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RATIONALE: Psychedelic research continues to garner significant public and scientific interest with a growing number of clinical studies examining a wide range of conditions and disorders. However, expectancy effects and effective condition masking have been raised as critical limitations to the interpretability of the research. OBJECTIVE: In this article, we review the many methodological challenges of conducting psychedelic clinical trials and provide recommendations for improving the rigor of future research. RESULTS: Although some challenges are shared with psychotherapy and pharmacology trials more broadly, psychedelic clinical trials have to contend with several unique sources of potential bias. The subjective effects of a high-dose psychedelic are often so pronounced that it is difficult to mask participants to their treatment condition; the significant hype from positive media coverage on the clinical potential of psychedelics influences participants’ expectations for treatment benefit; and participant unmasking and treatment expectations can interact in such a way that makes psychedelic therapy highly susceptible to large placebo and nocebo effects. Specific recommendations to increase the success of masking procedures and reduce the influence of participant expectancies are discussed in the context of study development, participant recruitment and selection, incomplete disclosure of the study design, choice of active placebo condition, as well as the measurement of participant expectations and masking efficacy. CONCLUSION: Incorporating the recommended design elements is intended to reduce the risk of bias in psychedelic clinical trials and thereby increases the ability to discern treatment-specific effects of psychedelic therapy.

Posttraumatic stress disorder (PTSD) is a debilitating, chronic disorder and efficacy rates of current PTSD treatments are underwhelming. There is a critical need for innovative approaches. We provide an overview of trauma and PTSD and cite literature providing converging evidence of the therapeutic potential of psilocybin for PTSD. No study to date has investigated psilocybin or psilocybin-assisted psychotherapy (PAP) as treatments for PTSD. An open-label study in traumatized AIDS survivors found that PAP reduced PTSD symptoms, attachment anxiety, and demoralization. Several PAP trials show preliminary efficacy in facilitating confronting traumatic memories, decreasing emotional avoidance, depression, anxiety, pessimism, and disconnection from others, and increasing acceptance, self-compassion, and forgiveness of abusers, all of which are relevant to PTSD recovery. There is also early evidence that other classic psychedelics may produce large reductions in PTSD symptoms in combat veterans. However, this body of literature is small, mechanisms are not yet well understood, and the risks of using psychedelic compounds for trauma-related disorders need further study. In sum, evidence supports further investigation of PAP as a radically new approach for treating PTSD.

Introduction Emotional disorders (such as anxiety and depression) are associated with considerable distress and impairment in day-to-day function for affected children and young people and for their families. Effective evidence-based interventions are available but require appropriate identification of difficulties to enable timely access to services. Standardised diagnostic assessment (SDA) tools may aid in the detection of emotional disorders, but there is limited evidence on the utility of SDA tools in routine care and equipoise among professionals about their clinical value. Methods and analysis A multicentre, two-arm, parallel group randomised controlled trial, with embedded qualitative and health economic components. Participants will be randomised in a 1:1 ratio to either the Development and Well-Being Assessment SDA tool as an adjunct to usual clinical care, or usual care only. A total of 1210 participants (children and young people referred to outpatient, specialist Child and Adolescent Mental Health Services with emotional difficulties and their parent/carers) will be recruited from at least 6 sites in England. The primary outcome is a clinician-made diagnosis about the presence of an emotional disorder within 12 months of randomisation. Secondary outcomes include referral acceptance, diagnosis and treatment of emotional disorders, symptoms of emotional difficulties and comorbid disorders and associated functional impairment. Ethics and dissemination The study received favourable opinion from the South Birmingham Research Ethics Committee (Ref. 19/WM/0133). Results of this trial will be reported to the funder and published in full in the Health Technology Assessment (HTA) Journal series and also submitted for publication in a peer reviewed journal. Trial registration number NCT15748675; Pre-results.

