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The overall objective of the guideline is to provide up-to-date, evidence-based recommendations for the management of delusional infestation (DI) in adults. Linked Comment: I. Coulson. Br J Dermatol 2022; 187:457.

Consumer engagement in clinical research is increasingly being prioritized by major funders such as the Australian National Health and Medical Research Council.We performed a systematic literature search of the Cochrane library, Embase, CINAHL PubMed and Medline to identify randomized clinical trials in surgery with perioperative outcomes conducted in Australia. All publications underwent review and thematic analysis to identify levels of consumer engagement and the inclusion of patient-reported outcome measures (PROMS).From 5373 records, the full texts of 809 articles were retrieved, of which 41 clinical trials met the inclusion criteria. PROMS were identified in 63% of the trials as a primary or secondary outcome. Despite multiple available checklists and analysis tools, less than 2% of studies documented any consumer engagement apart from PROMS.There was very little consumer engagement in formulation, management, conduct and dissemination of the trial findings.

Buprenorphine, an analgesic commonly used in rodent surgery, requires repeated dosing every 4 to 6 h in order to provide adequate analgesia. However, redosing requires repeated handling, which may itself cause stress. Buprenorphine SR-LAB, which reportedly maintains serum levels of buprenorphine greater than 1 ng/mL for 48 to 72 h, is commercially available. However, the viscosity of the product and small dosing volumes make accurate dosing a challenge. Simbadol is a concentrated formulation of buprenorphine hydrochloride labeled for use in cats with recommended dosing frequency of every 24 h. We measured serum concentrations over time after a single injection of this product in C57BL/6NCrl mice and compared it to standard buprenorphine (Buprenex) and Buprenorphine SR-LAB. Male and female mice were injected subcutaneously with one of the 3 buprenorphine formulations at a dose of 1 mg/kg at time 0. Groups of mice (n = 8) were euthanized at 1, 4, 8, 12, 16 h for all groups and 24 h for the Simbadol and the Buprenorphine SR-LAB. Liquid chromatography-mass spectrometry (LC-MS/MS) was used to determine concentrations of buprenorphine in each serum sample. High concentrations were observed in both Simbadol and standard buprenorphine groups one hour after injection (>50 ng/mL). These groups had similar buprenorphine concentration curves, including rates of decline. The standard buprenorphine group had mean concentrations less than 1 ng/mL by 12 h and the Simbadol group by 16 h. In contrast, the Buprenorphine SR-LAB group remained above the 1 ng/mL therapeutic threshold throughout the 24 h. In addition, clinical signs, including increased activity, that lasted for up to an hour after the injection in the Simbadol and standard buprenorphine groups. We conclude that Simbadol does not offer dosing advantages over the standard buprenorphine formulation when given at 1 mg/kg. Buprenorphine SR-LAB maintained a steady concentration of buprenorphine above 1 ng/mL for at least 24 h, and as such is a superior choice for providing long-term analgesia.

The Material Plasma Exposure eXperiment (MPEX) is a steady state linear device with the goal to perform plasma material interaction (PMI) studies at future fusion reactor relevant conditions. A prototype of MPEX referred as Porto-MPEX is designed to carry out research and development related to source, heating and transport concepts on the planned full MPEX device. The auxiliary heating schemes in MPEX are based on cyclotron resonance heating with radio frequency (RF) waves. Ion cyclotron heating (ICH) and electron cyclotron heating (ECH) in MPEX are used to independently heat the ions and electrons and provide fusion divertor conditions ranging from sheath-limited to fully detached divertor regimes at a material target. A Hybrid Particle-In-Cell code- PICOS++ is developed and applied to understand the plasma parallel transport during ICH heating in MPEX Proto-MPEX to the target. With this tool, evolution of the distribution function of MPEX/Proto-MPEX ions is modeled in the presence of (1) Coulomb collisions, (2) volumetric particle sources and (3) quasi-linear RF-based ICH. The code is benchmarked against experimental data from Proto-MPEX and simulation data from B2.5 EIRENE. The experimental observation of density-drop near the target in Proto-MPEX and MPEX during ICH heating is demonstrated and explained via physics-based arguments using PICOS++ modeling. In fact, the density drops at the target during ICH in Proto-MPEX/MPEX to conserve the flux and to compensate for the increased flow during ICH. Furthermore, sensitivity scans of various plasma parameters with respect to ICH power are performed for MPEX to investigate its role on plasma transport and particle and energy fluxes at the target. Finally, we discuss the pathway to model ECH in MPEX using the Hybrid PIC formulation herein presented for kinetic electrons and fluid ions.

