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Summary: Nanocarbons are often employed as coatings for neural electrodes to enhance surface area. However, processing and integrating them into microfabrication flows requires complex and harmful chemical and heating conditions. This article presents a safe, scalable, cost-effective method to produce reduced graphene oxide (rGO) coatings using vitamin C (VC) as the reducing agent. We spray coat GO + VC mixtures onto target substrates, and then heat samples for 15 min at 150°C. The resulting rGO films have conductivities of ∼44 S cm−1, and are easily integrated into an ad hoc microfabrication flow. The rGO/Au microelectrodes show ∼8x lower impedance and ∼400x higher capacitance than bare Au, resulting in significantly enhanced charge storage and injection capacity. We subsequently use rGO/Au arrays to detect dopamine in vitro, and to map cortical activity intraoperatively over rat whisker barrel cortex, demonstrating that conductive VC-rGO coatings improve the performance and stability of multimodal microelectrodes for different applications.

Driscoll, Rosch et al. design transparent graphene-based surface probes to achieve simultaneous electrophysiological recording and calcium imaging of epileptic seizures in mice. This method could be used to investigate circuit dynamics during seizure onset and evolution with high temporal and spatial resolution.

A low and stable impedance at the skin–electrode interface is key to high-fidelity acquisition of biosignals, both acutely and in the long term. However, recording quality is highly variable due to the complex nature of human skin. Here, we present an experimental and modeling framework to investigate the interfacial impedance behavior, and describe how skin interventions affect its stability over time. To illustrate this approach, we report experimental measurements on the skin–electrode impedance using pre-gelled, clinical-grade electrodes in healthy human subjects recorded over 24 h following four skin treatments: (i) mechanical abrasion, (ii) chemical exfoliation, (iii) microporation, and (iv) no treatment. In the immediate post-treatment period, mechanical abrasion yields the lowest initial impedance, whereas the other treatments provide modest improvement compared to untreated skin. After 24 h, however, the impedance becomes more uniform across all groups (

Transparent microelectrode arrays have proven useful in neural sensing, offering a clear interface for monitoring brain activity without compromising high spatial and temporal resolution. The current landscape of transparent electrode technology faces challenges in developing durable, highly transparent electrodes while maintaining low interface impedance and prioritizing scalable processing and fabrication methods. To address these limitations, we introduce artifact-resistant transparent MXene microelectrode arrays optimized for high spatiotemporal resolution recording of neural activity. With 60% transmittance at 550 nm, these arrays enable simultaneous imaging and electrophysiology for multimodal neural mapping. Electrochemical characterization shows low impedance of 563 ± 99 kΩ at 1 kHz and a charge storage capacity of 58 mC cm⁻² without chemical doping. In vivo experiments in rodent models demonstrate the transparent arrays' functionality and performance. In a rodent model of chemically-induced epileptiform activity, we tracked ictal wavefronts via calcium imaging while simultaneously recording seizure onset. In the rat barrel cortex, we recorded multi-unit activity across cortical depths, showing the feasibility of recording high-frequency electrophysiological activity. The transparency and optical absorption properties of Ti₃C₂Tx MXene microelectrodes enable high-quality recordings and simultaneous light-based stimulation and imaging without contamination from light-induced artifacts., (© 2024 The Author(s). Advanced Healthcare Materials published by Wiley‐VCH GmbH.)

Acid mine drainage (AMD) pollutes natural waters, but some impacted systems show natural attenuation. We sought to identify the biogeochemical mechanisms responsible for the natural attenuation of AMD. We hypothesized that biogenic sulfide-mediated iron reduction is one mechanism and tested this in an experimental model system. We found sulfate reduction occurred under acidic conditions and identified a suite of sulfate-reducing bacteria (SRB) belonging to the groups Desulfotomaculum , Desulfobacter , Desulfovibrio , and Desulfobulbus . Iron reduction was not detected in microcosms when iron-reducing bacteria or SRB were selectively inhibited. SRB also did not reduce iron enzymatically. Rather, the biogenic sulfide produced by SRB was found to be responsible for the reduction of iron at low pH. Addition of organic substrates and nutrients stimulated iron reduction and increased the pH. X-ray diffraction and an electron microprobe analysis revealed that the polycrystalline, black precipitate from SRB bioactive samples exhibited a greater diversity of iron chalcogenide minerals with reduced iron oxidation states, and minerals incorporating multiple metals compared to abiotic controls. The implication of this study is that iron reduction mediated by biogenic sulfide may be more significant than previously thought in acidic environments. This study not only describes an additional mechanism by which SRB attenuate AMD, which has practical implications for AMD-impacted sites, but also provides a link between the biogeochemical cycling of iron and sulfur.

Electronic health records (EHRs) are being introduced worldwide. The change from paper to electronic records has not always been a seamless or quick process; however, EHRs are viewed as central to updating modern health care, especially organization structures and delivery of sustainable care with the potential for joint decision-making with the patient. The objective of this viewpoint paper is to outline how an EHR is being developed in Ireland. The focus of the Maternal & Newborn Clinical Management System project is the design and implementation of an EHR for all women and babies in the maternity services in the Republic of Ireland. The paper also outlines the lessons learned from the planning to the optimization stage of the project. The paper was developed through discussions with the project management team and their completed reports that outline the lessons they acquired from each project stage. Key lessons learned from each stage of the project are highlighted. This viewpoint paper explains how the national project management team is implementing the EHR and outlines the experiences and lessons learned and the challenges ahead following the phase one introduction. The Maternal & Newborn Clinical Management System is an example of a clinician-led, patient-focused, change management project from its inception to implementation. The introduction of EHRs is essential in modernizing health care and optimizing patient outcomes through the accurate and appropriate use of data., (©Orla Maria Sheehan, Richard Anthony Greene, Joye McKernan, Brendan Murphy, Caroline Cahill, Brian Cleary, Fiona Lawlor, Michael Robson, MN-CMS National Project Team. Originally published in JMIR Formative Research (https://formative.jmir.org), 12.05.2023.)

