Diabetes mellitus is not a predictor of poor TB treatment outcomes.

OBJECTIVE: To investigate whether diabetes mellitus (DM) influences TB treatment outcomes.METHODS: This was a retrospective observational cohort study of all notified TB cases from a large London TB centre over a 5-year period. WHO criteria were used to define TB treatment outcomes.RESULTS: The prevalence of DM at TB treatment initiation was 15% (126/838). Most patients (83.3%, 105/126) were on hypoglycaemic treatment and well-controlled (median glycated haemoglobin 53.5 mmol/mol). DM patients were older, more likely to be of Asian ethnicity and had a higher pre-treatment weight. Time from presentation to treatment initiation was longer (median 87.5 vs. 63 days; P < 0.001), while they were significantly more comorbid (median Charlson Comorbidity Index 3 vs. 0; P < 0.001). Overall, favourable treatment outcomes were recorded for 89.5% of patients (87.7% vs. 89.8% for DM and non-DM patients respectively, P = 0.52). In multivariable analysis, DM was not associated with unfavourable TB treatment outcomes (OR 0.49, 95% CI 0.23-1.04, P = 0.06). Independent predictors of unfavourable outcome included age, cavitation, chronic neurological disease and malignant neoplasm.CONCLUSIONS: In a well-resourced setting, with predominantly well-controlled DM patients on treatment, DM was not an independent predictor of unfavourable TB treatment outcomes.

Heat stress associated with aerosol PPE and its impact.

BACKGROUND: Aerosol personal protective equipment (PPE) is subjectively reported to negatively impact healthcare workers' performance and well-being, but this has not been assessed objectively. AIMS: This randomized controlled crossover study aimed to quantify the heat stress associated with aerosol PPE and to investigate its impact upon mood, cognitive and motor function, and task performance. METHODS: Sixteen healthy, young, lean participants (eight males) undertook an exercise protocol, which simulated the metabolic expenditure of hospital work: once wearing aerosol PPE (PPE visit) and once wearing standard surgical attire (control visit). Participants walked on a treadmill for 2 h followed by 30-min rest. Core temperature, heart rate, urine specific gravity, weight, grip strength, mood (Bond-Lader scale) and task performance (Intubation of a Manikin) were recorded. Values are between-visit mean (standard deviation) differences. RESULTS: On the PPE visit core temperature (+0.2 (0.3)°C; P < 0.01), heart rate (+12 (13) bpm; P < 0.001), urine specific gravity (+0.003 (0.005); P < 0.05) and intubation task time (+50 (81) s; P < 0.01) were greater than on the control visit; and alertness (-14 (21) mm; P < 0.001), contentment (-14 (15) mm; P < 0.001) and grip strength (-4 (4) N; P < 0.01) were less. CONCLUSIONS: This study demonstrates that wearing aerosol PPE in a simulated hospital environment results in heat exhaustion and has a negative impact upon mood, motor function, and task performance. Whilst wearing PPE is important to prevent disease transmission, strategies should be developed to limit its impact upon healthcare workers' performance and well-being.

An open-source musculoskeletal model of the lumbar spine and lower limbs: a validation for movements of the lumbar spine.

Musculoskeletal models of the lumbar spine have been developed with varying levels of detail for a wide range of clinical applications. Providing consistency is ensured throughout the modelling approach, these models can be combined with other computational models and be used in predictive modelling studies to investigate bone health deterioration and the associated fracture risk. To provide precise physiological loading conditions for such predictive modelling studies, a new full-body musculoskeletal model including a detailed and consistent representation of the lower limbs and the lumbar spine was developed. The model was assessed against in vivo measurements from the literature for a range of spine movements representative of daily living activities. Comparison between model estimations and electromyography recordings was also made for a range of lifting tasks. This new musculoskeletal model will provide a comprehensive physiological mechanical environment for future predictive finite element modelling studies on bone structural adaptation. It is freely available on https://simtk.org/projects/llsm/.

Reliability and minimal detectable change of the 'Imperial Spine' marker set for the evaluation of spinal and lower limb kinematics in adults.