Parkinson's disease (PD) is a neurodegenerative disorder characterised by nigrostriatal dopaminergic (DA) neurodegeneration. There is a critical need for neuroprotective therapies, particularly those that do not require direct intracranial administration. Small molecule inhibitors of histone deacetylases (HDIs) are neuroprotective in in vitro and in vivo models of PD, however it is unknown whether Class IIa-specific HDIs are neuroprotective when administered peripherally. Here we show that 6-hydroxydopamine (6-OHDA) treatment induces protein kinase C (PKC)-dependent nuclear accumulation of the Class IIa histone deacetylase (HDAC)5 in SH-SY5Y cells and cultured DA neurons in vitro. Treatment of these cultures with the Class IIa-specific HDI, MC1568, partially protected against 6-OHDA-induced cell death. In the intrastriatal 6-OHDA lesion in vivo rat model of PD, MC1568 treatment (0.5 mg/kg i.p.) for 7 days reduced forelimb akinesia and partially protected DA neurons in the substantia nigra and their striatal terminals from 6-OHDA-induced neurodegeneration. MC1568 treatment prevented 6-OHDA-induced increases in microglial activation in the striatum and substantia nigra. Furthermore, MC1568 treatment decreased 6-OHDA-induced increases in nuclear HDAC5 in nigral DA neurons. These data suggest that peripheral administration of Class IIa-specific HDIs may be a potential therapy for neuroprotective in PD.

Rosacea is a chronic, symptomatic and potentially disfiguring inflammatory skin condition with high prevalence, particularly among women.1 Quantitative research into the psychosocial factors associated with rosacea has consistently reported the presence of anxiety, depression, decreased quality of life and feelings of stigmatisation.2,3 Such factors may be challenging to identify in clinical practice, since the objective severity of a visible difference does not always correlate with the lived experience.4.

Survey data indicates that 98% of patients with skin disease report that their condition affects their emotional and psychological wellbeing.1 Despite this, access to specialist mental health support for such patients remains limited throughout the UK.2 A significant proportion of patients with psychodermatological disease manifest a primary psychiatric or psychological disorder for which care may be sought in mental health settings rather than in dermatology services. It is recognised, however, that psychiatrists may lack confidence in diagnosing and managing psychodermatological problems.3,4 It is our impression that psychiatry trainees in particular may have limited awareness and experience of this important field. We conducted a survey to evaluate psychiatry trainees' awareness, experience, and education in psychodermatology.

Parkinson’s disease is the most common movement disorder worldwide, affecting over 6 million people. It is an age-related disease, occurring in 1% of people over the age of 60, and 3% of the population over 80 years. The disease is characterized by the progressive loss of midbrain dopaminergic neurons from the substantia nigra, and their axons, which innervate the striatum, resulting in the characteristic motor and non-motor symptoms of Parkinson’s disease. This is paralleled by the intracellular accumulation of α-synuclein in several regions of the nervous system. Current therapies are solely symptomatic and do not stop or slow disease progression. One promising disease-modifying strategy to arrest the loss of dopaminergic neurons is the targeted delivery of neurotrophic factors to the substantia nigra or striatum, to protect the remaining dopaminergic neurons of the nigrostriatal pathway. However, clinical trials of two well-established neurotrophic factors, glial cell line-derived neurotrophic factor and neurturin, have failed to meet their primary end-points. This failure is thought to be at least partly due to the downregulation by α-synuclein of Ret, the common co-receptor of glial cell line-derived neurorophic factor and neurturin. Growth/differentiation factor 5 is a member of the bone morphogenetic protein family of neurotrophic factors, that signals through the Ret-independent canonical Smad signaling pathway. Here, we review the evidence for the neurotrophic potential of growth/differentiation factor 5 in in vitro and in vivo models of Parkinson’s disease. We discuss new work on growth/differentiation factor 5’s mechanisms of action, as well as data showing that viral delivery of growth/differentiation factor 5 to the substantia nigra is neuroprotective in the α-synuclein rat model of Parkinson’s disease. These data highlight the potential for growth/differentiation factor 5 as a disease-modifying therapy for Parkinson’s disease.

Over the last decade, interest in the role of the microbiome in health and disease has increased. The use of germ-free animals and depletion of the microbial flora using antimicrobials are 2 methods commonly used to study the microbiome in laboratory mice. Germ-free mice are born, raised, and studied in isolators in the absence of any known microbes; however, the equipment, supplies, and training required for the use of these mice can be costly and time-consuming. The use of antibiotics to decrease the microbial flora does not require special equipment, can be used for any mouse strain, and is relatively inexpensive; however, mice treated in this manner still retain microbes and they do not live in a germ-free environment. One commonly used antibiotic cocktail regimen uses ampicillin, neomycin, metronidazole, and vancomycin in the drinking water for 2 to 4 wk. We found that the palatability of this mixture is low, resulting in weight loss and leading to removal of mice from the study. The addition of sucralose to the medicated water and making wet food (mash) with the medicated water improved intake; however, the low palatability still resulted in a high number of mice requiring removal. The current study evaluated a new combination of antibiotics designed to reduce the gut microbiota while maintaining body weights. C57BL/6NCrl mice were placed on one of the following drinking water regimens: ampicillin/neomycin/metronidazole/vancomycin water (n = 16), enrofloxacin/ampicillin water ( n = 12), or standard reverse osmosis deionized water (RODI) ( n = 11). During an 8 day regimen, mice were weighed and water consumption was measured. Feces were collected before and after 8 d of treatment. Quantitative real-time PCR (real-time qPCR) for 16S bacterial ribosome was performed on each sample, and values were compared among groups. The combination of enrofloxacin and ampicillin improved water intake, together with a greater reduction in gut flora.