Objectives: Lower extremity (LE) injuries are common in Gaelic games and lead to a significant economic and injury burden. Balance is considered a predictor of injury in other sports, however no research has examined its effect on LE injury in Gaelic games. This study aims to present normative data for the Y Balance Test (YBT), determine whether the YBT can identify those at risk of contact and non-contact LE and ankle injuries and generate population specific cut-off points in adolescent and collegiate Gaelic games., Design: Prospective cohort study., Methods: A convenience sample of 636 male adolescent (n=293, age=15.7±0.7 years) and collegiate (n=343, age=19.3±1.9 years) Gaelic footballers and hurlers were recruited. The YBT was completed and injuries were assessed at least weekly over one season. Univariate and logistic regression was performed to examine if the YBT can classify those at risk of LE-combined and ankle injuries. ROC curves were used to identify cut-off points., Results: Gaelic players performed poorly in the YBT and between 31-57% of all players were identified as at risk of injury at pre-season using previously published YBT cut-off points. However, poor YBT scores were unable to ascertain those at risk of contact or non-contact LE-combined and ankle injuries with sufficient sensitivity. High specificity was noted for contact LE-combined and non-contact ankle injuries., Conclusions: The YBT as a sole screening method to classify those at risk of LE and ankle injuries in Gaelic games is questionable. However, the YBT may be a useful preliminary screening tool to identify those not at risk of contact LE-combined or non-contact ankle injury. Generalising published cut-off points from other sports is not supported., (Copyright © 2020 Sports Medicine Australia. Published by Elsevier Ltd. All rights reserved.)

Implantable neuroelectronic interfaces have enabled breakthrough advances in the clinical diagnosis and treatment of neurological disorders, as well as in fundamental studies of brain function, behavior, and disease. Intracranial electroencephalography (EEG) mapping with stereo-EEG (sEEG) depth electrodes is routinely adopted for precise epilepsy diagnostics and surgical treatment, while deep brain stimulation has become the standard of care for managing movement disorders. Intracortical microelectrode arrays for high-fidelity recordings of neural spiking activity have led to impressive demonstrations of the power of brain-machine interfaces for motor and sensory functional recovery. Yet, despite the rapid pace of technology development, the issue of establishing a safe, long-term, stable, and functional interface between neuroelectronic devices and the host brain tissue still remains largely unresolved. A body of work spanning at least the last 15 years suggests that safe, chronic integration between invasive electrodes and the brain requires a close match between the mechanical properties of man-made components and the neural tissue. In other words, the next generation of invasive electrodes should be soft and compliant, without sacrificing biological and chemical stability. Soft neuroelectronic interfaces, however, pose a new and significant surgical challenge: bending and buckling during implantation that can preclude accurate and safe device placement. In this topical review, we describe the next generation of soft electrodes and the surgical implantation methods for safe and precise insertion into brain structures. We provide an overview of the most recent innovations in the field of insertion strategies for flexible neural electrodes such as dissolvable or biodegradable carriers, microactuators, biologically-inspired support structures, and electromagnetic drives. In our analysis, we also highlight approaches developed in different fields, such as robotic surgery, which could be potentially adapted and translated to the insertion of flexible neural probes.

Punch sticking during tablet manufacturing is a common problem facing the pharmaceutical industry. Using several model compounds, effects of crystal size and shape of active pharmaceutical ingredients (API) on punch sticking propensity were systematically investigated in this work to provide molecular insights into the punch-sticking phenomenon. In contrast to the common belief that smaller API particles aggravate punch sticking, results show that particle size reduction can either reduce or enhance API punch sticking, depending on the complex interplay among the particle surface area, plasticity, cohesive strength, and specific surface functional groups. Therefore, other factors, such as crystal mechanical properties, surface chemistry of crystal facets exposed to the punch face, and choice of excipients in a formulation, should be considered for a more reliable prediction of the initiation and progression of punch sticking. The exposure of strong electronegative groups to the punch face facilitates the onset of sticking, while higher plasticity and cohesive strength aggravate sticking.

Implantable microelectrode technologies have been widely used to elucidate neural dynamics at the microscale to gain a deeper understanding of the neural underpinnings of brain disease and injury. As electrodes are miniaturized to the scale of individual cells, a corresponding rise in the interface impedance limits the quality of recorded signals. Additionally, conventional electrode materials are stiff, resulting in a significant mechanical mismatch between the electrode and the surrounding brain tissue, which elicits an inflammatory response that eventually leads to a degradation of the device performance. To address these challenges, we have developed a process to fabricate flexible microelectrodes based on Ti3C2 MXene, a recently discovered nanomaterial that possesses remarkably high volumetric capacitance, electrical conductivity, surface functionality, and processability in aqueous dispersions. Flexible arrays of Ti3C2 MXene microelectrodes have remarkably low impedance due to the high conductivity and high specific surface area of the Ti3C2 MXene films, and they have proven to be exquisitely sensitive for recording neuronal activity. In this protocol, we describe a novel method for micropatterning Ti3C2 MXene into microelectrode arrays on flexible polymeric substrates and outline their use for in vivo micro-electrocorticography recording. This method can easily be extended to create MXene electrode arrays of arbitrary size or geometry for a range of other applications in bioelectronics and it can also be adapted for use with other conductive inks besides Ti3C2 MXene. This protocol enables simple and scalable fabrication of microelectrodes from solution-based conductive inks, and specifically allows harnessing the unique properties of hydrophilic Ti3C2 MXene to overcome many of the barriers that have long hindered the widespread adoption of carbon-based nanomaterials for high-fidelity neural microelectrodes.

