Machine learning methods to support personalized neuromusculoskeletal modelling.

Many biomedical, orthopaedic, and industrial applications are emerging that will benefit from personalized neuromusculoskeletal models. Applications include refined diagnostics, prediction of treatment trajectories for neuromusculoskeletal diseases, in silico design, development, and testing of medical implants, and human-machine interfaces to support assistive technologies. This review proposes how physics-based simulation, combined with machine learning approaches from big data, can be used to develop high-fidelity personalized representations of the human neuromusculoskeletal system. The core neuromusculoskeletal model features requiring personalization are identified, and big data/machine learning approaches for implementation are presented together with recommendations for further research.

Individuals with mild-to-moderate hip osteoarthritis walk with lower hip joint contact forces despite higher levels of muscle co-contraction compared to healthy individuals.

OBJECTIVE: To compare hip joint contact forces (HJCF), hip muscle forces, and hip muscle co-contraction levels between individuals with mild-to-moderate hip osteoarthritis (OA) and healthy controls during walking. DESIGN: Eighteen participants with mild-to-moderate hip OA and 23 healthy controls walked at a self-selected speed while motion capture and electromyographic data were synchronously collected. HJCF were computed using a calibrated electromyography-informed neuromusculoskeletal model. Hip joint contact forces, muscle forces, and co-contraction indices for flexor/extensor and adductor/abductor muscle groups were compared between groups using independent sample t-tests (P < 0.05). RESULTS: There was no between-group difference in self-selected walking speed. On average, participants with hip OA walked with 11% lower first peak (mean difference 235 [95% confidence interval (CI) 57-413] N) and 22% lower second peak (mean difference 574 [95%CI 304-844] N) HJCF compared to controls. Hip muscle forces were also significantly lower in the hip OA compared to control group at first (mean difference 224 [95%CI 66-382] N) and second (mean difference 782 [95%CI 399-1164] N) peak HJCF. Participants with hip OA exhibited higher levels of hip muscle co-contraction in both flexor/extensor and adductor/abductor muscle groups. Consistent with existing literature, hip joint angles (extension, adduction) and external moments (flexion, extension, adduction) were lower in hip OA compared to controls. CONCLUSION: Lower HJCF were detected in mild-to-moderate hip OA, primarily due to lower hip muscle force production, and despite higher levels of hip muscle co-contraction. Findings suggest that lower loading of the hip joint during walking is a feature of mild-to-moderate hip OA, which could have implications for the pathogenesis of hip OA and/or disease progression.

Carbon-based nanomaterials as stimulators of production of pharmaceutically active alkaloids in cell culture of Catharanthus roseus.

Carbon-based nanomaterials (CBNs) were previously described as regulators of plant cell division. Here, we demonstrated the ability of multi-walled carbon nanotubes (MWCNT) and graphene to enhance biomass production in callus culture of the medicinal plant Catharanthus roseus cultivated in dark conditions. Furthermore, both tested CBNs were able to stimulate biosynthesis of total produced alkaloids in CBN-exposed callus culture of Catharanthus. In one case, total alkaloids in CBN-exposed Catharanthus were double that of unexposed Catharanthus. Analysis of metabolites by HPLC revealed that production of the pharmaceutically active alkaloids vinblastine and vincristine was dramatically enhanced in callus exposed to MWCNT or graphene in both dark and light conditions of callus cultivation. In vitro assays (MTT, flow cytometry) demonstrated that total alkaloid extracts derived from Catharanthus callus treated with CBNs significantly reduced cell proliferation of breast cancer (MCF-7) and lung cancer (A549) cell lines compared to the application of extracts derived from untreated Catharanthus callus.

Hip joint moments during walking in people with hip osteoarthritis: a systematic review and meta-analysis.

