Development, Validation, and Field-Testing of an Instrument for Clinical Assessment of HIV-Associated Neuropathy and Neuropathic Pain in Resource-Restricted and Large Population Study Settings

HIV-associated sensory peripheral neuropathy (HIV-SN) afflicts approximately 50% of patients on antiretroviral therapy, and is associated with significant neuropathic pain. Simple accurate diagnostic instruments are required for clinical research and daily practice in both high- and low-resource setting. A 4-item clinical tool (CHANT: Clinical HIV-associated Neuropathy Tool) assessing symptoms (pain and numbness) and signs (ankle reflexes and vibration sense) was developed by selecting and combining the most accurate measurands from a deep phenotyping study of HIV positive people (Pain In Neuropathy Study–HIV-PINS). CHANT was alpha-tested in silico against the HIV-PINS dataset and then clinically validated and field-tested in HIV-positive cohorts in London, UK and Johannesburg, South Africa. The Utah Early Neuropathy Score (UENS) was used as the reference standard in both settings. In a second step, neuropathic pain in the presence of HIV-SN was assessed using the Douleur Neuropathique en 4 Questions (DN4)-interview and a body map. CHANT achieved high accuracy on alpha-testing with sensitivity and specificity of 82% and 90%, respectively. In 30 patients in London, CHANT diagnosed 43.3% (13/30) HIV-SN (66.7% with neuropathic pain); sensitivity = 100%, specificity = 85%, and likelihood ratio = 6.7 versus UENS, internal consistency = 0.88 (Cronbach alpha), average item-total correlation = 0.73 (Spearman’s Rho), and inter-tester concordance > 0.93 (Spearman’s Rho). In 50 patients in Johannesburg, CHANT diagnosed 66% (33/50) HIV-SN (78.8% neuropathic pain); sensitivity = 74.4%, specificity = 85.7%, and likelihood ratio = 5.29 versus UENS. A positive CHANT score markedly increased of pre- to post-test clinical certainty of HIV-SN from 43% to 83% in London, and from 66% to 92% in Johannesburg. In conclusion, a combination of four easily and quickly assessed clinical items can be used to accurately diagnose HIV-SN. DN4-interview used in the context of bilateral feet pain can be used to identify those with neuropathic pain

A systematic review of experimental methods to manipulate secondary hyperalgesia in humans: protocol

Background Neuropathic pain affects 7–10% of people, but responds poorly to pharmacotherapy, indicating a need for better treatments. Mechanistic research on neuropathic pain frequently uses human surrogate models of the secondary hyperalgesia that is a common feature of neuropathic pain. Experimentally induced secondary hyperalgesia has been manipulated with pharmacological and non-pharmacological methods to clarify the relative contributions of different mechanisms to secondary hyperalgesia. However, this literature has not been systematically synthesised. The aim of this systematic review is to identify, describe, and compare methods that have been used to manipulate experimentally induced secondary hyperalgesia in healthy humans. Methods A systematic search strategy will be supplemented by reference list checks and direct contact with identified laboratories to maximise the identification of data reporting the experimental manipulation of experimentally induced secondary hyperalgesia in healthy humans. Duplicated screening, risk of bias assessment, and data extraction procedures will be used. Authors will be asked to provide data as necessary. Data will be pooled and meta-analyses conducted where possible, with subgrouping according to manipulation method. Manipulation methods will be ranked for potency and risk. Discussion The results of this review will provide a useful reference for researchers interested in using experimental methods to manipulate secondary hyperalgesia in humans and will help to clarify the relative contributions of different mechanisms to secondary hyperalgesia

Quantum to Classical Transition in a Single-Ion Laser

Stimulated emission of photons from a large number of atoms into the mode of a strong light field is the principle mechanism for lasing in "classical" lasers. The onset of lasing is marked by a threshold which can be characterised by a sharp increase in photon flux as a function of external pumping strength. The same is not necessarily true for the fundamental building block of a laser: a single trapped atom interacting with a single optical radiation mode. It has been shown that such a "quantum" laser can exhibit thresholdless lasing in the regime of strong coupling between atom and radiation field. However, although theoretically predicted, a threshold at the single-atom level could not be experimentally observed so far. Here, we demonstrate and characterise a single-atom laser with and without threshold behaviour by changing the strength of atom-light field coupling. We observe the establishment of a laser threshold through the accumulation of photons in the optical mode even for a mean photon number substantially lower than for the classical case. Furthermore, self-quenching occurs for very strong external pumping and constitutes an intrinsic limitation of single-atom lasers. Moreover, we find that the statistical properties of the emitted light can be adjusted for weak external pumping, from the quantum to the classical domain. Our observations mark an important step towards fundamental understanding of laser operation in the few-atom limit including systems based on semiconductor quantum dots or molecules.Comment: 19 pages, 4 figures, 10 pages supplement, accepted by Nature Physic