Context: Hamstring injuries are a leading cause of injury in Gaelic games. Hamstring flexibility as a risk factor for hamstring injury has not yet been examined prospectively in Gaelic games., Objective: To examine whether hamstring flexibility, using the modified active knee extension (AKE) test, and previous injury are risk factors for hamstring injury in Gaelic players and to generate population-specific AKE cutoff points., Design: Prospective cohort study., Setting: School and colleges. Patients (or Other Participants): Adolescent and collegiate Gaelic footballers and hurlers (n = 570)., Intervention(s): The modified AKE test was completed at preseason, and hamstring injuries were assessed over the course of one season. Any previous hamstring injuries were noted in those who presented with a hamstring injury., Main Outcome Measures: Bilateral AKE scores and between-leg asymmetries were recorded. Receiver operating characteristic curves were implemented to generate cutoff points specific to Gaelic players. Univariate and backward stepwise logistic regression analyses were completed to predict hamstring injuries, hamstring injuries on the dominant leg, and hamstring injuries on the nondominant leg., Results: Mean flexibility of 64.2° (12.3°) and 64.1° (12.4°) was noted on the dominant and nondominant leg, respectively. Receiver operating characteristic curves generated a cutoff point of < 65° in the AKE on the nondominant leg only. When controlled for age, AKE on the nondominant leg was the only predictor variable left in the multivariate model (odds ratio = 1.03) and significantly predicted hamstring injury (χ2 = 9.20, P = .01). However, the sensitivity was 0% and predicted the same amount of cases as the null model. It was not possible to generate a significant model for hamstring injuries on the dominant leg (P > .05), and no variables generated a P value < .20 in the univariate analysis on the nondominant leg., Conclusions: Poor flexibility noted in the AKE test during preseason screening and previous injury were unable to predict those at risk of sustaining a hamstring strain in Gaelic games with adequate sensitivity.

Intracranial electrodes are a vital component of implantable neurodevices, both for acute diagnostics and chronic treatment with open and closed-loop neuromodulation. Their performance is hampered by acute implantation trauma and chronic inflammation in response to implanted materials and mechanical mismatch between stiff synthetic electrodes and pulsating, natural soft host neural tissue. Flexible electronics based on thin polymer films patterned with microscale conductive features can help alleviate the mechanically induced trauma; however, this strategy alone does not mitigate inflammation at the device-tissue interface. In this study, we propose a biomimetic approach that integrates microscale extracellular matrix (ECM) coatings on microfabricated flexible subdural microelectrodes. Taking advantage of a high-throughput process employing micro-transfer molding and excimer laser micromachining, we fabricate multi-channel subdural microelectrodes primarily composed of ECM protein material and demonstrate that the electrochemical and mechanical properties match those of standard, uncoated controls. In vivo ECoG recordings in rodent brain confirm that the ECM microelectrode coatings and the protein interface do not alter signal fidelity. Astrogliotic, foreign body reaction to ECM coated devices is reduced, compared to uncoated controls, at 7 and 30 days, after subdural implantation in rat somatosensory cortex. We propose microfabricated, flexible, biomimetic electrodes as a new strategy to reduce inflammation at the device-tissue interface and improve the long-term stability of implantable subdural electrodes., Competing Interests: The authors have declared that no competing interests exist.

Assessment of collision risk between pedestrians and automobiles offers a powerful and informative tool in urban planning applications, and can be leveraged to inform proper placement of improvements and treatment projects to improve pedestrian safety. Such assessment can be performed using existing datasets of crashes, pedestrian counts, and automobile traffic flows to identify intersections or corridors characterized by elevated collision risks to pedestrians. The Safety In Numbers phenomenon, which refers to the observable effect that pedestrian safety is positively correlated with increased pedestrian traffic in a given area (i.e. that the individual per-pedestrian risk of a collision decreases with additional pedestrians), is a readily observed phenomenon that has been studied previously, though its directional causality is not yet known. A sample of 488 intersections in Minneapolis were analyzed, and statistically-significant log-linear relationships between pedestrian traffic flows and the per-pedestrian crash risk were found, indicating the Safety In Numbers effect. Potential planning applications of this analysis framework towards improving pedestrian safety in urban environments are discussed., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Punch sticking is a complex phenomenon influenced primarily by particle size, tooling surface roughness, tooling design, and tooling construction material. When particle and environmental factors are controlled, compaction pressure has a distinct effect on punch sticking behavior for a given active pharmaceutical ingredient (API). This research focuses on the effect of compaction pressure on punch sticking using 5 compounds with different sticking propensities. The results collectively show that sticking tends to be more problematic under higher compaction pressures and for more ductile compounds. This is attributed to the greater punch surface coverage by the API and the stronger cohesion of API to the existing API layer on the punch., (Copyright © 2017 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.)

