Opioid-related deaths during hospital admissions or shortly after discharge in the United Kingdom: A thematic framework analysis of coroner reports

BACKGROUND: People who use heroin and other illicit opioids are at high risk of fatal overdose in the days after hospital discharge, but the reasons for this risk have not been studied. METHODS: We used the National Programme on Substance Abuse Deaths, a database of coroner reports for deaths following psychoactive drug use in England, Wales, and Northern Ireland. We selected reports where the death occurred between 2010 and 2021, an opioid was detected in toxicology testing, the death was related to nonmedical opioid use, and death was either during an acute medical or psychiatric hospital admission or within 14 days after discharge. We used thematic framework analysis of factors that may contribute to the risk of death during hospital admission or after discharge. RESULTS: We identified 121 coroners’ reports; 42 where a patient died after using drugs during hospital admission, and 79 where death occurred shortly after discharge. The median age at death was 40 (IQR 34–46); 88 (73%) were male; and sedatives additional to opioids were detected at postmortem in 88 cases (73%), most commonly benzodiazepines. In thematic framework analysis, we categorised potential causes of fatal opioid overdose into three areas: (a) hospital policies and actions. Zero-tolerance policies mean that patients conceal drug use and use drugs in unsafe places such as locked bathrooms. Patients may be discharged to locations such as temporary hostels or the street while recovering. Some patients bring their own medicines or illicit opioids due to expectations of low-quality care, including undertreated withdrawal or pain; (b) high-risk use of sedatives. People may increase sedative use to manage symptoms of acute illness or a mental health crisis, and some may lose tolerance to opioids during a hospital admission; (c) declining health. Physical health and mobility problems posed barriers to post-discharge treatment for substance use, and some patients had sudden deteriorations in health that may have contributed to respiratory depression. CONCLUSION: Hospital admissions are associated with acute health crises that increase the risk of fatal overdose for patients who use illicit opioids. Hospitals need guidance to help them care for this patient group, particularly in relation to withdrawal management, harm reduction interventions such as take-home naloxone, discharge planning including continuation of opioid agonist therapy during recovery, management of poly-sedative use, and access to palliative care

Expression of Wnt5a is downregulated by extracellular matrix and mutated c-Ha-ras in the human mammary epithelial cell line MCF-10A

Wnt genes are involved in tumour growth and regulate cell adhesion. Some (Wnt5a and Wnt7b) are more highly expressed in human breast cancer compared to normal tissues. Wnt5a is involved in the regulation of cell movement in Xenopus and is upregulated in several human cancers. Factors regulating Wnt gene expression in human breast epithelium are poorly understood, but c-erbB2 is amplified in many breast cancers and associated with rapid growth and metastasis, as is high expression of c-Ha-ras. To further understand the regulation of Wnt gene expression, this study investigated the effect of proto-oncogenes c-Ha-ras and c-erbB2, and collagen on Wnt mRNA expression, in a normal spontaneously immortalised human mammary epithelial cell line MCF-10A. Out of nine human Wnt genes investigated, Wnt5a and Wnt7b were expressed in the parental cell line, and neomycin-, c-Ha-ras- and c-erbB2-transfected cell lines. The level of Wnt5a mRNA expression was decreased 40-fold and 3-fold when parental cells were grown on collagen and in collagen, respectively. This downregulation correlated with cell branching. However, Wnt7b was not regulated by collagen. In the presence of activated c-Ha-ras, the level of Wnt5a mRNA expression was markedly decreased (> 200-fold) and cell growth rate was elevated. When treated with p21ras inhibitor, BZA-5B, there was a moderate reversal of Wnt5a mRNA expression (2-fold) with a parallel decrease in cell growth. The data indicate that c-Ha-ras is an upstream inhibitory regulator of Wnt5a, and provide further evidence of an inverse relationship between Wnt5a mRNA expression and cell branching. This demonstrates selectivity of regulation of individual members of the Wnt gene family by the ras pathway. Overexpression of c-erbB2 had no effect on Wnt5a or Wnt7b mRNA expression. Thus, extracellular matrix and ras regulate Wnt5a, providing a mechanism for feedback of morphogenetic movements, which is relevant also to cancer biology

Pattern scaling using ClimGen: monthly-resolution future climate scenarios including changes in the variability of precipitation

