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Aims: To investigate the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of BPL-003, a novel intranasal benzoate salt formulation of 5-methoxy- N,N -dimethyltryptamine (5-MeO-DMT), in healthy participants. Methods: In all, 44 psychedelic-naïve participants enrolled in the double-blind, placebo-controlled single ascending dose study (1–12 mg BPL-003). Concentrations of 5-MeO-DMT and its pharmacologically active metabolite, bufotenine, were determined in plasma and urine. PD endpoints included subjective drug intensity (SDI) rating, the Mystical Experience Questionnaire (MEQ-30) and the Ego Dissolution Inventory (EDI). Results: BPL-003 was well tolerated at doses up to 12 mg. There were no serious adverse events (AEs), and most AEs were mild; the most common being nasal discomfort, nausea, headache and vomiting. 5-MeO-DMT was rapidly absorbed and eliminated; the median time to peak plasma concentration was approximately 8–10 min and the mean terminal elimination half-life was <27 min. 5-MeO-DMT systemic exposure increased approximately dose-proportionally, while plasma bufotenine concentrations and urinary excretion of 5-MeO-DMT and bufotenine were negligible. The intensity of the SDI ratings was associated with plasma 5-MeO-DMT concentrations. MEQ-30 and EDI scores generally increased with the BPL-003 dose; 60% of participants had a 'complete mystical experience' at 10 and 12 mg doses. Profound and highly emotional consciousness-altering effects were observed with BPL-003, with a rapid onset and short-lasting duration. Conclusion: The novel intranasal formulation of BPL-003 was well tolerated with dose-proportional increases in PK and PD effects. The short duration of action and induction of mystical experiences suggest clinical potential, warranting further trials. Clinical trial registration: NCT05347849. [ABSTRACT FROM AUTHOR]

Adaptive rejection sampling requires that users provide points that span the distribution’s mode. If these points are far from the mode, it significantly increases computational costs. This paper introduces a simple, automated approach for selecting initial points that uses numerical optimization to quickly bracket the mode. When an initial point is given that resides in a high-density area, the method often requires just four function evaluations to draw a sample—just one more than the sampler’s minimum. This feature makes it well-suited for Gibbs sampling, where the previous round’s draw can serve as the starting point. [ABSTRACT FROM AUTHOR]

On March 7, 1962 the Royal College of Physicians published a report entitled Smoking and Health that made the causal link between smoking and lung cancer clear and explicit. Using a historical data set that contains information on smoking from 1958 to 1965, I find a decrease in smoking for those with more schooling after the report's publication. I do not find a difference in the effect for those with greater access to information (measured by TV ownership or newspaper readership). This suggests the education health gradient is more likely due to processing of information rather than access to information. [ABSTRACT FROM AUTHOR]

Objectives: Digital breast tomosynthesis (DBT) can improve diagnostic accuracy compared to 2D mammography, but DBT reporting is time-consuming and potentially more fatiguing. Changes in diagnostic accuracy and subjective and objective fatigue were evaluated over a DBT reporting session, and the impact of taking a reporting break was assessed. Materials and methods: Forty-five National Health Service (NHS) mammography readers from 6 hospitals read a cancer-enriched set of 40 DBT cases whilst eye tracked in this prospective cohort study, from December 2020 to April 2022. Eye-blink metrics were assessed as objective fatigue measures. Twenty-one readers had a reporting break, 24 did not. Subjective fatigue questionnaires were completed before and after the session. Diagnostic accuracy and subjective and objective fatigue measures were compared between the cohorts using parametric and non-parametric significance testing. Results: Readers had on average 10 years post-training breast screening experience and took just under 2 h (105.8 min) to report all cases. Readers without a break reported greater levels of subjective fatigue (44% vs. 33%, p = 0.04), which related to greater objective fatigue: an increased average blink duration (296 ms vs. 286 ms, p < 0.001) and a reduced eye-opening velocity (76 mm/s vs. 82 mm/s, p < 0.001). Objective fatigue increased as the trial progressed for the no break cohort only (ps < 0.001). No difference was identified in diagnostic accuracy between the groups (accuracy: 87% vs. 87%, p = 0.92). Conclusions: Implementing a break during a 2-h DBT reporting session resulted in lower levels of subjective and objective fatigue. Breaks did not impact diagnostic accuracy, which may be related to the extensive experience of the readers. Clinical relevance statement: DBT is being incorporated into many mammography screening programmes. Recognising that reporting breaks are required when reading large volumes of DBT studies ensures this can be factored in when setting up reading sessions. Trial registration: Clinical trials registration number: NCT03733106 Key Points: • Use of digital breast tomosynthesis (DBT) in breast screening programmes can cause significant reader fatigue. • The effectiveness of incorporating reading breaks into DBT reporting sessions, to reduce mammography reader fatigue, was investigated using eye tracking. • Integrating breaks into DBT reporting sessions reduced reader fatigue; however, diagnostic accuracy was unaffected. [ABSTRACT FROM AUTHOR]

This paper describes a simple and interesting application of structural equation modeling for a single lecture in an undergraduate econometrics course to introduce students to the concept of using data to recover latent variables. The application centers around using hourly observations on ride wait times at Disney's Magic Kingdom to infer how crowded it is at the theme park. Pedagogically, the material is presented in the context of the linear regression model, so the discussion works to enhance students' understanding of core material, not to introduce new disparate methods. The application provides interesting economic-based insights, like which ride's wait times are categorically most informative about how crowded it is at the park. [ABSTRACT FROM AUTHOR]