Background: Economic evidence for vitiligo treatments is absent. Objectives: To determine the cost-effectiveness of (i) handheld narrowband ultraviolet B (NB-UVB) and (ii) a combination of topical corticosteroid (TCS) and NB-UVB compared with TCS alone for localized vitiligo. Methods: Cost-effectiveness analysis alongside a pragmatic, three-arm, placebo-controlled randomized controlled trial with 9 months’ treatment. In total 517 adults and children (aged ≥ 5 years) with active vitiligo affecting < 10% of skin were recruited from secondary care and the community and were randomized 1: 1: 1 to receive TCS, NB-UVB or both. Cost per successful treatment (measured on the Vitiligo Noticeability Scale) was estimated. Secondary cost–utility analyses measured quality-adjusted life-years using the EuroQol 5 Dimensions 5 Levels for those aged ≥ 11 years and the Child Health Utility 9D for those aged 5 to < 18 years. The trial was registered with number ISRCTN17160087 on 8 January 2015. Results: The mean ± SD cost per participant was £775 ± 83·7 for NB-UVB, £813 ± 111.4 for combination treatment and £600 ± 96·2 for TCS. In analyses adjusted for age and target patch location, the incremental difference in cost for combination treatment compared with TCS was £211 (95% confidence interval 188–235), corresponding to a risk difference of 10·9% (number needed to treat = 9). The incremental cost was £1932 per successful treatment. The incremental difference in cost for NB-UVB compared with TCS was £173 (95% confidence interval 151–196), with a risk difference of 5·2% (number needed to treat = 19). The incremental cost was £3336 per successful treatment. Conclusions: Combination treatment, compared with TCS alone, has a lower incremental cost per additional successful treatment than NB-UVB only. Combination treatment would be considered cost-effective if decision makers are willing to pay £1932 per additional treatment success.

Epigenetic modifications in neurodegenerative disease are under investigation for their roles in disease progression. Alterations in acetylation rates of certain Parkinson's disease (PD)-linked genes have been associated with the pathological progression of this disorder. In light of this, and given the lack of disease-modifying therapies for PD, HDAC inhibitors (HDIs) are under consideration as potential pharmacological agents. The neuroprotective effects of pan-HDACs and some class-specific inhibitors have been tested in in vivo and in vitro models of PD, with varying outcomes. Here we used gene co-expression analysis to identify HDACs that are associated with human dopaminergic (DA) neuron development. We identified HDAC3, HDAC5, HDAC6 and HDAC9 as being highly correlated with the DA markers, SLC6A3 and NR4A2. RT-qPCR revealed that mRNA expression of these HDACs exhibited similar temporal profiles during embryonic mouse midbrain DA (mDA) neuron development. We tested the neuroprotective potential of a number of class-specific small molecule HDIs on human SH-SY5Y cells, using neurite growth as a phenotypic readout of neurotrophic action. Neither the class I-specific HDIs, RGFP109 and RGFP966, nor the HDAC6 inhibitor ACY1215, had significant effects on neurite outgrowth. However, the class IIa HDI, LMK235 (a HDAC4/5 inhibitor), significantly increased histone acetylation and neurite outgrowth. We found that LMK235 increased BMP-Smad-dependent transcription in SH-SY5Y cells and that this was required for its neurite growth-promoting effects on SH-SY5Y cells and on DA neurons in primary cultures of embryonic day (E) 14 rat ventral mesencephalon (VM). These effects were also seen in SH-SY5Y cells transfected with HDAC5 siRNA. Furthermore, LMK235 treatment exerted neuroprotective effects against degeneration induced by the DA neurotoxin 1-methyl-4-phenylpyridinium (MPP+), in both SH-SY5Y cells and cultured DA neurons. Treatment with LMK235 was also neuroprotective against axonal degeneration induced by overexpression of wild-type (WT) or A53T mutant α-synuclein in both SH-SY5Y cells and primary cultures of DA neurons. In summary, these data show the neuroprotective potential of the class IIa HDI, LMK235, in cell models of relevance to PD.

Letter to the Editor

Parkinson’s disease (PD) is a neurodegenerative disease characterised by the progressive degeneration of midbrain dopaminergic neurons, coupled with the intracellular accumulation of α-synuclein. Axonal degeneration is a central part of the pathology of PD. While the majority of PD cases are sporadic, some are genetic; the G2019S mutation in leucine-rich repeat kinase 2 (LRRK2) is the most common genetic form. The application of neurotrophic factors to protect dopaminergic neurons is a proposed experimental therapy. One such neurotrophic factor is growth differentiation factor (GDF)5. GDF5 is a dopaminergic neurotrophic factor that has been shown to upregulate the expression of a protein called nucleoside diphosphate kinase A (NME1). However, whether NME1 is neuroprotective in cell models of axonal degeneration of relevance to PD is unknown. Here we show that treatment with NME1 can promote neurite growth in SH-SY5Y cells, and in cultured dopaminergic neurons treated with the neurotoxin 6-hydroxydopamine (6-OHDA). Similar effects of NME1 were found in SH-SY5Y cells and dopaminergic neurons overexpressing human wild-type α-synuclein, and in stable SH-SY5Y cell lines carrying the G2019S LRRK2 mutation. We found that the effects of NME1 require the RORα/ROR2 receptors. Furthermore, increased NF-κB-dependent transcription was partially required for the neurite growth-promoting effects of NME1. Finally, a combined bioinformatics and biochemical analysis of the mitochondrial oxygen consumption rate revealed that NME1 enhanced mitochondrial function, which is known to be impaired in PD. These data show that recombinant NME1 is worthy of further study as a potential therapeutic agent for axonal protection in PD.

