SER-109: An Oral Investigational Microbiome Therapeutic for Patients with Recurrent Clostridioides difficile Infection (rCDI)

Clostridioides difficile infection (CDI) is classified as an urgent health threat by the Centers for Disease Control and Prevention (CDC), and affects nearly 500,000 Americans annually. Approximately 20–25% of patients with a primary infection experience a recurrence, and the risk of recurrence increases with subsequent episodes to greater than 40%. The leading risk factor for CDI is broad-spectrum antibiotics, which leads to a loss of microbial diversity and impaired colonization resistance. Current FDA-approved CDI treatment strategies target toxin or toxin-producing bacteria, but do not address microbiome disruption, which is key to the pathogenesis of recurrent CDI. Fecal microbiota transplantation (FMT) reduces the risk of recurrent CDI through the restoration of microbial diversity. However, FDA safety alerts describing hospitalizations and deaths related to pathogen transmission have raised safety concerns with the use of unregulated and unstandardized donor-derived products. SER-109 is an investigational oral microbiome therapeutic composed of purified spore-forming Firmicutes. SER-109 was superior to a placebo in reducing CDI recurrence at Week 8 (12% vs. 40%, respectively; p \u3c 0.001) in adults with a history of recurrent CDI with a favorable observed safety profile. Here, we discuss the role of the microbiome in CDI pathogenesis and the clinical development of SER-109, including its rigorous manufacturing process, which mitigates the risk of pathogen transmission. Additionally, we discuss compositional and functional changes in the gastrointestinal microbiome in patients with recurrent CDI following treatment with SER-109 that are critical to a sustained clinical response

Measuring academic research impact: creating a citation profile using the conceptual framework for implementation fidelity as a case study

The “citation score” remains the most commonly-used measure of academic impact, but is also viewed as practically and conceptually limited. The aim of this case study was to test the feasibility of creating a “citation profile” for a single, frequently-cited methods paper, the author’s own publication on the conceptual framework for implementation fidelity. This was a proof-of-concept study that involved an analysis of the citations of a single publication. This analysis involved identifying all citing publications and recording, not only how many times the key paper was cited within each citing publication, but also within which sections of that publication (e.g. Background, Methods, Results etc.). Level of impact could be categorised as high, moderate or low. The key paper had been cited more than 400 times and had a high impact in 25 % of publications based on citation frequency within publications, i.e. the key paper was cited three or more times; and a low impact in 58 % of citing publications, i.e. the key paper was cited just once. There were 41 “high impact” publications based on location of the citations, of which 35 (85 %) were also categorised as high impact by frequency. These results suggest that it is both possible and straightforward to categorise the level of impact of a key paper based on its “citation profile”, i.e., the frequency with which the paper is cited within citing publications, thus adding depth and value to the citation metric

Defecting or not defecting: how to "read" human behavior during cooperative games by EEG measurements

Understanding the neural mechanisms responsible for human social interactions is difficult, since the brain activities of two or more individuals have to be examined simultaneously and correlated with the observed social patterns. We introduce the concept of hyper-brain network, a connectivity pattern representing at once the information flow among the cortical regions of a single brain as well as the relations among the areas of two distinct brains. Graph analysis of hyper-brain networks constructed from the EEG scanning of 26 couples of individuals playing the Iterated Prisoner's Dilemma reveals the possibility to predict non-cooperative interactions during the decision-making phase. The hyper-brain networks of two-defector couples have significantly less inter-brain links and overall higher modularity - i.e. the tendency to form two separate subgraphs - than couples playing cooperative or tit-for-tat strategies. The decision to defect can be "read" in advance by evaluating the changes of connectivity pattern in the hyper-brain network

Semantics in active surveillance for men with localized prostate cancer - results of a modified Delphi consensus procedure

Active surveillance (AS) is broadly described as a management option for men with low-risk prostate cancer, but semantic heterogeneity exists in both the literature and in guidelines. To address this issue, a panel of leading prostate cancer specialists in the field of AS participated in a consensus-forming project using a modified Delphi method to reach international consensus on definitions of terms related to this management option. An iterative three-round sequence of online questionnaires designed to address 61 individual items was completed by each panel member. Consensus was considered to be reached if >= 70% of the experts agreed on a definition. To facilitate a common understanding among all experts involved and resolve potential ambiguities, a face-to-face consensus meeting was held between Delphi survey rounds two and three. Convenience sampling was used to construct the panel of experts. In total, 12 experts from Australia, France, Finland, Italy, the Netherlands, Japan, the UK, Canada and the USA participated. By the end of the Delphi process, formal consensus was achieved for 100% (n = 61) of the terms and a glossary was then developed. Agreement between international experts has been reached on relevant terms and subsequent definitions regarding AS for patients with localized prostate cancer. This standard terminology could support multidisciplinary communication, reduce the extent of variations in clinical practice and optimize clinical decision making.Peer reviewe

Integrin affinity modulation and survival signalling.