OBJECTIVES: As a step towards the comprehensive evaluation of movement in patients with low back pain, the aim of this study is to design a marker set (three rigid segment spine, pelvic and lower limb model) and evaluate the reliability and minimal detectable change (MDC) of this marker set in healthy adults during gait and sit to stand (STS) tasks using three dimensional motion capture. RESULTS: The 'Imperial Spine' marker set was used to assess relative peak angles during gait and STS tasks using the minimum recommended sample size (n = 10) for reliability studies with minimum Intraclass Correlation Coefficient (ICC) of 0.70, optimum ICC 0.90 and 9 trials replicated per subject per task. Intra- and inter-tester reliability between an experienced and inexperienced user was examined. ICC, mean, standard error (SEM), Bland Altman 95% limits of agreement (LOA) and MDC were computed. ICC values demonstrated excellent intra- and inter-tester reliability in both tasks, particularly in the sagittal plane (majority ICCs > 0.80). SEM measurements were lower in gait (0.8-5.5°) than STS tasks (1°-12.6°) as were MDC values. LOA demonstrated good agreement. The 'Imperial Spine' marker set is reliable for use in healthy adults during functional tasks. Future evaluation in patients is required.

The Functionality and Evolution of Eukaryotic Transcriptional Enhancers.

Enhancers regulate precise spatial and temporal patterns of gene expression in eukaryotes and, moreover, evolutionary changes in these modular cis-regulatory elements may represent the predominant genetic basis for phenotypic evolution. Here, we review approaches to identify and functionally analyze enhancers and their transcription factor binding sites, including assay for transposable-accessible chromatin-sequencing (ATAC-Seq) and clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9, respectively. We also explore enhancer functionality, including how transcription factor binding sites combine to regulate transcription, as well as research on shadow and super enhancers, and how enhancers can act over great distances and even in trans. Finally, we discuss recent theoretical and empirical data on how transcription factor binding sites and enhancers evolve. This includes how the function of enhancers is maintained despite the turnover of transcription factor binding sites as well as reviewing studies where mutations in enhancers have been shown to underlie morphological change.

Robust neurite extension following exogenous electrical stimulation within single walled carbon nanotube-composite hydrogels.

UNLABELLED: The use of exogenous electrical stimulation to promote nerve regeneration has achieved only limited success. Conditions impeding optimized outgrowth may arise from inadequate stimulus presentation due to differences in injury geometry or signal attenuation. Implantation of an electrically-conductive biomaterial may mitigate this attenuation and provide a more reproducible signal. In this study, a conductive nanofiller (single-walled carbon nanotubes [SWCNT]) was selected as one possible material to manipulate the bulk electrical properties of a collagen type I-10% Matrigel™ composite hydrogel. Neurite outgrowth within hydrogels (SWCNT or nanofiller-free controls) was characterized to determine if: (1) nanofillers influence neurite extension and (2) electrical stimulation of the nanofiller composite hydrogel enhances neurite outgrowth. Increased SWCNT loading (10-100-µg/mL) resulted in greater bulk conductivity (up to 1.7-fold) with no significant changes to elastic modulus. Neurite outgrowth increased 3.3-fold in 20-µg/mL SWCNT loaded biomaterials relative to the nanofiller-free control. Electrical stimulation promoted greater outgrowth (2.9-fold) within SWCNT-free control. The concurrent presentation of electrical stimulation and SWCNT-loaded biomaterials resulted in a 7.0-fold increase in outgrowth relative to the unstimulated, nanofiller-free controls. Local glia residing within the DRG likely contribute, in part, to the observed increases in outgrowth; but it is unknown which specific nanofiller properties influence neurite extension. Characterization of neuronal behavior in model systems, such as those described here, will aid the rational development of biomaterials as well as the appropriate delivery of electrical stimuli to support nerve repair. STATEMENT OF SIGNIFICANCE: Novel biomedical devices delivering electrical stimulation are being developed to mitigate symptoms of Parkinson's, treat drug-resistant depression, control movement or enhance verve regeneration. Carbon nanotubes and other novel materials are being explored for novel nano-neuro devices based on their unique properties. Neuronal growth on carbon nanotubes has been studied in 2D since the early 2000s demonstrating increased outgrowth, synapse formation and network activity. In this work, single-walled carbon nanotubes were selected as one possible electrically-conductive material, dispersed within a 3D hydrogel containing primary neurons; extending previous 2D work to 3D to evaluate outgrowth within nanomaterial composites with electrical stimulation. This is the first study to our knowledge that stimulates neurons in 3D composite nanomaterial-laden hydrogels. Examination of electrically conductive biomaterials may serve to promote regrowth following injury or in long term stimulation.