Parkinson's disease is a neurodegenerative disorder characterised by nigrostriatal dopaminergic degeneration, and intracellular a-synuclein aggregation. Current pharmacological treatments are solely symptomatic so there is a need to identify agents that can slow or stop dopaminergic degeneration. One proposed class of therapeutics are neurotrophic factors which promote the survival of nigrostriatal dopaminergic neurons. However, neurotrophic factors need to be delivered directly to the brain. An alternative approach may be to identify pharmacological agents which can reach the brain to stimulate neurotrophic factor expression and/or their signalling pathways in dopaminergic neurons. BMP2 is a neurotrophic factor that is expressed in the human substantia nigra; exogenous BMP2 administration protects against dopaminergic degeneration in in vitro models of PD. In this study, we investigated the neurotrophic potential of two FDA-approved drugs, quinacrine and niclosamide, that are modulators of BMP2 signalling. We report that quinacrine and niclosamide, like BMP2, significantly increased neurite length, as a readout of neurotrophic action, in SH-SY5Y cells and dopaminergic neurons in primary cultures of rat ventral mesencephalon. We also show that these effects of quinacrine and niclosamide require the activation of BMP-Smad signalling. Finally, we demonstrate that quinacrine and niclosamide are neuroprotective against degeneration induced by the neurotoxins, MPP+ and 6-OHDA, and by viral-mediated overexpression of a-synuclein in vitro. Collectively, this study identifies two drugs, that are safe for use in patients' to 'are approved for human use, that exert neurotrophic effects on dopaminergic neurons through modulation of BMP-Smad signalling. This rationalises the further study of drugs that target the BMP-Smad pathway as potential neuroprotective pharmacotherapy for Parkinson's disease.

BackgroundSystematic reviews suggest that narrowband ultraviolet B light combined with treatments such as topical corticosteroids may be more effective than monotherapy for vitiligo.ObjectiveTo explore the clinical effectiveness and cost-effectiveness of topical corticosteroid monotherapy compared with (1) hand-held narrowband ultraviolet B light monotherapy and (2) hand-held narrowband ultraviolet B light/topical corticosteroid combination treatment for localised vitiligo.DesignPragmatic, three-arm, randomised controlled trial with 9 months of treatment and a 12-month follow-up.SettingSixteen UK hospitals – participants were recruited from primary and secondary care and the community.ParticipantsAdults and children (aged ≥ 5 years) with active non-segmental vitiligo affecting ≤ 10% of their body area.InterventionsTopical corticosteroids [mometasone furoate 0.1% (Elocon®, Merck Sharp & Dohme Corp., Merck & Co., Inc., Whitehouse Station, NJ, USA) plus dummy narrowband ultraviolet B light]; narrowband ultraviolet B light (narrowband ultraviolet B light plus placebo topical corticosteroids); or combination (topical corticosteroids plus narrowband ultraviolet B light). Topical corticosteroids were applied once daily on alternate weeks and narrowband ultraviolet B light was administered every other day in escalating doses, with a dose adjustment for erythema. All treatments were home based.Main outcome measuresThe primary outcome was self-assessed treatment success for a chosen target patch after 9 months of treatment (‘a lot less noticeable’ or ‘no longer noticeable’ on the Vitiligo Noticeability Scale). Secondary outcomes included blinded assessment of primary outcome and percentage repigmentation, onset and maintenance of treatment response, quality of life, side effects, treatment burden and cost-effectiveness (cost per additional successful treatment).ResultsIn total, 517 participants were randomised (adults,n = 398; and children,n = 119; 52% male; 57% paler skin types I–III, 43% darker skin types IV–VI). At the end of 9 months of treatment, 370 (72%) participants provided primary outcome data. The median percentage of narrowband ultraviolet B light treatment-days (actual/allocated) was 81% for topical corticosteroids, 77% for narrowband ultraviolet B light and 74% for combination groups; and for ointment was 79% for topical corticosteroids, 83% for narrowband ultraviolet B light and 77% for combination. Target patch location was head and neck (31%), hands and feet (32%), and rest of the body (37%). Target patch treatment ‘success’ was 20 out of 119 (17%) for topical corticosteroids, 27 out of 123 (22%) for narrowband ultraviolet B light and 34 out of 128 (27%) for combination. Combination treatment was superior to topical corticosteroids (adjusted risk difference 10.9%, 95% confidence interval 1.0% to 20.9%;p = 0.032; number needed to treat = 10). Narrowband ultraviolet B light was not superior to topical corticosteroids (adjusted risk difference 5.2%, 95% confidence interval –4.4% to 14.9%;p = 0.290; number needed to treat = 19). The secondary outcomes supported the primary analysis. Quality of life did not differ between the groups. Participants who adhered to the interventions for > 75% of the expected treatment protocol were more likely to achieve treatment success. Over 40% of participants had lost treatment response after 1 year with no treatment. Grade 3 or 4 erythema was experienced by 62 participants (12%) (three of whom were using the dummy) and transient skin thinning by 13 participants (2.5%) (two of whom were using the placebo). We observed no serious adverse treatment effects. For combination treatment compared with topical corticosteroids, the unadjusted incremental cost-effectiveness ratio was £2328.56 (adjusted £1932) per additional successful treatment (from an NHS perspective).LimitationsRelatively high loss to follow-up limits the interpretation of the trial findings, especially during the post-intervention follow-up phase.ConclusionHand-held narrowband ultraviolet B light plus topical corticosteroid combination treatment is superior to topical corticosteroids alone for treatment of localised vitiligo. Combination treatment was relatively safe and well tolerated, but was effective in around one-quarter of participants only. Whether or not combination treatment is cost-effective depends on how much decision-makers are willing to pay for the benefits observed.Future workDevelopment and testing of new vitiligo treatments with a greater treatment response and longer-lasting effects are needed.Trial registrationCurrent Controlled Trials ISRCTN17160087.FundingThis project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full inHealth Technology Assessment; Vol. 24, No. 64. See the NIHR Journals Library website for further project information.