Exploring the equity of GP practice prescribing rates for selected coronary heart disease drugs: a multiple regression analysis with proxies of healthcare need

Background There is a small, but growing body of literature highlighting inequities in GP practice prescribing rates for many drug therapies. The aim of this paper is to further explore the equity of prescribing for five major CHD drug groups and to explain the amount of variation in GP practice prescribing rates that can be explained by a range of healthcare needs indicators (HCNIs). Methods The study involved a cross-sectional secondary analysis in four primary care trusts (PCTs 1–4) in the North West of England, including 132 GP practices. Prescribing rates (average daily quantities per registered patient aged over 35 years) and HCNIs were developed for all GP practices. Analysis was undertaken using multiple linear regression. Results Between 22–25% of the variation in prescribing rates for statins, beta-blockers and bendrofluazide was explained in the multiple regression models. Slightly more variation was explained for ACE inhibitors (31.6%) and considerably more for aspirin (51.2%). Prescribing rates were positively associated with CHD hospital diagnoses and procedures for all drug groups other than ACE inhibitors. The proportion of patients aged 55–74 years was positively related to all prescribing rates other than aspirin, where they were positively related to the proportion of patients aged >75 years. However, prescribing rates for statins and ACE inhibitors were negatively associated with the proportion of patients aged >75 years in addition to the proportion of patients from minority ethnic groups. Prescribing rates for aspirin, bendrofluazide and all CHD drugs combined were negatively associated with deprivation. Conclusion Although around 25–50% of the variation in prescribing rates was explained by HCNIs, this varied markedly between PCTs and drug groups. Prescribing rates were generally characterised by both positive and negative associations with HCNIs, suggesting possible inequities in prescribing rates on the basis of ethnicity, deprivation and the proportion of patients aged over 75 years (for statins and ACE inhibitors, but not for aspirin)

X Chromosome Inactivation during Drosophila Spermatogenesis

Genes with male- and testis-enriched expression are under-represented on the Drosophila melanogaster X chromosome. There is also an excess of retrotransposed genes, many of which are expressed in testis, that have “escaped” the X chromosome and moved to the autosomes. It has been proposed that inactivation of the X chromosome during spermatogenesis contributes to these patterns: genes with a beneficial function late in spermatogenesis should be selectively favored to be autosomal in order to avoid inactivation. However, conclusive evidence for X inactivation in the male germline has been lacking. To test for such inactivation, we used a transgenic construct in which expression of a lacZ reporter gene was driven by the promoter sequence of the autosomal, testis-specific ocnus gene. Autosomal insertions of this transgene showed the expected pattern of male- and testis-specific expression. X-linked insertions, in contrast, showed only very low levels of reporter gene expression. Thus, we find that X linkage inhibits the activity of a testis-specific promoter. We obtained the same result using a vector in which the transgene was flanked by chromosomal insulator sequences. These results are consistent with global inactivation of the X chromosome in the male germline and support a selective explanation for X chromosome avoidance of genes with beneficial effects late in spermatogenesis

Cerebellar-dependent delay eyeblink conditioning in adolescents with Specific Language Impairment

Cerebellar impairments have been hypothesized as part of the pathogenesis of Specific Language Impairment (SLI), although direct evidence of cerebellar involvement is sparse. Eyeblink Conditioning (EBC) is a learning task with well documented cerebellar pathways. This is the first study of EBC in affected adolescents and controls. 16 adolescent controls, 15 adolescents with SLI, and 12 adult controls participated in a delay EBC task. Affected children had low general language performance, grammatical deficits but no speech impairments. The affected group did not differ from the control adolescent or control adult group, showing intact cerebellar functioning on the EBC task. This study did not support cerebellar impairment at the level of basic learning pathways as part of the pathogenesis of SLI. Outcomes do not rule out cerebellar influences on speech impairment, or possible other forms of cerebellar functioning as contributing to SLI

