CLEAR - clozapine in early psychosis: study protocol for a multi-centre, randomised controlled trial of clozapine vs other antipsychotics for young people with treatment resistant schizophrenia in real world settings.

BACKGROUND: Clozapine is an antipsychotic drug with unique efficacy, and it is the only recommended treatment for treatment-resistant schizophrenia (TRS: failure to respond to at least two different antipsychotics). However, clozapine is also associated with a range of adverse effects which restrict its use, including blood dyscrasias, for which haematological monitoring is required. As treatment resistance is recognised earlier in the illness, the question of whether clozapine should be prescribed in children and young people is increasingly important. However, most research to date has been in older, chronic patients, and evidence regarding the efficacy and safety of clozapine in people under age 25 is lacking. The CLEAR (CLozapine in EARly psychosis) trial will assess whether clozapine is more effective than treatment as usual (TAU), at the level of clinical symptoms, patient rated outcomes, quality of life and cost-effectiveness in people below 25 years of age. Additionally, a nested biomarker study will investigate the mechanisms of action of clozapine compared to TAU. METHODS AND DESIGN: This is the protocol of a multi-centre, open label, blind-rated, randomised controlled effectiveness trial of clozapine vs TAU (any other oral antipsychotic monotherapy licenced in the British National Formulary) for 12 weeks in 260 children and young people with TRS (12-24 years old). AIM AND OBJECTIVES: The primary outcome is the change in blind-rated Positive and Negative Syndrome Scale scores at 12 weeks from baseline. Secondary outcomes include blind-rated Clinical Global Impression, patient-rated outcomes, quality of life, adverse effects, and treatment adherence. Patients will be followed up for 12 months and will be invited to give consent for longer term follow-up using clinical records and potential re-contact for further research. For mechanism of action, change in brain magnetic resonance imaging (MRI) biomarkers and peripheral inflammatory markers will be measured over 12 weeks. DISCUSSION: The CLEAR trial will contribute knowledge on clozapine effectiveness, safety and cost-effectiveness compared to standard antipsychotics in young people with TRS, and the results may guide future clinical treatment recommendation for early psychosis. TRIAL REGISTRATION: ISRCTN Number: 37176025, IRAS Number: 1004947. TRIAL STATUS: In set-up. Protocol version 4.0 01/08/23. Current up to date protocol available here: https://fundingawards.nihr.ac.uk/award/NIHR131175# /.

Detailed analysis of in-hospital transmission of SARS-CoV-2 using whole genome sequencing.

BACKGROUND: Hospital transmission of SARS-CoV-2 has proved difficult to control, with healthcare-associated infections troublesome throughout. AIM: To understand factors contributing to hospital transmission of infections, which is necessary for containing spread. METHODS: An outbreak of 56 staff and patient cases of COVID-19 over a 31-day period in a tertiary referral unit is presented, with at least a further 29 cases identified outside of the unit and the hospital by whole genome sequencing (WGS). FINDINGS: Transmission is documented from staff to staff, staff to patients, and patients to staff, showing disruption of a tertiary referral service, despite implementation of nationally recommended control measures, superior ventilation, and use of personal protective equipment. There was extensive spread from the index case, despite this patient spending only 10 h bed bound on the ward in strict cubicle isolation and with an initial single target low level (CT = 32) polymerase chain reaction test. CONCLUSION: This investigation highlights how effectively and rapidly SARS-CoV-2 can spread in certain circumstances. It raises questions about infection control measures in place at the time and calls into question the premise that transmissibility can be reliably detected by using lower sensitivity rapid antigen lateral flow tests. We also highlight the value of early intervention in reducing impact as well as the value of WGS in understanding outbreaks.

Genome-wide association analyses of symptom severity among clozapine-treated patients with schizophrenia spectrum disorders.