Punch sticking is a frequently occurring problem that challenges successful tablet manufacturing. A mechanistic understanding of the punch sticking phenomenon facilitates the design of effective strategies to solve punch sticking problems of a drug. The first step in this effort is to identify process parameters and particle properties that can profoundly affect sticking performance. This work was aimed at elucidating the key material properties and compaction parameters that influence punch sticking by statistically analyzing punch sticking data of 24 chemically diverse compounds obtained using a set of tooling with removable upper punch tip. Partial least square (PLS) analysis of the data revealed that particle surface area and tablet tensile strength are the most significant factors attributed to punch sticking. Die-wall pressure, ejection force, and take-off force also correlate with sticking, but to a lesser extent., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Adherence of powder onto tablet tooling, known as punch sticking, is one of the tablet manufacturing problems that need to be resolved. An important step toward the resolution of this problem is to quantify sticking propensity of different active pharmaceutical ingredients (APIs) and understand physicochemical factors that influence sticking propensity. In this study, mass of adhered material onto a removable upper punch tip as a function of number of compression is used to monitor sticking kinetics of 24 chemically diverse compounds. We have identified a mathematical model suitable for describing punch sticking kinetics of a wide range of compounds. Chemical analyses have revealed significant enrichment of API content in the adhered mass. Based on this large set of data, we have successfully developed a new punch sticking model based on a consideration of the interplay of interaction strength among API, excipient, and punch surface. The model correctly describes the general shape of sticking profile, that is, initial rise in accumulated mass followed by gradual increase to a plateau. It also explains why sometimes sticking is arrested after monolayer coverage of punch surface by API (punch filming), while in other cases, API buildup is observed beyond monolayer coverage., (Copyright © 2016 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.)

Traditional approaches to evaluating antitumor agents using human tumor xenograft models have generally used cohorts of 8 to 10 mice against a limited panel of tumor models. An alternative approach is to use fewer animals per tumor line, allowing a greater number of models that capture greater molecular/genetic heterogeneity of the cancer type. We retrospectively analyzed 67 agents evaluated by the Pediatric Preclinical Testing Program to determine whether a single mouse, chosen randomly from each group of a study, predicted the median response for groups of mice using 83 xenograft models. The individual tumor response from a randomly chosen mouse was compared with the group median response using established response criteria. A total of 2,134 comparisons were made. The single tumor response accurately predicted the group median response in 1,604 comparisons (75.16%). The mean tumor response correct prediction rate for 1,000 single mouse random samples was 78.09%. Models had a range for correct prediction (60%-87.5%). Allowing for misprediction of ± one response category, the overall mean correct single mouse prediction rate was 95.28%, and predicted overall objective response rates for group data in 66 of 67 drug studies. For molecularly targeted agents, occasional exceptional responder models were identified and the activity of that agent confirmed in additional models with the same genotype. Assuming that large treatment effects are targeted, this alternate experimental design has similar predictive value as traditional approaches, allowing for far greater numbers of models to be used that more fully encompass the heterogeneity of disease types. Cancer Res; 76(19); 5798-809. ©2016 AACR., Competing Interests: Conflict of Interest. The authors have no conflicts to report., (©2016 American Association for Cancer Research.)

Rapid proton migration is a key process in hydrocarbon photochemistry. Charge migration and subsequent proton motion can mitigate radiation damage when heavier atoms absorb X-rays. If rapid enough, this can improve the fidelity of diffract-before-destroy measurements of biomolecular structure at X-ray-free electron lasers. Here we study X-ray-initiated isomerization of acetylene, a model for proton dynamics in hydrocarbons. Our time-resolved measurements capture the transient motion of protons following X-ray ionization of carbon K-shell electrons. We Coulomb-explode the molecule with a second precisely delayed X-ray pulse and then record all the fragment momenta. These snapshots at different delays are combined into a 'molecular movie' of the evolving molecule, which shows substantial proton redistribution within the first 12 fs. We conclude that significant proton motion occurs on a timescale comparable to the Auger relaxation that refills the K-shell vacancy.

Background: Recent studies have described the bifidobacterial composition of neonates at a species level; however, with advancing technologies we can gain insight into the diversity of the bifidobacterial microbiota residing within the infant gut., Objective: To compare species and strain diversity of culturable bifidobacterial populations in faecal samples obtained from healthy term infants on three different feeding regimes., Study Design: In total, 51 healthy term infants were recruited for this study and divided equally into three different groups (n=17) based on their feeding regime during the first 4 weeks of life. Culturable bifidobacterial populations were analysed at week 1, week 4 and 6 months of age. Isolates were characterised to species level by 16s rRNA-internally transcribed spacer (ITS) gene sequence analysis and to strain level by pulsed field gel electrophoresis (PFGE)., Results: In total,173 bifidobacterial strains were detected across all three groups from 2295 isolates, 42% (72 of 173) of which were detected in the prebiotic-fed group, followed by 30% (52 of 173) and 28% (49 of 173) in the breastfed and non-prebiotic-fed groups, respectively. Surprisingly, only two of the 51 infants harboured an identical bifidobacterial strain which was not present in the other 49 infants. Prebiotic supplementation in the early neonatal period increased the prevalence of Bifidobacterium longum in infants, in addition to promoting strain diversity. B. longum was the dominant species recovered from all three groups during the first 6 months of life, followed by Bifidobacterium breve and Bifidobacterium bifidum., Conclusions: This study reveals a hitherto unknown level of diversity at the strain level among bifidobacteria isolated from different infants and the influence prebiotic formula feeding has on the bifidobacterial population., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)