Aims: The method of diagnosis of ductal carcinoma in situ (DCIS) has changed since the 1980s. The aim of this audit was to assess changes in the preoperative diagnosis of DCIS since the introduction of needle core biopsy, particularly the proportion with a preoperative biopsy diagnosis of DCIS. Methods and results: The preoperative diagnoses of patients with a final diagnosis of DCIS in the surgical specimen were reviewed (i) in 809 patients who presented through breast screening from 1997 to 2021, and (ii) in all patients in 5 individual years at 5‐year intervals from 2000 to 2020 (254 in total). For screening‐detected DCIS the proportion with a preoperative diagnosis of DCIS increased from 75% to 98% over the study period. In a detailed analysis of all cases of DCIS in 5 separate years the proportion with a preoperative diagnosis of DCIS increased from 68% in 2000 to 96% in 2020. For high‐grade DCIS the proportion increased from 87% to 97%, and for low‐ or intermediate‐grade DCIS from 48% to 93%. The proportion of women who had vacuum‐assisted biopsy increased from 7% in 2000 to 58% in 2015. There was a small increase in the number of biopsies that had basal cytokeratin and oestrogen receptor immunohistochemistry to aid diagnosis. Conclusion: There has been an increase in the preoperative diagnosis of DCIS, particularly of low‐ or intermediate‐grade, over the last two decades. The increasing use of vacuum‐assisted biopsy is likely to be a major contributory factor to this increase. [ABSTRACT FROM AUTHOR]

This paper examines the impact of daylight saving time (DST) on fatal road crashes in Australia. I exploit within year transitions to and from DST in a regression discontinuity in time framework. To examine the long run effect of the policy, I use trials of DST implemented in various states, and a DST extension due to the Sydney Olympics. Neither the transition to or out of DST, nor the long run effects of DST have an impact on fatalities on the road. However, there is evidence of reallocation of accidents over the day due to ambient light. [ABSTRACT FROM AUTHOR]

Simple Summary: Current AI algorithms show breast cancer detection rates that are comparable to human readers, but it is not clear whether AI and humans detect cancers with similar characteristics. As these factors will influence survival, we aimed to compare the invasiveness status, histological grade, lymph node stage, and tumour size of cancers. Women diagnosed with breast cancer between 2009 and 2019 from three UK double-reading sites were included in this retrospective cohort evaluation. From 1718 screen-detected cancers (SDCs) and 293 interval cancers (ICs), AI indicated 85.9% and 31.7%, respectively, as suspicious. The first human reader detected 90.8% of SDCs and 7.2% of ICs. There were no differences in the detected proportion for any of the investigated prognostic factors. The AI algorithm detected more ICs. These findings imply that using AI has limited or no downstream effects on screening programmes, supporting its potential role in the double-reading workflow. Invasiveness status, histological grade, lymph node stage, and tumour size are important prognostic factors for breast cancer survival. This evaluation aims to compare these features for cancers detected by AI and human readers using digital mammography. Women diagnosed with breast cancer between 2009 and 2019 from three UK double-reading sites were included in this retrospective cohort evaluation. Differences in prognostic features of cancers detected by AI and the first human reader (R1) were assessed using chi-square tests, with significance at p < 0.05. From 1718 screen-detected cancers (SDCs) and 293 interval cancers (ICs), AI flagged 85.9% and 31.7%, respectively. R1 detected 90.8% of SDCs and 7.2% of ICs. Of the screen-detected cancers detected by the AI, 82.5% had an invasive component, compared to 81.1% for R1 (p-0.374). For the ICs, this was 91.5% and 93.8% for AI and R1, respectively (p = 0.829). For the invasive tumours, no differences were found for histological grade, tumour size, or lymph node stage. The AI detected more ICs. In summary, no differences in prognostic factors were found comparing SDC and ICs identified by AI or human readers. These findings support a potential role for AI in the double-reading workflow. [ABSTRACT FROM AUTHOR]

Reducing preventable readmissions is important to help manage current strains on healthcare systems. The metric of 30‐day readmissions is commonly cited in discussions regarding this topic. While such thresholds have contemporary funding implications, the rationale for individual cut‐off points is partially historical in nature. Through the examination of the basis for the analysis of 30‐day readmissions, greater insight into the possible benefits and limitations of such a metric may be obtained. [ABSTRACT FROM AUTHOR]

Objective: To evaluate the effectiveness of a new strategy for using artificial intelligence (AI) as supporting reader for the detection of breast cancer in mammography-based double reading screening practice. Methods: Large-scale multi-site, multi-vendor data were used to retrospectively evaluate a new paradigm of AI-supported reading. Here, the AI served as the second reader only if it agrees with the recall/no-recall decision of the first human reader. Otherwise, a second human reader made an assessment followed by the standard clinical workflow. The data included 280 594 cases from 180 542 female participants screened for breast cancer at seven screening sites in two countries and using equipment from four hardware vendors. The statistical analysis included non-inferiority and superiority testing of cancer screening performance and evaluation of the reduction in workload, measured as arbitration rate and number of cases requiring second human reading. Results: Artificial intelligence as a supporting reader was found to be superior or noninferior on all screening metrics compared with human double reading while reducing the number of cases requiring second human reading by up to 87% (245 395/280 594). Compared with AI as an independent reader, the number of cases referred to arbitration was reduced from 13% (35 199/280 594) to 2% (5056/280 594). Conclusion: The simulation indicates that the proposed workflow retains screening performance of human double reading while substantially reducing the workload. Further research should study the impact on the second human reader because they would only assess cases in which the AI prediction and first human reader disagree. [ABSTRACT FROM AUTHOR]

Infrared detector technologies engineered from III-V semiconductors such as strained-layer superlattice, quantum well infrared photodetectors, and quantum dot infrared photodetectors provide additional flexibility to engineer bandgap or spectral response cut-offs compared to the historical high-performance detector technology of mercury/cadmium/telluride. The choice of detector cut-off depends upon the sensing application for which the system engineer is attempting to maximize performance within an expected ensemble of operational scenarios that define objects or targets to be detected against specific environmental backgrounds and atmospheric conditions. Sensor performance is typically characterised via one or more metrics that can be modelled or measured experimentally. In this paper, the authors will explore the impact of detector cut-off wavelength with respect to different performance metrics such as noise equivalent temperature difference and expected target detection or identification ranges using analytical models developed for several representative sensing applications encompassing a variety of terrestrial atmospheric conditions in the mid-wave and long-wave infrared wavelength bands. The authors will also report on their review of recently published literature concerning the relationships between cut-off wavelength and the other detector performance characteristics such as quantum efficiency or dark current for a variety of detector technologies. [ABSTRACT FROM AUTHOR]

