Chronic alcohol exposure alters action control via hyperactive premotor corticostriatal activity.

Alcohol use disorder (AUD) alters decision-making control over actions, but disruptions to the responsible neural circuit mechanisms are unclear. Premotor corticostriatal circuits are implicated in balancing goal-directed and habitual control over actions and show disruption in disorders with compulsive, inflexible behaviors, including AUD. However, whether there is a causal link between disrupted premotor activity and altered action control is unknown. Here, we find that mice chronically exposed to alcohol (chronic intermittent ethanol [CIE]) showed impaired ability to use recent action information to guide subsequent actions. Prior CIE exposure resulted in aberrant increases in the calcium activity of premotor cortex (M2) neurons that project to the dorsal medial striatum (M2-DMS) during action control. Chemogenetic reduction of this CIE-induced hyperactivity in M2-DMS neurons rescued goal-directed action control. This suggests a direct, causal relationship between chronic alcohol disruption to premotor circuits and decision-making strategy and provides mechanistic support for targeting activity of human premotor regions as a potential treatment in AUD.

Home-based narrowband UVB, topical corticosteroid or combination for children and adults with vitiligo: HI-Light Vitiligo three-arm RCT.

BACKGROUND: Systematic reviews suggest that narrowband ultraviolet B light combined with treatments such as topical corticosteroids may be more effective than monotherapy for vitiligo. OBJECTIVE: To 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. DESIGN: Pragmatic, three-arm, randomised controlled trial with 9 months of treatment and a 12-month follow-up. SETTING: Sixteen UK hospitals - participants were recruited from primary and secondary care and the community. PARTICIPANTS: Adults and children (aged ≥ 5 years) with active non-segmental vitiligo affecting ≤ 10% of their body area. INTERVENTIONS: Topical 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 MEASURES: The 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). RESULTS: In 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). LIMITATIONS: Relatively high loss to follow-up limits the interpretation of the trial findings, especially during the post-intervention follow-up phase. CONCLUSION: Hand-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 WORK: Development and testing of new vitiligo treatments with a greater treatment response and longer-lasting effects are needed. TRIAL REGISTRATION: Current Controlled Trials ISRCTN17160087. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 24, No. 64. See the NIHR Journals Library website for further project information.

The Home Interventions and Light therapy for the treatment of vitiligo (HI-Light Vitiligo) trial aimed to find out whether or not treating vitiligo at home with a narrowband ultraviolet B light, either by itself or with a steroid ointment, is better than treatment using a steroid ointment only. We enrolled 517 children (aged ≥ 5 years) and adults who had small, active (i.e. recently changing) patches of vitiligo into the study. Participants received one of three possible treatment options: steroid ointment (plus dummy light), hand-held narrowband ultraviolet B light therapy (plus placebo ointment) or both treatments used together. We asked participants to judge how noticeable their target vitiligo patch was after 9 months of treatment. We considered the treatment to be successful if the participants' responses were either 'a lot less noticeable' or 'no longer noticeable'. The results showed that using both treatments together was better than using a steroid ointment on its own. Around one-quarter of participants (27%) who used both treatments together said that their vitiligo was either 'no longer noticeable' or 'a lot less noticeable' after 9 months of treatment. This was compared with 17% of those using steroid ointment on its own and 22% of those using narrowband ultraviolet B light on its own. All treatments were able to stop the vitiligo from spreading. Patches on the hands and feet were less likely to respond to treatment than patches on other parts of the body. The trial found that the vitiligo tended to return once treatments were stopped, so ongoing intermittent treatment may be needed to maintain the treatment response. The treatments were found to be relatively safe and easy to use, but light treatment required a considerable time commitment (approximately 20 minutes per session, two or three times per week). This trial showed that using steroid ointment and narrowband ultraviolet B light together is likely to be better than steroid ointment alone for people with small patches of vitiligo. Steroid ointment alone can still be effective for some people and remains a useful treatment that is able to stop vitiligo from spreading. The challenge is to make hand-held narrowband ultraviolet B light treatment available as normal care in the NHS for people with vitiligo.

Modern microprocessor built from complementary carbon nanotube transistors.

Electronics is approaching a major paradigm shift because silicon transistor scaling no longer yields historical energy-efficiency benefits, spurring research towards beyond-silicon nanotechnologies. In particular, carbon nanotube field-effect transistor (CNFET)-based digital circuits promise substantial energy-efficiency benefits, but the inability to perfectly control intrinsic nanoscale defects and variability in carbon nanotubes has precluded the realization of very-large-scale integrated systems. Here we overcome these challenges to demonstrate a beyond-silicon microprocessor built entirely from CNFETs. This 16-bit microprocessor is based on the RISC-V instruction set, runs standard 32-bit instructions on 16-bit data and addresses, comprises more than 14,000 complementary metal-oxide-semiconductor CNFETs and is designed and fabricated using industry-standard design flows and processes. We propose a manufacturing methodology for carbon nanotubes, a set of combined processing and design techniques for overcoming nanoscale imperfections at macroscopic scales across full wafer substrates. This work experimentally validates a promising path towards practical beyond-silicon electronic systems.

HLA-C*06:02 genotype is a predictive biomarker of biologic treatment response in psoriasis.