Clozapine is the most effective antipsychotic for patients with treatment-resistant schizophrenia. However, response is highly variable and possible genetic underpinnings of this variability remain unknown. Here, we performed polygenic risk score (PRS) analyses to estimate the amount of variance in symptom severity among clozapine-treated patients explained by PRSs (R2) and examined the association between symptom severity and genotype-predicted CYP1A2, CYP2D6, and CYP2C19 enzyme activity. Genome-wide association (GWA) analyses were performed to explore loci associated with symptom severity. A multicenter cohort of 804 patients (after quality control N = 684) with schizophrenia spectrum disorder treated with clozapine were cross-sectionally assessed using the Positive and Negative Syndrome Scale and/or the Clinical Global Impression-Severity (CGI-S) scale. GWA and PRS regression analyses were conducted. Genotype-predicted CYP1A2, CYP2D6, and CYP2C19 enzyme activities were calculated. Schizophrenia-PRS was most significantly and positively associated with low symptom severity (p = 1.03 × 10-3; R2 = 1.85). Cross-disorder-PRS was also positively associated with lower CGI-S score (p = 0.01; R2 = 0.81). Compared to the lowest tertile, patients in the highest schizophrenia-PRS tertile had 1.94 times (p = 6.84×10-4) increased probability of low symptom severity. Higher genotype-predicted CYP2C19 enzyme activity was independently associated with lower symptom severity (p = 8.44×10-3). While no locus surpassed the genome-wide significance threshold, rs1923778 within NFIB showed a suggestive association (p = 3.78×10-7) with symptom severity. We show that high schizophrenia-PRS and genotype-predicted CYP2C19 enzyme activity are independently associated with lower symptom severity among individuals treated with clozapine. Our findings open avenues for future pharmacogenomic projects investigating the potential of PRS and genotype-predicted CYP-activity in schizophrenia.

Containing a measles outbreak in Minnesota, 2017: methods and challenges.

AIMS: We report on a measles outbreak largely occurring in Minnesota's under-vaccinated Somali community in the spring of 2017. The outbreak was already into its third generation when the first two cases were confirmed, and rapid public health actions were needed. The aim of our response was to quickly end transmission and contain the outbreak. METHODS: The state public health department performed laboratory testing on suspect cases and activated an Incident Command staffed by subject matter experts that was operational within 2 h of case confirmation. Epidemiologic interviews identified exposures in settings where risk of transmission was high, that is, healthcare, childcare, and school settings. Vaccination status of exposed persons was assessed, and postexposure prophylaxis (PEP) was offered, if applicable. Exposed persons who did not receive PEP were excluded from childcare centers or schools for 21 days. An accelerated statewide measles, mumps, and rubella (MMR) recommendation was made for Somali Minnesota children and children in affected outbreak counties. Partnerships with the Somali Minnesota community were deepened, building off outreach work done with the community since 2008. RESULTS: Public health identified 75 measles cases from 30 March to 25 August 2017: 43% were female, 81% Somali Minnesotan, 91% unvaccinated, and 28% hospitalized. The median age of cases was 2 years (range: 3 months-57 years). Most transmission (78%) occurred in childcare centers and households. A secondary attack rate of 91% was calculated for unvaccinated household contacts. Over 51,000 doses of MMR were administered during the outbreak above expected baseline. At least 8490 individuals were exposed to measles; 155 individuals received PEP; and over 500 persons were excluded from childcare and school. State and key public health partners spent an estimated $2.3 million on response. CONCLUSION: This outbreak demonstrates the necessity of immediate, targeted disease control actions and strong public health, healthcare, and community partnerships to end a measles outbreak.

Reducing opioid use for chronic pain in older adults.

PURPOSE: Implementation of the SAFE PAIN algorithm for reducing opioid use for chronic pain in older adults is described. SUMMARY: A multidisciplinary team at Sheppard Pratt Health System, the largest private provider of psychiatric care in Maryland, used lean methodology to identify the root causes for noncompliance to evidence-based practices for patients in the geropsychiatry unit treated for osteoarthritis or chronic back pain. The team collaborated to develop a facility-specific treatment algorithm, called SAFE PAIN (Sheppard Pratt Health System Algorithm For Elderly Patient Centered Analgesia Interdisciplinary Nagara), was based on the Center for Disease Control and Prevention's evidence-based recommendations that included nonpharmacologic interventions as a first-line therapy for patients with osteoarthritis or chronic back pain. Rates of prescribing new opioids and prescribing evidence-based alternative medications via the SAFE PAIN algorithm were evaluated from March 1 to September 30, 2017 and compared with baseline (2012-2016). The lean methodology interventions led to zero new opioid orders during the study period, a significant decrease compared with previous years (p < 0.01). The rates of prescribing evidence-based alternative medications increased significantly from the baseline period to postimplementation (p < 0.01). Lean methodology interventions also decreased waste in several processes. CONCLUSION: The prescribing rate of new opioids for osteoarthritis and chronic back pain decreased and the prescribing rate for evidence-based medications increased after implementation of the SAFE PAIN algorithm in a geropsychiatry unit.

