Mapping the adult human esophagus in vivo and in vitro.

Many esophageal diseases can arise during development or throughout life. Therefore, well-characterized in vitro models and detailed methods are essential for studying human esophageal development, homeostasis and disease. Here, we (1) create an atlas of the cell types observed in the normal adult human esophagus; (2) establish an ancestrally diverse biobank of in vitro esophagus tissue to interrogate homeostasis and injury; and (3) benchmark in vitro models using the adult human esophagus atlas. We created a single-cell RNA sequencing reference atlas using fresh adult esophagus biopsies and a continuously expanding biobank of patient-derived in vitro cultures (n=55 lines). We identify and validate several transcriptionally distinct cell classes in the native human adult esophagus, with four populations belonging to the epithelial layer, including basal, epibasal, early differentiating and terminally differentiated luminal cells. Benchmarking in vitro esophagus cultures to the in vivo reference using single-cell RNA sequencing shows that the basal stem cells are robustly maintained in vitro, and the diversity of epithelial cell types in culture is dependent on cell density. We also demonstrate that cultures can be grown in 2D or as 3D organoids, and these methods can be employed for modeling the complete epithelial layers, thereby enabling in vitro modeling of the human adult esophagus.

Parental practices and perspectives on health and digital technology use information seeking for children aged 0-36 months.

BACKGROUND: Parents commonly seek information to support the health and well-being of their children. The increasing availability of health information online and social changes related to the COVID-19 pandemic may have changed what information is sought, from whom, where, and why. This qualitative study explored parents' practices and perspectives on seeking health and digital technology use information for their young children. METHODS: Twenty parents, living in Australia (7 rural, 3 remote, and 10 metropolitan), with children aged 0-36 months completed a semi-structured interview. RESULTS: Parents commonly turned to friends and family and online sources to access health information for their young children. For all types of health information, including digital technology use, themes were identified surrounding aspects of information sources participants valued and accessibility of health services. Perceived credibility and trustworthiness, relatability with other parents, ease of accessibility and convenience, and actionable, bite-sized information were valued. Reduced accessibility to health services due to COVID-19 and geographical location, and need for agency in managing their child's health influenced parents' choice of source of information. Few participants actively sought information about digital technology use for their young child, with the main focus on screen time. CONCLUSION: Interactions with family and friends and online sources are important to parents when accessing health information for their child. Parents valued information sources which they considered trustworthy, credible, and relatable, as well as easily accessible and convenient. SO WHAT?: Dissemination of health information reflecting these values may empower parents during this early stage of parenthood.

Recruiting general practitioners and older patients with multimorbidity to randomized trials.

BACKGROUND: Older patients with multimorbidity are under-represented in experimental research. OBJECTIVE: To explore the barriers and facilitators to general practitioner (GP) and older patient recruitment and retention in a cluster randomized controlled trial (RCT). METHOD: This descriptive study uses qualitative and quantitative data from a cluster RCT, designed to evaluate the effectiveness of a medicines optimization intervention. The SPPiRE cluster RCT enrolled 51 general practices and 404 patients aged ≥65 years and prescribed ≥15 medicines. Quantitative data were collected from all recruited practices and 32 additional practices who were enrolled, but unable to recruit sufficient participants. Qualitative data were collected from purposive samples of intervention GPs (18/26), patients (27/208), and researcher logs and analysed thematically using inductive coding. RESULTS: Enrolment rates for practices and patients were 37% and 25%, respectively. Barriers to GP recruitment were lack of resources and to patient recruitment were difficulty understanding trial material and concern about medicines being taken away. GPs' primary motivation was perceived importance of the research question, whereas patients' primary motivation was trust in their GP. All general practices were retained. Thirty-five patients (8.6%) were lost to follow-up for primary outcomes, mainly because they had died and 45% did not return patient-reported outcome measures (PROMs). CONCLUSION: Patient retention for the primary outcome was high, as it was collected directly from patient records. Patient completion of PROM data was poor, reflecting difficulty in understanding trial material. Recruiting older patients with multimorbidity to clinical trials is possible but requires significant resource and planning. TRIAL REGISTRATION: ISRCTN Registry ISRCTN12752680.