Development, testing and example applications of the pattern-scaling approach for generating future climate change projections are reported here, with a focus on a particular software application called “ClimGen”. A number of innovations have been implemented, including using exponential and logistic functions of global-mean temperature to represent changes in local precipitation and cloud cover, and interpolation from climate model grids to a finer grid while taking into account land-sea contrasts in the climate change patterns. Of particular significance is a new approach for incorporating changes in the inter-annual variability of monthly precipitation simulated by climate models. This is achieved by diagnosing simulated changes in the shape of the gamma distribution of monthly precipitation totals, applying the pattern-scaling approach to estimate changes in the shape parameter under a future scenario, and then perturbing sequences of observed precipitation anomalies so that their distribution changes according to the projected change in the shape parameter. The approach cannot represent changes to the structure of climate timeseries (e.g. changed autocorrelation or teleconnection patterns) were they to occur, but is shown here to be more successful at representing changes in low precipitation extremes than previous pattern-scaling methods

Character building in childrens’ online information behaviours: applying a virtue epistemology perspective to information literacy.

This paper advances our understanding of the theoretical and practical challenges of developing intellectual character in children’s online information behaviours. We argue that widely reported issues such as misinformation and disinformation extend IL education beyond considerations of ability to considerations of disposition, and highlight this as an understudied topic within IL education. We introduce the classical concept of intellectual character and discuss virtues traits in the IL context. Applying Baehr’s nine intellectual virtues to two commonly cited IL models, we evidence limited presence of virtues in IL models, and propose an important agenda for future research

Neuropixels 2.0: A miniaturized high-density probe for stable, long-term brain recordings

Measuring the dynamics of neural processing across time scales requires following the spiking of thousands of individual neurons over milliseconds and months. To address this need, we introduce the Neuropixels 2.0 probe together with newly designed analysis algorithms. The probe has more than 5000 sites and is miniaturized to facilitate chronic implants in small mammals and recording during unrestrained behavior. High-quality recordings over long time scales were reliably obtained in mice and rats in six laboratories. Improved site density and arrangement combined with newly created data processing methods enable automatic post hoc correction for brain movements, allowing recording from the same neurons for more than 2 months. These probes and algorithms enable stable recordings from thousands of sites during free behavior, even in small animals such as mice

"The California critical thinking instruments for benchmarking, program assessment, and directing curricular change"

Charles R. Phillips is an Associate Professor of Pharmacy Administration/Dept. Chair of Pharmacy Practice, Renae J. Chesnut is Associate Dean for Academic and Student Affairs. Raylene M. Rospond is Dean, Pharmacy and Health Sciences. All three are in the College of Pharmacy and Health Sciences at Drake University. They can be contacted at: [email protected], [email protected], and [email protected]. To assess pharmacy students’ critical thinking (CT) measures and identify areas for curricular reform. Methods. Pharmacy students were given the California Critical Thinking Skills Test and Disposition Index at various points in the PharmD program. Scores were compared with a national referent group and evaluated for changes across the curriculum and between classes. Results. Students were comparable to national norms. Pretest and posttest scores for total disposition showed improvement. Scores in all subcategories except for truth-seeking were consistently above 40. The CT skills of the pharmacy students varied compared with those of referent students, but the pharmacy students’ overall score of 18 was in the 73rd percentile. Pre- and post-skills scores showed improvement. Students scoring low on the pretest improved more than those scoring high. Conclusions. Students had a consistent disposition towards CT and compared favorably to national norms. Both disposition and skills improved across the curriculum. Dimensions of critical thinking on which students score low should be areas for curricular and other program changes

Fluoroquinolones and isoniazid-resistant tuberculosis: implications for the 2018 WHO guidance.

INTRODUCTION: 2018 World Health Organization (WHO) guidelines for the treatment of isoniazid (H)-resistant (Hr) tuberculosis recommend a four-drug regimen: rifampicin (R), ethambutol (E), pyrazinamide (Z) and levofloxacin (Lfx), with or without H ([H]RZE-Lfx). This is used once Hr is known, such that patients complete 6 months of Lfx (≥6[H]RZE-6Lfx). This cohort study assessed the impact of fluoroquinolones (Fq) on treatment effectiveness, accounting for Hr mutations and degree of phenotypic resistance. METHODS: This was a retrospective cohort study of 626 Hr tuberculosis patients notified in London, 2009-2013. Regimens were described and logistic regression undertaken of the association between regimen and negative regimen-specific outcomes (broadly, death due to tuberculosis, treatment failure or disease recurrence). RESULTS: Of 594 individuals with regimen information, 330 (55.6%) were treated with (H)RfZE (Rf=rifamycins) and 211 (35.5%) with (H)RfZE-Fq. The median overall treatment period was 11.9 months and median Z duration 2.1 months. In a univariable logistic regression model comparing (H)RfZE with and without Fqs, there was no difference in the odds of a negative regimen-specific outcome (baseline (H)RfZE, cluster-specific odds ratio 1.05 (95% CI 0.60-1.82), p=0.87; cluster NHS trust). Results varied minimally in a multivariable model. This odds ratio dropped (0.57, 95% CI 0.14-2.28) when Hr genotype was included, but this analysis lacked power (p=0.42). CONCLUSIONS: In a high-income setting, we found a 12-month (H)RfZE regimen with a short Z duration to be similarly effective for Hr tuberculosis with or without a Fq. This regimen may result in fewer adverse events than the WHO recommendations