Insect genomes: progress and challenges.

In the wake of constant improvements in sequencing technologies, numerous insect genomes have been sequenced. Currently, 1219 insect genome-sequencing projects have been registered with the National Center for Biotechnology Information, including 401 that have genome assemblies and 155 with an official gene set of annotated protein-coding genes. Comparative genomics analysis showed that the expansion or contraction of gene families was associated with well-studied physiological traits such as immune system, metabolic detoxification, parasitism and polyphagy in insects. Here, we summarize the progress of insect genome sequencing, with an emphasis on how this impacts research on pest control. We begin with a brief introduction to the basic concepts of genome assembly, annotation and metrics for evaluating the quality of draft assemblies. We then provide an overview of genome information for numerous insect species, highlighting examples from prominent model organisms, agricultural pests and disease vectors. We also introduce the major insect genome databases. The increasing availability of insect genomic resources is beneficial for developing alternative pest control methods. However, many opportunities remain for developing data-mining tools that make maximal use of the available insect genome resources. Although rapid progress has been achieved, many challenges remain in the field of insect genomics.

The mechanical response of commercially available bone simulants for quasi-static and dynamic loading.

Bone is a complex hierarchal structured material with varying porosity and mechanical properties. In particular, human cranial bone is essentially a natural composite consisting of low porosity outer and inner tables and a cancellous interior, or diploë. Experimental studies of biomechanically accurate cranial bone analogues are of high importance for biomechanical, forensics, and clinical researchers, which could improve the understanding and prevention of traumatic injury. Many reported studies use commercially available bone surrogates to draw biomechanical and forensics conclusions; however, their mechanical properties are not tabulated over a range of strain rates. This study elucidates the mechanical viability of three leading commercially available bone surrogates, i.e. Synbone, Sawbone, and Bonesim, over a large range of strain rates (10-3 to 103 s-1). Quasi-static compression testing was conducted using a universal testing machine and a Split-Hopkinson Pressure bar system equipped with high-speed video was used to determine the dynamic mechanical behavior of these materials. Micro-computed X-ray tomography (XRT) were performed on each material to investigate their pore structures and distributions. All materials exhibited strain rate dependent strength behavior, particularly at high loading rates (≥103 s-1). The Young's modulus was found to increase with strain rate from 10-3 to 10-1 s-1 for transversely and longitudinally loaded surrogate materials except for Synbone and the higher density Bonesim. The higher density Bonesim was determined to be the most suitable cranial bone simulant tested based on a combination of transverse Young's Modulus (1500 MPa), yield strength (19 MPa), ultimate strength (49 MPa), and ultimate strain (17%). These materials show limited promise for applications where the measured elastic properties and strengths are of interest.

Genetic influences on eight psychiatric disorders based on family data of 4 408 646 full and half-siblings, and genetic data of 333 748 cases and controls.

