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Obsessive-compulsive disorder (OCD) is a chronic and debilitating psychiatric condition, with diagnosed patients typically experiencing moderate or severe symptoms. This study evaluated the cost-of-illness (CoI) of OCD in the UK, capturing the annual costs accrued to the National Health Service (NHS) and Personal Social Services (PSS), people with OCD, caregivers and society. The UK OCD population was estimated and stratified by age group (children, adults, elderly), symptom severity (mild, moderate, severe) and treatment received (including no treatment). Costs for each subpopulation were estimated through a prevalence-based approach. Cost inputs were sourced from national databases, while additional inputs were informed by literature searches or expert clinician opinion. Scenario analyses explored other factors including comorbid depression treatment and presenteeism. The base-case analysis estimated a total annual CoI of £378,356,004 to the NHS, rising to £5,095,759,464 when a societal perspective was considered. The annual cost of care per person with OCD increased with severity (mild: £174; moderate: £365; severe: £902) due to increasing healthcare resource utilisation. The largest contributor to healthcare costs was cognitive behavioural therapy, while societal costs were driven by lost productivity through absenteeism. The base-case results likely underestimated the true economic burden of OCD; including comorbid depression led to a 132% increase in treatment costs, while presenteeism in people with OCD and lost productivity in caregivers amplified indirect costs. The economic burden of OCD in the UK is substantial and extends beyond direct treatment costs, highlighting a need for research into alternative treatments with greater efficacy. •Obsessive-compulsive disorder (OCD) carries a high clinical and humanistic burden.•The cost-of-illness of OCD to UK healthcare provider and to society was estimated.•Annual healthcare provider costs were estimated at £378m, driven by therapy costs.•Healthcare provider costs were considerably outweighed by societal costs (£4.7bn).•Societal costs were driven by absenteeism, personal expenses and private therapy.

Alkaptonuria is a rare inherited disorder for which there was no disease-modifying treatment. In order to develop a successful approved therapy of AKU multiple barriers had to be overcome. These included activities before the conduct of the study including deciding on the drug therapy, the dose of the drug to be used, clarify the nature of the disease, develop outcome measures likely to yield a positive outcome, have a strategy to ensure appropriate patient participation through identification, build a consortium of investigators, obtain regulatory approval for proposed investigation plan and secure funding. Significant barriers were overcome during the conduct of the multicentre study to ensure harmonisation. Mechanisms were put in place to recruit and retain patients in the study. Barriers to patient access following completion of the study and regulatory approval were resolved.

Dear editor, On April 1st 2012, NHS England Highly Specialised Services (HSS) commissioned the National Alkaptonuria Service for adults in the Department of Clinical Biochemistry & Metabolic Medicine at the Royal Liverpool University Hospital. 1 The service is called the Robert Gregory National Alkaptonuria Centre (NAC) in memory of the alkaptonuria (AKU) patient who founded the Alkaptonuria Society (AKUS) in 2003.The AKUS is embedded in the NAC and crucial to its functioning and success, ensuring patients are at the centre of the service. The NAC has generated new knowledge about AKU and its management (Table S1); with a few examples being prevalent cataract before and after nitisinone, nitisinone-associated vitiligo, characterising spine and joint disease and demonstrating lack of cognitive impairment during nitisinone therapy of adults with AKU. 8–11 The NAC permitted research collaboration between the NAC and the University of Liverpool, allowing cutting edge research into AKU to be pioneered and carried out with examples including development of conditional mouse models of AKU including liver and kidney knockouts in which new therapies are tested such as tyrosine-reducing therapies, as well as enzyme replacement therapies involving gene and mRNA administration. 12 A new mechanism of joint damage in AKU was developed and found to apply in osteoarthritis. 13 Unachieved goals and further challenges: [...]we have developed an assay system using the MitraTM sampling device, which offers a more user-friendly and robust alternative. 14 Preliminary feedback from patients has been positive and we are in the process of integrating this into the patient pathway.

Despite urgent warnings about the spread of multidrug-resistant bacteria, the antibiotic development pipeline has remained sparsely populated. Naturally occurring antibacterial compounds may provide novel chemical starting points for antibiotic development programs and should be actively sought out. Evaluation of homogentisic acid (HGA), an intermediate in the tyrosine degradation pathway, showed that the compound had innate activity against Gram-positive and Gram-negative bacteria, which was lost following conversion into the degradation product benzoquinone acetic acid (BQA). Anti-staphylococcal activity of HGA can be attributed to effects on bacterial membranes. Despite an absence of haemolytic activity, the compound was cytotoxic to human HepG2 cells. We conclude that the antibacterial activity and in vitro safety profile of HGA render it more suitable for use as a topical agent or for inclusion in a small-molecule medicinal chemistry program.