Biomechanical determinants of elite rowing technique and performance.

In rowing, the parameters of injury, performance, and technique are all interrelated and in dynamic equilibrium. Whilst rowing requires extreme physical strength and endurance, a high level of skill and technique is essential to enable an effective transfer of power through the rowing sequence. This study aimed to determine discrete aspects of rowing technique, which strongly influence foot force production and asymmetries at the foot-stretchers, as these are biomechanical parameters often associated with performance and injury risk. Twenty elite female rowers performed an incremental rowing test on an instrumented rowing ergometer, which measured force at the handle and foot-stretchers, while three-dimensional kinematic recordings of the ankle, knee, hip, and lumbar-pelvic joints were made. Multiple regression analyses identified hip kinematics as a key predictor of foot force output (R(2) = 0.48), whereas knee and lumbar-pelvic kinematics were the main determinants in optimizing the horizontal foot force component (R(2) = .41). Bilateral asymmetries of the foot-stretchers were also seen to significantly influence lumbar-pelvic kinematics (R(2) = 0.43) and pelvic twisting (R(2) = 0.32) during the rowing stroke. These results provide biomechanical evidence toward aspects of technique that can be modified to optimize force output and performance, which can be of direct benefit to coaches and athletes.

Importance of cannulated prolactin test in the definition of hyperprolactinaemia.

PURPOSE: Recent guidelines suggest that a single prolactin measurement is adequate to confirm hyperprolactinaemia. This may lead to unnecessary investigation of artefactual hyperprolactinaemia. Prolactin measurement drawn from an indwelling cannula after rest removes stress as a confounding variable. The objective was to determine the frequency of true hyperprolactinaemia amongst patients referred following a single prolactin measurement. METHODS: A cannulated study was considered if prolactin on referral ('Referral Prolactin') was <5,500 mU/L (260 ng/mL) but >410 mU/L (19 ng/mL) in males or >510 mU/L (24 ng/mL) in females, irrespective of clinical context. Case-notes of 267 patients undergoing cannulated prolactin measurement over a 10-year period (2000-2010) were reviewed. Pre-existing pituitary disease, dopamine antagonist use, and macroprolactinaemia were excluded. Morning ante-cubital vein cannulation was followed immediately by withdrawal of 'Repeat Prolactin' sample. After 120-min bed-rest, 'Resting Prolactin' was withdrawn through the cannula. RESULTS: 235 patients were included for analysis. 64 (27%) were within normal range; following Repeat Prolactin in 41 (17%) and Resting Prolactin in 23 (9%) cases. Referral Prolactin was higher in patients with true hyperprolactinaemia, 1,637 ± 100 mU/L (77.2 ± 4.7 ng/mL) than with artefactual hyperprolactinaemia, 1,122 ± 68 mU/L (52.9 ± 3.2 ng/mL; P < 0.001) but there was substantial overlap. 21 out of 171 cases (12%) with true hyperprolactinaemia had a macroadenoma. Presenting symptoms did not predict true hyperprolactinaemia. Referral Prolactin of 2,000 mU/L (94 ng/mL) had 97% specificity to identify true hyperprolactinaemia. CONCLUSIONS: Reliance on a single, non-rested prolactin value may lead to over-diagnosis of hyperprolactinaemia. A resting sample should be considered with random values <2,000 mU/L (94 ng/mL).

Impaired neural drive in patients with low back pain.

