Determination of the

We report the first measurement of the parity-violating elastic electron scattering asymmetry on ^{27}Al. The ^{27}Al elastic asymmetry is A_{PV}=2.16±0.11(stat)±0.16(syst) ppm, and was measured at ⟨Q^{2}⟩=0.02357±0.00010 GeV^{2}, ⟨θ_{lab}⟩=7.61°±0.02°, and ⟨E_{lab}⟩=1.157 GeV with the Q_{weak} apparatus at Jefferson Lab. Predictions using a simple Born approximation as well as more sophisticated distorted-wave calculations are in good agreement with this result. From this asymmetry the ^{27}Al neutron radius R_{n}=2.89±0.12 fm was determined using a many-models correlation technique. The corresponding neutron skin thickness R_{n}-R_{p}=-0.04±0.12 fm is small, as expected for a light nucleus with a neutron excess of only 1. This result thus serves as a successful benchmark for electroweak determinations of neutron radii on heavier nuclei. A tree-level approach was used to extract the ^{27}Al weak radius R_{w}=3.00±0.15 fm, and the weak skin thickness R_{wk}-R_{ch}=-0.04±0.15 fm. The weak form factor at this Q^{2} is F_{wk}=0.39±0.04.

Precision Measurement of the Beam-Normal Single-Spin Asymmetry in Forward-Angle Elastic Electron-Proton Scattering.

A beam-normal single-spin asymmetry generated in the scattering of transversely polarized electrons from unpolarized nucleons is an observable related to the imaginary part of the two-photon exchange process. We report a 2% precision measurement of the beam-normal single-spin asymmetry in elastic electron-proton scattering with a mean scattering angle of θ_{lab}=7.9° and a mean energy of 1.149 GeV. The asymmetry result is B_{n}=-5.194±0.067(stat)±0.082 (syst) ppm. This is the most precise measurement of this quantity available to date and therefore provides a stringent test of two-photon exchange models at far-forward scattering angles (θ_{lab}→0) where they should be most reliable.

Minimally invasive and targeted therapeutic cell delivery to the skin using microneedle devices.

BACKGROUND: Translation of cell therapies to the clinic is accompanied by numerous challenges, including controlled and targeted delivery of the cells to their site of action, without compromising cell viability and functionality. OBJECTIVES: To explore the use of hollow microneedle devices (to date only used for the delivery of drugs and vaccines into the skin and for the extraction of biological fluids) to deliver cells into skin in a minimally invasive, user-friendly and targeted fashion. METHODS: Melanocyte, keratinocyte and mixed epidermal cell suspensions were passed through various types of microneedles and subsequently delivered into the skin. RESULTS: Cell viability and functionality are maintained after injection through hollow microneedles with a bore size ≥ 75 µm. Healthy cells are delivered into the skin at clinically relevant depths. CONCLUSIONS: Hollow microneedles provide an innovative and minimally invasive method for delivering functional cells into the skin. Microneedle cell delivery represents a potential new treatment option for cell therapy approaches including skin repigmentation, wound repair, scar and burn remodelling, immune therapies and cancer vaccines.

Topical propranolol for infantile haemangiomas: a systematic review.

Infantile haemangiomas are the most common tumour of infancy. Whilst the majority are left untreated to involute spontaneously, residual skin changes commonly occur, particularly in superficial haemangiomas. The current first-line treatment for problematic lesions is oral propranolol; however due to the risk of systemic adverse effects, the use of off-label topical preparations has recently been investigated. Our systematic review was conducted in accordance with PRISMA guidelines. Four databases were searched to identify original articles evaluating the use of topical propranolol as the primary therapy for infantile haemangiomas. Twelve articles with a total of 597 patients and 632 haemangiomas were included. Three topical propranolol preparations were used, creams, ointments and gels and were all prepared by local pharmaceutical laboratories. The concentration of propranolol ranged from 0.5% to 5%. Treatment duration ranged from two weeks to 16.5 months. Overall, 90% of lesions improved following the initiation of topical propranolol. A good or excellent response, defined as a reduction in the size of at least 50%, was seen in 59% of lesions. Earlier initiation of treatment (less than 3 months of age) was associated with improved outcomes. No systemic adverse effects were reported. Minor local reactions were seen in 1.3% of patients. Topical propranolol is safer than oral propranolol, though may be less effective. Topical propranolol may be more suitable for patients with small, superficial haemangiomas at risk of cosmetic sequelae, where the cosmetic or symptomatic impact does not warrant oral propranolol treatment.

A survey of O RhD-negative red cells in the South West: stocks and distribution compared to use and wastage.

