Are there three main subgroups within the patellofemoral pain population? A detailed characterisation study of 127 patients to help develop targeted Intervention (TIPPs)

• Background Current multimodal approaches for the management of non-specific patellofemoral pain are not optimal, however, targeted intervention for subgroups could improve patient outcomes. This study explores whether subgrouping of non-specific patellofemoral pain patients, using a series of low cost simple clinical tests, is possible. • Method The exclusivity and clinical importance of potential subgroups was assessed by applying à priori test thresholds (1 SD) from seven clinical tests in a sample of adult patients with non-specific patellofemoral pain. Hierarchical clustering and latent profile analysis, were used to gain additional insights into subgroups using data from the same clinical tests. • Results One hundred and thirty participants were recruited, 127 had complete data: 84 (66%) female, mean age 26 years (SD 5.7) and mean BMI 25.4 (SD 5.83), median (IQR) time between onset of pain and assessment was 24 (7-60) months. Potential subgroups defined by the à priori test thresholds were not mutually exclusive and patients frequently fell into multiple subgroups. Using hierarchical clustering and latent profile analysis three subgroups were identified using 6 of the 7 clinical tests. These subgroups were given the following nomenclature: (i) ‘strong’, (ii) ‘weak and tighter’, and (iii) ‘weak and pronated foot’. • Conclusions We conclude that three subgroups of patellofemoral patients may exist based on the results of six clinical tests which are feasible to perform in routine clinical practice. Further research is needed to validate these findings in other datasets and, if supported by external validation, to see if targeted interventions for these subgroups improve patient outcomes

Multichannel electrocardiogram diagnostics for the diagnosis of arrhythmogenic right ventricular dysplasia

Aims: The identification of arrhythmogenic right ventricular dysplasia (ARVD) from 12-channel standard electrocardiogram (ECG) is challenging. High density ECG data may identify lead locations and criteria with a higher sensitivity. Methods and results: Eighty-channel ECG recording from patients diagnosed with ARVD and controls were quantified by magnitude and integral measures of QRS and T waves and by a measure (the average silhouette width) of differences in the shapes of the normalized ECG cycles. The channels with the best separability between ARVD patients and controls were near the right ventricular wall, at the third intercostal space. These channels showed pronounced differences in P waves compared to controls as well as the expected differences in QRS and T waves. Conclusion: Multichannel recordings, as in body surface mapping, add little to the reliability of diagnosing ARVD from ECGs. However, repositioning ECG electrodes to a high anterior position can improve the identification of ECG variations in ARVD. Additionally, increased P wave amplitude appears to be associated with ARVD

Bio-inspired CO₂ conversion by iron sulfide catalysts under sustainable conditions

The mineral greigite presents similar surface structures to the active sites found in many modern-day enzymes. We show that particles of greigite can reduce CO2 under ambient conditions into chemicals such as methanol, formic, acetic and pyruvic acid. Our results also lend support to the Origin of Life theory on alkaline hydrothermal vents

Spontaneous Autoimmunity in 129 and C57BL/6 Mice—Implications for Autoimmunity Described in Gene-Targeted Mice

Systemic lupus erythematosus (SLE) is a multisystem autoimmune disorder in which complex genetic factors play an important role. Several strains of gene-targeted mice have been reported to develop SLE, implicating the null genes in the causation of disease. However, hybrid strains between 129 and C57BL/6 mice, widely used in the generation of gene-targeted mice, develop spontaneous autoimmunity. Furthermore, the genetic background markedly influences the autoimmune phenotype of SLE in gene-targeted mice. This suggests an important role in the expression of autoimmunity of as-yet-uncharacterised background genes originating from these parental mouse strains. Using genome-wide linkage analysis, we identified several susceptibility loci, derived from 129 and C57BL/6 mice, mapped in the lupus-prone hybrid (129 × C57BL/6) model. By creating a C57BL/6 congenic strain carrying a 129-derived Chromosome 1 segment, we found that this 129 interval was sufficient to mediate the loss of tolerance to nuclear antigens, which had previously been attributed to a disrupted gene. These results demonstrate important epistatic modifiers of autoimmunity in 129 and C57BL/6 mouse strains, widely used in gene targeting. These background gene influences may account for some, or even all, of the autoimmune traits described in some gene-targeted models of SLE

Fe(ii) and Fe(iii) dithiocarbamate complexes as single source precursors to nanoscale iron sulfides: a combined synthetic and in situ XAS approach