Integrins are heterodimeric transmembrane proteins that provide a bi-directional link between the cell’s internal biological mechanisms and the extracellular environment. During inside-out signalling, intracellular messages converge on the integrin cytoplasmic domain to induce a conformational change. This is transmitted to the extracellular domain where it results in an alteration in affinity for integrin ligands such as fibronectin and laminin. In this way the cell has developed the ability to modulate the critical functions of adhesion and cell movement. In outside-in signalling, the integrin performs a more complex function than simple adhesion; upon binding to ligand, the integrin extracellular domain undergoes a conformational change which is transmitted to the cytoplasmic domain. This alters the integrin’s cytoplasmic domain affinity for intracellular signalling proteins and results in the activation of intracellular second messenger pathways. In this way, the extracellular milieu is able to influence intracellular signalling including those involved in apoptosis. This thesis demonstrates data which provide original insights into bi-directional integrin signalling: Inside-out signalling: Constitutively active Notch1 increases β3-integrin affinity and abrogates Hras-mediated integrin suppression without increasing expression of β3- integrin. Dominant-Negative Rras blocks Notch-mediated integrin activation and Notch1-mediated reversal of Hras and Raf-mediated integrin suppression and this is independent of erk phosphorylation. Notch1 induces Rras activation. Functional adhesion assays confirm that Notch1IC increases K562 adhesion in a β1-integrin dependent manner and this is abrogated by Dominant-Negative Rras. This data supports a mechanism in which Notch1 increases integrin affinity via activation of Rras. Outside-in signalling: Evidence is presented demonstrating that extracellular matrix proteins, laminin and fibronectin, activate β1-integrins to protect SCLC cells against the apoptotic effects of etoposide and ionizing radiation via PI3Kinase activation. This occurs in two ways: 1) PI3Kinase-dependent β1-integrin signalling resulting in phosphorylation of Bad and reduced caspase-9 cleavage and 2) a β1-integrinmediated over-riding of etoposide and radiotherapy-induced cell cycle S phase delay and G2/M arrest. β1-integrin-mediated outside-in survival signalling was investigated further in the in vivo setting; MatrigelTM, a basement membrane product rich in extracellular matrix proteins, promoted SCLC xenograft survival and growth in a β1-integrin and tyrosine kinase-dependent manner. This data provides novel insights into the critical functions that integrins play in adhesion and survival signalling

A mixed methods process evaluation of a person-centred falls prevention program

Background RESPOND is a telephone-based falls prevention program for older people who present to a hospital emergency department (ED) with a fall. A randomised controlled trial (RCT) found RESPOND to be effective at reducing the rate of falls and fractures, compared with usual care, but not fall injuries or hospitalisations. This process evaluation aimed to determine whether RESPOND was implemented as planned, and identify implementation barriers and facilitators. Methods A mixed-methods evaluation was conducted alongside the RCT. Evaluation participants were the RESPOND intervention group (n=263) and the clinicians delivering RESPOND (n=7). Evaluation data were collected from participant recruitment and intervention records, hospital administrative records, audio-recordings of intervention sessions, and participant questionnaires. The Rochester Participatory Decision-Making scale (RPAD) was used to evaluate person-centredness (score range 0 (worst) - 9 (best)). Process factors were compared with pre-specified criteria to determine implementation fidelity. Six focus groups were held with participants (n=41), and interviews were conducted with RESPOND clinicians (n=6). Quantitative data were analysed descriptively and qualitative data thematically. Barriers and facilitators to implementation were mapped to the ‘Capability, Opportunity, Motivation – Behaviour’ (COM-B) behaviour change framework. Results RESPOND was implemented at a lower dose than the planned 10 hours over six months, with a median (IQR) of 2.9 hours (2.1, 4). The majority (76%) of participants received their first intervention session within one month of hospital discharge. Clinicians delivered the program in a person-centred manner with a median (IQR) RPAD score of 7 (6.5, 7.5) and 87% of questionnaire respondents were satisfied with the program. The reports from participants and clinicians suggested that implementation was facilitated by the use of positive and personally relevant health messages. Complex health and social issues were the main barriers to implementation. Conclusions RESPOND was person-centred and reduced falls and fractures at a substantially lower dose, using fewer resources, than anticipated. However, the low dose delivered may account for the lack of effect on falls injuries and hospitalisations. The results from this evaluation provide detailed information to guide future implementation of RESPOND of similar programs. Trial registration: This study was registered with the Australian New Zealand Clinical Trials Registry, number ACTRN12614000336684 (27 March 2014)

Elucidating Sensorimotor Control Principles with Myoelectric Musculoskeletal Models

There is an old saying that you must walk a mile in someone's shoes to truly understand them. This mini-review will synthesize and discuss recent research that attempts to make humans “walk a mile” in an artificial musculoskeletal system to gain insight into the principles governing human movement control. In this approach, electromyography (EMG) is used to sample human motor commands; these commands serve as inputs to mathematical models of muscular dynamics, which in turn act on a model of skeletal dynamics to produce a simulated motor action in real-time (i.e., the model's state is updated fast enough produce smooth motion without noticeable transitions; Manal et al., 2002). In this mini-review, these are termed myoelectric musculoskeletal models (MMMs). After a brief overview of typical MMM design and operation principles, the review will highlight how MMMs have been used for understanding human sensorimotor control and learning by evoking apparent alterations in a user's biomechanics, neural control, and sensory feedback experiences