BACKGROUND: O RhD-negative (ONeg) red cells can be used in an emergency for recipients of other blood groups. Matching supply and demand is currently a challenge; therefore, any service redesign, using more remote blood fridges, must consider ONeg red cell availability. OBJECTIVES: To identify whether the number of fridges stocking emergency ONeg units correlates with use and wastage. METHODS: The number and distribution of ONeg red cells was requested from the hospitals in South West England. For NHS Hospitals, comparison was made with ONeg National Health Service (NHS) organisation--NHS Blood and Transplant (NHSBT) issues (ONeg as a proportion of all red cells), wastage and the proportion of ONeg units given to ONeg patients (ONeg-to-ONeg use). Correlations were performed using Spearman's rank correlation coefficient. RESULTS: Of the 23 hospitals, 21 responded. Four hundred and forty three ONeg units were held across the region--56% as stock and the remaining as emergency units. ONeg issues increased with the number of fridges holding emergency units (ρ = 0.48, significance 0.046). No correlation was found between the number of fridges and ONeg wastage or ONeg-to-ONeg use. A longer unit shelf life on rotation back to stock was associated with lower wastage (ρ = -0.597, significance 0.009). CONCLUSIONS: Although there was a weak correlation between fridge numbers and overall percentage ONeg use, there was no correlation with ONeg wastage.

First determination of the weak charge of the proton.

The Q(weak) experiment has measured the parity-violating asymmetry in ep elastic scattering at Q(2)=0.025(GeV/c)(2), employing 145 µA of 89% longitudinally polarized electrons on a 34.4 cm long liquid hydrogen target at Jefferson Lab. The results of the experiment's commissioning run, constituting approximately 4% of the data collected in the experiment, are reported here. From these initial results, the measured asymmetry is A(ep)=-279±35 (stat) ± 31 (syst) ppb, which is the smallest and most precise asymmetry ever measured in ep scattering. The small Q(2) of this experiment has made possible the first determination of the weak charge of the proton Q(W)(p) by incorporating earlier parity-violating electron scattering (PVES) data at higher Q(2) to constrain hadronic corrections. The value of Q(W)(p) obtained in this way is Q(W)(p)(PVES)=0.064±0.012, which is in good agreement with the standard model prediction of Q(W)(p)(SM)=0.0710±0.0007. When this result is further combined with the Cs atomic parity violation (APV) measurement, significant constraints on the weak charges of the up and down quarks can also be extracted. That PVES+APV analysis reveals the neutron's weak charge to be Q(W)(n)(PVES+APV)=-0.975±0.010.

Measurement of the parity-violating asymmetry in inclusive electroproduction of π- near the Δ0 resonance.

The parity-violating (PV) asymmetry of inclusive π- production in electron scattering from a liquid deuterium target was measured at backward angles. The measurement was conducted as a part of the G0 experiment, at a beam energy of 360 MeV. The physics process dominating pion production for these kinematics is quasifree photoproduction off the neutron via the Δ0 resonance. In the context of heavy-baryon chiral perturbation theory, this asymmetry is related to a low-energy constant d(Δ)- that characterizes the parity-violating γNΔ coupling. Zhu et al. calculated d(Δ)- in a model benchmarked by the large asymmetries seen in hyperon weak radiative decays, and predicted potentially large asymmetries for this process, ranging from A(γ)-=-5.2 to +5.2 ppm. The measurement performed in this work leads to A(γ)-=-0.36±1.06±0.37±0.03 ppm (where sources of statistical, systematic and theoretical uncertainties are included), which would disfavor enchancements considered by Zhu et al. proportional to V(ud)/V(us). The measurement is part of a program of inelastic scattering measurements that were conducted by the G0 experiment, seeking to determine the N-Δ axial transition form factors using PV electron scattering.

Platelet transfusions in haematology patients: are we using them appropriately?

BACKGROUND AND OBJECTIVES: A large proportion of all platelet components are given to haematology patients. As there are risks associated with their transfusion, costs associated with production, and shortages may occur, it is important that their use is appropriate. STUDY DESIGN AND METHODS: The study was split into two parts, a survey to assess local practice guidelines and an assessment of platelet usage. A total of 123 hospitals completed the survey and 168 hospitals submitted data of 40 haematology patients over a 3-month period. RESULTS: The organizational survey found that 36% of hospitals routinely give prophylactic platelet transfusions to patients with long-term bone-marrow failure. Also, a significant minority of hospitals administer platelet transfusions if the platelet count is below a certain threshold prior to performing a bone-marrow aspirate (11%) or a bone-marrow aspirate and trephine (23%); both of these are contrary to UK platelet transfusion guidelines. Data were collected on a total of 3402 patients, of which 3296 cases were eligible for analysis. They received approximately 46% of all platelet components issued to participating hospitals in England during the study period. The majority (69%) of platelet transfusions were prophylactic; of these only 33% were given when the platelet count was ≤10×10(9)/l. Using an algorithm, based on current UK guidelines, 60% of prophylactic transfusions were appropriate, 6% could not be assessed and 34% were inappropriate. A total of 10% of all prophylactic transfusions were double the standard adult dose. CONCLUSIONS: There is considerable potential for decreased use of platelet transfusions with a consequent improvement in their appropriate use and cost reduction.