OBJECTIVE: This systematic review and meta-analysis investigated surrogate measures of hip joint loading during walking in people with hip osteoarthritis (OA). METHODS: Five databases were searched up to January 14th, 2018. Studies that measured hip joint moments in the frontal or sagittal plane during walking in people with hip OA and used either a healthy control group or the unaffected leg to compare hip joint moments were included. Standardised mean differences (SMD) in sagittal and frontal plane moments were pooled as appropriate, using a random effect approach. Methodological quality was assessed using the Downs and Black checklist. RESULTS: Thirteen studies with 1,141 participants were eligible and suitable for meta-analyses. Overall, people with hip OA had lower sagittal (SMD -0.55 (95% confidence interval (CI) -1.00 to -0.10) and frontal plane moments (SMD -0.63 (95% CI -0.92, -0.34) compared to controls. However, substantial heterogeneity was observed (I2 ≤ 89%). Results by disease stage suggest that people with end-stage hip OA have lower sagittal (SMD -0.96; -1.30, -0.61; I2 = 69%) and frontal (SMD -1.17; 95% CI -1.71, -0.64; I2 = 85%) plane moments compared to controls. People with less severe hip OA than end-stage disease have comparable sagittal (SMD 0.37; 95% CI -0.17, 0.90; I2 = 69%) and frontal (SMD -0.24; 95% CI -0.76, 0.27; I2 = 51%) plane moments compared to controls. CONCLUSION: Hip joint loading may be dependent on disease stage. People with end-stage hip OA under-loaded compared to controls, while those who were not awaiting hip joint replacement had comparable hip joint loads to controls.

Multiwalled Carbon Nanotubes Dramatically Affect the Fruit Metabolome of Exposed Tomato Plants.

Here, we reported that multiwalled carbon nanotubes (MWCNT) added to hydroponics system can enhance fruit production of exposed tomato plants. We quantified the exact amount of MWCNT accumulated inside of fruits collected by MWCNT-exposed plants using an advanced microwave induced heating technique (MIH). We found that absorption of MWCNT by tomato fruits significantly affected total fruit metabolome as was confirmed by LC-MS. Our data highlight the importance of comprehensive toxicological risk assessment of plants contaminated with carbon nanomaterials.

A systematic review and evidence synthesis of qualitative studies to identify primary care clinicians' barriers and enablers to the management of osteoarthritis.

OBJECTIVE: Primary care management of osteoarthritis (OA) is variable and often inconsistent with clinical practice guidelines (CPGs). This study aimed to identify and synthesize available qualitative evidence on primary care clinicians' views on providing recommended management of OA. DESIGN: Eligibility criteria included full reports published in peer-reviewed journals, with data collected directly from primary care clinicians using qualitative methods for collection and analysis. Five electronic databases (MEDLINE, Cochrane Central Register, EMBASE, CINAHL and PsychInfo) were searched to August 2016. Two independent reviewers identified eligible reports, conducted critical appraisal (based on Critical Appraisal Skills Programme (CASP) criteria), and extracted data. Three reviewers independently, then collaboratively, synthesized and interpreted data through an inductive and iterative process to derive new themes. The Confidence in Evidence from Reviews of Qualitative research (CERQual) approach was used to determine a confidence profile for each finding. RESULTS: Eight studies involving approximately 83 general practitioners (GPs), 24 practice nurses, 12 pharmacists and 10 physical therapists, from Australia, France, United Kingdom, Germany and Mexico were included. Four barriers were identified as themes 1) OA is not that serious, 2) Clinicians are, or perceive they are, under-prepared, 3) Personal beliefs at odds with providing recommended practice, and 4) Dissonant patient expectations. No themes were enablers. Confidence ratings were moderate or low. CONCLUSIONS: Synthesising available data revealed barriers that collectively point towards a need to address clinician knowledge gaps, and enhance clinician communication and behaviour change skills to facilitate patient adherence, enable effective conversations and manage dissonant patient expectations. REGISTRATION: PROSPERO (http://www.crd.york.ac.uk/PROSPERO) [4/11/2015, CRD42015027543].

Barriers and enablers in primary care clinicians' management of osteoarthritis: protocol for a systematic review and qualitative evidence synthesis.