Background: Preclinical data suggest that the loop-diuretic bumetanide might be an effective treatment for neonatal seizures. We aimed to assess dose and feasibility of intravenous bumetanide as an add-on to phenobarbital for treatment of neonatal seizures., Methods: In this open-label, dose finding, and feasibility phase 1/2 trial, we recruited full-term infants younger than 48 h who had hypoxic ischaemic encephalopathy and electrographic seizures not responding to a loading-dose of phenobarbital from eight neonatal intensive care units across Europe. Newborn babies were allocated to receive an additional dose of phenobarbital and one of four bumetanide dose levels by use of a bivariate Bayesian sequential dose-escalation design to assess safety and efficacy. We assessed adverse events, pharmacokinetics, and seizure burden during 48 h continuous electroencephalogram (EEG) monitoring. The primary efficacy endpoint was a reduction in electrographic seizure burden of more than 80% without the need for rescue antiepileptic drugs in more than 50% of infants. The trial is registered with ClinicalTrials.gov, number NCT01434225., Findings: Between Sept 1, 2011, and Sept 28, 2013, we screened 30 infants who had electrographic seizures due to hypoxic ischaemic encephalopathy. 14 of these infants (10 boys) were included in the study (dose allocation: 0·05 mg/kg, n=4; 0·1 mg/kg, n=3; 0·2 mg/kg, n=6; 0·3 mg/kg, n=1). All babies received at least one dose of bumetanide with the second dose of phenobarbital; three were withdrawn for reasons unrelated to bumetanide, and one because of dehydration. All but one infant also received aminoglycosides. Five infants met EEG criteria for seizure reduction (one on 0·05 mg/kg, one on 0·1 mg/kg and three on 0·2 mg/kg), and only two did not need rescue antiepileptic drugs (ie, met rescue criteria; one on 0·05 mg/kg and one on 0·3 mg/kg). We recorded no short-term dose-limiting toxic effects, but three of 11 surviving infants had hearing impairment confirmed on auditory testing between 17 and 108 days of age. The most common non-serious adverse reactions were moderate dehydration in one, mild hypotension in seven, and mild to moderate electrolyte disturbances in 12 infants. The trial was stopped early because of serious adverse reactions and limited evidence for seizure reduction., Interpretation: Our findings suggest that bumetanide as an add-on to phenobarbital does not improve seizure control in newborn infants who have hypoxic ischaemic encephalopathy and might increase the risk of hearing loss, highlighting the risks associated with the off-label use of drugs in newborn infants before safety assessment in controlled trials., Funding: European Community's Seventh Framework Programme., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Background: Clinical trials are the main method for evaluating safety and efficacy of medical interventions and have produced many advances in improving human health. The Women's Health Initiative overturned a half-century of harmful practice in hormone therapy, the National Lung Screening Trial identified the first successful lung cancer screening tool and the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial overturned decades-long assumptions. While some trials identify unforeseen safety issues or harms, many fail to demonstrate efficacy. Large trials require substantial resources; to ensure reliable outcomes, we must seek ways to improve the predictive information used as the basis of trials., Results: Here we demonstrate a modeling framework for linking knowledge of underlying biological mechanism to evaluate the expectation of trial outcomes. Key features include the ability to propagate uncertainty in biological mechanism to uncertainty in trial outcome and mechanisms for identifying knowledge gaps most responsible for unexpected outcomes. The framework was used to model the effect of selenium supplementation for prostate cancer prevention and parallels the Selenium and Vitamin E Cancer Prevention Trial that showed no efficacy despite suggestive data from secondary endpoints in the Nutritional Prevention of Cancer trial and found increased incidence of high-grade prostate cancer in certain subgroups., Conclusion: Using machine learning methods, we identified the parameters of the model that are most predictive of trial outcome and found that the top four are directly related to the rates of reactions producing methylselenol and transporting extracellular selenium into the cell as selenide. This modeling process demonstrates how the approach can be used in advance of a large clinical trial to identify the best targets for conducting further research to reduce the uncertainty in the trial outcome.

Glucokinase (hexokinase IV) continues to be a compelling target for the treatment of type 2 diabetes given the wealth of supporting human genetics data and numerous reports of robust clinical glucose lowering in patients treated with small molecule allosteric activators. Recent work has demonstrated the ability of hepatoselective activators to deliver glucose lowering efficacy with minimal risk of hypoglycemia. While orally administered agents require a considerable degree of passive permeability to promote suitable exposures, there is no such restriction on intravenously delivered drugs. Therefore, minimization of membrane diffusion in the context of an intravenously agent should ensure optimal hepatic targeting and therapeutic index. This work details the identification a hepatoselective GKA exhibiting the aforementioned properties., (Published by Elsevier Ltd.)

Caring for young people with first-episode psychosis (FEP) is challenging and can adversely affect carer well-being, with limited evidence-based support materials available. We aimed to examine whether completion of a self-directed problem-solving bibliotherapy among carers of young people with FEP led to a better experience of caring, less distress and expressed emotion, and better general health than carers who only received treatment as usual (TAU). A randomized controlled trial was conducted across two early-intervention psychosis services in Melbourne, Australia. A total of 124 carers were randomized to problem-solving bibliotherapy intervention (PSBI) or TAU and assessed at baseline, 6-week and 16-week follow-up. Intent-to-treat analyses were carried out and indicated that recipients of PSBI had a more favorable experience of caring than those receiving TAU, and these effects were sustained at both follow-up time points. Across the other measures, both groups demonstrated improvements by week 16, although the PBSI group tended to improve earlier. The PSBI group experienced a greater reduction in negative emotional evaluations of the need to provide additional support to young people with FEP than the TAU group by week 6, while the level of psychological distress decreased at a greater rate from baseline to 6 weeks in the PSBI compared with the TAU group. These findings support the use of problem-solving bibliotherapy for first-time carers, particularly as a cost-effective adjunct to TAU.

