Biodegradable Polyester Nanoparticle Vaccines Deliver Self-Amplifying mRNA in Mice at Low Doses

Delivery of self-amplifying mRNA (SAM) has high potential for infectious disease vaccination due to its self-adjuvanting and dose-sparing properties. Yet a challenge is the susceptibility of SAM to degradation and the need for SAM to reach the cytosol fully intact to enable self-amplification. Lipid nanoparticles are successfully deployed at incredible speed for mRNA vaccination, but aspects such as cold storage, manufacturing, efficiency of delivery, and the therapeutic window can benefit from further improvement. To investigate alternatives to lipid nanoparticles, a class of >200 biodegradable end-capped lipophilic poly(beta-amino ester)s (PBAEs) that enable efficient delivery of SAM in vitro and in vivo as assessed by measuring expression of SAM encoding reporter proteins is developed. The ability of these polymers to deliver SAM intramuscularly in mice is evaluated, and a polymer-based formulation that yields up to 37-fold higher intramuscular (IM) expression of SAM compared to injected naked SAM is identified. Using the same nanoparticle formulation to deliver a SAM encoding rabies virus glycoprotein, the vaccine elicits superior immunogenicity compared to naked SAM delivery, leading to seroconversion in mice at low RNA injection doses. These biodegradable nanomaterials may be useful in the development of next-generation RNA vaccines for infectious diseases.Copyright © 2023 The Authors. Advanced Therapeutics published by Wiley-VCH GmbH.

Paradoxical Narratives About Online Learning During the COVID-19 Pandemic: The Struggle Was Real, but so Was the Resilience

Though the COVID-19 pandemic presented ongoing challenges for the entire nation, it wreaked unprecedented havoc on communities of color. Despite the turbulence and upheaval, this exploratory study illustrates that first-gen Latinx college students at an HSI in South Texas persevered and even thrived. Undergraduate teacher candidates participated in focus group sessions to examine their lived experiences as online students from March 2020 to August 2021. Their narratives reveal paradoxical perspectives regarding online learning v. face-to-face instruction and the role of family during this era. More than half the participants were also mothers. Their stories of juggling their own classes while simultaneously caring for and managing online learning for their children provide the audience with a glimpse into the complex lifeworlds of the courageous and resilient students. Implications for university faculty and staff who work with Latinx student mothers and first-generation college students are discussed. © 2023 Taylor & Francis Group, LLC.

