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Sarah Candy,1,2 Julie Reeve,2 Rosie Dobson,3,4 Robyn Whittaker,3,4 Jeffrey Garrett,1 Jim Warren,5 Amanda Calder,3 Taria Tane,3 Trina Robertson,4 Usman Rashid,2 Denise Taylor2 1Te Whatu Ora Counties Manukau Health, Auckland, New Zealand; 2Health & Rehabilitation Research Institute, Auckland University of Technology, Auckland, New Zealand; 3National Institute for Health Innovation, University of Auckland, Auckland, New Zealand; 4Te Whatu Ora Waitematā, Auckland, New Zealand; 5School of Computer Science, University of Auckland, Auckland, New ZealandCorrespondence: Sarah Candy, Department of Respiratory Medicine, Te Whatu Ora Counties Manukau, Private Bag 93311, Otahuhu, Auckland, 1640, New Zealand, Tel +64274363116, Email scandy@middlemore.co.nzPurpose: Pulmonary rehabilitation (PR) is vital in the management of chronic respiratory disorders (CRDs) although uptake, attendance and completion are poor. Differing models of delivering PR are emerging in an attempt to increase the uptake and completion of this intervention. This study aimed to evaluate participant rate of attendance and completion of PR when given a preference regarding model of delivery (centre-based and mPR). Secondary aims were to evaluate the factors affecting patient preference for model of delivery and determine whether mPR is non-inferior to centre-based PR in health outcomes.Methods: A multi-centre non-inferiority preference based clinical trial in Auckland, New Zealand. Participants with a CRD referred for PR were offered the choice of centre-based or mHealth PR (mPR). The primary outcome was completion rate of chosen intervention.Results: A total of 105 participants were recruited to the study with 67 (64%) preferring centre-based and 38 (36%) mPR. The odds of completing the PR programme were higher in the centre-based group compared to mPR (odds ratio 1.90 95% CI [0.83– 4.35]). Participants opting for mPR were significantly younger (p = 0.002) and significantly more likely to be working (p = 0.0001). Results showed that mPR was not inferior to centre-based regarding changes in symptom scores (CAT) or time spent in sedentary behaviour (SBQ). When services were forced to transition to telehealth services during COVID-19 restrictions, the attendance and completion rates were higher with telephone calls and video conferencing compared to mPR – suggesting that synchronous interpersonal interactions with clinicians may facilitate the best attendance and completion rates.Conclusion: When offered the choice of PR delivery method, the majority of participants preferred centre-based PR and this facilitated the best completion rates. mPR was the preferred choice for younger, working participants suggesting that mPR may offer a viable alternative to centre-based PR for some participants, especially younger, employed participants.Keywords: chronic respiratory disorder, mHealth, preference, pulmonary rehabilitation, telehealth, telerehabilitation

Abstract Background Improved survival of neonates with esophageal atresia with/without tracheoesophageal fistula (EA/TEF) has resulted in increased prevalence of gastro-esophageal and respiratory-related morbidities. However, long-term outcome data on these patients remains limited, making it difficult to substantiate any guidelines on their chronic care. The purpose of our study is to report on their post-operative outcomes especially the long-term gastro-esophageal and respiratory morbidities. Methods This was a retrospective review of 65 patients (39 males, 26 females) who underwent EA/TEF repair from 1996 to 2019 at a single tertiary institution. Follow up data pertaining to clinical characteristics, operative management and long-term gastro-esophageal and respiratory morbidities was analyzed. Results Fifty-seven patients (87.7%) had Gross Type-C anatomy, followed by 5(7.7%) patients with Type-A, 1(1.5%) with Type-B and 1 with Type-D. One patient had a late diagnosis of H-type fistula (Type-E). Thirteen (20%) patients had long-gap EA. Median age at first surgery was day 1 (IQR 1–2) of life. All patients underwent bronchoscopy at their index surgery. All 52 non-long gap EA (LGEA) patients underwent primary anastomosis, while most (76.9%) LGEA patients underwent staged repair. Post-operatively, 4(6.2%) developed anastomotic leak which resolved with conservative management. Three (4.6%) had recurrent TEF, 2 underwent re-do ligation. Twenty (30.8%) patients developed anastomotic strictures, with 15 requiring serial dilatation. Long-term burden of gastro-esophageal and respiratory morbidity was high (63.1%; 64.6% respectively). The majority (n = 39,60%) of patients required active follow-up for a median duration of 5 years (IQR 1.5–10 years). Predominant conditions were gastroesophageal reflux disease (n = 28, 43.1%), dysphagia (n = 20, 30.8%), recurrent respiratory infections (n = 23, 35.3%), chronic cough (n = 19, 29.2%), and pneumonia (n = 19, 29.2%). Tracheomalacia was diagnosed in 22(33.8%), 2 of whom required tracheostomy for severe disease. Overall mortality rate was 10.8% (n = 7): 5 demised due to chronic respiratory failure, while 2 demised intra-operatively during the index surgery. Conclusion Despite successful surgical repair for EA/TEF, our data demonstrated significant morbidities among EA/TEF survivors, thus highlighting the importance of long-term multi-disciplinary care with collaboration between respiratory, gastroenterology, and otolaryngology specialists. Level of evidence Prognostic, Level IV.