A large proportion of animal species enjoy the benefits of being active at night, and have evolved the corresponding optical and neural adaptations to cope with the challenges of low light intensities. However, over the past century electric lighting has introduced direct and indirect light pollution into the full range of terrestrial habitats, changing nocturnal animals’ visual worlds dramatically. To understand how these changes affect nocturnal behavior, we here propose an animal-centered analysis method based on environmental imaging. This approach incorporates the sensitivity and acuity limits of individual species, arriving at predictions of photon catch relative to noise thresholds, contrast distributions, and the orientation cues nocturnal species can extract from visual scenes. This analysis relies on just a limited number of visual system parameters known for each species. By accounting for light adaptation in our analysis, we are able to make more realistic predictions of the information animals can extract from nocturnal visual scenes under different levels of light pollution. With this analysis method, we aim to provide context for the interpretation of behavioral findings, and to allow researchers to generate specific hypotheses for the behavior of nocturnal animals in observed light-polluted scenes. [ABSTRACT FROM AUTHOR]

In May 2018, Scotland introduced a minimum unit price on alcohol. We examine the impact of this policy on traffic fatalities and drunk driving accidents. Using administrative data on the universe of vehicle collisions in Britain and a range of quasi‐experimental modeling approaches, we do not find that the policy had an effect on road crash deaths and drunk driving collisions. The results are robust to several sensitivity exercises. There is no evidence of effect heterogeneity by income and other predictors of alcohol consumption or cross‐border effects. A brief discussion of the policy implications of our findings is provided. [ABSTRACT FROM AUTHOR]

A multichannel microfluidic platform for real-time monitoring of epithelial barrier integrity by electrical impedance has been developed. Growth and polarization of human epithelial cells from the airway or gastrointestinal tract was continuously monitored over 5 days in 8 parallel, individually perfused microfluidic chips. Electrical impedance data were continuously recorded to monitor cell barrier formation using a low-cost bespoke impedance analyser. Data was analysed using an electric circuit model to extract the equivalent transepithelial electrical resistance and epithelial cell layer capacitance. The cell barrier integrity steadily increased overtime, achieving an average resistance of 418 ± 121 Ω cm2 (airway cells) or 207 ± 59 Ω cm2 (gastrointestinal cells) by day 5. The utility of the polarized airway epithelial barrier was demonstrated using a 24 hour challenge with double stranded RNA to mimic viral infection. This caused a rapid decrease in barrier integrity in association with disruption of tight junctions, whereas simultaneous treatment with a corticosteroid reduced this effect. The platform is able to measure barrier integrity in real-time and is scalable, thus has the potential to be used for drug development and testing. [ABSTRACT FROM AUTHOR]

Background Venlafaxine is a dual serotonin (5-HT) and norepinephrine reuptake inhibitor. The specific dose at which it begins to efficiently engage the norepinephrine transporter (NET) remained to be determined. Paroxetine is generally considered as a selective 5-HT reuptake inhibitor but exhibits some affinity for NET. Atomoxetine is a NET inhibitor but also has some affinity for the 5-HT reuptake transporter (SERT). Methods This study examined the effects of forced titration of venlafaxine from 75 to 300 mg/d, paroxetine from 20 to 50 mg/d, or atomoxetine from 25 to 80 mg/d in 32 patients with major depressive disorder. Inhibition of SERT was estimated using the depletion of whole-blood 5-HT. Inhibition of NET was assessed using the attenuation of the systolic blood pressure produced by i.v. injections of tyramine. Results All 3 medications significantly reduced 5-HT levels at the initiating regimens: venlafaxine and paroxetine by approximately 60% and atomoxetine by 16%. The 3 subsequent regimens of venlafaxine and paroxetine reduced 5-HT levels by over 90%, but the highest dose of atomoxetine only reached a 40% inhibition. Atomoxetine dose dependently inhibited the tyramine pressor response from the lowest dose, venlafaxine from 225 mg/d, and paroxetine left it unaltered throughout. Conclusion These results confirm that venlafaxine and paroxetine are potent SERT inhibitors over their usual therapeutic range but that venlafaxine starts inhibiting NET only at 225 mg/d, whereas paroxetine remains selective for SERT up to 50 mg/d. Atomoxetine dose dependently inhibits NET from a low dose but does not inhibit SERT to a clinically relevant degree. [ABSTRACT FROM AUTHOR]

Contrast-enhanced spectral mammography (CESM) breast biopsy has been recently introduced into clinical practice. This short communication describes the technique and potential as an alternative to MRI-guided biopsy. An additional abnormality was detected on a breast MRI examination in a patient with lobular carcinoma. The lesion was occult on conventional mammography, tomosynthesis and ultrasound and required histological diagnosis. Traditionally, this would have necessitated an MRI-guided breast biopsy, but was performed under CESM guidance. A diagnostic CESM study was performed to ensure the lesion visibility with CESM and then targeted under CESM guidance. A limited diagnostic study, CESM scout and paired images for stereotactic targeting were obtained within a 10 min window following a single injection of iodinated contrast agent. The time from positioning in the biopsy device to releasing compression after biopsy and marker clip placement was 15 min. The biopsy confirmed the presence of multifocal breast cancer. CESM-guided breast biopsy is a new technique that can be successfully used as an alternative to MRI-guided breast biopsy. CESM-guided biopsy can be used to sample breast lesions which remain occult on standard mammography and ultrasound. [ABSTRACT FROM AUTHOR]