Optimized nanoparticle-mediated base editing of cystic fibrosis-causing variants

Background: Next-generation SARS-CoV-2 vaccines demonstrated that nanoparticle messenger ribonucleic acid (mRNA) delivery is effective and safe for in vivo delivery in humans. Current treatments for cystic fibrosis (CF) primarily focus on modulator drug therapies designed to correct malfunctioning CF transmembrane conductance regulator (CFTR) protein, but these modulators are ineffective for the 10% of people with CF with variants that do not allow protein production. Among these is the splice variant 3120 + 1G >A, the most common CF-causing mutation in native Africans. Gene editing would allow production of CFTR protein and enhancement of function using available CFTR modulators. We have demonstrated that electroporation of a modified CRISPR-Cas9 base editor to primary human bronchial epithelial cells carrying 3120 + 1G >A and F508del mutant alleles achieved 75% genome editing of the splice variant, resulting in approximately 40% wild-type (WT) CFTR function [1]. Here,we evaluate the effectiveness of several new nanoparticle formulations at delivering green fluorescent protein (GFP) mRNA to CF bronchial epithelial (CFBE41o-) cells. Using the optimal formulation,we then tested the efficacy correction of the 3120 + 1G >Avariant in a CFTR expression minigene (EMG) integrated into the genome of isogenic CFBE cells using mRNA and plasmid deoxyribonucleic acid (DNA) encoding adenine base editor (ABE) and guide (g)RNA. Method(s): GFP served as a reporter to evaluate transfection efficiency, cell viability, and mean fluorescence intensity (MFI) for three dosages (150, 75, 32.5 ng of mRNA), four polymer-to-mRNA to weight (w/w) ratios (60, 40, 30, 20), and four polymers (R, Y, G, B). 7-AAD served as a live/dead stain to quantify viability, with flow cytometry results analyzed using FlowJo software. CFBE cells stably expressing the 3120 + 1G >A EMG were transfected with the optimized nanoparticle formulation to deliver ABE and gRNA at two dosages (150, 75 ng) of mRNA and DNA. CFTR function in CFBE cellswas measured by short circuit current, forskolin stimulation, and inh-172 inhibition as a measure of editing efficiency. Result(s): Flow cytometry showed that polymer R achieved more than 85% GFP transfection, compared with a maximum of approximately 35% for the other three polymers at the maximum 150-ng dose, with approximately 80% viability normalized to untreated cells. In addition, polymer R achieved GFP MFI more than one order of magnitude as high as other formulations (~30 000 vs 2700 MFI) for the other three polymers at 150-ng dose and 40 w/w ratio. CFBE cells transfected with polymer R nanoparticles containing ABE and guide RNA at 75 ng and 150 ng showed mean CFTR function increase to 10 muA 6 (standard error of the mean [SEM] 1.1 muA) (~10% of WT) and 6.3 muA (SEM 0.9 muA) (~6% of WT), respectively. Greater toxicity at the higher dose could explain the larger increase in CFTR current at the lower dose. DNA-encoded ABE plasmid and gRNA showed a less robust increase in CFTR function (2.9 muA [SEM 0.4 muA] for 75-ng dose;3.0 muA [SEM 0.4 muA] for 150-ng dose), which was probably a result of the nanoparticle formulation being optimized for RNA instead of DNA cargo or the additional intracellular barriers that must be overcome for successful DNA delivery. Conclusion(s): We demonstrated that an optimized nanoparticle formulation containing ABE and gRNA can correct splicing of isogenic cells bearing the 3120 + 1G >A CFTR variant, resulting in recovery of CFTR function. In ongoing work, we are adapting these nanoparticles for RNA- and DNAencoded ABE and gRNA delivery to primary human bronchial epithelial cells.Copyright © 2022, European Cystic Fibrosis Society. All rights reserved

Depressive symptoms and conspiracy beliefs

Conspiratorial beliefs can endanger individuals and societies by increasing the likelihood of harmful behaviors such as the flouting of public health guidelines. While scholars have identified various correlates of conspiracy beliefs, one factor that has received scant attention is depressive symptoms. We use three large surveys to explore the connection between depression and conspiracy beliefs. We find a consistent association, with the extent of the relationship depending on individual and situational factors. Interestingly, those from relatively advantaged demographic groups (i.e., White, male, high income, educated) exhibit a stronger relationship between depression and conspiracy beliefs than those not from such groups. Furthermore, situational variables that ostensibly increase stress-such as having COVID-19 or parenting during COVID-19-exacerbate the relationship while those that seem to decrease stress, such as social support, vitiate it. The results provide insight about the development of targeted interventions and accentuate the need for theorizing about the mechanisms that lead depression to correlate with conspiracy beliefs.Copyright © 2022 The Authors. Applied Cognitive Psychology published by John Wiley & Sons Ltd.

Co-Occurring Physical Health Challenges in Neurodivergent Children and Young People: A Topical Review and Recommendation

Background: Neurodivergence has been established as associated with a significant number of co-occurring physical conditions, particularly for autistic individuals who are at risk for increased pain, hypermobility (including Ehlers-Danlos Syndrome) and gastrointestinal problems. However, data, so far, has been focused on adults and generally limited to discussions of condition prevalence alone. Method(s): The following article will present a topical review of the literature considering evidence for increased physical health concerns within neurodivergent populations, particularly autistic individuals, with a focus on the impact that these physical health concerns may have in an educational setting. Results and discussion: The impact of physical health concerns within neurodivergent populations in an educational setting may be concerning. Such populations may face a range of challenges in obtaining appropriate support for physical conditions. We discuss a number of said challenges including;communication challenges, misattributing physical health symptoms as a part of neurodivergence, and a history of not being believed, which limits symptomatic reporting. We further consider the potential impact these physical health concerns may have on scholastic and social development, such as impacts for attainment and attendance. Furthermore, we provide recommendations for teachers, parents/carers and other allied professionals in young people's lives, on supporting young neurodivergent people with physical health concerns.Copyright © 2023 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.

