Alarming dendritic cells for Th2 induction

There is an ever-increasing understanding of the mechanisms by which pathogens such as bacteria, viruses, and protozoa activate dendritic cells (DCs) to drive T helper type 1 (Th1) responses, but we know much less about how these cells elicit Th2 responses. This gap in our knowledge puts us at a distinct disadvantage in designing therapeutics for certain immune-mediated diseases. However, progress is being made with the identification of novel endogenous tissue factors that can enhance Th2 induction by DCs

The impact of the lung environment on macrophage development, activation and function:diversity in the face of adversity

The last decade has been somewhat of a renaissance period for the field of macrophage biology. This renewed interest, combined with the advent of new technologies and development of novel model systems to assess different facets of macrophage biology, has led to major advances in our understanding of the diverse roles macrophages play in health, inflammation, infection and repair, and the dominance of tissue environments in influencing all of these areas. Here, we discuss recent developments in our understanding of lung macrophage heterogeneity, ontogeny, metabolism and function in the context of health and disease, and highlight core conceptual advances and key unanswered questions that we believe should be focus of work in the coming years

Markers of cognitive function in individuals with metabolic disease: Morquio Syndrome and Tyrosinemia Type III

We characterized cognitive function in two metabolic diseases. MPS–IVa (mucopolysaccharidosis IVa, Morquio) and tyrosinemia type III individuals were assessed using tasks of attention, language and oculomotor function. MPS–IVa individuals were slower in visual search, but the display size effects were normal, and slowing was not due to long reaction times (ruling out slow item processing or distraction). Maintaining gaze in an oculomotor task was difficult. Results implicated sustained attention and task initiation or response processing. Shifting attention, accumulating evidence and selecting targets were unaffected. Visual search was also slowed in tyrosinemia type III, and patterns in visual search and fixation tasks pointed to sustained attention impairments, although there were differences from MPS–IVa. Language was impaired in tyrosinemia type III but not MPS–IVa. Metabolic diseases produced selective cognitive effects. Our results, incorporating new methods for developmental data and model selection, illustrate how cognitive data can contribute to understanding function in biochemical brain systems

Clinical deterioration after sildenafil cessation in patients with pulmonary hypertension

Sildenafil is a selective inhibitor of phosphodiesterase type 5 (PDE-5). Its chronic administration has been shown to improve exercise capacity, World Health Organization functional class, and haemodynamics in patients with symptomatic pulmonary arterial hypertension (PAH). There is however, no data describing the clinical consequences of sudden cessation of sildenafil treatment. In this series, 9 patients with NYHA Class II–IV PAH who were stable on 2 months of sildenafil monotherapy, had their sildenafil ceased to accommodate a 2-week washout period, required for enrollment in research involving an endothelin receptor antagonist. Six minute walk distance (SMWD) and clinical assessments were performed before cessation of sildenafil, and again 2 weeks later. Over the course of this 2-week washout period, 6 of the 9 patients reported increased breathlessness and fatigue, 1 of these was hospitalized with worsening right heart failure. The SMWD fell in 6 patients, with falls of greater than 100 m recorded in 4 patients. This was accompanied by a worsening of NYHA Class from 2.5 ± 0.2 to 3.1 ± 0.1 (mean ± SEM, p = 0.01). These data indicate that sudden cessation of sildenafil monotherapy, in patients with PAH, carries with it a significant and unpredictable risk of rapid clinical deterioration. We recommend that if sildenafil needs to be ceased, it would be more prudent to consider concurrent vasodilator therapy before the gradual cessation of sildenafil

The effect of the COVID-19 health disruptions on breast cancer mortality for older women: A semi-Markov modelling approach

We propose a methodology to quantify the impact on breast cancer mortality of diagnostic delays caused by public health measures introduced as a response to the COVID-19 pandemic. These measures affected cancer pathways by halting cancer screening, delaying diagnostic tests, and reducing the numbers of patients starting treatment. We introduce a semi-Markov model, to quantify the impact of the pandemic based on publicly available population data for women age 65{89 years in England and relevant medical literature. We quantify age-specific excess deaths, for a period up to 5 years, along with years of life expectancy lost and change in cancer mortality by cancer stage. Our analysis suggests a 3-6% increase in breast cancer deaths, corresponding to more than 40 extra deaths, per 100,000 women, after age 65 years old over 5 years, and a 4-6% increase in registrations of advanced (Stage 4) breast cancer. Our modelling approach exhibits consistent results in sensitivity analyses, providing a model that can account for changes in breast cancer diagnostic and treatment services