Objectives: Traditionally B3 breast lesions are treated surgically, but overtreatment is a concern, as the majority have a final benign diagnosis. A national screening program introduced vacuum-assisted excision (VAE) for managing B3 lesions in late 2016. This retrospective study aimed to assess the outcomes associated with this approach. Methods: All B3 lesions diagnosed between 01/2017 and 12/2019 were identified at two centres. Information was obtained on the initial biopsy and final histology, and method of VAE image guidance, needle size and number of cores. Lesions were excluded if there was cancer elsewhere in the breast at the time of diagnosis; the lesion was not suitable for VAE due to position in the breast or had B3 pathology for which open biopsy was still required. The final decision to offer VAE was always made at a multidisciplinary meeting (MDM). Risk difference was used to test the significance at p ≤.05. Results: In total, 258 B3 lesions were diagnosed, 105 (40.7%) met the inclusion criteria and underwent VAE. VAE was performed under X-ray (89/105) or ultrasound guidance (16/105), taking an average of 18.5 cores with the 10-G needle or 10.8 cores with the 7-G needle. Nine cases (8.6%) were upgraded to a malignant diagnosis following VAE. Malignancy was found in 15.5% (9/58) of B3 lesions with epithelial atypia, but in none without atypia (0/47) (p =.004). No new lesions or malignancy has occurred at the site of the VAE with an average mammographic follow-up of 2.2 years. Conclusion: Upgrade to malignancy following VAE was uncommon (8.6%) and associated with atypia in the initial biopsy. VAE is an alternative approach to the management of B3 lesions, reducing open surgical procedures. Key Points: • Upgrade to malignancy after a vacuum-assisted excision of a B3 breast lesion is uncommon with an 8.6% upgrade rate. • The risk of a malignant diagnosis after a vacuum-assisted excision was significantly higher for B3 lesions with atypia compared to those without (+15.5% difference, p =.004). [ABSTRACT FROM AUTHOR]

Well differentiated liposarcoma (WD‐LPS) is a relatively rare tumour, with fewer than 50 cases occurring per year in the UK. These tumours are both chemotherapy‐ and radiotherapy‐resistant and present a significant treatment challenge requiring radical surgery. Little is known of the molecular landscape of these tumours and no current targets for molecular therapy exist. We aimed to carry out a comprehensive molecular characterisation of WD‐LPS via whole genome sequencing, RNA sequencing, and methylation array analysis. A recurrent mutation within exon 1 of FOXD4L3 was observed (chr9:70,918,189A>T; c.322A>T; p.Lys108Ter). Recurrent mutations were also observed in Wnt signalling, immunity, DNA repair, and hypoxia‐associated genes. Recurrent amplification of HGMA2 was observed, although this was in fact part of a general amplification of the region around this gene. Recurrent gene fusions in HGMA2, SDHA, TSPAN31, and MDM2 were also observed as well as consistent rearrangements between chromosome 6 and chromosome 12. Our study has demonstrated a recurrent mutation within FOXD4L3, which shows evidence of interaction with the PAX pathway to promote tumourigenesis. © 2021 The Authors. The Journal of Pathology published by John Wiley & Sons, Ltd. on behalf of The Pathological Society of Great Britain and Ireland. [ABSTRACT FROM AUTHOR]

This paper studies the formation of math and verbal skills during compulsory education and their impact on educational attainment. Using longitudinal data that follow students in England from elementary school to university, we find that the production functions of math and verbal skills are inherently different, where cross effects are present only in the production of math skills. Results on long-term educational outcomes indicate that verbal skills play a substantially greater role in explaining university enrollment than math skills. This finding, combined with the large female advantage in verbal skills, has key implications for gender gaps in college enrollment. [ABSTRACT FROM AUTHOR]

Background: Pathological complete response (pathCR) in rectal cancer is beneficial, as up to 75% of patients do not experience regrowth of the primary tumour, but it is poorly understood. We hypothesised that the changes seen in the pre-treatment biopsies of pathCR but not seen in residual tumour after chemoradiotherapy were the determinants of responsiveness.Methods: Two groups of patients with either complete response (pathCR group, N = 24) or no response (poor response group, N = 24) were retrieved. Pre-treatment biopsies of cancers from these patients underwent high read depth amplicon sequencing for a targeted panel, exome sequencing, methylation profiling and immunohistochemistry for DNA repair pathway proteins.Results: Twenty four patients who underwent pathCR and twenty-four who underwent poor response underwent molecular characterisation. Patients in the pathCR group had significantly higher tumour mutational burden and neoantigen load, frequent copy number alterations but fewer structural variants and enrichment for driver mutations in the PI3K/AKT/mTOR signalling pathway. There were no significant differences in tumour heterogeneity as measured by MATH score. Methylation analysis demonstrated enrichment for hypomethyation in the PI3K/AKT/mTOR signalling pathway.Discussion: The phenomenon of pathCR in rectal cancer may be related to immunovisibility caused by a high tumour mutational burden phenotype. Potential therapy resistance mechanisms involve the PI3K/AKT/mTOR signalling pathway, but tumour heterogeneity does not seem to play a role in resistance. [ABSTRACT FROM AUTHOR]