BACKGROUND: Biologic therapies can be highly effective for the treatment of severe psoriasis, but response for individual patients can vary according to drug. Predictive biomarkers to guide treatment selection could improve patient outcomes and treatment cost-effectiveness. OBJECTIVE: We sought to test whether HLA-C*06:02, the primary genetic susceptibility allele for psoriasis, predisposes patients to respond differently to the 2 most commonly prescribed biologics for psoriasis: adalimumab (anti-TNF-α) and ustekinumab (anti-IL-12/23). METHODS: This study uses a national psoriasis registry that includes longitudinal treatment and response observations and detailed clinical data. HLA alleles were imputed from genome-wide genotype data for 1326 patients for whom 90% reduction in Psoriasis Area and Severity Index score (PASI90) response status was observed after 3, 6, or 12 months of treatment. We developed regression models of PASI90 response, examining the interaction between HLA-C*06:02 and drug type (adalimumab or ustekinumab) while accounting for potentially confounding clinical variables. RESULTS: HLA-C*06:02-negative patients were significantly more likely to respond to adalimumab than ustekinumab at all time points (most strongly at 6 months: odds ratio [OR], 2.95; P = 5.85 × 10-7), and the difference was greater in HLA-C*06:02-negative patients with psoriatic arthritis (OR, 5.98; P = 6.89 × 10-5). Biologic-naive patients who were HLA-C*06:02 positive and psoriatic arthritis negative demonstrated significantly poorer response to adalimumab at 12 months (OR, 0.31; P = 3.42 × 10-4). Results from HLA-wide analyses were consistent with HLA-C*06:02 itself being the primary effect allele. We found no evidence for genetic interaction between HLA-C*06:02 and ERAP1. CONCLUSION: This large observational study suggests that reference to HLA-C*06:02 status could offer substantial clinical benefit when selecting treatments for severe psoriasis.

Increasing throughput and information content for in vitro drug metabolism experiments using ultra-performance liquid chromatography coupled to a quadrupole time-of-flight mass spectrometer.

The field of drug metabolism has been revolutionized by liquid chromatography/mass spectrometry (LC/MS) applications with new technologies such as triple quadrupoles, ion traps and time-of-flight (ToF) instrumentation. Over the years, these developments have often relied on the improvements to the mass spectrometer hardware and software, which has allowed users to benefit from lower levels of detection and ease-of-use. One area in which the development pace has been slower is in high-performance liquid chromatography (HPLC). In the case of metabolite identification, where there are many challenges due to the complex nature of the biological matrices and the diversity of the metabolites produced, there is a need to obtain the most accurate data possible. Reactive or toxic metabolites need to be detected and identified as early as possible in the drug discovery process, in order to reduce the very costly attrition of compounds in late-phase development. High-resolution, exact mass measurement plays a very important role in metabolite identification because it allows the elimination of false positives and the determination of non-trivial metabolites in a much faster throughput environment than any other standard current methodology available to this field. By improving the chromatographic resolution, increased peak capacity can be achieved with a reduction in the number of co-eluting species leading to superior separations. The overall enhancement in the chromatographic resolution and peak capacity is transferred into a net reduction in ion suppression leading to an improvement in the MS sensitivity. To investigate this, a number of in vitro samples were analyzed using an ultra-performance liquid chromatography (UPLC) system, with columns packed with porous 1.7 mum particles, coupled to a hybrid quadrupole time-of-flight (ToF) mass spectrometer. This technique showed very clear examples for fundamental gains in sensitivity, chromatographic resolution and speed of analysis, which are all important factors for the demands of today's HTS in discovery.

Microwave ablation with loop antenna: in vivo porcine liver model.

PURPOSE: To determine the effectiveness of tissue ablation with a loop microwave antenna in various configurations in porcine liver tissue. MATERIALS AND METHODS: Microwave energy was applied for 7 minutes at 60 W in six porcine livers (mean weight, 68.2 kg) by using single (n = 7) or dual 2.7-cm loop microwave probes in parallel (n = 9) or orthogonal (n = 9) configurations. Volume, diameter, shape, and temperature of the zone of necrosis and the presence of viable tissue inside the loop were determined and compared by means of factorial analysis of variance. RESULTS: Mean lesion volume and maximum diameter, respectively, were 32.2 cm(3) +/- 14.4 (SD) and 4.6 cm +/- 1.4 for lesions ablated with parallel probes (parallel lesions), 29.5 cm(3) +/- 8.1 and 4.3 cm +/- 0.6 for lesions ablated with orthogonal probes (orthogonal lesions), and 6.4 cm(3) +/- 1.9 and 3.4 cm +/- 0.62 for lesions ablated with single probes (single lesions) (P <.05, single vs parallel and orthogonal lesions). Mean minimum diameter was greatest for orthogonal lesions (3.5 cm +/- 0.53; P =.017, parallel vs orthogonal lesions). Orthogonal lesions had the highest mean internal temperature (97.2 degrees C) versus parallel (91.9 degrees C) and single (60.0 degrees C) lesions. All orthogonal lesions heated to 60 degrees C in comparison to eight of nine parallel and four of seven single lesions. The mean time to reach 60 degrees C was shortest for orthogonal lesions (93.3 seconds) versus parallel (123.8 seconds) and single (263.0 seconds) lesions. Orthogonal lesions were the most spherical. Viable tissue was present in the center of five of seven single, six of nine parallel, and zero of nine orthogonal lesions. CONCLUSION: Loop microwave antennas allow precise control and effective ablation of targeted tissue, particularly in the orthogonal configuration.