Unlabelled: The human appendix has historically been considered a vestige of evolutionary development with an unknown function. While limited data are available on the microbial composition of the appendix, it has been postulated that this organ could serve as a microbial reservoir for repopulating the gastrointestinal tract in times of necessity. We aimed to explore the microbial composition of the human appendix, using high-throughput sequencing of the 16S rRNA gene V4 region. Seven patients, 5 to 25 years of age, presenting with symptoms of acute appendicitis were included in this study. Results showed considerable diversity and interindividual variability among the microbial composition of the appendix samples. In general, however, Firmicutes was the dominant phylum, with the majority of additional sequences being assigned at various levels to Proteobacteria, Bacteroidetes, Actinobacteria, and Fusobacteria. Despite the large diversity in the microbiota found within the appendix, however, a few major families and genera were found to comprise the majority of the sequences present. Interestingly, also, certain taxa not generally associated with the human intestine, including the oral pathogens Gemella, Parvimonas, and Fusobacterium, were identified among the appendix samples. The prevalence of genera such as Fusobacterium could also be linked to the severity of inflammation of the organ. We conclude that the human appendix contains a robust and varied microbiota distinct from the microbiotas in other niches within the human microbiome. The microbial composition of the human appendix is subject to extreme variability and comprises a diversity of biota that may play an important, as-yet-unknown role in human health., Importance: There are currently limited data available on the microbial composition of the human appendix. It has been suggested, however, that it may serve as a "safe house" for commensal bacteria that can reinoculate the gut at need. The present study is the first comprehensive view of the microbial composition of the appendix as determined by high-throughput sequencing. We have determined that the human appendix contains a wealth of microbes, including members of 15 phyla. Important information regarding the associated bacterial diversity of the appendix which will help determine the role, if any, the appendix microbiota has in human health is presented.

The infant gut microbiota undergoes dramatic changes during the first 2 years of life. The acquisition and development of this population can be influenced by numerous factors, and antibiotic treatment has been suggested as one of the most significant. Despite this, however, there have been relatively few studies which have investigated the short-term recovery of the infant gut microbiota following antibiotic treatment. The aim of this study was to use high-throughput sequencing (employing both 16S rRNA and rpoB-specific primers) and quantitative PCR to compare the gut microbiota of nine infants who underwent parenteral antibiotic treatment with ampicillin and gentamicin (within 48 h of birth), 4 and 8 weeks after the conclusion of treatment, relative to that of nine matched healthy controls. The investigation revealed that the gut microbiota of the antibiotic-treated infants had significantly higher proportions of Proteobacteria (P = 0.0049) and significantly lower proportions of Actinobacteria (P = 0.00001) (and the associated genus Bifidobacterium [P = 0.0132]) as well as the genus Lactobacillus (P = 0.0182) than the untreated controls 4 weeks after the cessation of treatment. By week 8, the Proteobacteria levels remained significantly higher in the treated infants (P = 0.0049), but the Actinobacteria, Bifidobacterium, and Lactobacillus levels had recovered and were similar to those in the control samples. Despite this recovery of total Bifidobacterium numbers, rpoB-targeted pyrosequencing revealed that the number of different Bifidobacterium species present in the antibiotic-treated infants was reduced. It is thus apparent that the combined use of ampicillin and gentamicin in early life can have significant effects on the evolution of the infant gut microbiota, the long-term health implications of which remain unknown.

Theory predicts that double-core-hole (DCH) spectroscopy can provide a new powerful means of differentiating between similar chemical systems with a sensitivity not hitherto possible. Although DCH ionization on a single site in molecules was recently measured with double- and single-photon absorption, double-core holes with single vacancies on two different sites, allowing unambiguous chemical analysis, have remained elusive. Here we report that direct observation of double-core holes with single vacancies on two different sites produced via sequential two-photon absorption, using short, intense X-ray pulses from the Linac Coherent Light Source free-electron laser and compare it with theoretical modeling. The observation of DCH states, which exhibit a unique signature, and agreement with theory proves the feasibility of the method. Our findings exploit the ultrashort pulse duration of the free-electron laser to eject two core electrons on a time scale comparable to that of Auger decay and demonstrate possible future X-ray control of physical inner-shell processes.

We investigated the impact of parenteral antibiotic treatment in the early neonatal period on the evolution of bifidobacteria in the newborn. Nine babies treated with intravenous ampicillin/gentamicin in the first week of life and nine controls (no antibiotic treatment) were studied. Denaturing gradient gel electrophoresis was used to investigate the composition of Bifidobacterium in stool samples taken at four and eight weeks. Bifidobacteria were detected in all control infants at both four and eight weeks, while only six of nine antibiotic-treated infants had detectable bifidobacteria at four weeks and eight of nine at eight weeks. Moreover, stool samples of controls showed greater diversity of Bifidobacterium spp. compared with antibiotic-treated infants. In conclusion, short-term parenteral antibiotic treatment of neonates causes a disturbance in the expected colonization pattern of bifidobacteria in the first months of life. Further studies are required to probiotic determine if supplementation is necessary in this patient group.