Objective: To examine the cost-effectiveness of self-managed computerised word finding therapy as an add-on to usual care for people with aphasia post-stroke. Design: Cost-effectiveness modelling over a life-time period, taking a UK National Health Service (NHS) and personal social service perspective. Setting: Based on the Big CACTUS randomised controlled trial, conducted in 21 UK NHS speech and language therapy departments. Participants: Big CACTUS included 278 people with long-standing aphasia post-stroke. Interventions: Computerised word finding therapy plus usual care; usual care alone; usual care plus attention control. Main measures: Incremental cost-effectiveness ratios (ICER) were calculated, comparing the cost per quality adjusted life year (QALY) gained for each intervention. Credible intervals (CrI) for costs and QALYs, and probabilities of cost-effectiveness, were obtained using probabilistic sensitivity analysis. Subgroup and scenario analyses investigated cost-effectiveness in different subsets of the population, and the sensitivity of results to key model inputs. Results: Adding computerised word finding therapy to usual care had an ICER of £42,686 per QALY gained compared with usual care alone (incremental QALY gain: 0.02 per patient (95% CrI: −0.05 to 0.10); incremental costs: £732.73 per patient (95% CrI: £674.23 to £798.05)). ICERs for subgroups with mild or moderate word finding difficulties were £22,371 and £21,262 per QALY gained respectively. Conclusion: Computerised word finding therapy represents a low cost add-on to usual care, but QALY gains and estimates of cost-effectiveness are uncertain. Computerised therapy is more likely to be cost-effective for people with mild or moderate, as opposed to severe, word finding difficulties.

Background Reducing low birthweight (LBW, weight at birth less than 2,500g) prevalence by at least 30% between 2012 and 2025 is a target endorsed by the World Health Assembly that can contribute to achieving Sustainable Development Goal 2 (Zero Hunger) by 2030. The 2019 LBW estimates indicated a global prevalence of 14.6% (20.5 million newborns) in 2015. We aim to develop updated LBW estimates at global, regional, and national levels for up to 202 countries for the period of 2000 to 2020. Methods Two types of sources for LBW data will be sought: national administrative data and population-based surveys. Administrative data will be searched for countries with a facility birth rate ≥80% and included when birthweight data account for ≥80% of UN estimated live births for that country and year. Surveys with birthweight data published since release of the 2019 edition of the LBW estimates will be adjusted using the standard methodology applied for the previous estimates. Risk of bias assessments will be undertaken. Covariates will be selected based on a conceptual framework of plausible associations with LBW, covariate time-series data quality, collinearity between covariates and correlations with LBW. National LBW prevalence will be estimated using a Bayesian multilevel-mixed regression model, then aggregated to derive regional and global estimates through population-weighted averages. Conclusion Whilst availability of LBW data has increased, especially with more facility births, gaps remain in the quantity and quality of data, particularly in low-and middle-income countries. Challenges include high percentages of missing data, lack of adherence to reporting standards, inaccurate measurement, and data heaping. Updated LBW estimates are important to highlight the global burden of LBW, track progress towards nutrition targets, and inform investments in programmes. Reliable, nationally representative data are key, alongside investments to improve the measurement and recording of an accurate birthweight for every baby.

Background People with aphasia may improve their communication with speech and language therapy many months/years after stroke. However, NHS speech and language therapy reduces in availability over time post stroke. Objective This trial evaluated the clinical effectiveness and cost-effectiveness of self-managed computerised speech and language therapy to provide additional therapy. Design A pragmatic, superiority, single-blind, parallel-group, individually randomised (stratified block randomisation, stratified by word-finding severity and site) adjunct trial. Setting Twenty-one UK NHS speech and language therapy departments. Participants People with post-stroke aphasia (diagnosed by a speech and language therapist) with long-standing (> 4 months) word-finding difficulties. Interventions The groups were (1) usual care; (2) daily self-managed computerised word-finding therapy tailored by speech and language therapists and supported by volunteers/speech and language therapy assistants for 6 months plus usual care (computerised speech and language therapy); and (3) activity/attention control (completion of puzzles and receipt of telephone calls from a researcher for 6 months) plus usual care. Main outcome measures Co-primary outcomes – change in ability to find treated words of personal relevance in a bespoke naming test (impairment) and change in functional communication in conversation rated on the activity scale of the Therapy Outcome Measures (activity) 6 months after randomisation. A key secondary outcome was participant-rated perception of communication and quality of life using the Communication Outcomes After Stroke questionnaire at 6 months. Outcomes were assessed by speech and language therapists using standardised procedures. Cost-effectiveness was estimated using treatment costs and an accessible EuroQol-5 Dimensions, five-level version, measuring quality-adjusted life-years. Results A total of 818 patients were assessed for eligibility and 278 participants were randomised between October 2014 and August 2016. A total of 240 participants (86 usual care, 83 computerised speech and language therapy, 71 attention control) contributed to modified intention-to-treat analysis at 6 months. The mean improvements in word-finding were 1.1% (standard deviation 11.2%) for usual care, 16.4% (standard deviation 15.3%) for computerised speech and language therapy and 2.4% (standard deviation 8.8%) for attention control. Computerised speech and language therapy improved word-finding 16.2% more than usual care did (95% confidence interval 12.7% to 19.6%; p n = 219); the mean differences in change in word-finding score were 12.7% (95% confidence interval 8.7% to 16.7%) higher in the computerised speech and language therapy group (n = 74) than in the usual-care group (n = 84) and 9.3% (95% confidence interval 4.8% to 13.7%) higher in the computerised speech and language therapy group than in the attention control group (n = 61). Computerised speech and language therapy did not show significant improvements on the Therapy Outcome Measures or Communication Outcomes After Stroke scale compared with usual care or attention control. Primary cost-effectiveness analysis estimated an incremental cost per participant of £732.73 (95% credible interval £674.23 to £798.05). The incremental quality-adjusted life-year gain was 0.017 for computerised speech and language therapy compared with usual care, but its direction was uncertain (95% credible interval –0.05 to 0.10), resulting in an incremental cost-effectiveness ratio of £42,686 per quality-adjusted life-year gained. For mild and moderate word-finding difficulty subgroups, incremental cost-effectiveness ratios were £22,371 and £28,898 per quality-adjusted life-year gained, respectively, for computerised speech and language therapy compared with usual care. Limitations This trial excluded non-English-language speakers, the accessible EuroQol-5 Dimensions, five-level version, was not validated and the measurement of attention control fidelity was limited. Conclusions Computerised speech and language therapy enabled additional self-managed speech and language therapy, contributing to significant improvement in finding personally relevant words (as specifically targeted by computerised speech and language therapy) long term post stroke. Gains did not lead to improvements in conversation or quality of life. Cost-effectiveness is uncertain owing to uncertainty around the quality-adjusted life-year gain, but computerised speech and language therapy may be more cost-effective for participants with mild and moderate word-finding difficulties. Exploring ways of helping people with aphasia to use new words in functional communication contexts is a priority. Trial registration Current Controlled Trials ISRCTN68798818. 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. 19. See the NIHR Journals Library website for further project information. The Tavistock Trust for Aphasia provided additional support to enable people in the control groups to experience the intervention after the trial had ended.