Effect of facemasks on speech intelligibility

With the advent of COVID, the wearing of face covering has been obligatory in both medical and everyday life. This paper describes three experiments undertaken to establish the effect of face coverings on speech sound power, speech directivity and speech intelligibility. The experiments used two different approaches: acoustic measurements and word scores. The face coverings assessed were a 'standard blue' surgical mask, a typical fabric mask, a prototype clear mask and a plastic transparent visor. The study showed that non-native English speakers had by far the most difficulty in comprehending English language speech when face coverings were worn during phonetically-balanced word list tests. All the masks were found to noticeably affect speech intelligibility, with the surgical mask having the least detrimental effect. The results are also compared to objective measurements of their physical acoustic characteristics to establish their performance. © 2022 Internoise 2022 - 51st International Congress and Exposition on Noise Control Engineering. All rights reserved.

Etrasimod for the treatment of ulcerative colitis: analysis of infection rates from the phase 3 ELEVATE UC 52 and ELEVATE UC 12 clinical trials

Background: Infections are an important safety concern in patients with IBD and may be due to its therapies, such as corticosteroids. Etrasimod is an investigational, once-daily, oral, selective sphingosine 1-phosphate receptor 1,4,5 (S1P1,4,5) modulator in development for the treatment of moderately to severely active ulcerative colitis (UC). The biologic effect of etrasimod leads to selective and reversible lymphocyte retention in lymph nodes with a decrease in peripheral lymphocyte count. We report the infection events from the phase 3 ELEVATE programme. Method(s): Infection events were evaluated in the pivotal UC pooled safety analyses set comprising two phase 3 studies: ELEVATE UC 52 (NCT03945188) and ELEVATE UC 12 (NCT03996369). Subjects (16- 80 years) with moderately to severely active UC were randomised 2:1 to once-daily etrasimod 2 mg or placebo (PBO). We report the n (%) and exposure-adjusted incidence rate (EAIR) of infections including serious infections, severe infections, opportunistic infections (including tuberculosis), and herpes infections. Infections were considered adverse events of special interest (AESI) if they were severe (>= CTCAE Grade 3), were opportunistic infections, or were herpes zoster or herpes simplex infections. Result(s): From the pooled ELEVATE UC 12 and ELEVATE UC 52 trials, 527 subjects received >=1 dose of etrasimod 2 mg (265.6 subject-years of exposure) and 260 subjects were randomised to PBO (103.0 subjectyears of exposure). Infections were similar between treatment groups (etrasimod: 99 [18.8%], EAIR=0.41;PBO: 46 [17.7%], EAIR=0.52). The most frequent infections in both groups were COVID-19, urinary tract infections, and nasopharyngitis (Table 1). Serious infections occurred in 3 (0.6%) subjects in the etrasimod arm (EAIR=0.01) and 5 (1.9%) in PBO arm (EAIR=0.05). Two cases of herpes zoster were reported in each treatment group (etrasimod: 0.4%, EAIR<0.01;PBO: 0.8%, EAIR=0.02);these were localised and nonserious. One opportunistic infection was reported in each arm (etrasimod: Subject withdrew from the study on day 20, the AE of Cytomegalovirus infection [Grade 2] was reported on day 36;PBO: Tuberculosis [Grade 2]). Overall, 3 cases of infection led to discontinuation: 2 in the etrasimod arm (both mild) and 1 in the PBO arm (Table 2). No subject with an absolute lymphocyte count <0.2x109/L subsequently reported a serious/ severe or opportunistic infection. There were no deaths. Downloaded from https://academic.oup.com/ecco-jcc/article/17/Supplement-1/i689/7010119 by guest on 04 February 2023 Sample output to test PDF Combine only i690 Poster presentations In these trials, etrasimod-treated subjects reported no in-crease in infections relative to PBO. Serious infections and herpes zoster were more commonly reported in the PBO-treated group. Longer-term follow-up data from the ongoing 5-year open-label extension will fur-ther characterize the etrasimod safety profile.

Implementing clinical guidelines for co-occurring substance use and major mental disorders in Swedish forensic psychiatry: An exploratory, qualitative interview study with mental health care staff.