Background: Evidence for the effectiveness of vitiligo treatments is limited. Objectives: To determine the effectiveness of (i) handheld narrowband UVB (NB-UVB) and (ii) a combination of potent topical corticosteroid (TCS) and NB-UVB, compared with TCS alone, for localized vitiligo. Methods: A pragmatic, three-arm, placebo-controlled randomized controlled trial (9-month treatment, 12-month follow-up). Adults and children, recruited from secondary care and the community, aged ≥ 5 years and with active vitiligo affecting

Purpose To describe the use of tumor necrosis factor-alpha inhibitors (TNFis) among pregnancies ending in a live birth and with a diagnosis of ankylosing spondylitis (AS), Crohn's disease (CD), juvenile idiopathic arthritis (JIA), psoriasis (PsO), psoriatic arthritis (PsA), rheumatoid arthritis (RA), or ulcerative colitis (UC). Methods We identified pregnancies among women aged 15 to 54 years between 01/01/2004 and 09/30/2015 from 16 health plans participating in Sentinel. We inferred indication using ICD-9-CM codes in the 183-day period before conception. We assessed proportion of infliximab, etanercept, adalimumab, certolizumab pegol, and golimumab by calendar year, indication, and maternal age, and compared them to proportions in an age-matched, indication-matched, and date-matched non-pregnant cohort. Results Among 19 681 pregnancies with at least one chronic inflammatory condition, 2990 (15.2%) received a TNFi. In both pregnancies and matched non-pregnant cohort, TNFi use was highest (34.4%; 55.8%) for PsA patients and lowest (6.2%; 13.4%) for PsO patients. Etanercept was most frequently used among AS/JIA/PsA/PsO/RA patients, while infliximab was the preferred TNFi for CD/UC patients. Except for infliximab and certolizumab, TNFi use during pregnancy decreased after the first trimester. Pregnancies among older pregnant women (45-54 years) were more likely to be treated compared with the matched non-pregnant cohort. Conclusion There was a preference for etanercept among pregnancies with AS/JIA/PsA/PsO/RA, despite the availability of other TNFis. Decline in TNFi use after the first trimester may be related to the desire to reduce TNFis transplacental transfer and to minimize infection risk to the fetus or baby associated with live vaccine immunizations after birth.

Delusional infestation describes the unshakeable belief that one's skin is infected or infested with an external organism or inanimate material, in the absence of supportive medical evidence. It is one of the most challenging psychodermatological conditions to manage, given the rigidity of patients' physically focused health beliefs, and the competing need to introduce antipsychotic therapy to bring about resolution. This is rendered exponentially more complex when partners or family members are similarly afflicted. This situation is known as shared delusional infestation, shared psychotic disorder (SPD), or folie à deux. We present a series of three couples with SPD who were referred to our tertiary psychodermatology service during the same year. On examining the literature we were intrigued to discover that subtly different subtypes of SPD have been recognized since the late 1800s. These include folie simultanée, imposée, communiquée and induite. Our cases neatly demonstrate three of these variants, and highlight the difficulties in facilitating effective treatment.

Management of patients with current or previous depression who require isotretinoin treatment for acne is a challenging area. Current opinion favours the view that isotretinoin-induced mood disturbance is a rare, idiosyncratic reaction, not reliably related to the presence of pre-existing depression. Nonetheless, in the absence of a definitive high-quality study, there remains a degree of legitimate uncertainty. With input from a psychiatrist, we created and administered a detailed survey featuring a range of low-, medium- and higher-risk clinical scenarios, designed to capture a snapshot of current dermatological practice. Respondents indicated a wide variability in their approach, with a substantial proportion referring on to Psychiatry where this was not deemed necessary. Few dermatologists appreciated the importance of behaviours suggesting impaired impulse control. We hope this study helps to refine guidance for isotretinoin prescribing, both to maximize safety and to ensure that deserving patients with acne are not excluded from appropriate treatment.

