated with a severe infant onset epileptic encephalopathy. Individuals with SCN8A encephalopathy have a mean age of seizure onset of 4-5 months, with multiple seizure types that are often refractory to treatment with available drugs.

Worldwide emergence of resistance to antifungal drugs challenges human health and food security.

The recent rate of emergence of pathogenic fungi that are resistant to the limited number of commonly used antifungal agents is unprecedented. The azoles, for example, are used not only for human and animal health care and crop protection but also in antifouling coatings and timber preservation. The ubiquity and multiple uses of azoles have hastened the independent evolution of resistance in many environments.

Cost-effectiveness of alternative changes to a national blood collection service.

Objectives: To evaluate the cost-effectiveness of changing opening times, introducing a donor health report and reducing the minimum inter-donation interval for donors attending static centres.

Background: Evidence is required about the effect of changes to the blood collection service on costs and the frequency of donation.

Methods/materials: This study estimated the effect of changes to the blood collection service in England on the annual number of whole-blood donations by current donors.

Catheter ablation of atrial fibrillation in heart failure with reduced ejection fraction.

Atrial fibrillation and heart failure are increasing in prevalence, and frequently coexist. Despite the desire to restore sinus rhythm in heart failure patients, large studies comparing rate control to pharmacologic rhythm control have failed to show superiority of either approach. This may in part be due to the inefficacy and higher risk of adverse effects with antiarrhythmic drugs in HF patients.

Digest: Plants adapt under attack: genotypic selection and phenotypic plasticity under herbivore pressure.

Plant species adapt to changing environmental conditions through phenotypic plasticity and natural selection. Agrawal et al. (2018) found that dandelions responded to the presence of insect pests by producing higher levels of defensive compounds.

A systematic review of hepatitis B screening economic evaluations in low- and middle-income countries.

Background: Chronic hepatitis B infection is a significant cause of morbidity and mortality worldwide; low- and middle-income countries (LMICs) are disproportionately affected. Economic evaluations are a useful decision tool to assess costs versus benefits of hepatitis B virus (HBV) screening. No published study reviewing economic evaluations of HBV screening in LMICs has been undertaken to date.

Analysing the structure and glass transition behaviour of silks for archaeology and conservation.

Silk is an iconic material in many cultures. Silk archaeology and conservation is affected by silk production technology as well as subsequent environmental effects such as humidity, temperature, UV radiation and ageing The complex interactions and various effects on silk materials affect the practical use of silk, for example, in the conservation of ancient manuscripts. This study examines the various influences of silk provenance and processing, adhesive coatings and chemical treatments as well as natural and artificial ageing of the silk material.

Johne's disease: a successful eradication programme in a dairy goat herd.

This retrospective analysis and report describes the successful eradication and posteradication surveillance programme for Johne's disease ( subspecies (MAP)) in a closed herd of dairy goats. In 1994, MAP's presence in the goat herd was first suspected through individual annual serological screening and then subsequently confirmed through faecal culture and histopathology in 1997 when implementation of a more aggressive programme of testing and eradication of the diseased animals began. This programme included frequent serological screening of all adult goats using ELISA and agar gel immunodiffusion assays.

Lymphocytic response to tumour and deficient DNA mismatch repair identify subtypes of stage II/III colorectal cancer associated with patient outcomes.

Objective: Tumour-infiltrating lymphocyte (TIL) response and deficient DNA mismatch repair (dMMR) are determinants of prognosis in colorectal cancer. Although highly correlated, evidence suggests that these are independent predictors of outcome. However, the prognostic significance of combined TIL/MMR classification and how this compares to the major genomic and transcriptomic subtypes remain unclear.

Communicating with Daughters About Familial Risk of Breast Cancer: Individual, Family, and Provider Influences on Women's Knowledge of Cancer Risk.

Introduction: Women facing complex and uncertain situations such as cancer in their families may seek information from a variety of sources to gain knowledge about cancer risk and reduce uncertainty. We describe and assess the relative importance of information sources about familial breast cancer at the individual, family, and healthcare provider levels influencing women's reporting they had enough information to speak with daughters about breast cancer. This outcome we refer to as being informed about breast cancer.

Clinical effectiveness of a systematic "pill-in-the-pocket" approach for the management of paroxysmal atrial fibrillation.

Background: For patients with symptomatic, sustained atrial fibrillation (AF), a "pill-in-the-pocket" antiarrhythmic drug (PIP-AAD) strategy has been proposed to reduce emergency department (ED) use.

Objective: To assess the clinical utility of a protocolled PIP-AAD approach within contemporary practice.

Methods: Consecutive patients who hemodynamically tolerated symptomatic, sustained AF were prospectively managed with the PIP-AAD strategy.

Generation of transgenic goats by pronuclear microinjection: a retrospective analysis of a commercial operation (1995-2012).

Production of transgenic founder goats involves introducing and stably integrating an engineered piece of DNA into the genome of the animal. At LFB USA, the ultimate use of these transgenic goats is for the production of recombinant human protein therapeutics in the milk of these dairy animals. The transgene or construct typically links a milk protein specific promoter sequence, the coding sequence for the gene of interest, and the necessary downstream regulatory sequences thereby directing expression of the recombinant protein in the milk during the lactation period.

Azole sensitivity in Leptosphaeria pathogens of oilseed rape: the role of lanosterol 14α-demethylase.

Lanosterol 14-α demethylase is a key enzyme intermediating the biosynthesis of ergosterol in fungi, and the target of azole fungicides. Studies have suggested that Leptosphaeria maculans and L. biglobosa, the causal agents of phoma stem canker on oilseed rape, differ in their sensitivity to some azoles, which could be driving pathogen frequency change in crops.

Comorbidity Status and Annual Total Medical Expenditures in U.S. Hypertensive Adults.

Introduction: The purpose of this study is to investigate comorbidity status and its impact on total medical expenditures in non-institutionalized hypertensive adults in the U.S.

Methods: Data from the 2011-2014 Medical Expenditure Panel Survey were used.

Dose-dependent selection drives lineage replacement during the experimental evolution of SDHI fungicide resistance in .

Fungicide resistance is a constant threat to agricultural production worldwide. Molecular mechanisms of fungicide resistance have been studied extensively in the wheat pathogen . However, less is known about the evolutionary processes driving resistance development.

The synthetic neuroactive steroid SGE-516 reduces seizure burden and improves survival in a Dravet syndrome mouse model.

Dravet syndrome is an infant-onset epileptic encephalopathy with multiple seizure types that are often refractory to conventional therapies. Treatment with standard benzodiazepines like clobazam, in combination with valproate and stiripentol, provides only modest seizure control. While benzodiazepines are a first-line therapy for Dravet syndrome, they are limited by their ability to only modulate synaptic receptors.