INTRODUCTION: Patients with substance use disorders (SUD) and co-occurring mental disorders (COD) within forensic psychiatric care often suffer poor treatment outcomes and high rates of criminal recidivism, substance use, and psychiatric problems. This study aimed to describe the conditions for, and mental health care staff's experiences with, implementing integrated SUD-focused clinical guidelines, including assessment and treatment for patients with COD at a high-security forensic mental health services (FMHS) facility in Sweden. METHODS: Study staff conducted nineteen semi-structured interviews with health care staff experienced in administering the new SUD assessment and treatment. The study conducted a thematic analysis to describe the health care staff's experiences with these guidelines and suggestions for improvement. RESULTS: Most participants reported appreciation for the implementation of clinical guidelines with an SUD focus, an area they considered to have previously been neglected, but also noted the need for more practical guidance in the administration of the assessments. Participants reported the dual roles of caregiver and warden as difficult to reconcile and a similar, hindering division was also present in the health care staff's attitudes toward SUD. Participants' reports also described an imbalance prior to the implementation, whereby SUD was rarely assessed but treatment was still initiated. One year after the implementation, an imbalance still existed, but in reverse: SUD was more frequently assessed, but treatment was difficult to initiate. CONCLUSIONS: Despite indications of some ambivalence among staff regarding the necessity of the assessment and treatment guidelines, many participants considered it helpful to have a structured way to assess and treat SUD in this patient group. The imbalance between frequent assessment and infrequent treatment may have been due to difficulties transitioning patients across the "gap" between assessment and treatment. To bridge this gap, mental health services should make efforts to increase patients' insight concerning their SUD, flexibility in the administration of treatment, and the motivational skills of the health care staff working with this patient group. Participants considered important for enhancing treatment quality a shared knowledge base regarding SUD, and increased collaboration between different professions and between in- and outpatient services.

A case series of 25 cats with effusive and non-effusive feline infectious peritonitis treated with a combination of remdesivir and GS-441524

Feline infectious peritonitis (FIP) has until recently carried a guarded prognosis due to a lack of efficacious treatments. Preliminary studies using remdesivir and GS-441524 for treatment of FIP have shown promising results. Licensing of these drugs for use in humans with COVID-19 has resulted in improved accessibility for veterinary use in the UK. This case series describes clinical outcomes of cats with FIP treated with injectable remdesivir and oral GS-441524. Twenty-five cats were diagnosed with FIP at a referral hospital in the UK between August 2021 and March 2022. Diagnosis was based on a combination of clinical signs, laboratory, imaging and cytological findings, and immunocytochemistry. Twenty cats presented with effusive FIP and 5 cats with non-effusive FIP. Five cats had neurological signs and 4 cats had significant ocular involvement. At the time of writing, 10 cats had successfully completed an 84-day course of remdesivir and GS-441524 treatment with complete clinical and biochemical remission. Ten cats were in clinical remission and still receiving treatment and 5 cats were euthanised a median of 2 days (range 1-13) after starting treatment. All surviving cats received remdesivir intravenously for a median of 5 days (range 2-9) at a median dose of 15 mg/kg (range 10-20). Higher doses were used for cats with non-effusive FIP, neurological or ocular signs, and for effusive cases presenting with severe clinical signs. All 20 cats demonstrated significant clinical response after a median of 2 days (range 2-5). Two cats received subcutaneous remdesivir treatment only following initial intravenous therapy. Eight cats received subcutaneous remdesivir for a median of 14 days (range 4-68) before transitioning onto an equivalent dose of oral GS- 441524. Ten cats received oral GS-441524 treatment immediately following intravenous remdesivir therapy. Both drugs were well tolerated although local skin reactions and pain with subcutaneous injections of remdesivir was observed. Of the five cats that were euthanised, three cats were euthanised within 3 days of starting treatment as a result of comorbidities or financial constraints. One ragdoll developed a T3-L3 myelopathy 7 days into treatment with 15mg/kg remdesivir, with no clinical improvement following dose escalation. Post-mortem confirmed FIP within the central nervous system. Another ragdoll also developed central nervous system signs 13 days into treatment with 20mg/kg remdesivir and was subsequently euthanised. This case series demonstrated the successful use of injectable remdesivir and oral GS-441524 for the treatment of FIP in 20 out of 25 (80%) cats.