OBJECTIVES: To assess the feasibility of a 30-minute education session for patients with patellofemoral pain on levels of catastrophizing and kinesiophobia. DESIGN: Randomised feasibility study SETTING: Three sites within a single NHS Organisation in England. PARTICIPANTS: Thirty-one adult patients were screened for inclusion, resulting in twenty-four who had a clinical diagnosis of patellofemoral pain being randomised equally to either the intervention or control group. INTERVENTION: Participants were randomised to either control or intervention conditions; both received standardized physiotherapy while the intervention/experimental group received a 30-minute educational session addressing causes of pain, beliefs about noise that comes from the joint, the impact of the pain on activity, the influence of other family members' experience and beliefs about knee pain. Intervention participants were also given an education leaflet: 'Managing My Patellofemoral Pain'. MAIN OUTCOMES: recruitment, retention, intervention fidelity. Patient reported outcome measures (PROMs): Knee injury and Osteoarthritis Outcome Score for patellofemoral pain and osteoarthritis (KOOS-PF), Pain Catastrophizing Scale (PCS) and Tampa Scale for Kinesiophobia (TSK). RESULTS: The study was successful in recruiting and retaining participants and was delivered as intended. In addition, sufficient clinical data were generated to calculate the required sample size for a future study of efficacy CONCLUSIONS: This study which featured a 30-minute education session targeting levels of catastrophizing and kinesiophobia is feasible and identified that the TSK may be the most appropriate PROMs for a future study of efficacy of this intervention. Allowing for a drop out of 20% as identified in similar studies, 86 participants (per arm) in a two-arm study would be required for a traditional randomised controlled trial design. [ABSTRACT FROM AUTHOR]

Background: Clinical-grade whole-genome sequencing (cWGS) has the potential to become the standard of care within the clinic because of its breadth of coverage and lack of bias towards certain regions of the genome. Colorectal cancer presents a difficult treatment paradigm, with over 40% of patients presenting at diagnosis with metastatic disease. We hypothesised that cWGS coupled with 3′ transcriptome analysis would give new insights into colorectal cancer. Methods: Patients underwent PCR-free whole-genome sequencing and alignment and variant calling using a standardised pipeline to output SNVs, indels, SVs and CNAs. Additional insights into the mutational signatures and tumour biology were gained by the use of 3′ RNA-seq. Results: Fifty-four patients were studied in total. Driver analysis identified the Wnt pathway gene APC as the only consistently mutated driver in colorectal cancer. Alterations in the PI3K/mTOR pathways were seen as previously observed in CRC. Multiple private CNAs, SVs and gene fusions were unique to individual tumours. Approximately 30% of patients had a tumour mutational burden of > 10 mutations/Mb of DNA, suggesting suitability for immunotherapy. Conclusions: Clinical whole-genome sequencing offers a potential avenue for the identification of private genomic variation that may confer sensitivity to targeted agents and offer patients new options for targeted therapies. [ABSTRACT FROM AUTHOR]

Marijuana reform legislation has created a lucrative industry for legal marijuana on the local and state level in some jurisdictions. Federal laws have forced legal marijuana dispensaries to be cash-only businesses with limited banking options. The lack of normal banking services has also affected firms' ability to manage profits earned from operations. Our hermeneutic phenomenological study was grounded by the conceptual framework of the motivations of humans and humans' need to feel safe. The participants in this study were owners and operators in the legal marijuana industry in Colorado. Data were collected through interviews, although the Coronavirus (COVID-19) pandemic of 2020 made data collection more challenging because of the added pressure on potential participants. The data analysis plan for this study consisted of transcribing and reviewing the data, coding themes and supporting themes, and synthesizing and reporting findings from the data collected. The study's findings included the participants' concerns about safety in their cash-only operations, their methods for conducting business, and the banking options available to them. Common themes that emerged from the interviews were cash, banking, safety, and the limitations of business size. Findings from my study contribute to fostering positive social change on the organization and industry level by providing accounts of how owners and operators navigate the banking dilemma in the legal marijuana industry. [ABSTRACT FROM AUTHOR]

The objective of this study was to identify the factors associated with the duration of criminal investigations and determine whether these factors influence the seriality of sexual murderers. To this end, data on the investigation of 62 sexual homicides (homicides committed by a serial sexual murderer = 24; homicides committed by a nonserial sexual murderer = 38), were analyzed. Organized behaviors, typical of serial sexual murderers, were not all associated with a longer criminal investigation. However, it was possible to develop a model of the duration of investigations, and predict the seriality of sexual murderers, by taking into account the decisions of murderers and investigators. [ABSTRACT FROM AUTHOR]

This paper evaluates a method of generating a unique dataset that has been underused—a Freedom of Information (FOI) request. The UK's FOI Act came into force in 2005, allowing the public to make requests of publicly held data. We set out to understand the determinants of the quality responses to FOI requests. We also explain how requests can be made and provide suggestions to construct effective data-driven requests. We applied for data on hate crime from all police forces and on uptake of maternity leave from all universities. We find that observable characteristics of the local area, police force and universities neither determine whether the request was fulfilled, nor the speed of response, suggesting that the data from these FOI requests are representative of the institutions from which they were requested. [ABSTRACT FROM AUTHOR]

This paper describes a simple and interesting method to introduce and teach undergraduate students about preference estimation using random utility models. The example centers around estimating preferences over rides at Disneyland theme parks and uses actual stated-preference survey data. The lesson is designed to be self-contained in a single 90 minute lecture. Given the strong background that many undergraduate economic students have with consumer choice theory, introducing preference estimation as a real-world application into econometrics curriculum can be an enriching experience. [ABSTRACT FROM AUTHOR]

We estimate the effect of binge drinking on road accidents, accident and emergency (A&E) attendances and arrests using a variety of unique English data and a two-sample instrumental variables estimation procedure. Drinking |$10+$| units of alcohol in a single session increases road accidents by 18.6%, injury-related A&E attendances by 6.6% and arrests by 71%. The marginal increase from eight to |$10+$| alcoholic units implies nearly 6,100 extra road accidents every year, 63,000 additional A&E attendances and 100,000 additional arrests. The externality per mile driven by a binge drinker is about five pence and the punishment that internalises this externality is equivalent to a fine of £22,800 per drunk driving arrest. [ABSTRACT FROM AUTHOR]

