Missense mutations in the perforin (PRF1) gene as a cause of hereditary cancer predisposition

Perforin, a pore-forming toxin released from secretory granules of NK cells and CTLs, is essential for their cytotoxic activity against infected or cancerous target cells. Bi-allelic loss-of-function mutations in the perforin gene are invariably associated with a fatal immunoregulatory disorder, familial haemophagocytic lymphohistiocytosis type 2 (FHL2), in infants. More recently, it has also been recognized that partial loss of perforin function can cause disease in later life, including delayed onset FHL2 and haematological malignancies. Herein we report a family in which a wide range of systemic inflammatory and neoplastic manifestations have occurred across three generations. We found that disease was linked to two missense perforin gene mutations (encoding A91V, R410W) that cause protein misfolding and partial loss of activity. These cases link the partial loss of perforin function with some solid tumours that are known to be controlled by the immune system, as well as haematological cancers. Our findings also demonstrate that perforin gene mutations can contribute to hereditary cancer predisposition

Epidemics on contact networks: a general stochastic approach

Dynamics on networks is considered from the perspective of Markov stochastic processes. We partially describe the state of the system through network motifs and infer any missing data using the available information. This versatile approach is especially well adapted for modelling spreading processes and/or population dynamics. In particular, the generality of our systematic framework and the fact that its assumptions are explicitly stated suggests that it could be used as a common ground for comparing existing epidemics models too complex for direct comparison, such as agent-based computer simulations. We provide many examples for the special cases of susceptible-infectious-susceptible (SIS) and susceptible-infectious-removed (SIR) dynamics (e.g., epidemics propagation) and we observe multiple situations where accurate results may be obtained at low computational cost. Our perspective reveals a subtle balance between the complex requirements of a realistic model and its basic assumptions.Comment: Main document: 16 pages, 7 figures. Electronic Supplementary Material (included): 6 pages, 1 tabl

Emerging pharmacotherapy of tinnitus

Tinnitus, the perception of sound in the absence of an auditory stimulus, is perceived by about 1 in 10 adults, and for at least 1 in 100, tinnitus severely affects their quality of life. Because tinnitus is frequently associated with irritability, agitation, stress, insomnia, anxiety and depression, the social and economic burdens of tinnitus can be enormous. No curative treatments are available. However, tinnitus symptoms can be alleviated to some extent. The most widespread management therapies consist of auditory stimulation and cognitive behavioral treatment, aiming at improving habituation and coping strategies. Available clinical trials vary in methodological rigor and have been performed for a considerable number of different drugs. None of the investigated drugs have demonstrated providing replicable long-term reduction of tinnitus impact in the majority of patients in excess of placebo effects. Accordingly, there are no FDA or European Medicines Agency approved drugs for the treatment of tinnitus. However, in spite of the lack of evidence, a large variety of different compounds are prescribed off-label. Therefore, more effective pharmacotherapies for this huge and still growing market are desperately needed and even a drug that produces only a small but significant effect would have an enormous therapeutic impact. This review describes current and emerging pharmacotherapies with current difficulties and limitations. In addition, it provides an estimate of the tinnitus market. Finally, it describes recent advances in the tinnitus field which may help overcome obstacles faced in the pharmacological treatment of tinnitus. These include incomplete knowledge of tinnitus pathophysiology, lack of well-established animal models, heterogeneity of different forms of tinnitus, difficulties in tinnitus assessment and outcome measurement and variability in clinical trial methodology. © 2009 Informa UK Ltd.Fil: Langguth, Berthold. Universitat Regensburg; AlemaniaFil: Salvi, Richard. State University of New York; Estados UnidosFil: Elgoyhen, Ana Belen. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular "Dr. Héctor N. Torres"; Argentin