BACKGROUND: Most studies underline the contribution of heritable factors for psychiatric disorders. However, heritability estimates depend on the population under study, diagnostic instruments, and study designs that each has its inherent assumptions, strengths, and biases. We aim to test the homogeneity in heritability estimates between two powerful, and state of the art study designs for eight psychiatric disorders. METHODS: We assessed heritability based on data of Swedish siblings (N = 4 408 646 full and maternal half-siblings), and based on summary data of eight samples with measured genotypes (N = 125 533 cases and 208 215 controls). All data were based on standard diagnostic criteria. Eight psychiatric disorders were studied: (1) alcohol dependence (AD), (2) anorexia nervosa, (3) attention deficit/hyperactivity disorder (ADHD), (4) autism spectrum disorder, (5) bipolar disorder, (6) major depressive disorder, (7) obsessive-compulsive disorder (OCD), and (8) schizophrenia. RESULTS: Heritability estimates from sibling data varied from 0.30 for Major Depression to 0.80 for ADHD. The estimates based on the measured genotypes were lower, ranging from 0.10 for AD to 0.28 for OCD, but were significant, and correlated positively (0.19) with national sibling-based estimates. When removing OCD from the data the correlation increased to 0.50. CONCLUSIONS: Given the unique character of each study design, the convergent findings for these eight psychiatric conditions suggest that heritability estimates are robust across different methods. The findings also highlight large differences in genetic and environmental influences between psychiatric disorders, providing future directions for etiological psychiatric research.

Guidelines for the investigation of chronic diarrhoea in adults: British Society of Gastroenterology, 3rd edition

Chronic diarrhoea is a common problem, hence clear guidance on investigations is required. This is an updated guideline from 2003 for the investigations of chronic diarrhoea commissioned by the Clinical Services and Standards Committee of the British Society of Gastroenterology (BSG). This document has undergone significant revision in content through input by 13 members of the Guideline Development Group (GDG) representing various institutions. The GRADE system was used to appraise the quality of evidence and grading of recommendations.

Genomic and Imaging Biomarkers in Schizophrenia.

Recent large-scale genomic studies have confirmed that schizophrenia is a polygenic syndrome and have implicated a number of biological pathways in its aetiology. Both common variants individually of small effect and rarer but more penetrant genetic variants have been shown to play a role in the pathogenesis of the disorder. No simple Mendelian forms of the condition have been identified, but progress has been made in stratifying risk on the basis of the polygenic burden of common variants individually of small effect, and the contribution of rarer variants of larger effect such as Copy Number Variants (CNVs). Pathway analysis of risk-associated variants has begun to identify specific biological processes implicated in risk for the disorder, including elements of the glutamatergic NMDA receptor complex and post synaptic density, voltage-gated calcium channels, targets of the Fragile X Mental Retardation Protein (FMRP targets) and immune pathways. Genetic studies have also been used to drive genomic imaging approaches to the investigation of brain markers associated with risk for the disorder. Genomic imaging approaches have been applied both to investigate the effect of polygenic risk and to study the impact of individual higher-penetrance variants such as CNVs. Both genomic and genomic imaging approaches offer potential for the stratification of patients and at-risk groups and the development of better biomarkers of risk and treatment response; however, further research is needed to integrate this work and realise the full potential of these approaches.

Genome-wide common and rare variant analysis provides novel insights into clozapine-associated neutropenia.

This corrects the article DOI: 10.1038/mp.2016.97.

Lean Methodology Reduces Inappropriate Use of Antipsychotics for Agitation at a Psychiatric Hospital.

OBJECTIVE: To Evaluate the Effects of Applying Lean Methodology-Improving Quality Increasing Efficiency by Eliminating Waste and Reducing Costs-An Approach To Decrease the Prescribing Frequency of Antipsychotics for The Indication of Agitation. DESIGN: Historically Controlled Study. SETTING: Bheppard Pratt Health System is the Largest Private Provider of Psychiatric Care in Maryland With a Total Bed Capacity of 300. There Were 4 337 Patient Days From November 1 2012 to October 31 2013 on the Dementia Unit. PATIENTS: All Patients Admitted on the Dementia Unit Were 65 Years of Age and Older with a Primary Diagnosis of Dementia. INTERVENTION: our Multidisciplinary Team Used Lean Methodology to Identify the Root Causes and Interventions Necessary to Reduce Inappropriate Antipsychotic Use. MAIN OUTCOME MEASURES: The Primary Outcome Was Rate of Inappropriately Indicating Agitation as the Rationale When Prescribing Antipsychotic Medications. RESULTS: There Was a 90% (P < 0.001) Reduction in Rate Of Antipsychotic Prescribing with an Indication of Agitation. CONCLUSION: The Lean Methodology Interventions Led To A 90% (P < 0.001) Reduction in the Rate of Antipsychotic Prescribing with an Indication of Agitation and a 10% Rate Reduction in Overall Antipsychotic Prescribing. Key Words: Agitation Alzheimer's Antipsychotics Behavioral and Psychological Symptoms of Dementia Centers For Medicare & Medicaid Services Dementia Root-cause Analysis. ABBREVIATIONS: BPSD = Behavioral and Psychological Symptoms of Dementia CATIE-AD = Clinical Antipsychotic Trials of Intervention Effectiveness in Alzheimer's Disease EMR = Electronic Medical Records GAO = Government Accountability Office GNCIS = Geriatric Neuropsychiatric Clinical Indicator Scale.