INTRODUCTION: Osteoarthritis is a highly prevalent and disabling condition. Primary care management of osteoarthritis is generally suboptimal despite evidence for several modestly effective interventions and the availability of high-quality clinical practice guidelines. This report describes a planned study to synthesise the views of primary care clinicians on the barriers and enablers to following recommended management of osteoarthritis, with the aim of providing new interpretations that may facilitate the uptake of recommended treatments, and in turn improve patient care. METHODS AND ANALYSIS: A systematic review and meta-synthesis of qualitative studies. 5 databases will be searched using key search terms for qualitative research, evidence-based practice, clinical practice guidelines, osteoarthritis, beliefs, perceptions, barriers, enablers and adherence. A priori inclusion/exclusion criteria include availability of data from primary care clinicians, reports on views regarding management of osteoarthritis, and studies using qualitative methods for both data collection and analysis. At least 2 independent reviewers will identify eligible reports, conduct a critical appraisal of study conduct, extract data and synthesise reported findings and interpretations. Synthesis will follow thematic analysis within a grounded theory framework of inductive coding and iterative theme identification. The reviewers plus co-authors will contribute to the meta-synthesis to find new themes and theories. The Confidence in the Evidence from Reviews of Qualitative research (CERQual) approach will be used to determine a confidence profile of each finding from the meta-synthesis. The protocol has been registered on PROSPERO and is reported using the Preferred Reporting Items for Systematic Review and Meta-Analyses Protocols (PRISMA-P) guidelines. ETHICS AND DISSEMINATION: Ethical approval is not required. The systematic review will be published in a peer-reviewed journal. The results will help to inform policy and practice and assist in the optimisation of management for people with osteoarthritis. PROSPERO REGISTRATION NUMBER: CRD42015027543.

Reconstruction of in-situ porosity and porewater compositions of low-permeability crystalline rocks: Magnitude of artefacts induced by drilling and sample recovery.

Geological site characterisation programmes typically rely on drill cores for direct information on subsurface rocks. However, porosity, transport properties and porewater composition measured on drill cores can deviate from in-situ values due to two main artefacts caused by drilling and sample recovery: (1) mechanical disruption that increases porosity and (2) contamination of the porewater by drilling fluid. We investigated the effect and magnitude of these perturbations on large drill core samples (12-20 cm long, 5 cm diameter) of high-grade, granitic gneisses obtained from 350 to 600 m depth in a borehole on Olkiluoto Island (SW Finland). The drilling fluid was traced with sodium-iodide. By combining out-diffusion experiments, gravimetry, UV-microscopy and iodide mass balance calculations, we successfully quantified the magnitudes of the artefacts: 2-6% increase in porosity relative to the bulk connected porosity and 0.9 to 8.9 vol.% contamination by drilling fluid. The spatial distribution of the drilling-induced perturbations was revealed by numerical simulations of 2D diffusion matched to the experimental data. This showed that the rims of the samples have a mechanically disrupted zone 0.04 to 0.22 cm wide, characterised by faster transport properties compared to the undisturbed centre (1.8 to 7.7 times higher pore diffusion coefficient). Chemical contamination was shown to affect an even wider zone in all samples, ranging from 0.15 to 0.60 cm, in which iodide enrichment was up to 180 mg/kg water, compared to 0.5 mg/kg water in the uncontaminated centre. For all samples in the present case study, it turned out that the magnitude of the artefacts caused by drilling and sample recovery is so small that no correction is required for their effects. Therefore, the standard laboratory measurements of porosity, transport properties and porewater composition can be taken as valid in-situ estimates. However, it is clear that the magnitudes strongly depend on site- and drilling-specific factors and therefore our results cannot be transferred simply to other locations. We recommend the approach presented in this study as a route to obtain reliable values in future drilling campaigns aimed at characterising in-situ bedrock properties.

Unrecognised cognitive impairment in hospice patients: a pilot study.

The presence of cognitive impairment in patients who are receiving hospice care can affect numerous practical, ethical and legal aspects of their healthcare. A number of factors can contribute to cognitive impairment in these patients. Prevalence rates of cognitive impairment vary widely, but it remains under-recognised and under-treated. The aims of this pilot study were to evaluate the presence and nature of cognitive deficits in patients receiving inpatient hospice care who did not have a known current or past diagnosis of a cognitive disorder or any obvious cognitive impairments. A convenience sample of 30 patients receiving inpatient hospice care underwent bedside cognitive testing. A comprehensive battery of tests was used, including the Mini-Mental State Examination (MMSE) and standardised neuropsychological tests of pre-morbid intellectual functioning, immediate and delayed recall, digit span forward and backward, verbal reasoning and letter and category fluency. On average, subjects were impaired on the MMSE and on tests of learning, verbal reasoning and letter and category fluency. Furthermore, 12 of the 30 subjects met DSM-IV cognitive impairment criteria for dementia based on impaired performance in memory and at least one other cognitive domain on testing. The results of this pilot study suggest that a sizable proportion of patients receiving inpatient hospice care have undetected but clinically significant cognitive impairments. Assessing for and helping patients, families and caregivers deal with cognitive impairment might benefit patients' quality of life, relationships and overall care at the end of life. Future research in this population is needed to evaluate the causes and time course of cognitive impairment over time, as well as any relationship between cognitive impairment and decision-making capacity.