Comparison of haemoglobin F detection by the acid elution test, flow cytometry and high-performance liquid chromatography in maternal blood samples analysed for fetomaternal haemorrhage.

BACKGROUND AND OBJECTIVE: All pregnant women undergoing blood grouping at Southmead Hospital are offered haemoglobinopathy screening by high-performance liquid chromatography (HPLC). RhD-negative women who deliver RhD-positive infants are tested for fetomaternal haemorrhage (FMH) by acid elution (AE). The effectiveness of these two assays for quantitation of FMH was compared with flow cytometry (FC). MATERIALS AND METHODS: The relationship between expression of haemoglobin F (HbF) in individual cells by AE and FC and quantitation of HbF in haemolysates by HPLC was investigated, using maternal samples with unusually high levels of HbF-positive maternal cells (F cells) or with large FMH (fetal cells). Standard anti-D FC was performed to quantitate fetal D-positive cells in D-negative women and compared with FMH estimated by AE and HbF FC. RESULTS: AE overestimated FMH when maternal F cells were increased. HbF FC distinguished F cells from fetal cells. Values of HbF determined by HPLC were less than the level of 5% used for investigation of raised fetal haemoglobin, even in the maternal samples with elevated F cells or massive FMH. CONCLUSIONS: To quantitate FMH, measurement of HbF using FC was more sensitive and accurate than AE or HPLC. HbF FC is the method of choice when results from routine investigation using AE or standard anti-D FC are discrepant or when there is maternal and fetal RhD compatibility.

Safety of the use of gold nanoparticles conjugated with proinsulin peptide and administered by hollow microneedles as an immunotherapy in type 1 diabetes.

Antigen-specific immunotherapy is an immunomodulatory strategy for autoimmune diseases, such as type 1 diabetes, in which patients are treated with autoantigens to promote immune tolerance, stop autoimmune ß-cell destruction and prevent permanent dependence on exogenous insulin. In this study, human proinsulin peptide C19-A3 (known for its positive safety profile) was conjugated to ultrasmall gold nanoparticles (GNPs), an attractive drug delivery platform due to the potential anti-inflammatory properties of gold. We hypothesised that microneedle intradermal delivery of C19-A3 GNP may improve peptide pharmacokinetics and induce tolerogenic immunomodulation and proceeded to evaluate its safety and feasibility in a first-in-human trial. Allowing for the limitation of the small number of participants, intradermal administration of C19-A3 GNP appears safe and well tolerated in participants with type 1 diabetes. The associated prolonged skin retention of C19-A3 GNP after intradermal administration offers a number of possibilities to enhance its tolerogenic potential, which should be explored in future studies.

Transverse beam spin asymmetries at backward angles in elastic electron-proton and quasielastic electron-deuteron scattering.

We have measured the beam-normal single-spin asymmetries in elastic scattering of transversely polarized electrons from the proton, and performed the first measurement in quasielastic scattering on the deuteron, at backward angles (lab scattering angle of 108°) for Q² = 0.22 GeV²/c² and 0.63 GeV²/c² at beam energies of 362 and 687 MeV, respectively. The asymmetry arises due to the imaginary part of the interference of the two-photon exchange amplitude with that of single-photon exchange. Results for the proton are consistent with a model calculation which includes inelastic intermediate hadronic (πN) states. An estimate of the beam-normal single-spin asymmetry for the scattering from the neutron is made using a quasistatic deuterium approximation, and is also in agreement with theory.

Strange quark contributions to parity-violating asymmetries in the backward angle G0 electron scattering experiment.

We have measured parity-violating asymmetries in elastic electron-proton and quasielastic electron-deuteron scattering at Q2=0.22 and 0.63 GeV2. They are sensitive to strange quark contributions to currents in the nucleon and the nucleon axial-vector current. The results indicate strange quark contributions of approximately < 10% of the charge and magnetic nucleon form factors at these four-momentum transfers. We also present the first measurement of anapole moment effects in the axial-vector current at these four-momentum transfers.