Immune responses, viral shedding, and COVID-19 symptom burden from breakthrough SARS-CoV-2 infection in a 2:1 randomized, double-blind, placebo-controlled Phase 3 study of AZD1222 (ChAdOx1 nCoV-19) vaccination

Background. Breakthrough infections post-COVID-19 vaccination increase with waning immunity and typically produce milder disease than infections in unvaccinated individuals. We investigated immuno-virologic responses and COVID-19 symptom burden upon breakthrough infection in participants from a Phase 3 study of 2-dose primary series AZD1222 vaccination (NCT04516746) to explore disease attenuation. Methods. Study participants who experienced protocol-defined COVID-19 symptoms initiated a series of illness visits over 28 days with collection of sera, nasopharyngeal (NP) swabs and saliva samples (SS), and documentation of symptoms (data-cut off: July 30, 2021). For baseline-seronegative participants with PCR-confirmed SARS-CoV-2 infection >=15 days after dose 2 of AZD1222 or placebo we assessed: anti-SARS-CoV-2 spike (S), nucleocapsid (N) and neutralizing antibody (Ab) titers by multiplex immunoassay and SARS-CoV-2 pseudovirus assay in sera;viral load by quantitative RT-PCR in NP swabs;and viral shedding by qualitative and quantitative RT-PCR in SS. Data were stratified by age and SARS-CoV-2 variant, and time since primary series dose 2. Results. Illness Day 1 (ILL-D1) S Ab GMTs in AZD1222 vaccinees were similar to peak GMTs seen 14 days after dose 2 of AZD1222 and were higher vs placebo at all timepoints. The magnitude of S Ab response differed by age: median GMTs were lower at ILL-D1 and higher at ILL-D14 in vaccinees aged >=65 vs 18-64 years (Fig.1). ILL-D1 overall, SARS-CoV-2 ancestral, alpha, and epsilon variant viral load titers in NP swabs were lower in vaccinees vs placebo (Fig 2). Mean viral load in NP swabs and viral shedding titers in SS were lower in vaccinees vs placebo at all timepoints. Vaccinees reported fewer COVID-19 symptoms than placebo participants, and experienced shorter symptom duration, particularly for fatigue and difficulty breathing. Figure 1. SARS-CoV-2 spike IgG antibody titers upon SARS-CoV-2 infection by participant age in AZD1222 vaccinees and placebo recipients during illness visits Figure 2. Quantification of viral load (nasopharyngeal swabs quantitative viral titer) by SARS- CoV-2 variant at Illness Visit Day 1 Conclusion. Improved S Ab responses, lower viral loads, and reduced symptom burden upon breakthrough infection in vaccinees vs placebo recipients, suggest that robust recall responses to AZD1222 vaccination may attenuate COVID-19 disease severity and duration. These findings alongside data on cellular immune responses to breakthrough infection will inform understanding of protective immunity to SARS-CoV-2 infection.

Clinical Features and Long-Term Follow-up of Children Evaluated for Persistent Unwellness Following Acute COVID-19

Background. Few data exist on the clinical features and outcome of pediatric patients with persistent unwellness following acute COVID. Methods. Norton Children's and the University of Louisville School of Medicine opened a Post-COVID Clinic (PCC) in Oct 2020. The study cohort included all 104 patients referred to the PCC through Dec 2021. Clinical data were collected using a standardized template during routine care. Diagnostic tests and subspecialty referrals were ordered at the discretion of clinic physicians. A telephone interview in 2022 assessed longterm outcomes. Results. The median age at first visit was 14 y (IQR=12,16);the age distribution of PCC patients was different from that of Pediatric Infectious Diseases Clinic (PIDC) patients in that there were few patients under 10 y. Males and females were equally represented. The racial distribution was similar to that of PIDC, but patients were more often from mid/upper socioeconomic status (using commercial insurance as a surrogate;p=0.001). The median interval from onset of COVID to the first PCC visit was 2 mo (IQR=1.5,4.4), and an increase in referrals was seen 2 mo after each COVID wave in the community (Figure 1). Most PCC patients reported good health prior to COVID. Fifty-four percent of patients experienced moderate or severe disability according to Modified Functional Disability Inventory scores at the first PCC visit (Figure 2;median score 14, IQR=6,19). Common symptoms were fatigue or lethargy (73%), headache (60%), shortness of breath or difficulty breathing (48%), exercise intolerance (47%), and chest pain (39%). Few abnormalities were found on routine diagnostic tests. Common subspecialty referrals were to Neurology, Cardiology, Pulmonology, Physical Therapy, and Psychiatry;the total number and types of referrals varied widely among patients. Most patients did not receive a specific diagnosis other than post-COVID syndrome. Sixty-three follow-up interviews were completed a median of 6 mo after the initial PCC visit;79% of patients were improved or back to normal. (Figure Presented) Upper and lower quartiles are marked by the top and bottom of the boxes. The median is marked by a horizontal line inside the box and the mean is shown by the 'x.' Top whiskers indicate the largest value <= the 3rd quartile plus 1.5 times the interquartile range;bottom whiskers indicate the smallest value >= the 1st quartile minus 1.5 times the interquartile range. Open circles extending beyond the whiskers represent outliers. Disability categories are from Kashikar-Zuck S, et al. Pain 2011;152:1600-1607. Conclusion. This large experience with a PCC established early in the pandemic demonstrates that symptoms of post-COVID unwellness are non-specific and varied, routine tests are seldom diagnostic, and the natural history is one of gradual recovery.