Randomized controlled trials (RCTs) often exclude older people with multiple medical conditions. The aim of this study was to explore how and why participants took part in a primary care based RCT that included 51 general practitioners (GPs) and 404 older patients prescribed ≥15 medicines. The RCT was designed to assess the usefulness of a supported medication review. The study team assessed information that was already collected as part of the RCT, to describe the process of inviting and enrolling GPs and older people. This included information on the numbers invited and enrolled and interviews from a smaller sample of GPs (18) and older people (27). The study successfully enrolled the required number of participants but it took 26 months more than planned. 37% of invited GPs and 25% of invited patients took part. GPs felt the research was important but they identified lack of time and resources as barriers to participation. Older people predominantly took part because they trusted their GP but some were wary of having medicines taken away and were put off by trial documentation. It is important that RCTs including older people with multiple medical conditions carefully plan recruitment and pay careful attention to trial documentation.

Oral cancer awareness and education within the pharmacy profession.

The incidence of oral cancers are rising in the UK, with early detection a significant positive prognostic factor. The Covid-19 pandemic has negatively impacted patients access to dental services, reducing a potential avenue to diagnosis. Community pharmacists are well positioned to play an expanded role in supporting earlier detection. This study seeks to identify levels of awareness and knowledge of oral cancer amongst community pharmacists, to inform development of educational resources.A cross-sectional digital survey was distributed via social media between August and September 2021. Data were collected on participant's demographics, oral cancer awareness and educational resources relevant to oral cancer. The results obtained were analysed using descriptive statistics in IBM SPSS software.61 pharmacists completed the survey. The majority were female (n = 40; 65.6%) aged 18-30 (n = 33; 54.1%). Less than half of respondents reported feeling confident in recognising risk factors (37.7%; n = 23). A substantial minority (n = 8; 13.1%) incorrectly selected fluoride toothpaste use as a risk factor for oral cancer. Most respondents correctly suggested signposting patients with signs or symptoms of oral cancer to a General Medical or General Dental Practitioner (GDP) (n = 35; 57.3%, n = 46; 75.4%). 91.8% of respondents (n = 56) would welcome an educational resource to support professional development.This study demonstrates a need for further educational resources regarding oral cancer, specifically aimed at community pharmacists. Community Pharmacists have a crucial role in efforts to improve rates of early detection of oral cancers. Work should be completed to explore the establishment of direct referral pathways from community pharmacy to secondary care.

GP-delivered medication review of polypharmacy, deprescribing, and patient priorities in older people with multimorbidity in Irish primary care (SPPiRE Study): A cluster randomised controlled trial.

BACKGROUND: There is a rising prevalence of multimorbidity, particularly in older patients, and a need for evidence-based medicines management interventions for this population. The Supporting Prescribing in Older Adults with Multimorbidity in Irish Primary Care (SPPiRE) trial aimed to investigate the effect of a general practitioner (GP)-delivered, individualised medication review in reducing polypharmacy and potentially inappropriate prescriptions (PIPs) in community-dwelling older patients with multimorbidity in primary care. METHODS AND FINDINGS: We conducted a cluster randomised controlled trial (RCT) set in 51 GP practices throughout the Republic of Ireland. A total of 404 patients, aged ≥65 years with complex multimorbidity, defined as being prescribed ≥15 regular medicines, were recruited from April 2017 and followed up until October 2020. Furthermore, 26 intervention GP practices received access to the SPPiRE website where they completed an educational module and used a template for an individualised patient medication review that identified PIP, opportunities for deprescribing, and patient priorities for care. A total of 25 control GP practices delivered usual care. An independent blinded pharmacist assessed primary outcome measures that were the number of medicines and the proportion of patients with any PIP (from a predefined list of 34 indicators based predominantly on the STOPP/START version 2 criteria). We performed an intention-to-treat analysis using multilevel modelling. Recruited participants had substantial disease and treatment burden at baseline with a mean of 17.37 (standard deviation [SD] 3.50) medicines. At 6-month follow-up, both intervention and control groups had reductions in the numbers of medicines with a small but significantly greater reduction in the intervention group (incidence rate ratio [IRR] 0.95, 95% confidence interval [CI]: 0.899 to 0.999, p = 0.045). There was no significant effect on the odds of having at least 1 PIP in the intervention versus control group (odds ratio [OR] 0.39, 95% CI: 0.140 to 1.064, p = 0.066). Adverse events recorded included mortality, emergency department (ED) presentations, and adverse drug withdrawal events (ADWEs), and there was no evidence of harm. Less than 2% of drug withdrawals in the intervention group led to a reported ADWE. Due to the inability to electronically extract data, primary outcomes were measured at just 2 time points, and this is the main limitation of this work. CONCLUSIONS: The SPPiRE intervention resulted in a small but significant reduction in the number of medicines but no evidence of a clear effect on PIP. This reduction in significant polypharmacy may have more of an impact at a population rather than individual patient level. TRIAL REGISTRATION: ISRCTN Registry ISRCTN12752680.

