Long-term benzodiazepine and Z-drugs use in England:a survey of general practice

BackgroundCurrent British National Formulary (BNF) guidelines state that benzodiazepines and zolpidem, zopiclone, and zaleplon, commonly known as Z-drugs (BZD), be prescribed for no more than 4 weeks, although anecdotal data suggest that many patients are prescribed BZDs for much longer. As there are no recent, evidence-based estimates of long-term (&gt;12 months) BZD use in England, the scale of this potential problem is unknown.AimTo produce the first reliable, evidence-based estimate of long-term BZD use in England.Design and settingEstimates of long-term BZD use in England were projected from data obtained from a survey conducted in 2014–2015 by the Bridge Project, a prescribed-drug withdrawal support charity in the North of England (Bradford).MethodPercentages of long-term users of BZD were derived from the survey, by sampling primary care GP surgeries with around 100 000 registered patients, and these were applied to English NHS patient numbers. The data were filtered to exclude the very young and old, and those with other health issues.ResultsThe mean percentage of registered patients prescribed BZDs for more than a year in the survey sample is 0.69% (95% confidence interval [CI] = 0.54 to 0.84). Applying this value to national patient numbers yields a mean projection of 296 929 (95% CI = 232 553 to 361 305) long-term users of BZD in England. The data also suggest that as many as 119 165 of these patients may be willing to accept prescribed drug dependency withdrawal services.ConclusionMore than a quarter of a million people in England are likely to be taking highly dependency-forming hypnotic medication far beyond the recommended time scales. As there is evidence that long-term use of BZDs causes adverse physiological and neurological effects, and protracted withdrawal (with associated complications), this represents a serious public health problem.</jats:sec

Control of macrophage homeostasis

Tissue resident macrophages are extremely heterogeneous, which reflects their unique microenvironments and tissue specific functions. They are a constituent of all tissues, and are involved in homeostatic processes and inflammatory disease. Recent studies have shown that select tissue resident macrophage populations, such as Langerhans cells of the skin and microglia of the brain, are able to self-renew independently from the bone marrow. This is contrary to the prevailing model macrophage origins, the ‘mononuclear phagocyte system’, which dictates that all macrophages are derived from bone marrow monocytes. The work carried out in this thesis investigated the self-renewing potential of peritoneal tissue resident macrophages, and its control. Several novel discoveries were made: i) peritoneal resident macrophages proliferate at low levels to maintain their numbers during homeostasis, at higher levels during neonatal growth, and undergo a burst in proliferation during acute inflammation to restore their depleted population; ii) renewal of peritoneal resident macrophages during an acute inflammatory episode was found to be independent from the bone marrow, and dependent upon macrophage colony stimulating factor, but importantly, not interleukin-4; iii) Monocyte-derived macrophages could also proliferate within an inflammatory lesion. Collectively, these observations challenge the dogma of the mononuclear phagocyte system: they demonstrate that in vascular tissues, tissue resident macrophages could self-renewal independently of monocytes, and that monocyte-derived cells are not terminally-differentiated. Additional work leading up to these studies implicated Gata6 as a peritoneal macrophage-specific transcription factor. In this thesis, Gata6 was found to be necessary for peritoneal macrophage phenotype, normal proliferation, euploidy, and normal responses to inflammation. In summary, these studies demonstrate not only are macrophages capable of self-renewal, but this is dependent upon discrete transcriptional control. Understanding the molecular controls of tissue macrophage heterogeneity and renewal could provide novel avenues for the therapeutic manipulation of their activities

Diversity and environmental adaptation of phagocytic cell metabolism

Phagocytes are cells of the immune system that play important roles in phagocytosis, respiratory burst and degranulation-key components of innate immunity and response to infection. This diverse group of cells includes monocytes, macrophages, dendritic cells, neutrophils, eosinophils, and basophils-heterogeneous cell populations possessing cell and tissue-specific functions of which cellular metabolism comprises a critical underpinning. Core functions of phagocytic cells are diverse and sensitive to alterations in environmental- and tissue-specific nutrients and growth factors. As phagocytic cells adapt to these extracellular cues, cellular processes are altered and may contribute to pathogenesis. The considerable degree of functional heterogeneity among monocyte, neutrophil, and other phagocytic cell populations necessitates diverse metabolism. As we review our current understanding of metabolism in phagocytic cells, gaps are focused on to highlight the need for additional studies that hopefully enable improved cell-based strategies for counteracting cancer and other diseases

Managing hostile subsoils in the high rainfall zone of south-western Australia

This report is designed to complement existing information on the management of crops in the High Rainfall Zone of south-western Australia and to identify limitations for crop production arising from the soil properties in this area

Order alpha_s^2 beta_0 Correction to the Charged Lepton Spectrum in b \to c \ell \bar\nu_\ell decays

We compute the \alpha_s^2\beta_0 part of the two-loop QCD corrections to the charged lepton spectrum in b \to c \ell \bar\nu_\ell decays and find them to be about 50\% of the first order corrections at all lepton energies, except those close to the end point. Including these corrections we extract the central values \bar\Lambda=0.33 GeV and \lambda_1=-0.17 GeV^2 for the HQET matrix elements and use them to determine the $\overline{\rm MS}$ b and c quark masses, and |V_{cb}|.Comment: 15 pages, 1 Postscript figur