The primary objective of this study was to describe and compare the modus operandi, and associated contextual and situational factors, of French serial sexual murderers (SSMs) and nonserial sexual murderers (NSMs). A further objective was to verify the generalizability of the conclusions of James and Proulx's 2016 systematic review of the modus operandi of sexual murderers, the majority of whom were American or English. Detailed data on the precrime, modus operandi, postcrime, and victimology factors of 120 French sexual murderers (SSMs: n = 33; NSMs: n = 87) were compared. The results suggest that choice-structuring properties that shape the modus operandi of French sexual murderers are similar to those reported by James and Proulx: The modus operandi of French SSMs was shaped by homicidal, sadistic, and rape fantasies, while that of NSMs was shaped by the need to satisfy immediate, especially sexual, needs. However, it should be noted that while the modus operandi of American and English NSMs is primarily shaped by general deviance, that of French NSMs appear be primarily shaped by sexual deviance. [ABSTRACT FROM AUTHOR]

Sexual homicide typically implies a crime involving two people: perpetrator and victim. Thus, multiple-perpetrator and multiple concurrent victim sexual murderers are unusual, empirically invisible due to their exclusion from (or burying within) research samples. The present study examines 21 such cases of male sexual murderers having perpetrated at least one sexual homicide either together with a co-offender or alone but killing two victims at once. The aim was to investigate just how unusual, or not, these cases may be in relation to current scientific understanding of sexual murderers and their crimes. A descriptive analysis of offenses (co-offender and offender-victim dynamics, modus operandi) and offender characteristics is presented. Main findings, that multiple-perpetrator and multiple concurrent victim sexual murderers are not so unusual in that they are well conceptualized through application of the established sexualized, grievance, and rape murderer typology, are discussed in relation to clinical and empirical implications. [ABSTRACT FROM AUTHOR]

Summary: We estimate a sequential model of schooling to assess the major contributing factors to the large gender imbalance in educational attainment within racial groups. First, we find that differences between males and females in measures of early behavior account for the majority of the gender gap for each racial group. Second, we show that black males have the largest response to improvements in family background characteristics, such that equalizing the distribution of family background characteristics for black and white youths reduces the gender gap in college enrollment among black youth by 50%. [ABSTRACT FROM AUTHOR]

Selective serotonin (5-HT) reuptake inhibitors (SSRIs) are first-line antidepressants but require several weeks to elicit their actions. Chronic SSR1 treatment induces desensitization of 5-HT 1A autoreceptors to enhance 5-HT neurotransmission. Mice (both sexes) with gene deletion of 5-HT1A autoreceptors in adult 5-HT neurons (lAcKO) were tested for response to SSRIs. Tamoxifen-induced recombination in adult lAcKO mice specifically reduced 5-HT1A autoreceptor levels. The lAcKO mice showed a loss of 5-HT1A autoreceptormediated hypothermia and electrophysiological responses, but no changes in anxiety- or depression-like behavior. Subchronic fluoxetine (FLX) treatment induced an unexpected anxiogenic effect in lAcKO mice in the novelty suppressed feeding and elevated plus maze tests, as did escitalopram in the novelty suppressed feeding test. No effect was seen in wild-type (WT) mice. Subchronic FLX increased 5-HT metabolism in prefrontal cortex, hippocampus, and raphe of lAcKO but not WT mice, suggesting hyperactivation of 5-HT release. To detect chronic cellular activation, FosB+ cells were quantified. FosB+ cells were reduced in entorhinal cortex and hippocampus (CA2/3) and increased in dorsal raphe 5-HT cells of lAcKO mice, suggesting increased raphe activation. In WTbut not lAcKO mice, FLX reduced FosB+ cells in the median raphe, hippocampus, entorhinal cortex, and median septum, which receive rich 5-HT projections. Thus, in the absence of 5-HT 1A autoreceptors, SSRIs induce a paradoxical anxiogenic response. This may involve imbalance in activation of dorsal and median raphe to regulate septohippocampal or fimbria-fornix pathways. These results suggest that markedly reduced 5-HT1A autoreceptors may provide a marker for aberrant response to SSRI treatment. [ABSTRACT FROM AUTHOR]

Objective: To develop and evaluate a low-cost computer-based tool to elicit dietary choices in an incentive compatible manner, which can be used on-line or as part of a laboratory study. Methods: The study was conducted with around 255 adults. Respondents were asked to allocate a fixed monetary budget across a choice of around a hundred grocery items with the prospect of receiving these items with some probability delivered to their home by a real supermarket. The tool covers a broad range of food items, allows inference of macro-nutrients and calories, and allows the researcher to fix the choice set participants can choose from. We compare the information derived from our incentivized tool, and compare it to alternative low-cost ways of measuring dietary intake, namely the food frequency questionnaire and a one-shot version of the 24-hour dietary recall, which are both based on self-reports. We compare the calorie intake indicators derived from each tool with a number of biometric measures for each subject, namely weight, body-mass-index (BMI) and waist size. Results: The results show that the dietary information collected is only weakly correlated across the three methods. We find that only the calorie intake measure from our incentivized tool is positively and significantly related to each of the biometric indicators. Specifically, a 10% increase in calorie intake is associated with a 1.5% increase in BMI. By contrast, we find no significant correlations for either of the two measures based on self-reports. Conclusion: The computer-based tool is a promising new, low-cost measure of dietary choices, particularly in one-shot situations where such behaviours are only observed once, whereas other tools like 24-hour dietary recalls and food frequency questionnaires may be more suited when they are administered repeatedly. The tool may be useful for research conducted with limited time and budget. [ABSTRACT FROM AUTHOR]