Epidemiology of Subpatent Plasmodium Falciparum Infection: Implications for Detection of Hotspots with Imperfect Diagnostics.

At the local level, malaria transmission clusters in hotspots, which may be a group of households that experience higher than average exposure to infectious mosquitoes. Active case detection often relying on rapid diagnostic tests for mass screen and treat campaigns has been proposed as a method to detect and treat individuals in hotspots. Data from a cross-sectional survey conducted in north-western Tanzania were used to examine the spatial distribution of Plasmodium falciparum and the relationship between household exposure and parasite density. Dried blood spots were collected from consenting individuals from four villages during a survey conducted in 2010. These were analysed by PCR for the presence of P. falciparum, with the parasite density of positive samples being estimated by quantitative PCR. Household exposure was estimated using the distance-weighted PCR prevalence of infection. Parasite density simulations were used to estimate the proportion of infections that would be treated using a screen and treat approach with rapid diagnostic tests (RDT) compared to targeted mass drug administration (tMDA) and Mass Drug Administration (MDA). Polymerase chain reaction PCR analysis revealed that of the 3,057 blood samples analysed, 1,078 were positive. Mean distance-weighted PCR prevalence per household was 34.5%. Parasite density was negatively associated with transmission intensity with the odds of an infection being subpatent increasing with household exposure (OR 1.09 per 1% increase in exposure). Parasite density was also related to age, being highest in children five to ten years old and lowest in those > 40 years. Simulations of different tMDA strategies showed that treating all individuals in households where RDT prevalence was above 20% increased the number of infections that would have been treated from 43 to 55%. However, even with this strategy, 45% of infections remained untreated. The negative relationship between household exposure and parasite density suggests that DNA-based detection of parasites is needed to provide adequate sensitivity in hotspots. Targeting MDA only to households with RDT-positive individuals may allow a larger fraction of infections to be treated. These results suggest that community-wide MDA, instead of screen and treat strategies, may be needed to successfully treat the asymptomatic, subpatent parasite reservoir and reduce transmission in similar settings

Concordance of CSF measures of Alzheimer's pathology with amyloid PET status in a preclinical cohort: A comparison of Lumipulse and established immunoassays

INTRODUCTION: We assessed the concordance of cerebrospinal fluid (CSF) amyloid beta (Aβ) and tau measured on the fully automated Lumipulse platform with pre-symptomatic Alzheimer's disease (AD) pathology on amyloid positron emission tomography (PET). METHODS: In 72 individuals from the Insight 46 study, CSF Aβ40, Aβ42, total tau (t-tau), and phosphorylated tau at site 181 (p-tau181) were measured using Lumipulse, INNOTEST, and Meso Scale Discovery (MSD) assays and inter-platform Pearson correlations derived. Lumipulse Aβ42 measures were adjusted to incorporate standardization to certified reference materials. Logistic regressions and receiver operating characteristics analysis generated CSF cut-points optimizing concordance with 18F-florbetapir amyloid PET status (n = 63). RESULTS: Measurements of CSF Aβ, p-tau181, and their ratios correlated well across platforms (r 0.84 to 0.94, P < .0001); those of t-tau and t-tau/Aβ42 correlated moderately (r 0.57 to 0.79, P < .0001). The best concordance with amyloid PET (100% sensitivity and 94% specificity) was afforded by cut-points of 0.075 for Lumipulse Aβ42/Aβ40, 0.087 for MSD Aβ42/Aβ40 and 17.3 for Lumipulse Aβ42/p-tau181. DISCUSSION: The Lumipulse platform provides comparable sensitivity and specificity to established CSF immunoassays in identifying pre-symptomatic AD pathology