Social Disruption, Gun Buying, and Anti-System Beliefs

Gun ownership is a highly consequential political behavior. It often signifies a belief about the inadequacy of state-provided security and leads to membership in a powerful political constituency. As a result, it is important to understand why people buy guns and how shifting purchasing patterns affect the composition of the broader gun-owning community. We address these topics by exploring the dynamics of the gun-buying spike that took place during the COVID-19 pandemic, which was one of the largest in American history. We find that feelings of diffuse threat prompted many individuals to buy guns. Moreover, we show that new gun owners, even more than buyers who already owned guns, exhibit strong conspiracy and anti-system beliefs. These findings have substantial consequences for the subsequent population of gun owners and provide insight into how social disruptions can alter the nature of political groups.

The COVID-19 Pandemic Disrupted Both School Bullying and Cyberbullying

One-fifth of US high school students report being bullied each year. We use internet search data for real-time tracking of bullying pat-terns as COVID-19 disrupted in-person schooling. We first show that pre-pandemic internet searches contain useful information about actual bullying behavior. We then show that searches for school bul-lying and cyberbullying dropped 30-35 percent as schools shifted to remote learning in spring 2020. The gradual return to in-person instruction starting in fall 2020 partially returned bullying searches to pre-pandemic levels. This rare positive effect may partly explain recent mixed evidence on the pandemic's impact on students' mental health and well-being. (JEL H75, I12, I21, I28, I31)

Prescription Opioid Nonmedical Use via Oral Manipulation: An Under-Recognized Risk