Fracture prevention: a population-based intervention delivered in primary care.

BACKGROUND: Osteoporosis is common, increasing as the population ages and has significant consequences including fracture. Effective treatments are available. AIM: To support proactive fracture risk assessment (FRAX) and optimizing treatment for high-risk patients in primary care. DESIGN: Clinical cohort. SETTING: November 2017 to November 2018, support was provided to 71 practices comprising 69 of 90 practices within two National Health Service Clinical Commissioning Groups areas. Total population 579 508 (207 263 aged over 50 years). PARTICIPANTS: FRAX (National Institute for Care and Clinical Excellence, NICE CG146) in (i) males aged 75 years and over, (ii) females aged 65 years and over, (iii) females aged under 65 years and males aged under 75 years with risk factors and (iv) under 50 years with major risk factors. RESULTS: A total of 158 946 met NICE CG146, 11 961 were coded with an osteoporosis diagnosis (7.5%), of those, 42% were prescribed treatment with a bone sparing agent (BSA). In total, 6942 were assessed to initiate BSA. Thirty percent of untreated osteoporosis diagnosis patients had never been prescribed BSA. Even when prescribed, 1700 people (35%) were for less than minimum recommended duration. Of the total 9784 patients within the FRAX recommended to treat threshold, 3197 (33%) were currently treated with BSA and 3684 (37%) had no history of ever receiving BSA. From untreated patients, expected incidence of 875 fractures over a 3-year period (approximately £3.4 million). Treatment would prevent 274 fractures (cost reduction: £1 274 045, with prescribing costs: saving £805 145 after 3 years of treatment). CONCLUSION: Underdiagnosis and suboptimal treatment of osteoporosis was identified. Results suggest that implementing NICE guidance and optimizing treatment options in practice is possible and could prevent significant fractures.

Clinical administration of microneedles: skin puncture, pain and sensation.

Injections using hypodermic needles cause pain, discomfort, localised trauma and apprehension. Additionally, careful use and disposal of needles is required to avoid transmission of blood-borne pathogens. As an alternative, microneedles can facilitate drug delivery without significantly impacting on pain receptors or blood vessels that reside beneath the skin outer layers. In this study we aim to determine the pain and sensory response to the application of wet-etch silicon microneedles, when used in such a way as to reliably penetrate skin, and provide a preliminary indication of how skin responds to microneedle injury with time. Twelve subjects received single-blinded insertions of a 25-G hypodermic needle and two microneedle arrays (36 needles of 180 and 280 mum height). The optimal method for microneedle application was determined in a pilot study. Pain intensity was scored using a visual analogue scale (VAS) and sensory perception determined using an adapted McGill Pain Questionnaire Short Form. Skin penetration was determined by external staining and measurement of trans-epidermal water loss (TEWL). Mean VAS scores, verbal descriptions and questionnaire responses showed that the 180 and 280 mum microneedles caused significantly less pain and discomforting sensation in participants than the hypodermic needle. Methylene blue staining and TEWL analysis confirmed that microchannels were formed in the skin following microneedle application. Evidence of microchannel repair and resealing was apparent at 8-24 h post-application. In summary, this study shows that pyramidal wet-etch microneedles can penetrate human skin with minimal pain and sensory discomfort, creating transient pathways for potential drug, vaccine and DNA delivery.

HIV opt-out increases HIV testing in low-risk patients.

We audited the effect of introducing HIV opt-out in a genitourinary medicine clinic in central London, UK. We found that opt-out increased the rate at which HIV testing was offered to low-risk patients and that more tests were done.

Conjugation of a peptide autoantigen to gold nanoparticles for intradermally administered antigen specific immunotherapy.

Antigen specific immunotherapy aims to tolerise patients to specific autoantigens that are responsible for the pathology of an autoimmune disease. Immune tolerance is generated in conditions where the immune response is suppressed and thus gold nanoparticles (AuNPs) are an attractive drug delivery platform due to their anti-inflammatory effects and their potential to facilitate temporal and spatial delivery of a peptide autoantigen in conjunction with pro-tolerogenic elements. In this study we have covalently attached an autoantigen, currently under clinical evaluation for the treatment of type 1 diabetes (PIC19-A3 peptide), to AuNPs to create nanoscale (<5 nm), negatively charged (-40 to -60 mV) AuNP-peptide complexes for immunotherapy. We also employ a clinically approved microneedle delivery system, MicronJet600, to facilitate minimally-invasive intradermal delivery of the nanoparticle constructs to target skin-resident antigen presenting cells, which are known to be apposite target cells for immunotherapy. The AuNP-peptide complexes remain physically stable upon extrusion through microneedles and when delivered into ex vivo human skin they are able to diffuse rapidly and widely throughout the dermis (their site of deposition) and, perhaps more surprisingly, the overlying epidermal layer. Intracellular uptake was extensive, with Langerhans cells proving to be the most efficient cells at internalising the AuNP-peptide complex (94% of the local population within the treated region of skin). In vitro studies showed that uptake of the AuNP-peptide complexes by dendritic cells reduced the capacity of these cells to activate naïve T cells. This indicator of biological functionality encourages further development of the AuNP-peptide formulation, which is now being evaluated in clinical trials.