Objective Osteoarthritis (OA) affects 8.75 million people in the UK. Physical activity (PA) is recommended as a core treatment, yet nearly half of people with OA are inactive. Accessible and user-friendly interventions are needed to motivate people with OA to be active. Digital behaviour change interventions (DBCIs) might help to support people with OA to self-manage their own levels of PA. The aim of this project was to co-develop and test a DBCI to motivate people with OA to be active. Methods A mixed methods design was adopted to build the theoretical foundations, develop, and test a complex DBCI. Two patient research partners with lived experience of OA were recruited onto the project team to assist with intervention development, which was guided by the intervention mapping (IM) approach. Interviews and think-aloud sessions were then used to explore attitudes, values, and perceived effectiveness of the website. Results The IM approach enabled the development of a prototype website to be illustrated in a clear and transparent way, showing a link between the practical materials adopted within the website and the theoretical constructs they were attempting to change. Potential users highlighted the importance of clear, easy-to-understand information, focusing on enjoyment and social connectedness. Conclusions DBCI development should be based on theory, adequately described, and thoroughly tested with potential users to understand how they might choose to integrate digital interventions into everyday life.

Purpose: The purpose of this study was to study the presentation of patients who underwent Meckel's diverticulectomy (MD) and utility of pertechnetate Meckel's scan in the diagnosis of MD. Methods: The clinical presentation of a retrospective cohort of patients who underwent MD from January 2007 to December 2019 was studied. The modes of presentation, treatment, and the diagnostic utility of pertechnetate Meckel's scans were evaluated. False-positive and false-negative scans were reviewed. The presence of gastric mucosa on histology of Meckel's was correlated with presentation as gastrointestinal bleeding and positive scan results. Results: Ninety-nine patients underwent MD. Thirty-five out of 263 (13.3%) Meckel's scans done were positive. There was a male preponderance (86.9%). The peak age of presentation was 0–4 years (rectal bleeding or intestinal obstruction). Only a third of the patients with Meckel's diverticulum Meckel's had a preoperative diagnosis of Meckel's. The sensitivity/specificity of Meckel's scan was higher in patients presenting with painless rectal bleeding. Seven patients were false positive (weak tracer uptake or ectopic uptake) and five were false negative. Two patients with false-negative Meckel's scan, having gastrointestinal bleeding had gastric mucosa on histology of Meckel's. Conclusion: Meckel's diverticulum has a male predominance. Meckel's scan has a high sensitivity in the children presenting with fresh painless rectal bleeding but is of limited use in the diagnosis of Meckel's diverticulum in other forms of presentations. False-positive scans can be anticipated in the presence of weak or ectopic uptake. False-negative scans can occur even in the presence of bleeding and in spite of the presence of gastric mucosa in the Meckel's diverticulum. Laparoscopy is a useful tool in diagnosis and treatment.