Learing Objectives (1) Define nonmedical use of prescription opioids and the routes of administration used, including oral intact, oral manipulation, and non-oral routes. (2) Describe differences in patient characteristics and behaviors of those who report nonmedical use of prescription opioids via oral intact versus oral manipulation versus nonoral routes of administration. (3) Describe the reasons why nonmedical use of prescription opioids via oral manipulation should be considered high risk behavior in your patient population. Purpose While overdose deaths involving prescription opioid medications are decreasing, the latest data regarding overall substance abuse in the United States are daunting, exacerbated by the collision of the opioid epidemic and the COVID-19 pandemic. Recent studies have focused on closing the knowledge gap regarding the substance use pathways and behavioral profiles contributing to this ongoing public health crisis. The increased risk of prescription opioid abuse via non-oral routes of administration has been studied, suggesting the relative risk of an exposure resulting in a life-threatening event or death was 2.43 (95% CI 1.97, 2.99) if non-oral routes were reported compared to exposures involving oral route only. The increased risk associated with non-oral routes of administration of a prescription opioid is important, however, the majority of prescription opioid use occurs via the oral route of administration. Oral route of administration includes ingesting an intact tablet or capsule ('oral intact'), as well as manipulation of prescription opioid products prior to ingestion (chewing, crushing or dissolving) for the purpose of changing the user experience, for example, to increase the speed and intensity of a psychotropic effect ('oral manipulation'). Regardless of intent, oral manipulation is considered nonmedical use (NMU), meaning that the prescription medication is being used in a different way or for a different purpose than intended, whether it be for therapeutic reasons (misuse) or for psychotropic effect such as to get high (abuse). It is unknown whether those who engage in prescription opioid oral manipulation are at an increased risk of also using illicit drugs or engaging in even higher risk non-oral routes of administration. The purpose of this study was to utilize data from a general population study in the United States (US) to compare biopsychosocial and behavioral characteristics among those reporting prescription opioid NMU via oral intact route only, oral manipulation, and non-oral routes of administration. Methods This was an observational study conducted with a nationally representative sample of the general adult US population. Participants were recruited via e-mail through YouGov, a survey panel company that has an established participant registry as well as a validated sampling methodology to ensure representativeness of the research. The study used a self-administered online survey drawn from the opt-in panelists using samplematching methods to represent a target population of US adults ages 18-49 years. Inclusion criteria was a history of prescription opioid NMU. Four mutually exclusive groups were studied: (1) those who only reported prescription opioid NMU via oral intact route of administration, (2) those who reported oral manipulation but no non-oral routes of administration, (3) those who reported non-oral route of administration but no oral manipulation, and (4) those who reported both oral manipulation and non-oral routes of administration. Prescription opioid NMU via oral intact route of administration may have also been reported in groups 2, 3, and 4. Data were collected on demographics (age, sex, race, ethnicity, education, college enrollment, employment, etc.), select co-morbidities (diagnosis of anxiety, depression, alcohol use disorder, substance use disorder, etc.), routes of administration, sources of drug procurement, primary reason for use, factors influencing use of non-oral routes of administration, and concomitant use of other substances wi h prescription opioid NMU. Prescription opioid product names, active ingredients, and photos were used to aid in selection of substances used. Prescription opioid NMU included ANY of the following: (1) use for any reason, even once, without your own prescription, (2) use in ways other than prescribed (such as taking more than prescribed, more often than prescribed, or for any other reason or way than prescribed), and (3) use for the feeling or experience the medication caused (such as a feeling of being high, enhancement of other drugs, prevention or treatment of withdrawal symptoms, or other feelings). The route referenced as oral manipulation was defined as physical alteration of a prescription medication, such as chewing, crushing, cutting, or dissolving, prior to ingestion. Results Of the 24,000 study participants, 4,590 reported a history of prescription opioid NMU and met inclusion criteria for analysis: 3,477 (75.8%) reported prescription opioid NMU via oral intact only;438 (9.5%) reported oral manipulation but no non-oral routes of administration;390 (8.5%) reported non-oral routes of administration but no oral manipulation;and 285 (6.2%) reported both oral manipulation and nonoral route of administration. Compared to oral intact only users, those who reported oral manipulation and/or nonoral routes were more likely to be male, younger in age, and cover healthcare costs through Medicare and/or Medicaid. They were also more likely to have been arrested compared to oral intact only users. Those who reported oral manipulation (with or without non-oral routes) were more likely to be currently enrolled in a college or university than those who reported prescription opioid NMU via oral intact route only. The prevalence of lifetime diagnosis of select behavioral and mental health comorbidities was significantly higher among all oral manipulation and non-oral route study groups compared to the oral intact only group. The prevalence of anxiety, ADHD, bipolar, and alcohol use disorder was similar between those who reported prescription opioid NMU via oral manipulation and those who reported non-oral routes. The prevalence of substance use disorder significantly increased from the oral manipulation group to the non-oral route group to the oral manipulation plus non-oral route group. The age of initiation for most substances was younger among those in the oral manipulation and non-oral route groups compared to the oral intact only group. In relation to polysubstance use, the prevalence of concomitant use of tobacco, alcohol, marijuana, cocaine, sedatives, methamphetamine, prescription stimulants, heroin, and street fentanyl was significantly higher for those reporting prescription opioid NMU via oral manipulation and those reporting any non-oral route of administration compared to the oral intact only group. The prevalence of use to treat or prevent opioid-related withdrawal was similar between those who reported prescription opioid NMU via oral manipulation only (11.9) and non-oral routes only (13.6), yet over 3 times that (42.5) for those who reported both oral manipulation and non-oral routes of administration. Interestingly, those who reported oral manipulation were significantly more likely to do so to treat pain, for energy/stimulation, or to enhance the effect of other drugs than those who reported prescription opioid NMU via non-oral routes. Conclusion This study illustrates that biopsychosocial characteristics and behaviors of individuals that engage in prescription opioid NMU via oral manipulation are more similar to those that engage in non-oral routes of administration than with those that engage in oral intact route only. Hence, oral manipulation cannot be presumed as benign or insignificant. While this study did not allow for determination of causation, the data suggest a greater likelihood of high-risk behaviors in those who engage in prescription opioid NMU via oral manipulation than oral intact. These conclusions may be surprising to clinicians who view non-oral (intranasal or intravenous) use as the firs sign of concerning behavior. Overall, these findings have significant implications for clinicians and the greater research community as they highlight why oral manipulation (chewing, crushing, dissolving prior to ingestion) of a prescription opioid medication is not to be ignored and should be as concerning as non-oral use: both oral manipulated and non-oral routes suggest a significant potential for prescription opioid misuse, abuse and diversion, and related consequences such as overdose and death.