Seasonality constraints to livestock grazing intensity

Increasing food production is essential to meet the future food demand of a growing world population. In the light of pressing sustainability challenges like climate change and the importance of the global livestock system for food security as well as GHG emissions, finding ways to increasing food production sustainably and without increasing competition for food crops is essential. Yet, many unknowns relate to livestock grazing, in particular grazing intensity, an essential variable to assess the sustainability of livestock systems. Here we explore ecological limits to grazing intensity (GI; i.e., the fraction of Net Primary Production consumed by grazing animals) by analysing the role of seasonality in natural grasslands. We estimate seasonal limitations to GI by combining monthly Net Primary Production data and a map of global livestock distribution with assumptions on the length of non-favourable periods that can be bridged by livestock (e.g., by browsing dead standing biomass, storage systems or biomass conservation). This allows us to derive a seasonality-limited potential GI, which we compare with the GI prevailing in 2000. We find that GI in 2000 lies below its potential on 39% of the total global natural grasslands, which has a potential for increasing biomass extraction of up to 181 MtC/yr. In contrast, on 61% of the area GI exceeds the potential, made possible by management. Mobilizing this potential could increase milk production by 5%, meat production by 4%, or contribute to free up to 2.8 Mio km² of grassland area at the global scale if the numerous socio-ecological constraints can be overcome. We discuss socio-ecological trade-offs, which may reduce the estimated potential considerably and require the establishment of sound monitoring systems and an improved understanding of livestock system’s role in the Earth system

Transition from reciprocal cooperation to persistent behaviour in social dilemmas at the end of adolescence.

While human societies are extraordinarily cooperative in comparison with other social species, the question of why we cooperate with unrelated individuals remains open. Here we report results of a lab-in-the-field experiment with people of different ages in a social dilemma. We find that the average amount of cooperativeness is independent of age except for the elderly, who cooperate more, and a behavioural transition from reciprocal, but more volatile behaviour to more persistent actions towards the end of adolescence. Although all ages react to the cooperation received in the previous round, young teenagers mostly respond to what they see in their neighbourhood regardless of their previous actions. Decisions then become more predictable through midlife, when the act of cooperating or not is more likely to be repeated. Our results show that mechanisms such as reciprocity, which is based on reacting to previous actions, may promote cooperation in general, but its influence can be hindered by the fluctuating behaviour in the case of children

Protocol for Northern Ireland Caries Prevention in Practice Trial (NIC-PIP) trial: a randomised controlled trial to measure the effects and costs of a dental caries prevention regime for young children attending primary care dental services

<p>Abstract</p> <p>Background</p> <p>Dental caries is a persistent public health problem with little change in the prevalence in young children over the last 20 years. Once a child contracts the disease it has a significant impact on their quality of life. There is good evidence from Cochrane reviews including trials that fluoride varnish and regular use of fluoride toothpaste can prevent caries.</p> <p>The Northern Ireland Caries Prevention in Practice Trial (NIC-PIP) trial will compare the costs and effects of a caries preventive package (fluoride varnish, toothpaste, toothbrush and standardised dental health education) with dental health education alone in young children.</p> <p>Methods/Design</p> <p>A randomised controlled trial on children initially aged 2 and 3 years old who are regular attenders at the primary dental care services in Northern Ireland. Children will be recruited and randomised in dental practices. Children will be randomised to the prevention package of both fluoride varnish (twice per year for three years), fluoride toothpaste (1,450 ppm F) (supplied twice per year), a toothbrush (supplied twice a year) or not; both test and control groups receive standardised dental health education delivered by the dentist twice per year. Randomisation will be conducted by the Belfast Trust Clinical Research Support Centre ([CRSC] a Clinical Trials Unit).</p> <p>1200 participants will be recruited from approximately 40 dental practices. Children will be examined for caries by independent dental examiners at baseline and will be excluded if they have caries. The independent dental examiners will examine the children again at 3 years blinded to study group.</p> <p>The primary end-point is whether the child develops caries (cavitation into dentine) or not over the three years. One secondary outcome is the number of carious surfaces in the primary dentition in children who experience caries. Other secondary outcomes are episodes of pain, extraction of primary teeth, other adverse events and costs which will be obtained from parental questionnaires.</p> <p>Discussion</p> <p>This is a pragmatic trial conducted in general dental practice. It tests a composite caries prevention intervention, which represents an evidence based approach advocated by current guidance from the English Department of Health which is feasible to deliver to all low risk (caries free) children in general dental practice. The trial will provide valuable information to policy makers and clinicians on the costs and effects of caries prevention delivered to young children in general dental practice.</p> <p>Trial registration</p> <p>EudraCT No: 2009 - 010725 - 39</p> <p>ISRCTN: <a href="http://www.controlled-trials.com/ISRCTN36180119">ISRCTN36180119</a></p> <p>Ethics Reference No: 09/H1008/93:</p