Summary Background Post-stroke aphasia might improve over many years with speech and language therapy; however speech and language therapy is often less readily available beyond a few months after stroke. We assessed self-managed computerised speech and language therapy (CSLT) as a means of providing more therapy than patients can access through usual care alone. Methods In this pragmatic, superiority, three-arm, individually randomised, single-blind, parallel group trial, patients were recruited from 21 speech and language therapy departments in the UK. Participants were aged 18 years or older and had been diagnosed with aphasia post-stroke at least 4 months before randomisation; they were excluded if they had another premorbid speech and language disorder caused by a neurological deficit other than stroke, required treatment in a language other than English, or if they were currently using computer-based word-finding speech therapy. Participants were randomly assigned (1:1:1) to either 6 months of usual care (usual care group), daily self-managed CSLT plus usual care (CSLT group), or attention control plus usual care (attention control group) with the use of computer-generated stratified blocked randomisation (randomly ordered blocks of sizes three and six, stratified by site and severity of word finding at baseline based on CAT Naming Objects test scores). Only the outcome assessors and trial statistician were masked to the treatment allocation. The speech and language therapists who were doing the outcome assessments were different from those informing participants about which group they were assigned to and from those delivering all interventions. The statistician responsible for generating the randomisation schedule was separate from those doing the analysis. Co-primary outcomes were the change in ability to retrieve personally relevant words in a picture naming test (with 10% mean difference in change considered a priori as clinically meaningful) and the change in functional communication ability measured by masked ratings of video-recorded conversations, with the use of Therapy Outcome Measures (TOMs), between baseline and 6 months after randomisation (with a standardised mean difference in change of 0·45 considered a priori as clinically meaningful). Primary analysis was based on the modified intention-to-treat (mITT) population, which included randomly assigned patients who gave informed consent and excluded those without 6-month outcome measures. Safety analysis included all participants. This trial has been completed and was registered with the ISRCTN, number ISRCTN68798818. Findings From Oct 20, 2014, to Aug 18, 2016, 818 patients were assessed for eligibility, of which 278 (34%) participants were randomly assigned (101 [36%] to the usual care group; 97 [35%] to the CSLT group; 80 [29%] to the attention control group). 86 patients in the usual care group, 83 in the CSLT group, and 71 in the attention control group contributed to the mITT. Mean word finding improvements were 1·1% (SD 11·2) in the usual care group, 16·4% (15·3) in the CSLT group, and 2·4% (8·8) in the attention control group. Word finding improvement was 16·2% (95% CI 12·7 to 19·6; p