BACKGROUND: Control of trunk movement relies on the integration between central neuronal circuits and peripheral skeletomuscular activities and it can be altered by pain. There is increasing evidence that there are deficits within the central nervous system controlling the trunk muscles in people with low back pain (LBP). However, it is unclear how LBP impacts upon neural drive to back muscles at different levels of voluntary contraction. Therefore, the purpose of this study was to investigate if neural drive is impaired in these patients. METHODS: Seventeen patients with LBP and 11 healthy controls were recruited. Bilateral electromyographic (EMG) recordings were obtained from the erector spinae (ES) muscles at two vertebral levels (T12 and L4). Participants performed a series of brief isometric back extensions (50-100% maximum voluntary contraction - MVC), during which transcranial magnetic stimulation was delivered. The size of the evoked (superimposed) twitch was measured using dynamometry. RESULTS: The size of the superimposed twitch decreased linearly with increasing contraction strength in the controls; however, this linear relationship was not observed in the patients. Additionally, patients had larger superimposed twitches and longer time-to-peak amplitudes during MVCs than those observed in controls. Furthermore, patients had lower MVC and root-mean-square EMG activity of ES muscles during MVCs. CONCLUSIONS: A decline of central neural drive to the back muscles at high level of voluntary contraction was observed in patients with LBP. These results suggest that it might be pertinent to include neuromuscular facilitation programmes and therapeutic exercise utilizing high voluntary contractions for patients with LBP.

Phaeochromocytoma [corrected] crisis.

Phaeochromocytoma [corrected] crisis is an endocrine emergency associated with significant mortality. There is little published guidance on the management of phaeochromocytoma [corrected] crisis. This clinical practice update summarizes the relevant published literature, including a detailed review of cases published in the past 5 years, and a proposed classification system. We review the recommended management of phaeochromocytoma [corrected] crisis including the use of alpha-blockade, which is strongly associated with survival of a crisis. Mechanical circulatory supportive therapy (including intra-aortic balloon pump or extra-corporeal membrane oxygenation) is strongly recommended for patients with sustained hypotension. Surgical intervention should be deferred until medical stabilization is achieved.

Differential Changes in Postsynaptic Density Proteins in Postmortem Huntington's Disease and Parkinson's Disease Human Brains.

NMDA and AMPA-type glutamate receptors and their bound membrane-associated guanylate kinases (MAGUKs) are critical for synapse development and plasticity. We hypothesised that these proteins may play a role in the changes in synapse function that occur in Huntington's disease (HD) and Parkinson's disease (PD). We performed immunohistochemical analysis of human postmortem brain tissue to examine changes in the expression of SAP97, PSD-95, GluA2 and GluN1 in human control, and HD- and PD-affected hippocampus and striatum. Significant increases in SAP97 and PSD-95 were observed in the HD and PD hippocampus, and PSD95 was downregulated in HD striatum. We observed a significant increase in GluN1 in the HD hippocampus and a decrease in GluA2 in HD and PD striatum. Parallel immunohistochemistry experiments in the YAC128 mouse model of HD showed no change in the expression levels of these synaptic proteins. Our human data show that major but different changes occur in glutamatergic proteins in HD versus PD human brains. Moreover, the changes in human HD brains differ from those occurring in the YAC128 HD mouse model, suggesting that unique changes occur at a subcellular level in the HD human hippocampus.

IGF-I redirects doublecortin-positive cell migration in the normal adult rat brain.

The migration of subventricular zone (SVZ)-derived neural precursor cells through the rostral migratory stream (RMS) to the olfactory bulb is tightly regulated by local micro-environmental cues. Insulin-like Growth Factor-I (IGF-I) can stimulate the migration of several neuronal cell types and acts as a 'departure' factor in the avian SVZ. To establish whether IGF-I can also act as a migratory factor for adult neuronal precursor cells in vivo, in addition to its well established role in precursor cell proliferation and differentiation, we used AAV2-mediated gene transfer to produce ectopic expression of IGF-I in the normal adult rat striatum. We then assessed whether the expression of IGF-I would recruit SVZ-derived neuronal precursor cells from the RMS into the striatum. Ectopic expression of IGF-I in the normal adult rat brain significantly increased the number of doublecortin (Dcx)-positive cells and the extent of their migration into the striatum 4 and 8 weeks after AAV2-IGF-I injection but did not promote neuronal differentiation. In vitro migration assays confirmed that IGF-I is an inducer of migration and directs SVZ-derived adult neuronal precursor cell migration by both chemotaxis and chemokinesis. These results demonstrate that overexpression of IGF-I in the normal adult rat brain can override the normal cues directing precursor cell migration along the RMS and can redirect precursor cell migration into a non-neurogenic region. Enhanced expression of IGF-I following brain injury may therefore act as a diffusible factor mediating precursor cell migration to areas of neuronal cell damage.