The juvenile period is marked by a reorganization and growth of important brain regions including structures associating with reward seeking behaviors such as the nucleus accumbens (NA) and prefrontal cortex (PFC). These changes are impacted by stressors during the juvenile period and may lead to a predisposition to stress induced psychopathology and abnormal development of brain reward systems. Like in humans, adult rodents engage certain coping mechanisms such as increases in the consumption of calorie-rich palatable foods to reduce stress, but this behavior can lead to obesity and metabolic disorders. In this study, we examined whether stressors during the juvenile period led to increased caloric intake when a palatable diet was accessible, and whether this diet attenuated adult stress responses. In addition, we examined if the stress buffering effects produced by the palatable diet were also accompanied by an offset propensity towards obesity, and by alterations in mRNA expression of dopamine (DA) receptors in the NA and PFC in adulthood. To this end, juvenile male Wistar rats underwent episodic stressor exposure (forced swim, elevated platform stress and restraint) on postnatal days (PD) 27–29 and received access to regular chow or daily limited access to a palatable diet until adulthood. At the age of 2 months, rats were tested on a social interaction test that screens for anxiety-like behaviors and their endocrine responses to an acute stressor. Animals were sacrificed, and their brains processed to detect differences in DA receptor subtype expression in the PFC and NA using qPCR. Results showed that rats that were stressed during the juvenile period displayed higher social anxiety and a sensitized corticosterone response as adults and these effects were attenuated by access to the palatable diet. Nevertheless, rats that experienced juvenile stress and consumed a palatable diet showed greater adiposity in adulthood. Interestingly, the same group displayed greater mRNA expression of DA receptors at the NA. This suggests that access to a palatable diet mitigates the behavioral and endocrine effects of juvenile stressor exposure in adulthood, but at the cost of metabolic imbalances and a sensitized dopaminergic system. [ABSTRACT FROM AUTHOR]

Freud-1/Cc2d1a represses the gene transcription of serotonin-1A (5-HT1A) autoreceptors, which negatively regulate 5-HT tone. To test the roleof Freud-1 in vivo, we generated mice with adulthood conditional knock-out ofFreud-1 in 5-HT neurons (cF1ko). In cF1ko mice, 5-HT1A autoreceptor protein, binding and hypothermia response were increased, with reduced 5-HT content and neuronal activity in the dorsal raphe. The cF1ko mice displayed increased anxiety- and depression-like behavior that was resistant to chronic antidepressant (fluoxetine) treatment. Using conditional Freud-1/5-HT1 A double knock-out (cF1/1A dko) to disrupt both Freud-1 and 5-HT1A genes in 5-HT neurons, no increase in anxiety- or depression-like behavior was seen upon knock-out ofFreud-1 on the 5-HT1A autoreceptornegative background; rather, a reduction in depression-like behavior emerged. These studies implicate transcriptional dysregulation of 5-HT 1A auto receptors by the repressor Freud-1 in anxiety and depression and provide a clinically relevant genetic model of antidepressant resistance. Targeting specific transcription factors, such as Freud-1, to restore transcriptional balance may augment response to antidepressant treatment. [ABSTRACT FROM AUTHOR]

This paper investigates optimal central bank disclosure in an economy in which only a proportion of firms adjusts prices each period to reflect current information. Such information comprises a firm-specific signal of the current state of aggregate demand and, potentially (depending on the transparency regime) a public signal disseminated by the central bank. The economy has two sources of price dispersion: first, the heterogeneity of the private signals of firms whose prices always reflect current information, and second, the non-adjustment of prices by firms that fail to update their information from period-to-period. Monetary policy is conducted by the central bank to maximize expected welfare, with the study's focus on the optimal degree of transparency. A key finding is that, for plausible values of model parameters, full transparency cannot be optimal: whether zero or partial transparency is desirable then depends on the proportion of firms failing to update their information each period. [ABSTRACT FROM AUTHOR]

This paper develops a new technique for estimating mixed logit models with a simple minorization-maximization (MM) algorithm. The algorithm requires minimal coding and is easy to implement for a variety of mixed logit models. Most importantly, the algorithm has a very low cost per iteration relative to current methods, producing substantial computational savings. In addition, the method is asymptotically consistent, efficient and globally convergent. Copyright © 2016 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

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Objectives: The interpretation of digital breast tomosynthesis (DBT) screening examinations is a complex task for an already overstretched workforce which has the potential to increase pressure on readers leading to fatigue and patient safety issues. Studies in non‐medical and medical settings have suggested that changes in blink characteristics can reflect fatigue. The purpose of this study is to investigate the use of blink characteristics as an objective marker of fatigue in readers interpreting DBT breast screening examinations. Methods: Twenty‐six DBT readers involved in the UK PROSPECTS trial interpreted a test set of 40 DBT cases while being observed by an eye tracking device from November 2019 to February 2021. Raw data from the eye tracker were collected and automated processing software was used to produce eye blinking characteristics data which were analysed using multiple linear regression statistical models. Results: Of the 26 DBT readers recruited, eye tracking data from 23 participants were analysed due to missing data rendering 3 participants' data uninterpretable. The mean reading time per DBT case was 2.81 min. There was a statistically significant increase in blinking duration of 0.38 ms/case as the reading session progressed (p < 0.0001). This was the result of a significant decrease in the number of ultra‐short blinks lasting ≤50 ms (p = 0.0005) and a significant increase in longer blinks lasting 51–100 ms (p = 0.008). Conclusion: Changes in blinking characteristics could serve as objective measures of reader fatigue and may prove useful in the development of DBT reading protocols. Advances in knowledge: Blink characteristics can be used as an objective measure of fatigue; however there is limited evidence of their use in radiological settings. Our study suggests that changes in blink duration and frequency could be used to monitor fatigue in DBT reading sessions. [ABSTRACT FROM AUTHOR]