Patient and general practitioner experiences of implementing a medication review intervention in older people with multimorbidity: Process evaluation of the SPPiRE trial.

INTRODUCTION: The SPPiRE cluster randomized controlled trial found that a general practitioner (GP)-delivered medication review that incorporated screening for potentially inappropriate prescriptions (PIP), a brown bag review and a patient priority assessment, resulted in a significant but small reduction in the number of medicines and no significant reduction in PIP. This process evaluation aims to explore the experiences of GPs and patients and the potential for system-wide implementation. METHODS: The trial included 51 general practices and 404 participants with multimorbidity aged ≥65 years, prescribed ≥15 medicines. The process evaluation used mixed methods and ran parallel to the trial. Quantitative data was collected from the SPPiRE intervention website and analysed descriptively. Qualitative data on medication changes were collected from intervention GPs (18/26) and a purposive sample of intervention patients (27/208) via semi-structured telephone interviews. All interviews were transcribed verbatim and analysed using a thematic analysis. Qualitative and quantitative data were integrated using a triangulation protocol. RESULTS: The analysis generated two themes, intervention implementation and mechanisms of action, and both were underpinned by the theme of context. Intervention delivery varied among practices and 45 patients (28%) had no review, primarily due to insufficient GP time. 80% of reviewed patients had ≥1 PIP identified, 59% had ≥1 problem identified during the brown bag review and 79% had ≥1 priority recorded. The brown bag review resulted in the most deprescription of medications. GPs and patients responded positively to the intervention but most GPs did not engage with the patient priority-setting process. GPs identified a lack of integration into practice software and resources as barriers to future implementation. CONCLUSION: The SPPiRE intervention had a small effect in reducing the number of medicines and this was primarily mediated through the brown bag review. The context of resource shortages and deep-seated views around medical decision-making influenced intervention implementation. PATIENT OR PUBLIC CONTRIBUTION: Qualitative data on the implementation of the medication review and their wider views on their medicines was collected from older people with multimorbidity through semi-structured telephone interviews. CLINICAL TRIAL REGISTRATION: The SPPiRE trial was registered prospectively on the ISRCTN registry (ISRCTN12752680).

DNA damage marker phosphorylated histone H2AX is a potential predictive marker for progression of epithelial dysplasia of the oral cavity.

AIMS: To evaluate the relationships between immunohistochemical markers related to cellular senescence, cell proliferation and histological grade of epithelial dysplasia (OD) of the oral cavity. In addition, the predictive value of these markers for progression of OD was assessed. METHODS AND RESULTS: Retrospective immunohistochemical analyses were performed on 86 formalin-fixed paraffin-embedded specimens of OD and oral squamous cell carcinoma (OSCC) for Ki67, phosphorylated histone H2AX (γH2AX), p53, p16, trimethyl-histone H3 (Lys9) (H3K9me3) and cyclin D1 (CycD1). Three separate areas representing the highest severity of OD on each slide were annotated digitally by two independent pathologists. Mean automated histoscores of the selected markers were generated and compared to that of age-matched healthy controls (n = 24). Follow-up data of OD were retrieved and anonymized by a clinical team member and linked using unique participant identifiers. The median follow-up was 10.9 years (interquartile range: 10.1-11.5). Ki67 (P < 0.0001), γH2AX (P = 0.03) and p53 (P = 0.04) were increased significantly with higher histological grade of OD. γH2AX (P = 0.03), but not histological grade of OD (P = 0.73), was associated prospectively with disease progression. Using the median histoscore for γH2AX (median histoscore = 17) as a cut-off, histoscore ≥17 was associated with an increased risk of disease progression [hazard ratio (HR) = 3.15, 95% confidence interval (CI): 1.41-7.39, P = 0.0064]. CONCLUSIONS: Although proliferation marker Ki67, DNA damage/checkpoint markers γH2AX and p53 were increased in higher grade of OD, only γH2AX was predictive of disease progression. These observations may reflect the role of DNA replicative stress in the transformation from OD to OSCC. Larger studies should evaluate whether γH2AX can be used as a predictive marker of OD.