Validation of lymphatic mapping and sentinel node biopsy in patients with symptomatic breast cancer.

BACKGROUND: Lymphatic mapping and sentinel node biopsy in breast cancer aims to allow lymph node negative women to avoid axillary clearance by providing a minimally invasive means of staging the axilla. However, before its implementation into routine clinical practice, initiating departments must verify their expertise in each of the surgical, radiological and pathological components necessary for its successful performance. Here, we present our validation experience. METHODS: Thirty patients with breast cancer of any stage (but without clinical axillary lymphadenopathy) undergoing definitive resection of their primary tumour underwent lymphatic mapping (using blue dye alone or in combination with radioisotope) and sentinel node biopsy concurrent with standard level II axillary clearance over a ten month period. RESULTS: All patients had sentinel nodes identified intraoperatively. The sentinel node in 29 patients correctly predicted the status of axillary involvement. One patient had non-sentinel nodal disease without metastases being identified in their sentinel node. Such a single false negative out of thirty patients is considered acceptable by current guidelines. CONCLUSION: Validation of expertise in sentinel node identification and analysis is feasible over a relatively short period of time in a regional symptomatic breast unit. We now feel confident in offering this procedure to selected patients with breast cancer in our catchment area in place of routine axillary clearance.

Co-administration of low doses of intranasal PT-141, a melanocortin receptor agonist, and sildenafil to men with erectile dysfunction results in an enhanced erectile response.

OBJECTIVES: To evaluate the safety and pharmacodynamic effect of co-administration of subtherapeutic doses of PT-141, a cyclic heptapeptide melanocortin analogue, and sildenafil to patients with erectile dysfunction. METHODS: Nineteen patients with erectile dysfunction who were responders to either Viagra or Levitra by self-report were given 25 mg sildenafil and 7.5 mg intranasal PT-141, 25 mg sildenafil and an intranasal placebo spray, and a placebo tablet and an intranasal placebo spray in a randomized cross-over design. Erectile activity in response to two 30-minute episodes of visual sexual stimulation was assessed by RigiScan during a 6-hour postdose period. RESULTS: The erectile response induced by co-administration of PT-141 and sildenafil was significantly greater than the response elicited by administration of sildenafil alone. Co-administration of PT-141 and sildenafil was safe and well-tolerated and did not result in new adverse events or adverse events that were increased in frequency or severity compared with monotherapy. CONCLUSIONS: Co-administration of intranasal PT-141 and a phosphodiesterase type 5 inhibitor may constitute a treatment alternative for patients in whom higher doses of a single therapy are not effective or well tolerated.

Evaluation of the safety, pharmacokinetics and pharmacodynamic effects of subcutaneously administered PT-141, a melanocortin receptor agonist, in healthy male subjects and in patients with an inadequate response to Viagra.

PT-141, a cyclic heptapeptide melanocortin analog, was evaluated following subcutaneous administration to healthy male subjects and to patients with erectile dysfunction (ED) who report an inadequate response to Viagra. An inadequate response was defined for this study by patient report indicating that achievement of an erection suitable for vaginal penetration occurred < or =50% of the time while taking 100 mg Viagra. Erectile responses were assessed by RigiScan in healthy subjects in the absence of visual sexual stimulation (VSS) and in ED patients in the presence of VSS. Doses ranging from 0.3 to 10 mg were administered to healthy male subjects, resulting in a statistically significant erectile response at doses greater than 1.0 mg. ED patients were treated with placebo, 4 or 6 mg PT-141 in a crossover design in the presence of VSS. The erectile response induced by PT-141 was statistically significant at both doses. PT-141 was safe and well tolerated in both studies. The erectogenic potential of PT-141, its tolerability profile and its ability to cause significant erections in patients who do not have an adequate response to a PDE5 inhibitor suggest that PT-141 may provide an alternative treatment for ED with a potentially broad patient base.

Double-blind, placebo-controlled evaluation of the safety, pharmacokinetic properties and pharmacodynamic effects of intranasal PT-141, a melanocortin receptor agonist, in healthy males and patients with mild-to-moderate erectile dysfunction.