Background: Community-based studies of patellofemoral pain (PFP) need a questionnaire tool that discriminates between those with and those without the condition. To overcome these issues, we have designed a self-report questionnaire which aims to identify people with PFP in the community.Methods: Study Designs: comparative study and cross-sectional study.Study Population: comparative study: PFP patients, soft-tissue injury patients and adults without knee problems. Cross-sectional study: adults attending a science festival.Intervention: comparative study participants completed the questionnaire at baseline and two weeks later. Cross-sectional study participants completed the questionnaire once. The optimal scoring system and threshold was explored using receiver operating characteristic curves, test-retest reliability using Cohen's kappa and measurement error using Bland-Altman plots and standard error of measurement. Known-group validity was explored by comparing PFP prevalence between genders and age groups.Results: Eighty-four participants were recruited to the comparative study. The receiver operating characteristic curves suggested limiting the questionnaire to the clinical features and knee pain map sections (AUC 0.97 95 % CI 0.94 to 1.00). This combination had high sensitivity and specificity (over 90 %). Measurement error was less than the mean difference between the groups. Test-retest reliability estimates suggest good agreement (N = 51, k = 0.74, 95 % CI 0.52-0.91). The cross-sectional study (N = 110) showed expected differences between genders and age groups but these were not statistically significant.Conclusion: A shortened version of the questionnaire, based on clinical features and a knee pain map, has good measurement properties. Further work is needed to validate the questionnaire in community samples. [ABSTRACT FROM AUTHOR]

Characterization of the default mode network (DMN) as a complex network of functionally interacting dynamic systems has received great interest for the study of DMN neural mechanisms. In particular, understanding the relationship of intrinsic resting-state DMN brain network with cognitive behaviors is an important issue in healthy cognition and mental disorders. However, it is still unclear how DMN functional connectivity links to cognitive behaviors during resting-state. In this study, we hypothesize that static and dynamic DMN nodal topology is associated with upcoming cognitive task performance. We used graph theory analysis in order to understand better the relationship between the DMN functional connectivity and cognitive behavior during resting-state and task performance. Nodal degree of the DMN was calculated as a metric of network topology. We found that the static and dynamic posterior cingulate cortex (PCC) nodal degree within the DMN was associated with task performance (Reaction Time). Our results show that the core node PCC nodal degree within the DMN was significantly correlated with reaction time, which suggests that the PCC plays a key role in supporting cognitive function. [ABSTRACT FROM AUTHOR]

Background: Highly sensitive and specific urine-based tests to detect either primary or recurrent bladder cancer have proved elusive to date. Our ever increasing knowledge of the genomic aberrations in bladder cancer should enable the development of such tests based on urinary DNA. Methods: DNA was extracted from urine cell pellets and PCR used to amplify the regions of the TERT promoter and coding regions of FGFR3, PIK3CA, TP53, HRAS, KDM6A and RXRA which are frequently mutated in bladder cancer. The PCR products were barcoded, pooled and paired-end 2 x 250 bp sequencing performed on an Illumina MiSeq. Urinary DNA was analysed from 20 non-cancer controls, 120 primary bladder cancer patients (41 pTa, 40 pT1, 39 pT2+) and 91 bladder cancer patients post-TURBT (89 cancer-free). Results: Despite the small quantities of DNA extracted from some urine cell pellets, 96% of the samples yielded mean read depths >500. Analysing only previously reported point mutations, TERT mutations were found in 55% of patients with bladder cancer (independent of stage), FGFR3 mutations in 30% of patients with bladder cancer, PIK3CA in 14% and TP53 mutations in 12% of patients with bladder cancer. Overall, these previously reported bladder cancer mutations were detected in 86 out of 122 bladder cancer patients (70% sensitivity) and in only 3 out of 109 patients with no detectable bladder cancer (97% specificity). Conclusion: This simple, cost-effective approach could be used for the non-invasive surveillance of patients with non-muscle-invasive bladder cancers harbouring these mutations. The method has a low DNA input requirement and can detect low levels of mutant DNA in a large excess of normal DNA. These genes represent a minimal biomarker panel to which extra markers could be added to develop a highly sensitive diagnostic test for bladder cancer. [ABSTRACT FROM AUTHOR]

Objective: To compare the accuracy of standard supplementary views and GE digital breast tomosynthesis (DBT) for assessment of soft-tissue mammographic abnormalities. Methods: Women recalled for further assessment of soft-tissue abnormalities were recruited and received standard supplementary views (typically spot compression views) and two-view GE DBT. The added value of DBT in the assessment process was determined by analysing data collected prospectively by radiologists working up the cases. Following anonymization of cases, there was also a retrospective multireader review. The readers first read bilateral standard two-view digital mammography (DM) together with the supplementary mammographic views and gave a combined score for suspicion of malignancy on a five-point scale. The same readers then read bilateral standard two-view DM together with two-view DBT. Pathology data were obtained. Differences were assessed using receiver operating characteristic analysis. Results: The study population was 342 lesions in 322 patients. The final diagnosis was malignant in 113 cases (33%) and benign/normal in 229 cases (67%). In the prospective analysis, the performance of two-view DM plus DBT was at least equivalent to the performance of two-view DM and standard mammographic supplementary views--the area under the curve (AUC) was 0.946 and 0.922, respectively, which did not reach statistical significance. Similar results were obtained for the retrospective review--AUC was 0.900 (DBT) and 0.873 (supplementary views), which did not reach statistical significance. Conclusion: The accuracy of GE DBT in the assessment of screen detected soft-tissue abnormalities is equivalent to the use of standard supplementary mammographic views. Advances in knowledge: The vast majority of evidence relating to the use of DBT has been gathered from research using Hologic equipment. This study provides evidence for the use of the commercially available GE DBT system demonstrating that it is at least equivalent to supplementary mammographic views in the assessment of soft-tissue screen-detected abnormalities. [ABSTRACT FROM AUTHOR]

Conventional wisdom has it that a central bank that uses an informational advantage to undertake active policy intervention can do as well, at least so far as real outcomes are concerned, by making its information publicly available and abstaining from stabilization. This notion is examined using a framework incorporating heterogeneous private sector information concerning aggregate demand shocks. An activist regime, in which the central bank exploits its own information to engage in stabilization, is found to be unambiguously superior to a noninterventionist regime, where the central bank maintains a constant setting of policy but publicly discloses its own information. [ABSTRACT FROM AUTHOR]