Nanoparticulate iron sulfides have many potential applications and are also proposed to be prebiotic catalysts for the reduction of CO2 to biologically important molecules, thus the development of reliable routes to specific phases with controlled sizes and morphologies is important. Here we focus on the use of iron dithiocarbamate complexes as single source precursors (SSPs) to generate greigite and pyrrhotite nanoparticles. Since these minerals contain both iron(III) and iron(II) centres, SSPs in both oxidation states, [Fe(S2CNR2)3] and cis-[Fe(CO)2(S2CNR2)2] respectively, have been utilised. Use of this Fe(II) precursor is novel and it readily loses both carbonyls in a single step (as shown by TGA measurements) providing an in situ source of the extremely air-sensitive Fe(II) dithiocarbamate complexes [Fe(S2CNR2)2]. Decomposition of [Fe(S2CNR2)3] alone in oleylamine affords primarily pyrrhotite, although by careful control of reaction conditions (ca. 230 °C, 40–50 nM SSP) a window exists in which pure greigite nanoparticles can be isolated. With cis-[Fe(CO)2(S2CNR2)2] we were unable to produce pure greigite, with pyrrhotite formation dominating, a similar situation being found with mixtures of Fe(II) and Fe(III) precursors. In situ X-ray absorption spectroscopy (XAS) studies showed that heating [Fe(S2CNiBu2)3] in oleylamine resulted in amine coordination and, at ca. 60 °C, reduction of Fe(III) to Fe(II) with (proposed) elimination of thiuram disulfide (S2CNR2)2. We thus carried out a series of decomposition studies with added thiuram disulfide (R = iBu) and found that addition of 1–2 equivalents led to the formation of pure greigite nanoparticles between 230 and 280 °C with low SSP concentrations. Average particle size does not vary significantly with increasing concentration, thus providing a convenient route to ca. 40 nm greigite nanoparticles. In situ XAS studies have been carried out and allow a decomposition pathway for [Fe(S2CNiBu2)3] in oleylamine to be established; reduction of Fe(III) to Fe(II) reduction triggers substitution of the secondary amide backbone by oleylamine (RNH2) resulting in the in situ formation of a primary dithiocarbamate derivative [Fe(RNH2)2(S2CNHR)2]. This in turn extrudes RNCS to afford molecular precursors of the observed FeS nanomaterials. The precise role of thiuram disulfide in the decomposition process is unknown, but it likely plays a part in controlling the Fe(III)–Fe(II) equilibrium and may also act as a source of sulfur allowing control over the Fe : S ratio in the mineral products

Half a Century of Wilson & Jungner: Reflections on the Governance of Population Screening.

Background: In their landmark report on the "Principles and Practice of Screening for Disease" (1968), Wilson and Jungner noted that the practice of screening is just as important for securing beneficial outcomes and avoiding harms as the formulation of principles. Many jurisdictions have since established various kinds of "screening governance organizations" to provide oversight of screening practice. Yet to date there has been relatively little reflection on the nature and organization of screening governance itself, or on how different governance arrangements affect the way screening is implemented and perceived and the balance of benefits and harms it delivers. Methods: An international expert policy workshop convened by Sturdy, Miller and Hogarth. Results: While effective governance is essential to promote beneficial screening practices and avoid attendant harms, screening governance organizations face enduring challenges. These challenges are social and ethical as much as technical. Evidence-based adjudication of the benefits and harms of population screening must take account of factors that inform the production and interpretation of evidence, including the divergent professional, financial and personal commitments of stakeholders. Similarly, when planning and overseeing organized screening programs, screening governance organizations must persuade or compel multiple stakeholders to work together to a common end. Screening governance organizations in different jurisdictions vary widely in how they are constituted, how they relate to other interested organizations and actors, and what powers and authority they wield. Yet we know little about how these differences affect the way screening is implemented, and with what consequences. Conclusions: Systematic research into how screening governance is organized in different jurisdictions would facilitate policy learning to address enduring challenges. Even without such research, informal exchange and sharing of experiences between screening governance organizations can deliver invaluable insights into the social as well as the technical aspects of governance

Collective intuition : implications for improved decision making and organizational learning

This article establishes the foundation for research on collective intuition through a study of decision making and organizational learning processes in police senior management teams. We conceptualize collective intuition as independently formed judgement based on domain-specific knowledge, experience and cognitive ability, shared and interpreted collectively. We contribute to intuition research, which has tended to focus its attention at the individual level, by studying intuition collectively in team settings. From a dual-process perspective, we investigate how expert intuition and deliberation affect decision making and learning at various levels of the organization. Furthermore, we contribute to organizational learning research by offering an empirically derived elaboration of the foundational 4I framework, identifying additional ‘feed-forward’ and ‘feedback’ loop processes, and thereby providing a more complete account of this organizational learning model. Bridging a variety of relevant but previously unconnected literatures via our focal concept of collective intuition, our research provides a foundation for future studies of this vitally important but under-researched organizational phenomenon. We offer theoretical and practical implications whereby expert intuitions can be developed and leveraged collectively as valuable sources of organizational knowledge and learning, and contribute to improved decision making in organizations.PostprintPeer reviewe

Identification of strata for a trial of a targeted multimodal physiotherapy intervention in patellofemoral pain patients