How do patients perceive the British orthodontic society online information resource about orthognathic treatment? A qualitative study.

OBJECTIVES: To explore the accessibility, usability and relevance of the British Orthodontic Society (BOS) online information resource (OIR), Your Jaw Surgery. DESIGN: Qualitative, cross-sectional study. SETTING: 5 UK sites. PARTICIPANTS: Patients before, during and after treatment for non-cleft skeletal discrepancy. METHODS: Patients were identified at joint clinics and recruited after having time to view the OIR. Semi-structured interviews were conducted with 17 patients (aged 16-46 years). The interviews were transcribed and thematic analysis was undertaken using a framework approach. RESULTS: The main themes identified were the overall usefulness, personal relevance and positive perceptions of the OIR. The OIR was seen to be useful for patients considering treatment, and potentially useful for patients undergoing treatment. Participants were looking for a personally relevant resource that would give them the best possible idea of how they would look and feel after surgery. The OIR was perceived as trusted, positive and reassuring. CONCLUSIONS: Patients at different stages of treatment found the OIR helpful and reassuring. Clinicians may find it useful to direct patients to the OIR to complement a professional consultation, but should be aware that patients may perceive it as presenting a positive image of the long-term benefits of orthognathic surgery.

Tetany During Intravenous Conscious Sedation in Dentistry Resulting From Hyperventilation-Induced Hypocapnia.

Hyperventilation can be a manifestation of anxiety that involves abnormally fast breathing (tachypnea) and an elevated minute ventilation that exceeds metabolic demand. This report describes a case of hyperventilation-induced hypocapnia resulting in tetany in a 16-year-old girl undergoing orthodontic extractions under intravenous conscious sedation. Pulse oximetry is the gold standard respiratory-related index in conscious sedation. Although the parameter has great utility in determining oxygen desaturation, it provides no additional information on respiratory function, including, for example, respiratory rate. In this case, we found capnography to be a very useful aid to monitor respiration in this patient and also to treat the hypocapnia.

Does the British Orthodontic Society orthognathic DVD aid a prospective patient's decision making? A qualitative study.

OBJECTIVES: To explore the views of potential orthognathic patients regarding the influence of the BOS Orthognathic DVD in their decision making process. DESIGN: Qualitative, cross-sectional study. SETTING: A UK dental teaching hospital. PARTICIPANTS: Patients considering orthognathic treatment. METHODS: New patients were recruited from orthognathic clinics following an initial consultation. After an appropriate time to view the DVD, in-depth interviews were conducted with 10 patients (aged 16-48 years) in their homes. Interviews explored the attitudes and perceptions that influenced decisions about surgery, with a focus on the role of the DVD in this process. The interviews were transcribed and a framework analysis was undertaken. RESULTS: The main themes identified were participant perceptions on the patient stories, use of images, the nature of the DVD itself and its usefulness in the decision making process. Participants reported they were heavily influenced by the patient stories. Virtual animations of surgery were seen as useful; whereas the before and after images of surgery were found to be disorientating. The design of the menu resulted in confusion or information being missed. The DVD was seen as a trusted resource, whereas the Internet was seen as biased, general and sensationalistic. CONCLUSIONS: The DVD gives trusted information that patients cannot obtain or process from professional sources or the Internet. If used properly it can have a role in the decision making process, but should be seen within the context of other influences on the patient. This research has highlighted some aspects of the DVD that could be improved upon.

Recommendations for managing adults with chronic non-cancer pain in primary care: A systematic clinical guideline review.