Management of allergic rhinitis symptoms in the pharmacy Pocket guide 2022

Allergic rhinitis (AR) management requires a coordinated effort from healthcare providers and patients. Pharmacists are key members of these integrated care pathways resolving medication-related problems, optimizing regimens, improving adherence and recommending therapies while establishing liaisons between patients and physicians.Allergic Rhinitis and its Impact on Asthma (ARIA) first published a reference document on the pharmacist's role in allergic rhinitis management in 2004. Several guidelines were developed over the past 20 years improving the care of allergic rhinitis patients through an evidence-based, integrated care approach.This ARIA/EAACI/FIP Position Paper is based on the latest ARIA in the Pharmacy guidelines and provides: (a) a structured approach to pharmacists identifying people with AR and/or allergic conjunctivitis as well as those at risk of poor disease control; (b) an evidence-based clinical decision support tool for optimising the management of allergic rhinitis in the community pharmacy; and (c) a framework of referral to the physician.This document is not intended to be a mandatory standard of care but is provided as a basis for pharmacists and their staff to develop relevant local standards of care for their patients, within their local practice environment. Pharmacy care varies between countries, and the guide should be adapted to the local situation.© 2022 The Authors. Clinical and Translational Allergy published by John Wiley & Sons Ltd on behalf of European Academy of Allergy and Clinical Immunology

Association of Same-Day Discharge After Elective Percutaneous Coronary Intervention in the United States With Costs and Outcomes

Importance Same-day discharge (SDD) after elective percutaneous coronary intervention (PCI) is associated with lower costs and preferred by patients. However, to our knowledge, contemporary patterns of SDD after elective PCI with respect to the incidence, hospital variation, trends, costs, and safety outcomes in the United States are unknown. Objective To examine (1) the incidence and trends in SDD; (2) hospital variation in SDD; (3) the association between SDD and readmissions for bleeding, acute kidney injury (AKI), acute myocardial infarction (AMI), or mortality at 30, 90, and 365 days after PCI; and (4) hospital costs of SDD and its drivers. Design, Setting, and Participants This observational cross-sectional cohort study included 672 470 patients enrolled in the nationally representative Premier Healthcare Database who underwent elective PCI from 493 hospitals between January 2006 and December 2015 with 1-year follow-up. Exposures Same-day discharge, defined by identical dates of admission, PCI procedure, and discharge. Main Outcomes and Measures Death, bleeding requiring a blood transfusion, AKI and AMI at 30, 90, or 365 days after PCI, and costs from hospitals’ perspective, inflated to 2016. Results Among 672 470 elective PCIs, 221 997 patients (33.0%) were women, 30 711 (4.6%) were Hispanic, 51 961 (7.7%) were African American, and 491 823 (73.1%) were white. The adjusted rate of SDD was 3.5% (95% CI, 3.0%-4.0%), which increased from 0.4% in 2006 to 6.3% in 2015. We observed substantial hospital variation for SDD from 0% to 83% (median incidence rate ratio, 3.82; 95% CI, 3.48-4.23), implying an average (median) 382% likelihood of SDD at one vs another hospital. Among SDD (vs non-SDD) patients, there was no higher risk of death, bleeding, AKI, or AMI at 30, 90, or 365 days. Same-day discharge was associated with a large cost savings of $5128 per procedure (95$5006-$5248), driven by reduced supply and room and boarding costs. A shift from existing SDD practices to match top-decile SDD hospitals could annually save$129 million in this sample and $577 million if adopted throughout the United States. However, residual confounding may be present, limiting the precision of the cost estimates. Conclusions and Relevance Over 2006 to 2015, SDD after elective PCI was infrequent, with substantial hospital variation. Given the safety and large savings of more than$5000 per PCI associated with SDD, greater and more consistent use of SDD could markedly increase the overall value of PCI care