A comparison of the puncturing properties of gelatin and hypromellose capsules for use in dry powder inhalers.

This study investigates capsule puncture in dry powder inhalers. Gelatin and hydroxypropylmethyl cellulose (HPMC) capsules (stored at 11 and 33% relative humidities) were punctured using a pin from a Foradil inhaler, with insertion force measurement via an Instron tester. In HPMC capsules, the force after capsule puncture reduced by half and then increased to a second maximum as the pin shaft entered the hole. In gelatin capsules, the postpuncture force reduced to zero, indicating shell flaps losing contact with the pin. At lower moisture contents, both capsules were less flexible. This provides a tool to measure the shell properties of inhalation capsules.

Recombinant factor VIIa for the prevention and treatment of bleeding in patients without haemophilia.

BACKGROUND: Recombinant factor VIIa (rFVIIa) is licensed for use in patients with haemophilia and inhibitory allo-antibodies. It is also increasingly being used for off-license indications to prevent bleeding in operations where blood loss is likely to be high, and/or to stop bleeding that is proving difficult to control by other means. OBJECTIVES: To assess the effectiveness of rFVIIa when used therapeutically to control active bleeding, or prophylactically to prevent (excessive) bleeding in patients without haemophilia. SEARCH STRATEGY: We searched the Cochrane Injuries Group's Specialised Register, CENTRAL, MEDLINE, EMBASE and other specialised databases up to March 2006. We also searched reference lists of articles and contacted experts in the field. SELECTION CRITERIA: Randomised controlled trials (RCTs) comparing rFVIIa with placebo, or one dose of rFVIIa with another, in any patient population with the exception of those with haemophilia. There was no restriction by outcomes examined, but this review focuses on mortality, blood loss or control of bleeding, red cell transfusion requirements, number of patients transfused and thromboembolic adverse events. DATA COLLECTION AND ANALYSIS: Two authors independently assessed potentially relevant studies for inclusion. Data were extracted and methodological quality was examined. Studies using rFVIIa prophylactically and those using rFVIIa therapeutically have been considered separately. Data were pooled using fixed and random effects models, but random effects models were preferred because of the variability in clinical features of the included studies. MAIN RESULTS: Thirteen trials met the inclusion criteria; all were placebo-controlled double-blind RCTs. Six trials involving 724 participants examined the prophylactic use of rFVIIa; 379 received rFVIIa. There were no outcomes by which any observed advantage, or disadvantage, of rFVIIa over placebo could not have been observed by chance alone. There were trends in favour of rFVIIa for a number of outcomes, particularly the number of participants transfused, pooled RR 0.85 (95% CI 0.72 to 1.01) but this was balanced by a trend against rFVIIa with respect to thromboembolic adverse events, pooled RR 1.25 (95% CI 0.76 to 2.07). Seven trials involving 1214 participants examined the therapeutic use of rFVIIa; 687 received rFVIIa. There were no outcomes where any observed advantage, or disadvantage, of rFVIIa over placebo could not have been observed by chance alone. There was a trend in favour of rFVIIa for reducing mortality, RR 0.82 (95% CI 0.64 to 1.04), although no other clear trends in favour of rFVIIa were noted for other desired outcomes. Interpretation of these results must take into account one study which could not be included in the quantitative summary but which showed results strongly in favour of rFVIIa for the treatment of intra-cerebral haemorrhage. There was a trend against rFVIIa with respect to thromboembolic adverse events; the RR 1.50 (95% CI 0.86 to 2.62). AUTHORS' CONCLUSIONS: Although rFVIIa has a role in the management of patients with haemophilia, its effectiveness as a more general haemostatic drug, either prophylactically or therapeutically, remains uncertain. Its effectiveness as a therapeutic agent, particularly for intra-cerebral haemorrhage, looks more encouraging than prophylactic use. The use of rFVIIa outside its current licensed indications should be very limited and its wider use await the results of ongoing and possibly newly commissioned RCTs. In the interim, rFVIIa use should be restricted to clinical trials.