When is an outbreak not an outbreak? Fit, divergent strains of Mycobacterium tuberculosis display independent evolution of drug resistance in a large London outbreak.

OBJECTIVES: To study the evolutionary relationship of Mycobacterium tuberculosis isolates from 13 patients in a large outbreak of isoniazid-resistant tuberculosis in London. METHODS: Genotypic and phenotypic susceptibility tests were performed. Molecular genotyping using restriction fragment length polymorphisms and mycobacterial interspersed repetitive units was carried out. Additionally, the generation times of 13 strains of M. tuberculosis from the outbreak were measured to determine relative fitness. RESULTS: Genotypic and phenotypic susceptibility testing demonstrated variations between isolates. Polymorphisms causing isoniazid resistance varied within clusters of isolates that were indistinguishable by standard genotyping. The measurement of in vitro generation times demonstrated that the fitness of the resistant strains was not significantly different from either wild-type or susceptible isolates in the outbreak, indicating that apparently no fitness cost was associated with the acquisition of drug resistance. CONCLUSIONS: It appears that this outbreak comprised a heterogeneous collection of closely related strains, which appear to exhibit more variation than would usually be associated with a point source outbreak. These strains appear to have evolved by acquisition of additional antimicrobial resistance mutations while remaining competitive. The acquired resistance and retained competitiveness may be partly responsible for the difficulty in controlling the outbreak.

The pathogenesis of degeneration of the intervertebral disc and emerging therapies in the management of back pain.

This article reviews the current knowledge of the intervertebral disc (IVD) and its association with low back pain (LBP). The normal IVD is a largely avascular and aneural structure with a high water content, its nutrients mainly diffusing through the end plates. IVD degeneration occurs when its cells die or become dysfunctional, notably in an acidic environment. In the process of degeneration, the IVD becomes dehydrated and vascularised, and there is an ingrowth of nerves. Although not universally the case, the altered physiology of the IVD is believed to precede or be associated with many clinical symptoms or conditions including low back and/or lower limb pain, paraesthesia, spinal stenosis and disc herniation. New treatment options have been developed in recent years. These include biological therapies and novel surgical techniques (such as total disc replacement), although many of these are still in their experimental phase. Central to developing further methods of treatment is the need for effective ways in which to assess patients and measure their outcomes. However, significant difficulties remain and it is therefore an appropriate time to be further investigating the scientific basis of and treatment of LBP.

Effect of primary percutaneous coronary intervention on stress hyperglycaemia in myocardial infarction.

AIM: To measure the effect of primary percutaneous coronary intervention on stress hyperglycaemia induced by ST segment elevation myocardial infarction. METHODS: We measured blood glucose before primary percutaneous coronary intervention and 1 h after intervention in all patients presenting with ST segment elevation myocardial infarction for 2 months in our unit. A paired t-test was used for a statistical analysis. RESULTS: From 157 patients accepted for primary percutaneous coronary intervention, 90 patients were included in the analysis. Blood glucose before intervention was 8.4 ± 2.46 mmol/l (mean ± SD) and after intervention was 7.9 ± 2.0 mmol/l (mean ± sd) (P = 0.003). In the subset of 15 patients with hyperglycaemia (glucose greater than 10 mmol/l), glucose before intervention was 12.7 ± 2.62 mmol/l (mean ± SD) and after intervention was 9.8 ± 3.42 mmol/l (mean ± sd) (P = 0.0002). CONCLUSIONS: Blood glucose in patients with ST segment elevation myocardial infarction is significantly lower after primary percutaneous coronary intervention and this reduction is most marked in patients with hyperglycaemia. Waiting for the stress response to diminish means that 11.1% of patients' glucose levels fell below the treatment threshold of 10 mmol/l. Using the post-intervention blood glucose level avoids the need for treatment with insulin in this population. Further randomized studies are warranted to investigate the impact on mortality and morbidity of administering insulin triggered by pre-invention blood glucose vs. post-intervention blood glucose.

Patients' views on an education booklet following spinal surgery.