Background: Increased death due to the opioid epidemic in the United States has necessitated the development of new strategies to treat addiction. Monoclonal antibodies and antidrug vaccines provide a tool that both aids addiction management and reduces the potential for overdose. Dual drug vaccines formulated by successive conjugation or by mixture have certain drawbacks. The current study examines an approach for combatting the dangers of fentanyl-laced heroin, by using a hapten with one epitope that has domains for both fentanyl and heroin.Results: We evaluated a series of nine vaccines developed from chemically contiguous haptens composed of both heroin- and fentanyl-like domains. Analysis of the results obtained by SPR and ELISA revealed trends in antibody affinity and titers for heroin and fentanyl based on epitope size and linker location. In antinociception studies, the best performing vaccines offered comparable protection against heroin as our benchmark heroin vaccine, but exhibited attenuated protection against fentanyl compared to our fentanyl vaccine.Conclusion: After thorough investigation of this strategy, we have identified key considerations for the development of a chemically contiguous heroin–fentanyl vaccine. Importantly, this is the first report of such a strategy in the opioid–drug–vaccine field.

Growing nonmedical use of prescription opioids is a global problem, motivating research on ways to reduce use and combat addiction. Medical cannabis ("medical marijuana") legalization has been associated epidemiologically with reduced opioid harms and cannabinoids have been shown to modulate effects of opioids in animal models. This study was conducted to determine if Δ9-tetrahydrocannabinol (THC) enhances the behavioral effects of oxycodone. Male rats were trained to intravenously self-administer (IVSA) oxycodone (0.15 mg/kg/infusion) during 1 h, 4 h or 8 h sessions. Following acquisition rats were exposed to THC by vapor inhalation (1 h and 8 h groups) or injection (0-10 mg/kg, i.p.; all groups) prior to IVSA sessions. Fewer oxycodone infusions were obtained by rats following vaporized or injected THC compared with vehicle treatment prior to the session. Follow-up studies demonstrated parallel dose-dependent effects of THC, i.p., on self-administration of different per-infusion doses of oxycodone and a preserved loading dose early in the session. These patterns are inconsistent with behavioral suppression. Additional groups of male and female Wistar rats were assessed for nociception following inhalation of vaporized THC (50 mg/mL), oxycodone (100 mg/mL) or the combination. Tail withdrawal latency was increased more by the THC/oxycodone combination compared to either drug alone. Similar additive antinociceptive effects were produced by injection of THC (5.0 mg/kg, i.p.) and oxycodone (2.0 mg/kg, s.c.). Together these data demonstrate additive effects of THC and oxycodone and suggest the potential use of THC to enhance therapeutic efficacy, and to reduce the abuse, of opioids.

The two major impetuses to improve STEM education are the shift to online learning and increasing active learning and engagement. Although the COVID-19 pandemic necessitated a rapid shift to online learning, this shift came at the cost of losing on-ground active learning strategies. This study provides descriptive analytical information on the impact of COVID-19 as it relates to student engagement, attendance, and viewership of video-recorded lectures for a nonmajors chemistry course. After the shift online, lecture video views significantly increased and weekly attendance significantly decreased. Prior to the pandemic, on-ground engagement via an active learning activity (i.e., Plickers) was significantly associated with on-ground achievement (i.e., exam 1). However, no significant association was found between online engagement (i.e., written responses/feedback submitted via a learning management system, referred to as LMS student feedback) and online achievement (i.e., final exam), potentially because the engagement resembled a formative assessment more than an active learning activity. Nonetheless, there was tremendous value in soliciting LMS student feedback for directing the course. Throughout the online period, there was an average of 112 responses per assignment, for a total of 1,344 responses, representing roughly a third of the students. Finally, analyses revealed no significant association of on-ground and online engagement, which suggests a different subset of students engaged while on-ground vs online. Instructors should highly consider soliciting weekly feedback through low-stakes assignments to gauge student learning and improve their courses while online.

