Heterogeneous efflux pump expression underpins phenotypic resistance to antimicrobial peptides.

Antimicrobial resistance threatens the viability of modern medical interventions. There is a dire need to develop novel approaches to counter resistance mechanisms employed by starved or slow-growing pathogens that are refractory to conventional antimicrobial therapies. Antimicrobial peptides have been advocated as potential therapeutic solutions due to the low levels of genetic resistance observed in bacteria against these compounds.

A systematic review of the role of quantitative CT in the prognostication and disease monitoring of interstitial lung disease.

Background: The unpredictable trajectory and heterogeneity of interstitial lung disease (ILDs) make prognostication challenging. Current prognostic indices and outcome measures have several limitations. Quantitative computed tomography (qCT) provides automated numerical assessment of CT imaging and has shown promise when applied to the prognostication and disease monitoring of ILD.

Fully personalized modelling of Duchenne Muscular Dystrophy ambulation.

Duchenne Muscular Dystrophy is a progressive neuromuscular disorder characterized by the gradual weakening and deterioration of muscles, leading to loss of ambulation in affected individuals. This decline in mobility can be effectively assessed using the North Star Ambulatory Assessment (NSAA) scores, along with measures such as the 10-m walk time and the time taken to rise from the floor. We propose a dynamic linear model to predict the trajectories of these clinical outcomes, with a primary focus on NSAA scores.

Decoding uncertainty for clinical decision-making.

In this opinion piece, we examine the pivotal role that uncertainty quantification (UQ) plays in informing clinical decision-making processes. We explore challenges associated with healthcare data and the potential barriers to the widespread adoption of UQ methodologies. In doing so, we highlight how these techniques can improve the precision and reliability of medical evaluations.

Estradiol elicits distinct firing patterns in arcuate nucleus kisspeptin neurons of females through altering ion channel conductances.

Hypothalamic kisspeptin (Kiss1) neurons are vital for pubertal development and reproduction. Arcuate nucleus Kiss1 (Kiss1) neurons are responsible for the pulsatile release of gonadotropin-releasing hormone (GnRH). In females, the behavior of Kiss1 neurons, expressing Kiss1, neurokinin B (NKB), and dynorphin (Dyn), varies throughout the ovarian cycle.

Antibiotic resistant bacteria survive treatment by doubling while shrinking.

Unlabelled: Many antibiotics that are used in healthcare, farming, and aquaculture end up in environments with different spatial structures that might promote heterogeneity in the emergence of antibiotic resistance. However, the experimental evolution of microbes at sub-inhibitory concentrations of antibiotics has been mainly carried out at the population level which does not allow capturing single-cell responses to antibiotics. Here, we investigate and compare the emergence of resistance to ciprofloxacin in in well-mixed and structured environments using experimental evolution, genomics, and microfluidics-based time-lapse microscopy.

Exploring and Accounting for Genetically Driven Effect Heterogeneity in Mendelian Randomization.

Mendelian randomization (MR) is a framework to estimate the causal effect of a modifiable health exposure, drug target or pharmaceutical intervention on a downstream outcome by using genetic variants as instrumental variables. A crucial assumption allowing estimation of the average causal effect in MR, termed homogeneity, is that the causal effect does not vary across levels of any instrument used in the analysis. In contrast, the science of pharmacogenetics seeks to actively uncover and exploit genetically driven effect heterogeneity for the purposes of precision medicine.

Neuronal network dynamics in the posterodorsal amygdala: shaping reproductive hormone pulsatility.

Normal reproductive function and fertility rely on the rhythmic secretion of gonadotropin-releasing hormone (GnRH), which is driven by the hypothalamic GnRH pulse generator. A key regulator of the GnRH pulse generator is the posterodorsal subnucleus of the medial amygdala (MePD), a brain region that is involved in processing external environmental cues, including the effect of stress. However, the neuronal pathways enabling the dynamic, stress-triggered modulation of GnRH secretion remain largely unknown.

Phage-induced efflux down-regulation boosts antibiotic efficacy.

The interactions between a virus and its host vary in space and time and are affected by the presence of molecules that alter the physiology of either the host or the virus. Determining the molecular mechanisms at the basis of these interactions is paramount for predicting the fate of bacterial and phage populations and for designing rational phage-antibiotic therapies. We study the interactions between stationary phase Burkholderia thailandensis and the phage ΦBp-AMP1.

Estradiol elicits distinct firing patterns in arcuate nucleus kisspeptin neurons of females through altering ion channel conductances.

Hypothalamic kisspeptin (Kiss1) neurons are vital for pubertal development and reproduction. Arcuate nucleus Kiss1 (Kiss1) neurons are responsible for the pulsatile release of Gonadotropin-releasing Hormone (GnRH). In females, the behavior of Kiss1 neurons, expressing Kiss1, Neurokinin B (NKB), and Dynorphin (Dyn), varies throughout the ovarian cycle.

Combined multiplex panel test results are a poor estimate of disease prevalence without adjustment for test error.

Multiplex panel tests identify many individual pathogens at once, using a set of component tests. In some panels the number of components can be large. If the panel is detecting causative pathogens for a single syndrome or disease then we might estimate the burden of that disease by combining the results of the panel, for example determining the prevalence of pneumococcal pneumonia as caused by many individual pneumococcal serotypes.