RATIONALE: Chronic non-cancer pain (CNCP) is a leading driver of disability. Primary care clinicians treat most patients with CNCP. Yet, they are often unable to identify appropriate pain treatments, mainly due to concerns about the safety and effectiveness of available medications. Clinical practice guidelines (CPGs) can be useful tools to guide primary care clinicians in selecting pain treatments based on the best available evidence. OBJECTIVES: To undertake a systematic review of CPGs that address the management of adults with CNCP, regardless of underlying condition type, in primary care. METHOD: We systematically reviewed and synthesised current CPGs for managing adults with CNCP in primary care (2013-2023). We followed a stepwise systematic process to synthesise key CPG recommendations: extracted and analysed each recommendation, synthesised by compiling similar recommendations using a thematic analysis approach, and assessed the strength of CPG recommendations to create a final, unified set of recommendations. We focused on identifying CPGs containing recommendations on the following topics: (a) opioid pain management, (b) non-opioid pharmacological pain management, (c) non-pharmacological pain management, and (d) patient-centred communication around pain management, prevention, and organisation of care. RESULTS: We included 13 CPGs, 8 of which focused solely on use of opioids, emphasising the lack of long-term effectiveness and safety concerns, being mainly based on the expert consensus. As an exception, high-quality evidence recommended referring patients with suspected opioid use disorder to specialist addiction services for medication-assisted treatment. Recommendations for non-opioid pain management were often contradictory and based on the expert consensus. Patient-centred pain management combined with exercise-based interventions and psychological therapies are appropriate strategies for managing patients with CNCP. CONCLUSION: Most CPGs focused on opioid management, with contradictory recommendations for non-opioid management based on low-quality evidence. Additional research is needed to strengthen the evidence for using non-opioid and non-pharmacological interventions to manage patients with CNCP.

Cost effectiveness of a GP delivered medication review to reduce polypharmacy and potentially inappropriate prescribing in older patients with multimorbidity in Irish primary care: the SPPiRE cluster randomised controlled trial.

BACKGROUND: Evidence on the cost effectiveness of deprescribing in multimorbidity is limited. OBJECTIVE: To investigate the cost effectiveness of a general practitioner (GP) delivered, individualised medication review to reduce polypharmacy and potentially inappropriate prescribing in older patients with multimorbidity in Irish primary care. METHODS: Within trial economic evaluation, from a healthcare perspective and based on a cluster randomised controlled trial with a 6 month follow up and 403 patients (208 Intervention and 195 Control) recruited between April 2017 and December 2019. Intervention GPs used the SPPiRE website which contained educational materials and a template to support a web-based individualised medication review. Control GPs delivered usual care. Incremental costs, quality adjusted life years (QALYs) generated using the EQ-5D-5L instrument, and expected cost effectiveness were estimated using multilevel modelling and multiple imputation techniques. Uncertainty was explored using parametric, deterministic and probabilistic methods. RESULTS: On average, the SPPiRE intervention was dominant over usual care, with non-statistically significant mean cost savings of €410 (95% confidence interval (CI): - 2211, 1409) and mean health gains of 0.014 QALYs (95% CI - 0.011, 0.039). At cost effectiveness threshold values of €20,000 and €45,000 per QALY, the probability of SPPiRE being cost effective was 0.993 and 0.988. Results were sensitive to missing data and data collection period. CONCLUSIONS: The study observed a pattern towards dominance for the SPPiRE intervention, with high expected cost effectiveness. Notably, observed differences in costs and outcomes were consistent with chance, and missing data and related uncertainty was non trivial. The cost effectiveness evidence may be considered promising but equivocal. TRIAL REGISTRATION: ISRCTN: 12752680, 20th October 2016.

Clinical and molecular features of acquired resistance to immunotherapy in non-small cell lung cancer.

Although immunotherapy with PD-(L)1 blockade is routine for lung cancer, little is known about acquired resistance. Among 1,201 patients with non-small cell lung cancer (NSCLC) treated with PD-(L)1 blockade, acquired resistance is common, occurring in >60% of initial responders. Acquired resistance shows differential expression of inflammation and interferon (IFN) signaling. Relapsed tumors can be separated by upregulated or stable expression of IFNγ response genes. Upregulation of IFNγ response genes is associated with putative routes of resistance characterized by signatures of persistent IFN signaling, immune dysfunction, and mutations in antigen presentation genes which can be recapitulated in multiple murine models of acquired resistance to PD-(L)1 blockade after in vitro IFNγ treatment. Acquired resistance to PD-(L)1 blockade in NSCLC is associated with an ongoing, but altered IFN response. The persistently inflamed, rather than excluded or deserted, tumor microenvironment of acquired resistance may inform therapeutic strategies to effectively reprogram and reverse acquired resistance.

Association between patient attitudes towards deprescribing and subsequent prescription changes.

