Fluid Flow Model for Predicting the Intrusion Rate of Subsurface Contaminant Vapors into Buildings.

A new method is presented for calculating a building-specific subslab to indoor air attenuation factor for use in assessing subsurface vapor intrusion to indoor air. The technique includes (1) subslab gas extraction with flow and vacuum measurements and mathematical modeling to characterize the bulk average vertical gas conductivity of the floor slab, (2) monitoring of the ambient pressure gradient across the floor slab with a micromanometer, (3) calculating the volumetric flow of soil gas into the building ( Qsoil), and (4) dividing Qsoil by the building ventilation rate ( Qbuilding) to calculate a building-specific attenuation factor. Sample calculations using order statistics from 121 individual tests are comparable to the U.S. Environmental Protection Agency empirical attenuation factors for residential buildings and the U.S. Navy empirical attenuation factors for commercial/industrial buildings. A case study of a commercial building shows encouraging agreement between the attenuation factors calculated via this method and via conventional subslab and indoor air sampling.

Piloting a new model of personalised care for people with fibromyalgia in primary care with secondary care multidisciplinary support.

OBJECTIVE: An estimated 5.5 million people in England have high-impact chronic pain, which is severe pain associated with significant disability. Current models of healthcare often fail to address their broad range of symptoms and address their complex non-medical needs. METHODS: A pilot project was designed with the aim of improving the quality of care and addressing unmet needs of patients high-impact musculoskeletal (MSK) pain through providing a personalised approach to their pain and wider psychosocial needs. The model comprised a longer initial appointment with a general practitioner, a later follow-appointment, and support of the multidisciplinary team (MDT) (informally and through a formal MDT meeting) with both primary care clinicians and specialists based in secondary care. RESULTS: Forty six patients were seen using this model, with prominent themes of consultations including self-management, social needs, mental health and understanding their diagnosis. Evaluation of the pilot demonstrated improvements in MSK and non-MSK symptoms, together with improved patient confidence in self-management and knowledge and understanding of their condition. Multidisciplinary working proved to be invaluable in addressing patients' wider needs but also upskilling and supporting primary care clinicians. Primary care staff also found it to be a satisfying way to care for patients, and developed increasing skills and confidence in supporting patients with chronic pain. CONCLUSION: This model of care appears to be an effective way to help primary care teams to provide more holistic personalised care to a group of patients who are highly complex and so often forgotten.

Impacts of groundwater metal loads from bedrock fractures on water quality of a mountain stream.

Acid mine drainage and metal loads from hardrock mines to surface waters is a significant problem in the western USA and many parts of the world. Mines often occur in mountain environments with fractured bedrock aquifers that serve as pathways for metals transport to streams. This study evaluates impacts from current and potential future groundwater metal (Cd, Cu, and Zn) loads from fractures underlying the Gilt Edge Mine, South Dakota, on concentrations in Strawberry Creek using existing flow and water quality data and simple mixing/dilution mass balance models. Results showed that metal loads from bedrock fractures to the creek currently contribute <1% of total loads. Even if background water quality is achieved upstream in Strawberry Creek, fracture metal loads would be <5%. Fracture loads could increase substantially and cause stream water quality standards exceedances once groundwater with elevated metals concentrations in the aquifer matrix migrates to the fractures and discharges to the stream. Potential future metal loads from an upstream fracture would contribute a small proportion of the total load relative to current loads in the stream. Cd has the highest stream concentrations relative to standards. Even if all stream water was treated to remove 90% of the Cd, the standard would still not be achieved. At a fracture farther downstream, the Cd standard can only be met if the upstream water is treated achieving a 90% reduction in Cd concentrations and the median stream flow is maintained.

Identification and Optimization of Novel Small c-Abl Kinase Activators Using Fragment and HTS Methodologies.

Abelson kinase (c-Abl) is a ubiquitously expressed, nonreceptor tyrosine kinase which plays a key role in cell differentiation and survival. It was hypothesized that transient activation of c-Abl kinase via displacement of the N-terminal autoinhibitory "myristoyl latch", may lead to an increased hematopoietic stem cell differentiation. This would increase the numbers of circulating neutrophils and so be an effective treatment for chemotherapy-induced neutropenia. This paper describes the discovery and optimization of a thiazole series of novel small molecule c-Abl activators, initially identified by a high throughput screening. Subsequently, a scaffold-hop, which exploited the improved physicochemical properties of a dihydropyrazole analogue, identified through fragment screening, delivered potent, soluble, cell-active c-Abl activators, which demonstrated the intracellular activation of c-Abl in vivo.

A national survey of pain clinics within the United Kingdom and Ireland focusing on the multidisciplinary team and the incorporation of the extended nursing role.