Insurance pricing for breast cancer under different multiple state models

In this paper we consider pricing of insurance contracts for breast cancer risk based on three multiple state models. Using population data in England and data from the medical literature, we calibrate a collection of semi-Markov and Markov models. Considering an industry-based Markov model as a baseline model, we demonstrate the strengths of a more detailed model while showing the importance of accounting for duration dependence in transition rates. We quantify age-specific cancer incidence and cancer survival by stage along with type-specific mortality rates based on the semi-Markov model which accounts for unobserved breast cancer cases and progression through breast cancer stages. Using the developed models, we obtain actuarial net premiums for a specialised critical illness and life insurance product. Our analysis shows that the semi-Markov model leads to results aligned with empirical evidence. Our findings point out the importance of accounting for the time spent with diagnosed or undiagnosed pre-metastatic breast cancer in actuarial applications

Innate type 2 immunity in helminth infection is induced redundantly and acts autonomously following CD11c+ cell depletion

Infection with gastrointestinal helminths generates a dominant type 2 response among both adaptive (Th2) and innate (macrophage, eosinophil, and innate lymphoid) immune cell types. Two additional innate cell types, CD11chigh dendritic cells (DCs) and basophils, have been implicated in the genesis of type 2 immunity. Investigating the type 2 response to intestinal nematode parasites, including Heligmosomoides polygyrus and Nippostrongylus brasiliensis, we first confirmed the requirement for DCs in stimulating Th2 adaptive immunity against these helminths through depletion of CD11chigh cells by administration of diphtheria toxin to CD11c.DOG mice. In contrast, responsiveness was intact in mice depleted of basophils by antibody treatment. Th2 responses can be induced by adoptive transfer of DCs, but not basophils, exposed to soluble excretory-secretory products from these helminths. However, innate type 2 responses arose equally strongly in the presence or absence of CD11chigh cells or basophils; thus, in CD11c.DOG mice, the alternative activation of macrophages, as measured by expression of arginase-1, RELM-α, and Ym-1 (Chi3L3) in the intestine following H. polygyrus infection or in the lung following N. brasiliensis infection, was unaltered by depletion of CD11c-expressing DCs and alveolar macrophages or by antibody-mediated basophil depletion. Similarly, goblet cell-associated RELM-β in lung and intestinal tissues, lung eosinophilia, and expansion of innate lymphoid (“nuocyte”) populations all proceeded irrespective of depletion of CD11chigh cells or basophils. Thus, while CD11chigh DCs initiate helminth-specific adaptive immunity, innate type 2 cells are able to mount an autonomous response to the challenge of parasite infection

Influence of reactive ion etching on the minority carrier lifetime in P-type Si

Quasi-steady-state photoconductance (QSSPC) and deep level transient spectroscopy (DLTS) were used to characterize the recombination properties of reactive ion etched p-type Si. The effective lifetime of the plasma-processed samples degraded after etching, with the densities of recombination centers increasing linearly with etch time, before reaching a plateau. Evidence is provided for the long-range (> 2 µm) migration of defects in the samples plasma-etched at room temperature. The relationship between rf power and lifetime degradation is also discussed. A defect with energy position at (0.31 ± 0.02) eV was detected by DLTS in RIE p-Si, whereas no defect level was measured in n-type Si. We demonstrate that this energy level could be used to adequately model the injection-dependence of the measured carrier lifetimes using the Shockley-Read-Hall model

Collective modes of coupled phase oscillators with delayed coupling

We study the effects of delayed coupling on timing and pattern formation in spatially extended systems of dynamic oscillators. Starting from a discrete lattice of coupled oscillators, we derive a generic continuum theory for collective modes of long wavelength. We use this approach to study spatial phase profiles of cellular oscillators in the segmentation clock, a dynamic patterning system of vertebrate embryos. Collective wave patterns result from the interplay of coupling delays and moving boundary conditions. We show that the phase profiles of collective modes depend on coupling delays.Comment: 5 pages, 2 figure