Abuse of prescription opioids is a growing public health crisis in the United States, with drug overdose deaths increasing dramatically over the past 15 years. Few preclinical studies exist on the reinforcing effects of oxycodone or on the development of therapies for oxycodone abuse. This study was conducted to determine if immunopharmacotherapy directed against oxycodone would be capable of altering oxycodone-induced antinociception and intravenous self-administration. Male Wistar rats were administered a small-molecule immunoconjugate vaccine (Oxy-TT) or the control carrier protein, tetanus toxoid (TT), and trained to intravenously self-administer oxycodone (0.06 or 0.15 mg/kg/infusion). Brain oxycodone concentrations were 50% lower in Oxy-TT rats compared to TT rats 30 min after injection (1 mg/kg, s.c.) whereas plasma oxycodone was 15-fold higher from drug sequestration by circulating antibodies. Oxy-TT rats were also less sensitive to 1-2 mg/kg, s.c. oxycodone on a hot water nociception assay. Half of the Oxy-TT rats failed to acquire intravenous self-administration under the 0.06 mg/kg/infusion training dose. Oxycodone self-administration of Oxy-TT rats trained on 0.15 mg/kg/infusion was higher than controls; however under progressive ratio (PR) conditions the Oxy-TT rats decreased their oxycodone intake, unlike TT controls. These data demonstrate that active vaccination provides protection against the reinforcing effects of oxycodone. Anti-oxycodone vaccines may entirely prevent repeated use in some individuals who otherwise would become addicted. Vaccination may also reduce dependence in those who become addicted and therefore facilitate the effects of other therapeutic interventions which either increase the difficulty of drug use or incentivize other behaviors.

The Nrf1 (Nuclear factor E2-related factor 1) transcription factor performs a critical role in regulating cellular homeostasis. Using a proteomic approach, we identified Host Cell Factor-1 (HCF1), a co-regulator of transcription, and O-GlcNAc transferase (OGT), the enzyme that mediates protein O-GlcNAcylation, as cellular partners of Nrf1a, an isoform of Nrf1. Nrf1a directly interacts with HCF1 through the HCF1 binding motif (HBM), while interaction with OGT is mediated through HCF1. Overexpression of HCF1 and OGT leads to increased Nrf1a protein stability. Addition of O-GlcNAc decreases ubiquitination and degradation of Nrf1a. Transcriptional activation by Nrf1a is increased by OGT overexpression and treatment with PUGNAc. Together, these data suggest that OGT can act as a regulator of Nrf1a.

RNA polymerase II (pol II) utilizes a complex interaction network to select and incorporate correct nucleoside triphosphate (NTP) substrates with high efficiency and fidelity. Our previous 'synthetic nucleic acid substitution' strategy has been successfully applied in dissecting the function of nucleic acid moieties in pol II transcription. However, how the triphosphate moiety of substrate influences the rate of P-O bond cleavage and formation during nucleotide incorporation is still unclear. Here, by employing β,γ-bridging atom-'substituted' NTPs, we elucidate how the methylene substitution in the pyrophosphate leaving group affects cognate and non-cognate nucleotide incorporation. Intriguingly, the effect of the β,γ-methylene substitution on the non-cognate UTP/dT scaffold (∼3-fold decrease in kpol) is significantly different from that of the cognate ATP/dT scaffold (∼130-fold decrease in kpol). Removal of the wobble hydrogen bonds in U:dT recovers a strong response to methylene substitution of UTP. Our kinetic and modeling studies are consistent with a unique altered transition state for bond formation and cleavage for UTP/dT incorporation compared with ATP/dT incorporation. Collectively, our data reveals the functional interplay between NTP triphosphate moiety and base pair hydrogen bonding recognition during nucleotide incorporation.

Background: Investigations have shown the different impacts that ACEs have on an individual’s adult life, on both physical and mental health, but they have not yet shown the issue of the influence of ACEs on adults and young adults. Objective/Participants and Setting: This systematic review, performed according to the PRISMA norms and guidelines, intended to understand the most frequent outcomes of adverse childhood experiences in the life of young adults and adults. Methods: Studies were identified through multiple literature search databases at EBSCOhost, Web of Science, and PubMed April 2023, and a total of 279 studies, published between 1999 and 2002, were excluded, 256 because of multiple factors: being duplicates, showing statistical analysis with correlations only, being systematic reviews or case studies, comprising individuals under the age of 18, and not meeting the intended theme; ultimately, we selected for the review a total of 23 studies. Results and Conclusions: The impacts of the various articles are subdivided into three main themes: antisocial and criminal behaviour; sexual Behaviour and intimate partner violence; and attachment, quality of life, and therapeutic alliance.