Smoking during pregnancy and its effect on placental weight: a Mendelian randomization study.

Background: The causal relationship between maternal smoking in pregnancy and reduced offspring birth weight is well established and is likely due to impaired placental function. However, observational studies have given conflicting results on the association between smoking and placental weight. We aimed to estimate the causal effect of newly pregnant mothers quitting smoking on their placental weight at the time of delivery.

NK3R signalling in the posterodorsal medial amygdala is involved in stress-induced suppression of pulsatile LH secretion in female mice.

Psychosocial stress negatively impacts reproductive function by inhibiting pulsatile luteinizing hormone (LH) secretion. The posterodorsal medial amygdala (MePD) is responsible in part for processing stress and modulating the reproductive axis. Activation of the neurokinin 3 receptor (NK3R) suppresses the gonadotropin-releasing hormone (GnRH) pulse generator, under hypoestrogenic conditions, and NK3R activity in the amygdala has been documented to play a role in stress and anxiety.

HormoneBayes: A novel Bayesian framework for the analysis of pulsatile hormone dynamics.

The hypothalamus is the central regulator of reproductive hormone secretion. Pulsatile secretion of gonadotropin releasing hormone (GnRH) is fundamental to physiological stimulation of the pituitary gland to release luteinizing hormone (LH) and follicle stimulating hormone (FSH). Furthermore, GnRH pulsatility is altered in common reproductive disorders such as polycystic ovary syndrome (PCOS) and hypothalamic amenorrhea (HA).

Chemogenetic activation of PVN CRH neurons disrupts the estrous cycle and LH dynamics in female mice.

Introduction: The impact of stress on reproductive function is significant. Hypothalamic paraventricular nucleus (PVN) corticotrophin-releasing hormone (CRH) plays a major role in regulating the stress response. Understanding how the hypothalamic-pituitary-adrenal (HPA) axis and the hypothalamic-pituitary-gonadal (HPG) axis interact is crucial for comprehending how stress can lead to reproductive dysfunction.

Real-world experience of nintedanib for progressive fibrosing interstitial lung disease in the UK.

Background: Nintedanib slows progression of lung function decline in patients with progressive fibrosing (PF) interstitial lung disease (ILD) and was recommended for this indication within the United Kingdom (UK) National Health Service in Scotland in June 2021 and in England, Wales and Northern Ireland in November 2021. To date, there has been no national evaluation of the use of nintedanib for PF-ILD in a real-world setting.

Methods: 26 UK centres were invited to take part in a national service evaluation between 17 November 2021 and 30 September 2022.

Quantifying the variability in the assessment of reproductive hormone levels.

Objective: To quantify how representative a single measure of reproductive hormone level is of the daily hormonal profile using data from detailed hormonal sampling in the saline placebo-treated arm conducted over several hours.

Design: Retrospective analysis of data from previous interventional research studies evaluating reproductive hormones.

Setting: Clinical Research Facility at a tertiary reproductive endocrinology centre at Imperial College Hospital NHS Foundation Trust.

The potential of digital behavioural tests as a diagnostic aid for psychosis.

Timely interventions have a proven benefit for people experiencing psychotic illness. One bottleneck to accessing timely interventions is the referral process to the specialist team for early psychosis (STEP). Many general practitioners lack awareness or confidence in recognising psychotic symptoms or state.

Smoking during pregnancy and its effect on placental weight: A Mendelian randomization study.

Background: The causal relationship between maternal smoking in pregnancy and reduced offspring birth weight is well established and is likely due to impaired placental function. However, observational studies have given conflicting results on the association between smoking and placental weight. We aimed to estimate the causal effect of newly pregnant mothers quitting smoking on their placental weight at the time of delivery.

Using immersive virtual reality to remotely examine performance differences between dominant and non-dominant hands.

Unlabelled: Circle drawing may be a useful task to study upper-limb function in patient populations. However, previous studies rely on expensive and bulky robotics to measure performance. For clinics or hospitals with limited budgets and space, this may be unfeasible.

Synthesis of vancomycin fluorescent probes that retain antimicrobial activity, identify Gram-positive bacteria, and detect Gram-negative outer membrane damage.

Antimicrobial resistance is an urgent threat to human health, and new antibacterial drugs are desperately needed, as are research tools to aid in their discovery and development. Vancomycin is a glycopeptide antibiotic that is widely used for the treatment of Gram-positive infections, such as life-threatening systemic diseases caused by methicillin-resistant Staphylococcus aureus (MRSA). Here we demonstrate that modification of vancomycin by introduction of an azide substituent provides a versatile intermediate that can undergo copper-catalysed azide-alkyne cycloaddition (CuAAC) reaction with various alkynes to readily prepare vancomycin fluorescent probes.

Quasipotentials for coupled escape problems and the gate-height bifurcation.

The escape statistics of a gradient dynamical system perturbed by noise can be estimated using properties of the associated potential landscape. More generally, the Freidlin and Wentzell quasipotential (QP) can be used for similar purposes, but computing this is nontrivial and it is only defined relative to some starting point. In this paper we focus on computing quasipotentials for coupled bistable units, numerically solving a Hamilton- Jacobi-Bellman type problem.