PURPOSE: This study evaluated an evidence-based education booklet developed for patients undergoing spinal surgery which was used as a treatment intervention in a multi-centre, factorial, randomised controlled trial (FASTER: Function after spinal treatment, exercise and rehabilitation) investigating the post-operative management of spinal surgery patients. This study sought to determine the acceptability and content of the booklet to patients. METHODS: Patients receiving the educational booklet before discharge from hospital as part of the FASTER study were asked to complete an evaluation, which rated the booklet "Your Back Operation" with regard to content, information, usability, etc. using forced and open questions. This assessment was conducted at the same time as the initial 6-week post-operative review performed as part of the larger study. RESULTS: Therefore, 97% of the 117 trial participants who returned their 6-week evaluation and randomised to receive a booklet returned their questionnaire. The booklet was highly rated receiving an overall rating of 7 or more out of 10 from 101/111 (91%), and high ratings for content, readability and information. The booklet's key messages were clear to the majority of patients; however, many patients highlighted deficiencies with respect to content particularly in relation to wound care and exercise. CONCLUSIONS: Patients valued the booklet and rated its content highly. Many suggested that the booklet be developed further and there was a clear desire for specific exercises to be included even though there is no evidence to support specific exercise prescription.

Response of glutathione S-transferase Pi (GSTP1) to neoadjuvant therapy in rectal adenocarcinoma.

AIM: The response of rectal adenocarcinoma to neoadjuvant therapy is variable. Accurate prediction of response would enable selective administration of therapy. The enzyme glutathione S-transferase Pi (GSTP1) has been shown to influence response to therapy in some solid tumours. Few data are available for rectal cancer. METHOD: The GSTP1 levels in rectal adenocarcinoma and adjacent normal mucosa were quantified before and after exposure to neoadjuvant therapy. Venous blood samples and biopsies of normal rectal mucosa and tumour were prospectively obtained from patients with primary rectal cancer. Patients were stratified by exposure to neoadjuvant therapy or surgery alone. GSTP1 was quantitatively measured using an enzyme-linked immunosorbent assay. RESULTS: Ninety-two patients (54 men; median age 68 years) were recruited. The median GSTP1 level was significantly higher in rectal adenocarcinoma than in matched normal mucosa [6.59 µg/mg vs 4.57 µg/mg; P < 0.001]. The median tumour GSTP1 level was significantly lower in the therapy group compared with unmatched samples from the no-therapy group [4.47 µg/mg vs 7.76 µg/mg; P < 0.001]. CONCLUSION: The GSTP1 level is increased in rectal adenocarcinoma compared with adjacent normal mucosa. It decreases following neoadjuvant therapy. Future studies correlating pre-therapy GSTP1 levels with pathological response would be of interest.

Helicobacter pylori infection assessed by ELISA and by immunoblot and noncardia gastric cancer risk in a prospective study: the Eurgast-EPIC project.

BACKGROUND: In epidemiological studies, Helicobacter pylori infection is usually detected by enzyme-linked immunosorbent assay (ELISA). However, infection can spontaneously clear from the mucosa during the progression of atrophy and could lead to substantial under-detection of infection and underestimation of its effect on gastric cancer (GC) risk. Antibodies detected by western blot are known to persist longer after the loss of the infection. METHODS: In a nested case-control study from the Eurogast-EPIC cohort, including 88 noncardia GC cases and 338 controls, we assessed the association between noncardia GC and H. pylori infection comparing antibodies detected by western blot (HELICOBLOT2.1) to those detected by ELISA (Pyloriset EIA-GIII(®)). RESULTS: By immunoblot, 82 cases (93.2%) were H. pylori positive, 10 of these cases (11.4%) were negative by ELISA and only 6 cases (6.8%) were negative by both ELISA and immunoblot. Multivariable odds ratio (OR) for noncardia GC comparing immunoglobulin G positive versus negative by ELISA was 6.8 [95% confidence interval (CI) 3.0-15.1], and by immunoblot, the OR was 21.4 (95% CI 7.1-64.4). CONCLUSIONS: Using a western blot assay, nearly all noncardia GC were classified as H. pylori positive and the OR was more than threefold higher than the OR assessed by ELISA, supporting the hypothesis that H. pylori infection is a necessary condition for noncardia GC.