What drives the 'August effect'?: an observational study of the effect of junior doctor changeover on out of hours work

Objective: To investigate whether measurements of junior doctor on-call workload and performance can clarify the mechanisms underlying the increase in morbidity and mortality seen after junior doctor changeover: the ‘August effect’. Design: Quantitative retrospective observational study of routinely collected data on junior doctor workload. Setting: Two large teaching hospitals in England. Participants: Task level data from a wireless out of hours system (n = 29,885 requests) used by medical staff, nurses, and allied health professionals. Main outcome measures: Number and type of tasks requested by nurses, time to completion of tasks by junior doctors. Results: There was no overall change in the number of tasks requested by nurses out of hours around the August changeover (median requests per hour 15 before and 14 after, p = 0.46). However, the number of tasks classified as urgent was greater (p = 0.016) equating to five more urgent tasks per day. After changeover, doctors took less time to complete tasks overall due to a reduction in time taken for routine tasks (median 74 vs. 66 min; p = 3.9 × 10−9). Conclusion: This study suggests that the ‘August effect’ is not due to new junior doctors completing tasks more slowly or having a greater workload. Further studies are required to investigate the causes of the increased number of urgent tasks seen, but likely factors are errors, omissions, and poor prioritization. Thus, improved training and quality control has the potential to address this increased duration of unresolved patient risk. The study also highlights the potential of newer technologies to facilitate quantitative study of clinical activity

A Quantitative, Non-Destructive Methodology for Habitat Characterisation and Benthic Monitoring at Offshore Renewable Energy Developments

Following governments' policies to tackle global climate change, the development of offshore renewable energy sites is likely to increase substantially over coming years. All such developments interact with the seabed to some degree and so a key need exists for suitable methodology to monitor the impacts of large-scale Marine Renewable Energy Installations (MREIs). Many of these will be situated on mixed or rocky substrata, where conventional methods to characterise the habitat are unsuitable. Traditional destructive sampling is also inappropriate in conservation terms, particularly as safety zones around (MREIs) could function as Marine Protected Areas, with positive benefits for biodiversity. Here we describe a technique developed to effectively monitor the impact of MREIs and report the results of its field testing, enabling large areas to be surveyed accurately and cost-effectively. The methodology is based on a high-definition video camera, plus LED lights and laser scale markers, mounted on a “flying array” that maintains itself above the seabed grounded by a length of chain, thus causing minimal damage. Samples are taken by slow-speed tows of the gear behind a boat (200 m transects). The HD video and randomly selected frame grabs are analysed to quantify species distribution. The equipment was tested over two years in Lyme Bay, UK (25 m depth), then subsequently successfully deployed in demanding conditions at the deep (>50 m) high-energy Wave Hub site off Cornwall, UK, and a potential tidal stream energy site in Guernsey, Channel Islands (1.5 ms−1 current), the first time remote samples from such a habitat have been achieved. The next stage in the monitoring development process is described, involving the use of Remote Operated Vehicles to survey the seabed post-deployment of MREI devices. The complete methodology provides the first quantitative, relatively non-destructive method for monitoring mixed-substrate benthic communities beneath MPAs and MREIs pre- and post-device deployment