Genome-wide common and rare variant analysis provides novel insights into clozapine-associated neutropenia.

The antipsychotic clozapine is uniquely effective in the management of schizophrenia; however, its use is limited by its potential to induce agranulocytosis. The causes of this, and of its precursor neutropenia, are largely unknown, although genetic factors have an important role. We sought risk alleles for clozapine-associated neutropenia in a sample of 66 cases and 5583 clozapine-treated controls, through a genome-wide association study (GWAS), imputed human leukocyte antigen (HLA) alleles, exome array and copy-number variation (CNV) analyses. We then combined associated variants in a meta-analysis with data from the Clozapine-Induced Agranulocytosis Consortium (up to 163 cases and 7970 controls). In the largest combined sample to date, we identified a novel association with rs149104283 (odds ratio (OR)=4.32, P=1.79 × 10-8), intronic to transcripts of SLCO1B3 and SLCO1B7, members of a family of hepatic transporter genes previously implicated in adverse drug reactions including simvastatin-induced myopathy and docetaxel-induced neutropenia. Exome array analysis identified gene-wide associations of uncommon non-synonymous variants within UBAP2 and STARD9. We additionally provide independent replication of a previously identified variant in HLA-DQB1 (OR=15.6, P=0.015, positive predictive value=35.1%). These results implicate biological pathways through which clozapine may act to cause this serious adverse effect.

Challenges in Interpretation of Diagnostic Test Results in a Mumps Outbreak in a Highly Vaccinated Population.

In spite of a greatly reduced incidence rate due to vaccination, mumps outbreaks continue to occur in several areas of the world, sometimes in vaccinated populations. This article describes an outbreak in a highly vaccinated population in southwestern Ontario, Canada, and the challenges encountered in interpreting the results of diagnostic tests used in the outbreak. During the outbreak, patients were interviewed and classified according to the outbreak case definition, and specimens were collected for diagnostic testing according to Ontario guidelines. Twenty-seven individuals were classified as confirmed cases (n = 19) or suspect cases (n = 8) according to the case definition, only 9 of which were laboratory-confirmed cases: 7 confirmed by reverse transcriptase PCR (RT-PCR) and 2 by IgM serology. All 19 confirmed cases represented patients who were associated with secondary schools in the local area and had been vaccinated against mumps with one (n = 2) or two (n = 17) doses of the measles-mumps-rubella (MMR) vaccine. This is the first published report of an outbreak of mumps in Ontario in which all confirmed cases had been vaccinated against the disease. It highlights the limitations of and difficulties in interpreting current mumps diagnostic tests when used in vaccinated individuals.

Public Health Follow-up of Suspected Exposure to Echinococcus multilocularis in Southwestern Ontario.

In the 3 years since the first report of canine alveolar echinococcosis (AE) in Ontario, three additional cases have been diagnosed in the province. Of the four cases reported to date, three have had no known history of travel outside the province. It is possible that this development is an indication of previously unrecognized environmental contamination with Echinococcus multilocularis eggs in some areas of the province. If so, there is the potential for an emerging threat to human health. This article describes a local public health department's investigation of the possible exposure to E. multilocularis of a number of individuals who had had contact with the latest of the four cases of canine AE, and summarizes a comprehensive decision process that can be used by public health departments to assist in the follow-up of such exposures.