PT-141, a cyclic heptapeptide melanocortin analog, was evaluated following intranasal administration in healthy male subjects and in Viagra-responsive erectile dysfunction (ED) patients. Erectile response was assessed by RigiScan trade mark in healthy subjects without visual sexual stimulation (VSS) and in Viagra-responsive ED patients with VSS. In healthy subjects, mean C(max) and AUC((0-t)) increased in a dose-dependent manner. Median T(max) was 0.50 h and mean t(1/2) ranged from 1.85 to 2.09 h. In both studies, an erectile response induced by PT-141 administration was statistically significant, compared to placebo, at doses greater than 7 mg, with the onset of the first erection occurring in approximately 30 min. PT-141 was safely administered and well tolerated in both studies. A maximum-tolerated dose was not identified. Flushing and nausea were the most common adverse events reported in both studies and no clinically significant changes in vital signs, laboratory tests, ECGs, or physical exams were observed. Based upon its erectogenic potential and tolerability profile, PT-141 is a promising candidate for further evaluation as a treatment for male ED.

PT-141: a melanocortin agonist for the treatment of sexual dysfunction.

PT-141, a synthetic peptide analogue of alpha-MSH, is an agonist at melanocortin receptors including the MC3R and MC4R, which are expressed primarily in the central nervous system. Administration of PT-141 to rats and nonhuman primates results in penile erections. Systemic administration of PT-141 to rats activates neurons in the hypothalamus as shown by an increase in c-Fos immunoreactivity. Neurons in the same region of the central nervous system take up pseudorabies virus injected into the corpus cavernosum of the rat penis. Administration of PT-141 to normal men and to patients with erectile dysfunction resulted in a rapid dose-dependent increase in erectile activity. The results suggest that PT-141 holds promise as a new treatment for sexual dysfunction.

CEO/supplier dialogue on patient safety. Panel discussion.

Leaders and vendors candidly explore new opportunities for industry standards, work-force training, and patient-focused care.

Eagle's syndrome: a report of 4 patients treated using a modified extraoral approach.

PURPOSE: This study evaluated a slightly modified extraoral approach to removing the symptomatic elongated styloid process. A brief description of this surgical technique and its comparison to the intraoral approach is provided. PATIENTS AND METHODS: Four patients in whom an extraoral approach was used to expose and remove the elongated calcified stylohyoid complex were evaluated. Five sides were treated and reviewed individually. All patients were interviewed preoperatively and postoperatively, and their records were thoroughly examined. Patients were objectively evaluated for pain, function, sensory and motor nerve deficits, and aesthetics. RESULTS: Follow-up time ranged from 6 to 39 months with an average of 21 months. Improvement in the original symptoms was reported for 4 of the 5 operated sides. Three of 5 procedures resulted in more than an 80% reduction in pain and improvement in function. All patients had a satisfactory cosmetic result and no paresthesia. CONCLUSIONS: The advantages of the extraoral approach are reflected in this small retrospective study by the absence of perioperative complications and the minimal blood loss, surgical morbidity, and hospital stay.

Patient safety in end-stage renal disease: How do we create a safe environment?

The Institute of Medicine estimated that 44,000 to 98,000 hospitalized patients die annually as a direct result of preventable medical errors. Errors occur because competent practitioners are human, and the systems we design are imperfect. Improving patient safety requires acknowledging medical errors, encouraging the reporting of errors, and improving systems to reduce the likelihood of future errors. Several challenges must be addressed to accomplish this goal. The definition of medical errors must be widely agreed on and accepted. Adverse outcomes are often the result of multiple systems failures. Therefore systems analysis, not blaming an individual, should be the focus of error reduction. A "culture of safety" should be created, which encourages reporting errors and "near-misses." An effective reporting system has 2 components, one for public accountability for errors that result in serious injury and another for confidential reporting of mistakes that have the potential for serious injury. Regulatory protection from discovery must be established for voluntary error and near-miss reporting systems. In the nephrology community, novel uses of technology should be sought to prevent errors, human factors leading to errors should be identified and anticipated, and patterns of interaction at the machine-human interface should be studied. Progress in improving patient safety has occurred in some areas, such as pharmacy services. Such known and tested patient safety practices should be deployed in dialysis facilities. Success in improving patient safety will require leadership, collaborative efforts among the many stakeholders in the ESRD program, and adequate allocation of resources.