Background Obsessive–compulsive disorder (OCD) is a neuropsychiatric disorder which often proves refractory to current treatment approaches. Transcranial direct current stimulation (tDCS), a noninvasive form of neurostimulation, with potential for development as a self-administered intervention, has shown potential as a safe and efficacious treatment for OCD in a small number of trials. The two most promising stimulation sites are located above the orbitofrontal cortex (OFC) and the supplementary motor area (SMA). Methods The aim of this feasibility study is to inform the development of a definitive trial, focussing on the acceptability, safety of the intervention, feasibility of recruitment, adherence and tolerability to tDCS and study assessments and the size of the treatment effect. To this end, we will deliver a double-blind, sham-controlled, crossover randomised multicentre study in 25 adults with OCD. Each participant will receive three courses of tDCS (SMA, OFC and sham), randomly allocated and given in counterbalanced order. Each course comprises four 20-min stimulations, delivered over two consecutive days, separated by at least 4 weeks’ washout period. We will collect information about recruitment, study conduct and tDCS delivery. Blinded raters will assess clinical outcomes before, during and up to 4 weeks after stimulation using validated scales. We will include relevant objective neurocognitive tasks, testing cognitive flexibility, motor disinhibition, cooperation and habit learning. Discussion We will analyse the magnitude of the effect of the interventions on OCD symptoms alongside the standard deviation of the outcome measure, to estimate effect size and determine the optimal stimulation target. We will also measure the duration of the effect of stimulation, to provide information on spacing treatments efficiently. We will evaluate the usefulness and limitations of specific neurocognitive tests to determine a definitive test battery. Additionally, qualitative data will be collected from participants to better understand their experience of taking part in a tDCS intervention, as well as the impact on their overall quality of life. These clinical outcomes will enable the project team to further refine the methodology to ensure optimal efficiency in terms of both delivering and assessing the treatment in a full-scale trial. Trial registration ISRCTN17937049 . (date applied 08/07/2019). Recruitment (ongoing) began 23rd July 2019 and is anticipated to complete 30th April 2021.

Alkaptonuria is a rare inborn error of metabolism caused by the deficiency of homogentisate 1,2-dioxygenase activity. The consequent homogentisic acid (HGA) accumulation in body fluids and tissues leads to a multisystemic and highly debilitating disease whose main features are dark urine, ochronosis (HGA-derived pigment in collagen-rich connective tissues), and a painful and severe form of osteoarthropathy. Other clinical manifestations are extremely variable and include kidney and prostate stones, aortic stenosis, bone fractures, and tendon, ligament and/or muscle ruptures. As an autosomal recessive disorder, alkaptonuria affects men and women equally. Debilitating symptoms appear around the third decade of life, but a proper and timely diagnosis is often delayed due to their non-specific nature and a lack of knowledge among physicians. In later stages, patients’ quality of life might be seriously compromised and further complicated by comorbidities. Thus, appropriate management of alkaptonuria requires a multidisciplinary approach, and periodic clinical evaluation is advised to monitor disease progression, complications and/or comorbidities, and to enable prompt intervention. Treatment options are patient-tailored and include a combination of medications, physical therapy and surgery. Current basic and clinical research focuses on improving patient management and developing innovative therapies and implementing precision medicine strategies. Alkaptonuria is a rare metabolic disease that has multisystemic and debilitating effects. In this Primer, Bernardini et al. summarize current knowledge of epidemiology and mechanisms, and discuss diagnosis, management and quality of life of patients with this disorder. They also highlight outstanding research questions.