Inconsistencies in the availability and quality of pain service provision have been noted nationally, as have lengthy waiting times for appointments and lack of awareness of the Pain Clinic role. The 2013 NHS England report stated that specialist pain services must offer multispecialty and multidisciplinary pain clinics. This national survey of multidisciplinary pain service provision in the United Kingdom and Ireland provides a snapshot of pain service provision in order to review and highlight what variations exist in multidisciplinary team (MDT) provision and working patterns. A common perception among clinicians is that financial pressures have led to alternate ways of staff utilisation with variable degrees of success. The survey included 143 pain clinics, focusing principally on MDT working patterns, MDT composition and adoption of the extended role. The results identified that the majority of Pain Clinics utilise the MDT approach. However, provision of critical components such as regular MDT meetings is highly variable as is the composition of the MDT itself and also working patterns of the individual clinicians. The survey reports the successful use of the extended roles for specialist nurses in follow up clinics. In contrast, the survey highlights that a large proportion of clinicians surveyed have reservations about both the effectiveness and the safety of utilising specialist nurses in the extended role to see new referrals of complex pain patients to pain clinics. This survey underlines the essential requirement for incorporation of greater MDT working locally and nationally and allocation of appropriate resources to facilitate this.

Diagnostic uncertainty, guilt, mood, and disability in back pain.

OBJECTIVE: In the majority of patients a definitive cause for low back pain (LBP) cannot be established, and many patients report feeling uncertain about their diagnosis, accompanied by guilt. The relationship between diagnostic uncertainty, guilt, mood, and disability is currently unknown. This study tested 3 theoretical models to explore possible pathways between these factors. In Model 1, diagnostic uncertainty was hypothesized to correlate with pain-related guilt, which in turn would positively correlate with depression, anxiety and disability. Two alternative models were tested: (a) a path from depression and anxiety to guilt, from guilt to diagnostic uncertainty, and finally to disability; (b) a model in which depression and anxiety, and independently, diagnostic uncertainty, were associated with guilt, which in turn was associated with disability. METHOD: Structural equation modeling was employed on data from 413 participants with chronic LBP. RESULTS: All 3 models showed a reasonable-to-good fit with the data, with the 2 alternative models providing marginally better fit indices. Guilt, and especially social guilt, was associated with disability in all 3 models. Diagnostic uncertainty was associated with guilt, but only moderately. Low mood was also associated with guilt. CONCLUSIONS: Two newly defined factors, pain related guilt and diagnostic uncertainty, appear to be linked to disability and mood in people with LBP. The causal path of these links cannot be established in this cross sectional study. However, pain-related guilt especially appears to be important, and future research should examine whether interventions directly targeting guilt improve outcomes.

The effectiveness of a novel neuromuscular electrostimulation method versus intermittent pneumatic compression in enhancing lower limb blood flow.

OBJECTIVE: This study compares the effectiveness of a neuromuscular electrostimulation device (geko T-1; Firstkind Ltd, High Wycombe, UK) in enhancing lower limb blood perfusion with two leading intermittent pneumatic compression (IPC) devices, the Huntleigh Flowtron Universal (Huntleigh Healthcare Ltd, Cardiff, UK) and the Kendall SCD Express (Covidien plc, Dublin, Ireland). The subjects' tolerance of the devices was also compared. METHODS: Ten healthy subjects were recruited. The devices were fitted bilaterally, in a sequential manner, for 30 minutes. Ultrasound and laser Doppler fluxmetry assessments were performed. RESULTS: The geko T-1 device was superior to both IPC devices in increasing both venous and arterial blood volume flow by ∼30% (95% confidence interval [CI], 23.7%-82.4%; P ≤ .001). The geko T-1 increased arterial blood velocity by 24% (95% CI, 9.7%-24.5%; P ≤ .001). A substantial increase in the total microcirculatory blood velocity by ∼370% (95% CI, 13.5%-39.7%) was reported after the use of the geko T-1 (P ≤ .001). With use of the visual analog scale, no significant differences in discomfort were found between the geko T-1 device and the IPC devices (P >.05). CONCLUSIONS: The geko T-1 device is more effective than the IPC devices in increasing venous, arterial, and microcirculatory blood velocity. The devices studied were safe and well tolerated by healthy subjects.

Optimized chemical probes for REV-ERBα.

REV-ERBα has emerged as an important target for regulation of circadian rhythm and its associated physiology. Herein, we report on the optimization of a series of REV-ERBα agonists based on GSK4112 (1) for potency, selectivity, and bioavailability. (1) Potent REV-ERBα agonists 4, 10, 16, and 23 are detailed for their ability to suppress BMAL and IL-6 expression from human cells while also demonstrating excellent selectivity over LXRα. Amine 4 demonstrated in vivo bioavailability after either iv or oral dosing.