One element of gametophytic apomixis is unreduced embryo sac (ES) formation, which often occurs precociously displacing or replacing meiosis and causing apospory or diplospory, respectively. This study evaluated a premise that apomixis may evolve in hybridogenous plants that contain duplicate sets of allelically divergent ovule development heterochrony genes. The duplicate sets of genes would belong to duplicate genomic regions that are recombinationally isolated from each other (no gene flow) by allopolyploidy or paleopolyploidy, and this isolation would genetically stabilize apomixis. For apomixis to evolve, the ancestral donors of the duplicate regions must have differed from each other in timing of megasporogenesis, ES formation and embryony such that epigenetic misexpressions, or competitions in expression, of the duplicate heterochrony genes in hybridogenous derivatives would cause apomixis. Herein, we report substantial heterochrony in onset timing of germline stages among several sexual diploid Tripsacum genotypes, which may have been progenitors of apomictic polyploid Tripsacum. Tripsacum floridanum and Tripsacum zopilotense genotypes entered meiosis early. The former advanced rapidly through ES formation, but the latter entered a lengthy lag phase prior to ES formation. In two Tripsacum dactyloides var. dactyloides genotypes, meiosis occurred late and was followed by a distinct lag phase prior to ES formation. Likewise, the T. dactyloides var. meridonale genotype entered meiosis late, but the lag phase was brief. These differences appear to reflect allelic diversity at loci responsible for onset timing of different germline development stages within and across species and possibly across the recombinationally isolated duplicate chromosome regions in the Tripsacum paleopolyploid haplome (x = 18). Unique combinations of divergent alleles in hybridogenous plants coupled with polyploidy induced gene misexpressions may be required for apomixis to evolve.

Objective: The objective was to develop effective weight-loss methods for women who have had breast cancer, because obesity may result in an adverse prognosis. Research Methods and Procedures: This randomized pilot study tested an individualized approach toward weight loss in obese women who have had a diagnosis of breast cancer. An individualized approach was applied either alone or combined with the commercial Weight Watchers program. Forty-eight women (body mass index of 30 to 44 kg/m2) were enrolled. Results: Weight change after 12 months of intervention was as follows (mean ± SD): 0.85 ± 6.0 kg in the control group, −2.6 ± 5.9 kg in the Weight Watchers group, −8.0 ± 5.5 kg in the individualized group, and −9.4 ± 8.6 kg in the comprehensive group that used both individualized counseling and Weight Watchers. Weight loss relative to control was statistically significant in the comprehensive group 3, 6, and 12 months after randomization, whereas weight loss in the individualized group was significant only at 12 months. Weight loss of 10% or more of initial body weight was observed in 6 of 10 women in the comprehensive group at 12 months. In the comprehensive and Weight Watchers–only groups, weight loss was significantly related to frequency of attendance at Weight Watchers meetings, and attendance was more frequent in the comprehensive group. Discussion: These data indicate that the most weight loss was achieved when the counseling approach combined both Weight Watchers and individualized contacts. This was effective even though most of the individualized contacts were by telephone.

The purpose of this paper is to describe bulletin features found most and least appealing to a sample of highly literate, middle class adults for the print series, HG232:17, "Dietary Guidelines and Your Health" (1). Use of print materials is the most common means of conveying nutrition information to the public (2, 3). Many professionals (e.g., 3, 4) have urged nutrition educators to focus research on strategies that will increase the effectiveness of print materials. In an age of resource constraints and fiscal responsibility, such evaluation could facilitate the learning process and increase the efficiency of educator resources and efforts. The appearance of printed materials is thought to be a crucial factor in determining whether people read or dispose of them (3). Gillespie's (5) communication model also indicates that individual predispositions (e.g., nutrition knowledge, attitudes, and gender) will interact with an incoming message to affect the attention, comprehension and acceptance given to that message. Within the nutrition literature, the positive value of typographical cueing, e.g., use of underlining, arrows, and boldfaced print (6, 7), color coding (8, 9), color illustration (9-11), and personal relevance to the reader (3) has been reported. Shepherd et al. (9) performed the most comprehensive evaluation to date of print design features in nutrition education materials. They emphasized the importance to household food managers of clear, bright colors and the use of "how to" information, tips, selfassessment quizzes and lists of foods to avoid. Taken together, these studies, though limited in scope, provide evidence that print design features may have an effect on audience attention and message acceptance. None of the above studies compared the response of

Bacterially contaminated skin used as a biological dressing on burn wounds can cause serious or even lethal infections, three examples of which are cited. Cadaver-skin allografts were frequently found to contain pathogenic bacteria. The frequency of infections due to the use of contaminated skin grafts on open wounds is unknown. ( JAMA 235:1248-1249, 1976)