The publics of public health: learning from COVID-19

This commentary reflects on what has been learnt from government and public health responses to COVID-19, suggesting a tension between ‘business as usual’ forms of public health in the face of crisis, and the possibilities for a step-change towards a ‘healthy publics’ approach. We set out a range of ways that diverse, multiple publics have been implicated or brought into being during the COVID-19 pandemic, and we argue that these have generally been ignored or erased by agents or agencies of public health, keen to preserve certainty in their messaging and public confidence in their authority. We conclude with five principles for re-organising pandemic responses around a richer, more context-dependent and diverse account of ‘the public’.

Developing & centralising a nurse-led local anaesthetic (LA) transperineal (TP) biopsy service during COVID: A success story

Introduction: During the first COVID-19 wave, the BAUS Section of Oncology issued guidance to minimise risks of sepsis and general anaesthesia at prostate biopsy. Consequently, and as a result of diminished diagnostics capacity on Trust acute sites, we implemented a centralised network-wide nurse-led LA TP biopsy service on a COVID-secure 'green' site and abandoned trans-rectal biopsies. We evaluated the impact of this service improvement on patient waiting times before and after national lockdown in March 2020. Method: Classic Quality Improvement (QI) methodology was used with continuous data collection and waiting list management by clinical staff with standard admin support. Balancing measurements were collected. Run charts were used to confirm whether a change led to a real and sustainable improvement. Results: The number of days waiting, from time of request to date of biopsy, is presented in the following run chart. The mean waiting time for those pre lockdown was 145 days (SD 57) whereas post lockdown was 23 days (SD 20). This identified that there was a significant difference between the average waiting time pre and post lockdown (U=55.5, p= ,0.001) There were also reductions in waiting time when subcategorised into planned Active Surveillance cases, target cases and delayed cases. Conclusions: Centralising the TP biopsy service and converting to a nurse led LA service has led to reductions in waiting lists and was safely expedited and resilient even in the COVID-19 pandemic. Allowing a second advanced TP practitioner to be fully trained, during COVID. The service was highly valued by patients and staff.

Designing Hybrid Spaces for Learning in Higher Education Health Contexts

In Aotearoa New Zealand, undergraduate, professional health courses include social work, nursing, and biosciences courses that focus on learning how to support people with physical, mental, spiritual, and psychosocial/relational health and well-being concerns. Recently, the need for a nuanced understanding of how technologies might extend students’ experiences across and beyond physical classrooms has emerged. Drawing on contemporary ecological perspectives in education, this paper emphasises that design for learning involves a complex web of elements. Anchored in practice theory, the paper uses the analytical lens of the Activity-Centred Analysis and Design (ACAD) framework to explore how tools, tasks, and various social arrangements influence student learning activity. A multiple case study investigated the experiences and insights of five higher education teacher-designers, discussing the relationship between features of course design and their perceived impact on emergent learning activity. Design elements are also discussed in relation to the experience of teacher-designers adapting and transitioning to hybrid environments during Covid-19, whilst working with diverse learners in different contexts and disciplines. Interviews with teacher-designers revealed what they believe contributes to productive learning activity, such as the importance of creating safe learning environments, an overall appreciation for the opportunity to use technology for teaching and learning, and their use of a heutagogical approach, which emphasizes the development of knowledge and skills for teaching in hybrid learning environments. The paper argues for practical and targeted support to acknowledge, encourage, and enhance teacher-designers’ capabilities for transformational use of hybrid learning environments in health education. © 2021, The Author(s), under exclusive licence to Springer Nature Switzerland AG.