Physical activity confers many health benefits, but the underlying mechanisms require further exploration. In this pilot randomized controlled trial we tested the association between longitudinal measures of DNA methylation and changes in objective measures, including physical activity, weight loss, and C-reactive protein levels in community-dwelling women aged 55 to 70 years. We assessed DNA methylation from 20 healthy postmenopausal women, who did not have a mobility disability and allocated them to a group-based intervention, Everyday Activity Supports You, or a control group (monthly group-based health-related education sessions). The original randomized controlled trial was 6 months in duration and consisted of nine 2-h sessions that focused on reducing sedentary behaviour for the intervention group, or six 1-h sessions that focused on other topics for the control group. We collected peripheral blood mononuclear cells, both at baseline and 6 months later. Samples were processed using the Illumina 450k Methylation array to quantify DNA methylation at >485 000 CpG sites in the genome. There were no significant associations between DNA methylation and physical activity, but we did observe alterations at epigenetic modifications that correlated with change in percent body weight over a 6-month period at 12 genomic loci, 2 of which were located near the previously reported weight-associated genes RUNX3 and NAMPT. We also generated a potential epigenetic predictor of weight loss using baseline DNA methylation at 5 CpG sites. These exploratory findings suggest a potential biological link between body weight changes and epigenetic processes.

Purpose The US Food and Drug Administration's Sentinel system developed tools for sequential surveillance. Methods In patients with non-valvular atrial fibrillation, we sequentially compared outcomes for new users of rivaroxaban versus warfarin, employing propensity score matching and Cox regression. A total of 36 173 rivaroxaban and 79 520 warfarin initiators were variable-ratio matched within 2 monitoring periods. Results Statistically significant signals were observed for ischemic stroke (IS) (first period) and intracranial hemorrhage (ICH) (second period) favoring rivaroxaban, and gastrointestinal bleeding (GIB) (second period) favoring warfarin. In follow-up analyses using primary position diagnoses from inpatient encounters for increased definition specificity, the hazard ratios (HR) for rivaroxaban vs warfarin new users were 0.61 (0.47, 0.79) for IS, 1.47 (1.29, 1.67) for GIB, and 0.71 (0.50, 1.01) for ICH. For GIB, the HR varied by age

Purpose Assess angioedema risk with exposure to angiotensin converting enzyme inhibitors (ACEIs) or angiotensin II receptor blockers (ARBs) compared with beta-blockers, by race/ethnicity. Methods New-user cohorts of Medicare beneficiaries 65 years or older initiating ACEI, ARB, or beta-blocker treatment from March 2007 to March 2014 were constructed. Angioedema incidence rates by drug and race/ethnicity were computed for 1-30 and 31-365 days of treatment. Cox proportional hazards regression was used to examine angioedema risk between cohorts. Results Angioedema incidence rates (per 1000 person years) in beta-blocker users were 1.80 (whites), 4.11 (blacks), 1.89 (Asians), and 2.10 (Hispanics); in ACEI users, 4.03, 23.77, 2.94, and 4.27; and in ARB users, 1.73, 3.11, 1.10, and 1.90, respectively. Incidence rates were significantly higher in the first 30 days of exposure for all drug × race/ethnic groups. Overall, angioedema risk increased among ACEI users (hazard ratio, 2.91; 95% confidence interval, 2.75-3.07) but not ARB users (0.93, 0.85-1.02) versus beta-blocker users. Angioedema risk with ACEIs versus beta-blockers increased more in blacks (6.28, 5.44-7.24) than whites (2.33, 2.19-2.48), Hispanics (2.04, 1.36-3.07), and Asians (1.48, 0.94-2.35). Compared with white beta-blocker users, angioedema risk was increased 2.9-fold in whites, 20.2-fold in blacks, and 2.3-fold in other race/ethnic groups combined during the first 30 days of ACEI exposure. Conclusions There was significant effect modification of angioedema risk by race and ACEI use for blacks, but not for other race/ethnicity groups. Angioedema risk was significantly greater in the first 30 days of exposure for all, and highest among blacks.

Parkinson’s disease is the second most common neurodegenerative disorder; it affects 1% of the population over the age of 65. The number of people with Parkinson’s disease is set to rapidly increase due to changing demographics and there is an unmet clinical need for disease-modifying therapies. The pathological hallmarks of Parkinson’s disease are the progressive degeneration of dopaminergic neurons in the substantia nigra and their axons which project to the striatum, and the aggregation of α-synuclein; these result in a range of debilitating motor and non-motor symptoms. The application of neurotrophic factors to protect and potentially regenerate the remaining dopaminergic neurons is a major area of research interest. However, this strategy has had limited success to date. Clinical trials of two well-known neurotrophic factors, glial cell line-derived neurotrophic factor and neurturin, have reported limited efficacy in Parkinson’s disease patients, despite these factors showing potent neurotrophic actions in animal studies. There is therefore a need to identify other neurotrophic factors that can protect against α-synuclein-induced degeneration of dopaminergic neurons. The bone morphogenetic protein (BMP) family is the largest subgroup of the transforming growth factor-β superfamily of proteins. BMPs are naturally secreted proteins that play crucial roles throughout the developing nervous system. Importantly, many BMPs have been shown to be potent neurotrophic factors for dopaminergic neurons. Here we discuss recent work showing that transcripts for the BMP receptors and BMP2 are co-expressed with several key markers of dopaminergic neurons in the human substantia nigra, and evidence for downregulation of BMP2 expression at distinct stages of Parkinson’s disease. We also discuss studies that explored the effects of BMP2 treatment, in in vitro and in vivo models of Parkinson’s disease. These studies found potent effects of BMP2 on dopaminergic neurites, which is important given that axon degeneration is increasingly recognized as a key early event in Parkinson’s disease. Thus, the aim of this mini-review is to give an overview of the BMP family and the BMP-Smad signalling pathway, in addition to reviewing the available evidence demonstrating the potential of BMP2 for Parkinson’s disease therapy.