Background Patellofemoral Pain (PFP) is a musculoskeletal disorder causing significant pain and dysfunction around the knee, commonly leading to long term limitations. People with PFP are commonly referred for physiotherapy, although current multimodal physiotherapy approaches tend to be rather ad-hoc and are failing in the long term. Identification of patient strata (or subgroups) who may respond differentially to interventions has been recognised as an international priority. It has been proposed that there are PFP patient strata, classified based on clinical tests, who would respond to modes of interventions targeted at the individual's stratum. Methods Participants with PFP underwent clinical assessment of muscle weakness, muscle length, patellar mobility and foot posture. The presence of strata was explored using two classification techniques: hierarchical cluster analysis and latent profile analysis (LPA); for LPA, the Bayesian Information Criterion was used to guide model selection. Results One hundred and twenty seven (of 130) recruited participants had complete assessment data. A three strata solution appeared optimal from modelling and clinical perspectives. The three suggested strata were characterised as: stronger; weaker and tighter; weaker with pronated feet. However, although membership of the stronger stratum was consistent, there were substantial differences in the other composition of the other two strata between the two classification approaches. Conclusion PFP patients can be classified into clinical strata, although further investigation is needed to identify thresholds upon which stratification should be performed. Interventions are currently being mapped onto the strata and feasibility and evaluation trials of these interventions should then be performed

Conflicted Emotions Following Trust-based Interaction

We investigated whether 20 emotional states, reported by 170 participants after participating in a Trust game, were experienced in a patterned way predicted by the “Recalibrational Model” or Valence Models. According to the Recalibrational Model, new information about trust-based interaction outcomes triggers specific sets of emotions. Unlike Valence Models that predict reports of large sets of either positive or negative emotional states, the Recalibrational Model predicts the possibility of conflicted (concurrent positive and negative) emotional states. Consistent with the Recalibrational Model, we observed reports of conflicted emotional states activated after interactions where trust was demonstrated but trustworthiness was not. We discuss the implications of having conflicted goals and conflicted emotional states for both scientific and well-being pursuits

A novel formulation of inhaled sodium cromoglicate (PA101) in idiopathic pulmonary fibrosis and chronic cough: a randomised, double-blind, proof-of-concept, phase 2 trial

Background Cough can be a debilitating symptom of idiopathic pulmonary fibrosis (IPF) and is difficult to treat. PA101 is a novel formulation of sodium cromoglicate delivered via a high-efficiency eFlow nebuliser that achieves significantly higher drug deposition in the lung compared with the existing formulations. We aimed to test the efficacy and safety of inhaled PA101 in patients with IPF and chronic cough and, to explore the antitussive mechanism of PA101, patients with chronic idiopathic cough (CIC) were also studied. Methods This pilot, proof-of-concept study consisted of a randomised, double-blind, placebo-controlled trial in patients with IPF and chronic cough and a parallel study of similar design in patients with CIC. Participants with IPF and chronic cough recruited from seven centres in the UK and the Netherlands were randomly assigned (1:1, using a computer-generated randomisation schedule) by site staff to receive PA101 (40 mg) or matching placebo three times a day via oral inhalation for 2 weeks, followed by a 2 week washout, and then crossed over to the other arm. Study participants, investigators, study staff, and the sponsor were masked to group assignment until all participants had completed the study. The primary efficacy endpoint was change from baseline in objective daytime cough frequency (from 24 h acoustic recording, Leicester Cough Monitor). The primary efficacy analysis included all participants who received at least one dose of study drug and had at least one post-baseline efficacy measurement. Safety analysis included all those who took at least one dose of study drug. In the second cohort, participants with CIC were randomly assigned in a study across four centres with similar design and endpoints. The study was registered with ClinicalTrials.gov (NCT02412020) and the EU Clinical Trials Register (EudraCT Number 2014-004025-40) and both cohorts are closed to new participants. Findings Between Feb 13, 2015, and Feb 2, 2016, 24 participants with IPF were randomly assigned to treatment groups. 28 participants with CIC were enrolled during the same period and 27 received study treatment. In patients with IPF, PA101 reduced daytime cough frequency by 31·1% at day 14 compared with placebo; daytime cough frequency decreased from a mean 55 (SD 55) coughs per h at baseline to 39 (29) coughs per h at day 14 following treatment with PA101, versus 51 (37) coughs per h at baseline to 52 (40) cough per h following placebo treatment (ratio of least-squares [LS] means 0·67, 95% CI 0·48–0·94, p=0·0241). By contrast, no treatment benefit for PA101 was observed in the CIC cohort; mean reduction of daytime cough frequency at day 14 for PA101 adjusted for placebo was 6·2% (ratio of LS means 1·27, 0·78–2·06, p=0·31). PA101 was well tolerated in both cohorts. The incidence of adverse events was similar between PA101 and placebo treatments, most adverse events were mild in severity, and no severe adverse events or serious adverse events were reported. Interpretation This study suggests that the mechanism of cough in IPF might be disease specific. Inhaled PA101 could be a treatment option for chronic cough in patients with IPF and warrants further investigation