Implications of the B→XℓνˉℓB \to X \ell \bar\nu_\ell lepton spectrum for heavy quark physics

The shape of the lepton spectrum in inclusive semileptonic $B\to X\,\ell\,\bar\nu_\ell$ decay is sensitive to matrix elements of the heavy quark effective theory, $\bar\Lambda$ and $\lambda_1$. From CLEO data we extract $\bar\Lambda=0.39\pm0.11\,$GeV and $\lambda_1=-0.19\pm0.10\,{\rm GeV}^2$, where the uncertainty is the $1\sigma$ statistical error only. Systematic uncertainties are discussed. These values for $\bar\Lambda$ and $\lambda_1$ are used to determine $|V_{cb}|$ and the $\overline{\rm MS}$ bottom and charm quark masses. We discuss the theoretical uncertainties related to order $(\Lambda_{\rm QCD}/m_b)^3$ effects and higher orders in the perturbative expansion.Comment: 10 pages revtex + one figure. Corrections from secondary leptons included, that affect the numerical results. Thus the central values become $\bar\Lambda=0.39\pm0.11GeV$ and $\lambda_1=-0.19\pm0.10GeV^2

Scattering in the PT-symmetric Coulomb potential

Scattering on the ${\cal PT}$-symmetric Coulomb potential is studied along a U-shaped trajectory circumventing the origin in the complex $x$ plane from below. This trajectory reflects ${\cal PT}$ symmetry, sets the appropriate boundary conditions for bound states and also allows the restoration of the correct sign of the energy eigenvalues. Scattering states are composed from the two linearly independent solutions valid for non-integer values of the 2L parameter, which would correspond to the angular momentum in the usual Hermitian setting. Transmission and reflection coefficients are written in closed analytic form and it is shown that similarly to other ${\cal PT}$-symmetric scattering systems the latter exhibit handedness effect. Bound-state energies are recovered from the poles of the transmission coefficients.Comment: Journal of Physics A: Mathematical and Theoretical 42 (2009) to appea

Immune-metabolic adaptations in pregnancy: A potential stepping-stone to sepsis

Physiological shifts during pregnancy predispose women to a higher risk of developing sepsis resulting from a maladapted host-response to infection. Insightful studies have delineated subtle point-changes to the immune system during pregnancy. Here, we present an overlay of these point-changes, asking what changes and when, at a physiological, cellular, and molecular systems-level in the context of sepsis. We identify distinct immune phases in pregnancy delineated by placental hormone-driven changes in homeostasis setpoints of the immune and metabolic systems that subtly mirrors changes observed in sepsis. We propose that pregnancy immune-metabolic setpoint changes impact feedback thresholds that increase risk for a maladapted host-response to infection and thus act as a stepping-stone to sepsis. Defining maternal immune-metabolic setpoint changes is not only vital for tailoring the right diagnostic tools for early management of maternal sepsis but will facilitate an unravelling of the pathophysiological pathways that predispose an individual to sepsis

Adaptive single-shot phase measurements: The full quantum theory

The phase of a single-mode field can be measured in a single-shot measurement by interfering the field with an effectively classical local oscillator of known phase. The standard technique is to have the local oscillator detuned from the system (heterodyne detection) so that it is sometimes in phase and sometimes in quadrature with the system over the course of the measurement. This enables both quadratures of the system to be measured, from which the phase can be estimated. One of us [H.M. Wiseman, Phys. Rev. Lett. 75, 4587 (1995)] has shown recently that it is possible to make a much better estimate of the phase by using an adaptive technique in which a resonant local oscillator has its phase adjusted by a feedback loop during the single-shot measurement. In Ref.~[H.M. Wiseman and R.B. Killip, Phys. Rev. A 56, 944] we presented a semiclassical analysis of a particular adaptive scheme, which yielded asymptotic results for the phase variance of strong fields. In this paper we present an exact quantum mechanical treatment. This is necessary for calculating the phase variance for fields with small photon numbers, and also for considering figures of merit other than the phase variance. Our results show that an adaptive scheme is always superior to heterodyne detection as far as the variance is concerned. However the tails of the probability distribution are surprisingly high for this adaptive measurement, so that it does not always result in a smaller probability of error in phase-based optical communication.Comment: 17 pages, LaTeX, 8 figures (concatenated), Submitted to Phys. Rev.

The effects of social service contact on teenagers in England

Objective: This study investigated outcomes of social service contact during teenage years. Method: Secondary analysis was conducted of the Longitudinal Survey of Young People in England (N = 15,770), using data on reported contact with social services resulting from teenagers’ behavior. Outcomes considered were educational achievement and aspiration, mental health, and locus of control. Inverse-probability-weighted regression adjustment was used to estimate the effect of social service contact. Results: There was no significant difference between those who received social service contact and those who did not for mental health outcome or aspiration to apply to university. Those with contact had lower odds of achieving good exam results or of being confident in university acceptance if sought. Results for locus of control were mixed. Conclusions: Attention is needed to the role of social services in supporting the education of young people in difficulty. Further research is needed on the outcomes of social services contact