Simulation survey performed at TAE Technologies, has demonstrated that high harmonic fast wave (HHFW) heating is a promising scenario to heat core electrons of FRC plasma. To prepare the proposed experimental study of HHFW antenna-plasma coupling and wave propagation on LAPD machine at UCLA, a high-power-capable 4-strap antenna has been calculated and designed through collaboration among TAE, ORNL, ASIPP, and UCLA. This antenna was mechanically designed and fabricated by ASIPP and it has been installed recently on LAPD. Meanwhile, by using the Petra-M code, a newly developed generic electromagnetic simulation tool for modeling RF wave propagation, the RF-SciDAC team starts 3D full wave simulations. Detailed information on antenna electromagnetic simulations and mechanical design, as well as preliminary experimental results of wave propagation study with the newly installed phased- array antenna, will be presented in this paper.

There exists a wide spectrum of self-induced skin disease that may present to primary care clinicians. At one end are commonly recognised entities, such as lichen simplex chronicus, nodular prurigo, and chronic atopic eczema perpetuated by habitual scratching. At the other end are a range of complex, multifactorial psychodermatological conditions that are challenging to diagnose and manage. This article focuses on skin-picking disorder (SPD), trichotillomania, and dermatitis artefacta (DA), to assist primary care clinicians in managing these conditions effectively. SPD is characterised by repeated picking of the skin, resulting in recalcitrant skin lesions. To satisfy the criteria for a diagnosis of SPD, there must have been persistent attempts by the patient to reduce or discontinue picking, with clinically significant distress or impairment of functioning.1 Females tend to be affected more often, with onset typically in adolescence. Patients may spend several hours at a time picking or gouging at the skin, often in a ritualised fashion, sometimes using various implements. Picking episodes are commonly triggered by increased stress, and comorbid mental health disorders are often associated. All patients with SPD will acknowledge their tendency to pick, to a greater or lesser extent, if questioned sensitively.2 Self-induced skin lesions in SPD are usually obvious on examination. Discrete, monomorphic, eroded, or ulcerated papules, nodules, and plaques tend to be distributed symmetrically over easily accessible sites. Lesions at all stages of the healing process …

Esther H Zhou,1 Sally Seymour,2 Margie R Goulding,1 Elizabeth M Kang,1 Jacqueline M Major,1 Solomon Iyasu1 1Division of Epidemiology, Office of Surveillance and Epidemiology, 2Office of New Drugs, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, MD, USA Background: Emerging safety issues associated with long-acting beta2-agonist (LABA) have led to multiple regulatory activities by the US Food and Drug Administration (FDA) since 2003, including Drug Safety Communications (DSCs) in 2010. These DSCs had three specific recommendations for the safe use of LABA products in adult asthma treatment. Methods: We examined the initiation of LABA-containing products for adult asthma treatment using an intermittent time series approach in a claims database from 2003 to 2012. We assessed the alignment of dispensing patterns with the following 2010 FDA recommendations: 1) contraindicated use of single-ingredient (SI)-LABA without an asthma controller medication (ACM); 2) a LABA should only be used when asthma is not adequately controlled on inhaled corticosteroids (ICSs) or ACM; and 3) step-down asthma therapy (e.g., discontinue LABA) when asthma control is achieved. Results: There were 477,922 adults (18–64years old) dispensed a new LABA during 2003–2012. Among LABA initiators, patients who initiated an SI-LABA and who did “not” have an ACM dispensed on the same date decreased from >9% in 2003 (the initial labeling change) to

Trichotillomania is a condition characterized by the pulling of hair from anywhere on the body and is classified as an obsessive-compulsive and related disorder. Patients with hair disorders are commonly referred to psychodermatology services, and can represent a management challenge. Few publications exist that report outcomes for patients with trichotillomania in real clinical practice. We report 12 such patients seen within our own psychodermatology service, who were managed using a variety of treatment strategies. The rate of defaulting of appointments was high, but improvements were seen in patients engaging with services.