Background: Debate persists regarding the role of Desulfovibrio subspecies in ulcerative colitis. Combined microscopic and molecular techniques enable this issue to be investigated by allowing precise enumeration of specific bacterial species within the colonic mucous gel. The aim of this study was to combine laser capture microdissection and quantitative polymerase chain reaction to determine Desulfovibrio copy number in crypt-associated mucous gel in health and in acute and chronic ulcerative colitis., Methods: Colonic mucosal biopsies were harvested from healthy controls (n = 19) and patients with acute (n = 10) or chronic (n = 10) ulcerative colitis. Crypt-associated mucous gel was obtained by laser capture microdissection throughout the colon. Pan-bacterial 16S rRNA and Desulfovibrio copy number/mm were obtained by polymerase chain reaction at each locus. Bacterial copy numbers were interrogated for correlation with location and disease activity. Data were evaluated using a combination of ordinary linear methods and linear mixed-effects models to cater for multiple interactions., Results: Desulfovibrio positivity was significantly increased in acute and chronic ulcerative colitis at multiple levels within the colon, and after normalization with total bacterial signal, the relative Desulfovibrio load was increased in acute colitis compared with controls. Desulfovibrio counts did not significantly correlate with age, disease duration, or disease activity but interlevel correlations were found in adjacent colonic segments in the healthy control and chronic ulcerative colitis groups., Conclusion: The presence of Desulfovibrio subspecies is increased in ulcerative colitis and the data presented suggest that these bacteria represent an increased percentage of the colonic microbiome in acute ulcerative colitis.

This article discusses institutional changes that may facilitate an adaptive approach to biosecurity risk management where governance is viewed as a multidisciplinary, interactive experiment acknowledging uncertainty. Using the principles of adaptive governance, evolved from institutional theory, we explore how the concepts of lateral information flows, incentive alignment, and policy experimentation might shape Australia's invasive species defense mechanisms. We suggest design principles for biosecurity policies emphasizing overlapping complementary response capabilities and the sharing of invasive species risks via a polycentric system of governance., (© 2010 Society for Risk Analysis)

This study compared the effects of three doses of cannabis and alcohol (placebo, low and high doses), both alone and in combination, on the driving performance of young, novice drivers and more experienced drivers. Alcohol was administered as ethanol (95%) mixed with orange juice in doses of approximately 0, 0.4 and 0.6g/kg. Cannabis was administered by inhalation of smoke from pre-rolled cannabis cigarettes (supplied by the National Institute of Drug Abuse, USA). Active cigarettes contained 19 mg delta-9-THC. Using a counterbalanced design, the simulated driving performance of 25 experienced and 22 inexperienced drivers was tested under the nine different drug conditions in an arterial driving environment during which workload was varied through the drive characteristics as well as through the inclusion of a secondary task. High levels of cannabis generally induced greater impairment than lower levels, while alcohol at the doses used had few effects and did not produce synergistic effects when combined with cannabis. Both cannabis and alcohol were associated with increases in speed and lateral position variability, high dose cannabis was associated with decreased mean speed, increased mean and variability in headways, and longer reaction time, while in contrast alcohol was associated with a slight increase in mean speed. Given the limitations of the study, it is of great interest to further explore the qualitative impairments in driving performance associated with cannabis and alcohol separately and how these impairments may manifest in terms of crash characteristics., (Copyright (c) 2009 Elsevier Ltd. All rights reserved.)

Aims: To review the evidence that supports early intervention in the treatment of bipolar disorder., Background: Bipolar disorder is a pleomorphic condition, with varying manifestations that are determined by a number of complex factors including the "stage" of illness. It is consequently a notoriously difficult illness to diagnose and as a corollary is associated with lengthy delays in recognition and the initiation of suitable treatment., Methods: A literature search was conducted using MEDLINE augmented by a manual search., Results: Emerging neuroimaging data suggests that, in contrast to schizophrenia, where at the time of a first-episode of illness there is already discernible volume loss, in bipolar disorder, gross brain structure is relatively preserved, and it is only with recurrences that there is a sequential, but marked loss of brain volume. Recent evidence suggests that both pharmacotherapy and psychotherapy are more effective if instituted early in the course of bipolar disorder, and that with multiple episodes and disease progression there is a noticeable decline in treatment response., Conclusions: Such data supports the notion of clinical staging, and the tailored implementation of treatments according to the stage of illness. The progressive nature of bipolar disorder further supports the concept that the first episode is a period that requires energetic broad-based treatment, with the hope that this could alter the temporal trajectory of the illness. It also raises hope that prompt treatment may be neuroprotective and that this perhaps attenuates or even prevents the neurostructural and neurocognitive changes seen to emerge with chronicity. This highlights the need for early identification at a population level and the necessity of implementing treatments and services at a stage of the illness where prognosis is optimal.

This article focuses on the impact of increased duration of exercise therapy on functional recovery after stroke. A comprehensive literature search using multiple databases was used to identify all relevant randomized controlled trials. Their quality was reviewed by two independent assessors, and a narrative systematic review and meta-analysis was completed. Methodological quality of all the 20 randomized controlled trials (RCTs) identified had a median of 6 points (range 5-8) on the 10-point PEDro scale. A meta-analysis was completed for studies that had a common outcome measure. For each outcome measure, the estimated effect size (ES) and the summary effect size (SES) were expressed as standardized mean differences (SMD). The results of the meta-analysis demonstrated that increased duration of exercise therapy time has a small but positive effect on activities of daily living as measured by the Barthel Index (SES 0.13; CI 0.01-0.25; Z = 2.15; p = .03) and that these improvements are maintained over a 6-month period (SES 0.15; CI 0.05-0.26; Z = 2.8; p = .00). Pooling reported differences in the various upper and lower extremity outcome measures demonstrated no significant SESs. However, the meta-analysis is supportive of the hypothesis that additional, focused exercise on the lower extremity has a favourable effect on lower extremity impairment and walking speed. The narrative review raises a number of issues that need to be considered in the development of future RCTs.