Ecological character displacement in the face of gene flow: Evidence from two species of nightingales

<p>Abstract</p> <p>Background</p> <p>Ecological character displacement is a process of phenotypic differentiation of sympatric populations caused by interspecific competition. Such differentiation could facilitate speciation by enhancing reproductive isolation between incipient species, although empirical evidence for it at early stages of divergence when gene flow still occurs between the species is relatively scarce. Here we studied patterns of morphological variation in sympatric and allopatric populations of two hybridizing species of birds, the Common Nightingale (<it>Luscinia megarhynchos</it>) and the Thrush Nightingale (<it>L. luscinia</it>).</p> <p>Results</p> <p>We conducted principal component (PC) analysis of morphological traits and found that nightingale species converged in overall body size (PC1) and diverged in relative bill size (PC3) in sympatry. Closer analysis of morphological variation along geographical gradients revealed that the convergence in body size can be attributed largely to increasing body size with increasing latitude, a phenomenon known as Bergmann's rule. In contrast, interspecific interactions contributed significantly to the observed divergence in relative bill size, even after controlling for the effects of geographical gradients. We suggest that the divergence in bill size most likely reflects segregation of feeding niches between the species in sympatry.</p> <p>Conclusions</p> <p>Our results suggest that interspecific competition for food resources can drive species divergence even in the face of ongoing hybridization. Such divergence may enhance reproductive isolation between the species and thus contribute to speciation.</p

How equitable are GP practice prescribing rates for statins?: an ecological study in four primary care trusts in North West England

BACKGROUND: There is a growing body of literature highlighting inequities in GP practice prescribing rates for a number of drug therapies. The small amount of research on statin prescribing has either focussed on variations rather than equity per se, been based on populations other than GP practices or has used cost-based prescribing rates. AIM: To explore the equity of GP practice prescribing rates for statins, using the theoretical framework of equity of treatment (also known as horizontal equity or comparative need). METHODS: The study involved a cross-sectional secondary analysis in four primary care trusts (PCTs 1–4) in the North West of England, including 132 GP practices. Prescribing rates and health care needs indicators (HCNIs) were developed for all GP practices. RESULTS: Scatter-plots revealed large differences between individual GP practices, both within and between PCTs, in terms of the relationship between statin prescribing and healthcare need. In addition, there were large differences between GP practices in terms of the relationship between actual and expected prescribing rates for statins. Multiple regression analyses explained almost 30% of the variation in prescribing rates in the combined dataset, 25% in PCT1, 31% in PCT3, 51% in PC4 and 58% in PCT2. There were positive associations with variables relating to CHD hospital diagnoses and procedures and negative associations with variables relating to ethnicity, material deprivation, the proportion of patients aged over 75 years and single-handed GP practices. CONCLUSION: Overall, this study found inequitable relationships between actual and expected prescribing rates, and possible inequities in statin prescribing rates on the basis of ethnicity, deprivation, single-handed practices and the proportion of patients aged over 75 years

Centre of pressure characteristics in normal, planus and cavus feet

Background The aim of this study was to compare centre of pressure (COP) characteristics between healthy adults with normal, planus or cavus feet who were allocated to groups based on reliable foot posture measurement techniques. Methods Ninety-two healthy adult participants (aged 18 to 45) were recruited and classified as either normal (n = 35), pes planus (n = 31) or pes cavus (n = 26) based on Foot Posture Index, Arch Index and normalised navicular height truncated measurements. Barefoot walking trials were conducted using an emed®-x 400 plantar pressure system (Novel GmbH, Munich, Germany). Average, maximum, minimum and range (difference between maximum and minimum) values were calculated for COP velocity and lateral-medial force index during loading response, midstance, terminal stance and pre-swing phases of stance. The COP excursion index was also calculated. One-way analyses of variance were used to compare the three foot posture groups. Results The cavus foot exhibited the slowest average and minimum COP velocity during terminal stance, but this pattern was reversed during pre-swing, when the cavus foot exhibited the fastest maximum COP velocity. The planus foot exhibited the smallest lateral medial force index range during terminal stance. There were no differences between the groups for COP excursion index. Conclusion These findings indicate that there are differences in COP characteristics between foot postures, which may represent different mechanisms for generating force to facilitate forward progression of the body during the propulsive phases of gait