AimsObsessive Compulsive Disorder is a disabling and difficult-to-treat condition, new treatment options are needed to improve health outcomes. Transcranial Direct Current Stimulation, a non-invasive form of neurostimulation, has shown positive results in a small number of studies as a safe and potentially efficacious treatment for OCD. There nevertheless remains uncertainty about the optimal stimulation protocol, magnitude and duration of effect, acceptability, tolerability and practicality of applying tDCS clinical settings. As existing data are inadequate to support a full-scale trial, we will deliver a feasibility study to address key research questions and knowledge gaps to enable the design and the development of the most efficient, cost effective, definitive trial.MethodWe designed Feasibility And Acceptability Of Transcranial Stimulation In Obsessive Compulsive Symptoms (FEATSOCS), a double-blind, sham-controlled, cross-over randomised multicentre study in 25 adults with OCD. We will stimulate the two most promising cortical sites, the orbitofrontal cortex (OFC) and the supplementary motor area (SMA). Each participant will receive three courses of tDCS (SMA, OFC and sham), randomly allocated, given in counterbalanced order. Each course comprises four 20 minutes-stimulations, delivered over two consecutive days, separated by at least four weeks’ washout period. Blinded raters will regularly assess clinical outcomes before, during and up to four weeks after stimulation using validated scales. We will include relevant neurocognitive tasks, testing cognitive flexibility, motor disinhibition, cooperation and habit learning.ResultFEATSOCS trial is currently underway and recruiting. Owing to the impact of COVID-19, a recruitment extension has been granted. At the study end, we will analyse the feasibility outcomes, magnitude of the effect of the interventions on OCD symptoms alongside the standard deviation of the outcome measure to estimate effect size, and determine the optimal stimulation target. We will also measure the duration of the effect of stimulation, to provide information on spacing treatments efficiently. We will evaluate the usefulness and limitations of specific neurocognitive tests to determine a definitive test battery. Qualitative data will be collected from participants to better understand their experience of taking part in a tDCS intervention, the impact on their overall quality of life and their views on the potential of tDCS as home based-intervention.ConclusionFurther evidence is needed to establish whether tDCS could join the treatment armamentarium of OCD. The clinical outcomes in FEATSOCS will enable to further refine the methodology to ensure optimal efficiency in terms of both delivering and assessing the tDCS in OCD in a full scale trial.The funder for this study is the National Institute for Health Research Programme, Research for Patient Benefit (RfPB) [Ref. no PB-PG-1216-20005]. Extra funding to allow study extension was provided by Orchard OCD. This study has received full ethics committee approval and protocol amendments approval form the Cambridge and Hertfordshire NHS Research Ethics Committee, IRAS Project ID 254507, REC ref: 19/EE/0046.

Background Obsessive-compulsive disorder (OCD) is a neuropsychiatric disorder which often proves refractory to current treatment approaches. Transcranial direct current stimulation (tDCS), a noninvasive form of neurostimulation, with potential for development as a self-administered intervention, has shown potential as a safe and efficacious treatment for OCD in a small number of trials. The two most promising stimulation sites are located above the orbitofrontal cortex (OFC) and the supplementary motor area (SMA). Methods The aim of this feasibility study is to inform the development of a definitive trial, focussing on the acceptability, safety of the intervention, feasibility of recruitment, adherence and tolerability to tDCS and study assessments and the size of the treatment effect. To this end, we will deliver a double-blind, sham-controlled, crossover randomised multicentre study in 25 adults with OCD. Each participant will receive three courses of tDCS (SMA, OFC and sham), randomly allocated and given in counterbalanced order. Each course comprises four 20-min stimulations, delivered over two consecutive days, separated by at least 4 weeks' washout period. We will collect information about recruitment, study conduct and tDCS delivery. Blinded raters will assess clinical outcomes before, during and up to 4 weeks after stimulation using validated scales. We will include relevant objective neurocognitive tasks, testing cognitive flexibility, motor disinhibition, cooperation and habit learning. Discussion We will analyse the magnitude of the effect of the interventions on OCD symptoms alongside the standard deviation of the outcome measure, to estimate effect size and determine the optimal stimulation target. We will also measure the duration of the effect of stimulation, to provide information on spacing treatments efficiently. We will evaluate the usefulness and limitations of specific neurocognitive tests to determine a definitive test battery. Additionally, qualitative data will be collected from participants to better understand their experience of taking part in a tDCS intervention, as well as the impact on their overall quality of life. These clinical outcomes will enable the project team to further refine the methodology to ensure optimal efficiency in terms of both delivering and assessing the treatment in a full-scale trial. Trial registration ISRCTN17937049. (date applied 08/07/2019). Recruitment (ongoing) began 23rd July 2019 and is anticipated to complete 30th April 2021. Keywords: Obsessive-compulsive disorder (OCD), Transcranial direct current stimulation (tDCS), Noninvasive neurostimulation, Feasibility study, Randomised controlled trial