Introduction α-synuclein-induced degeneration of dopaminergic neurons has been proposed to be central to the early progression of Parkinson's disease. This highlights the need to identify factors that are neuroprotective or neuroregenerative against α-synuclein-induced degeneration. Due to their potent neurotrophic effects on nigrostriatal dopaminergic neurons, we hypothesized that members of the bone morphogenetic protein (BMP) family have potential to protect these cells against α-synuclein. Methods To identify the most relevant BMP ligands, we used unbiased gene co-expression analysis to identify all BMP family members having a significant positive correlation with five markers of dopaminergic neurons in the human substantia nigra (SN). We then tested the ability of lead BMPs to promote neurite growth in SH-SY5Y cells and in primary cultures of ventral mesencephalon (VM) dopaminergic neurons, treated with either 6-OHDA or MPP+, or overexpressing wild-type or A53T α-synuclein. Results Only the expression of BMP2 was found to be significantly correlated with multiple dopaminergic markers in the SN. We found that BMP2 treatment promoted neurite growth in SH-SY5Y cells and in dopaminergic neurons. Moreover, BMP2 treatment promoted neurite growth in both SH-SY5Y cells and VM neurons, treated with the neurotoxins 6-OHDA or MPP+. Furthermore, BMP2 promoted neurite growth in cells overexpressing wild-type or A53T-α-synuclein. Conclusion These findings are important given that clinical trials of two neurotrophic factors, GDNF and neurturin, have failed to meet their primary endpoints. Our findings are a key first step in rationalising the further study of BMP2 as a potential neurotrophic factor in α-synuclein-based translational models of Parkinson's disease.

In recent years, several genome-wide association studies have identified candidate regions for genetic susceptibility in major mood disorders. Most notable are regions in a locus in chromosome 3p21, encompassing the genes NEK4-ITIH1-ITIH3-ITIH4. Three of these genes represent heavy chains of the composite protein inter-α-inhibitor (IαI). In order to further establish associations of these genes with mood disorders, we evaluated behavioral phenotypes in mice deficient in either Ambp/bikunin, which is necessary for functional ITIH1 and ITIH3 complexes, or in Itih4, the gene encoding the heavy chain Itih4. We found that loss of Itih4 had no effect on the behaviors tested, but loss of Ambp/bikunin led to increased anxiety-like behavior in the light/dark and open field tests and reduced exploratory activity in the elevated plus maze, light/dark preference and open field tests. Ambp/bikunin knockout mice also exhibited a sex-dependent exaggeration of acoustic startle responses, alterations in social approach during a three-chamber choice test, and an elevated fear conditioning response. These results provide experimental support for the role of ITIH1/ITIH3 in the development of mood disorders.

Aim Adverse drug events lead to increased morbidity, mortality and health care costs. Pharmacogenetic testing that guides drug prescribing has the potential to reduced adverse drug events and increase drug effectiveness. Our aim was to quantify the clinical effectiveness of genotype-guided prescribing. Methods Three electronic databases were searched from January 1980 through December 2013. Studies were eligible if they were RCTs comparing genotype-guided prescribing with non-genetic informed prescribing, reported drug specific adverse drug events and clinical effectiveness outcomes. Two reviewers independently screened titles and abstracts, extracted data and assessed study quality. Meta-analyses of specific outcomes were conducted where data allowed. Results Fifteen studies, involving 5688 patients and 19 drugs, met the inclusion and exclusion criteria. Eight studies had statistically significant results for their primary outcome in favour of genotype-guided prescribing. Nine studies evaluated genotype-guided warfarin dosing. Analysis of percentage of time in therapeutic international normalized ratio range (1952 individuals) showed a statistically significant benefit in favour of genotype-guided warfarin dosing (mean difference = 6.67; 95% CI 1.34, 12.0, I2 = 80%). There was a statistically significant reduction in numbers of warfarin-related minor bleeding, major bleeding and thromboembolisms associated with genotype guided warfarin dosing, relative risk 0.57 (95% CI 0.33, 0.99; I2 = 60%). It was not possible to meta-analyze genotype-guided dosing for other drugs. Of the six non-warfarin genotype-guided trials, two demonstrated a statistically significant benefit for their primary outcome, odds ratio 0.03 (95% CI 0.00, 0.62, P < 0.001) for abacavir. Conclusions There is evidence of improved clinical effectiveness associated with genotype-guided warfarin dosing.

BACKGROUND Dermatology specialty trainees (STs) in the United Kingdom (UK) are few in number and will join a thinly spread national consultant body. It is of paramount importance to deliver training programmes of the highest quality for these doctors, central to which is the establishment and maintenance of an educational climate conducive to learning. OBJECTIVE To conduct a pilot study to evaluate the educational climate for dermatology STs in one UK deanery (West Midlands). METHODS Secondary analysis of published data was performed, from the UK's General Medical Council (GMC) national training survey, and the Job Evaluation Survey Tool (JEST) administered by the West Midlands deanery. A modified online version of the Postgraduate Hospital Educational Environment Measure (PHEEM) was circulated among dermatology STs. RESULTS The GMC's survey data show that UK dermatology STs rated their training highly in comparison with undifferentiated UK postgraduate trainees. West Midlands dermatology STs (n = 22) scored very similarly to UK dermatology STs. The JEST gave broadly encouraging results, with 21/22 (95%) happy to recommend their posts to colleagues. The modified PHEEM yielded a global mean score of 96.5/152, attracting the descriptor 'more positive than negative but room for improvement'. CONCLUSION Despite inherent methodological limitations, the GMC, JEST and modified PHEEM surveys have revealed useful comparative triangulated data which allows the conclusion that West Midlands dermatology STs seem to be training in a favourable educational climate. This represents an important facet of the quality assurance process for medical education, and allows insight into areas which may require improvement.