Objective: To evaluate the effect of robot-mediated therapy on arm dysfunction post stroke., Design: A series of single-case studies using a randomized multiple baseline design with ABC or ACB order. Subjects (n = 20) had a baseline length of 8, 9 or 10 data points. They continued measurement during the B - robot-mediated therapy and C - sling suspension phases., Setting: Physiotherapy department, teaching hospital., Subjects: Twenty subjects with varying degrees of motor and sensory deficit completed the study. Subjects attended three times a week, with each phase lasting three weeks., Interventions: In the robot-mediated therapy phase they practised three functional exercises with haptic and visual feedback from the system. In the sling suspension phase they practised three single-plane exercises. Each treatment phase was three weeks long., Main Measures: The range of active shoulder flexion, the Fugl-Meyer motor assessment and the Motor Assessment Scale were measured at each visit., Results: Each subject had a varied response to the measurement and intervention phases. The rate of recovery was greater during the robot-mediated therapy phase than in the baseline phase for the majority of subjects. The rate of recovery during the robot-mediated therapy phase was also greater than that during the sling suspension phase for most subjects., Conclusion: The positive treatment effect for both groups suggests that robot-mediated therapy can have a treatment effect greater than the same duration of non-functional exercises. Further studies investigating the optimal duration of treatment in the form of a randomized controlled trial are warranted.

Background and Objectives: Concern about primary fistula failure may contribute to the underuse of arteriovenous fistula. The objective of this study was to investigate the baseline clinical parameters associated with primary fistula success., Design, Setting, Participants, & Measurements: Consecutive incident patients who commenced dialysis during a 28-mo period in a regional renal program were studied. Data on patient-related variables and on surgical approach (e.g., whether the surgeons routinely assess vessel size during the operation) were collected. Primary fistula success was defined as an arteriovenous fistula that was able to afford successful dialysis for 3 h with blood pump speed of > or =300 ml/min for three consecutive sessions., Results: A total of 205 (69%) patients had an AVF attempted as their first vascular access. The overall primary success rate was 64% and was similar for radiocephalic and brachiocephalic fistula. Logistic regression was done separately for patients with the two types of fistula because of the presence of statistical interaction. For radiocephalic fistula, male gender was the only parameter associated with primary fistula success (odds ratio 3.57; P = 0.01). The presence of comorbidity was not significantly associated with primary fistula failure., Conclusions: Despite significant patient comorbidity, there was a high primary fistula success rate among this incident hemodialysis cohort. Given that vessel size may be the ultimate determinant of fistula success, if surgeons assess vessel size perioperatively, then the presence of significant comorbidity might not preclude arteriovenous fistula from being attempted as the initial access.

This paper outlines the increasing need for new health care practitioners to work under delegation or as substitutes for medical practitioners to resolve the Australian health workforce crisis. The personal experience of the author and common issues for medical practitioners related to the introduction of these new roles are discussed.

The objective of this study was to investigate the cultivable Lactobacillus population in adult and infant faecal material to identify strains shared across a number of individuals. A range of lactobacilli isolated on Lactobacillus-selective agar from faeces of 16 infants and 11 adults were genetically fingerprinted and further characterized by 16S rRNA gene sequencing. The relatedness of all the Lactobacillus strains isolated to known species was also determined both genetically and phenotypically. This study revealed that the human intestine is initially colonized by only a few (1-2) different cultivable strains whereas in adults the pattern becomes more complex with a higher diversity of strains. The adult samples contained three genetically distinct Lactobacillus strains in some cases, while infant samples generally harboured only one dominant Lactobacillus strain. Moreover, the species in general appeared to differ with Lactobacillus rhamnosus and Lactobacillus casei/paracasei found mainly in adults, whereas Lactobacillus gasseri and Lactobacillus salivarius were more commonly isolated in infant samples. The data reaffirm the differences in Lactobacillus populations both between individual subjects and between the infant and adult, with an overall change in the diversity and complexity from early stages of life to adulthood.

The chemokine receptors CXCR4 and CCR5 are required for HIV-1 to enter cells, and the progression of HIV-1 infection to AIDS involves a switch in the co-receptor usage of the virus from CCR5 to CXCR4. These receptors therefore make attractive candidates for therapeutic intervention, and we have investigated the silencing of their genes by using ribozymes and single-stranded antisense RNAs. In the present study, we demonstrate using ribozymes that a depletion of CXCR4 and CCR5 mRNAs can be achieved simultaneously in human PBMCs (peripheral blood mononuclear cells), cells commonly used by the virus for infection and replication. Ribozyme activity leads to an inhibition of the cell-surface expression of both CCR5 and CXCR4, resulting in a significant inhibition of HIV-1 replication when PBMCs are challenged with the virus. In addition, we show that small single-stranded antisense RNAs can also be used to silence CCR5 and CXCR4 genes when delivered to PBMCs. This silencing is caused by selective degradation of receptor mRNAs.