Deprescribing is an essential component of safe prescribing, especially for people with higher levels of polypharmacy. Identifying individuals prepared to consider medicine changes may facilitate deprescribing-orientated reviews. We aimed to explore the relationship between revised patients' attitudes towards deprescribing (rPATD) scores and medication changes in older people prescribed ≥15 medicines. A secondary analysis of rPATD scores and prescription data from a cluster randomised controlled trial of a GP-delivered, deprescribing-orientated medication review was conducted. The association between number of medicines stopped, started and changed and baseline rPATD scores was assessed using Poisson regression, adjusting for patient age, gender, study group allocation, baseline number of medicines and effects of clustering. Participants (n = 404) had a mean age of 76.4 years and were prescribed a mean of 17.1 medicines at baseline. Willingness to stop a medicine was associated with higher rates of both deprescribing (IRR: 1.40; 95% CI: 1.06-1.84) and initiating medicines (IRR: 1.43; 95% CI: 1.09-1.88). Satisfaction with current medicines was associated with a lower rate of deprescribing (IRR: 0.69; 95% CI: 0.57-0.85). The rPATD questionnaire could be used as part of a deprescribing intervention to identify participants who may be prepared to engage in deprescribing, enabling more efficient use of clinician time during complex consultations.

Medication changes and potentially inappropriate prescribing in older patients with significant polypharmacy.

BACKGROUND: Number of medicines and medicines appropriateness are often used as outcome measures to evaluate the effectiveness of deprescribing interventions. AIM: The aim of this study was to evaluate changes in prescribing, potentially inappropriate prescriptions (PIP) and prescribing of low-value medicines in older people with multimorbidity and significant polypharmacy. METHOD: This study was a retrospective secondary analysis of prescription data from a cluster randomised controlled trial involving 404 participants aged ≥ 65 years and prescribed ≥ 15 repeat medicines from 51 different general practices. For this study, repeat medications at baseline and follow-up (~ 1 year later) were assigned Anatomical Therapeutic Classification (ATC) codes. Outcomes were the most commonly prescribed and potentially inappropriately prescribed drug groups, the most frequently discontinued or initiated drug groups and the number of changes per person between baseline and follow-up. RESULTS: There were 7051 medicines prescribed to 404 participants at baseline. There was a median of 17 medicines (IQR 15-19) at baseline and 16 (IQR 14-19) at follow-up. PIP represented 17.1% of prescriptions at baseline and 15.7% (n = 6777) at follow-up. There were reductions in the prescription of most drug groups with the largest reduction in antiplatelet prescriptions. Considering medication discontinuations, initiations and switches, there was a median of five medication changes per person (range 0-30, IQR 3-9) by follow-up. There were 95 low-value prescriptions at baseline reducing to 78 at follow-up. CONCLUSION: The number of medication changes per person was not reflected by summarising medication count at two time points, highlighting the complexity of prescribing for patients with polypharmacy. Frequent medication changes has potentially important implications for patients in terms of adherence and medication safety. TRIAL REGISTRY: The SPPiRE trial was registered prospectively on the ISRCTN registry (ISRCTN12752680).

Chemoselective amide formation using O-(4-nitrophenyl)hydroxylamines and pyruvic acid derivatives.

A series of O-(4-nitrophenyl)hydroxylamines were synthesized from their respective oximes using a pulsed addition of excess NaBH(3)CN at pH 3 in 65-75% yield. Steric hindrance near the oxime functional group played a key role in both the ease by which the oxime could be reduced and the subsequent reactivity of the respective hydroxylamine. Reaction of the respective hydroxylamines with pyruvic acid derivatives generated the desired amides in good yields. A comparison of phenethylamine systems bearing different leaving groups revealed significant differences in the rates of these systems and suggested that the leaving group ability of the N-OR substituent plays an important role in determining their reactivity with pyruvic acid. Competition experiments (in 68% DMSO/phosphate buffered saline) using 1 equiv of N-phenethyl-O-(4-nitrophenyl)hydroxylamine and 2 equiv of pyruvic acid in the presence of other nucleophiles such as glycine, cysteine, phenol, hexanoic acid, and lysine demonstrated that significant chemoselectivity is present in this reaction. The results suggest that this chemoselective reaction can occur in the presence of excess α-amino acids, phenols, acids, thiols, and amines.

Mucolytic bacteria license pathobionts to acquire host-derived nutrients during dietary nutrient restriction.

Pathobionts employ unique metabolic adaptation mechanisms to maximize their growth in disease conditions. Adherent-invasive Escherichia coli (AIEC), a pathobiont enriched in the gut mucosa of patients with inflammatory bowel disease (IBD), utilizes diet-derived L-serine to adapt to the inflamed gut. Therefore, the restriction of dietary L-serine starves AIEC and limits its fitness advantage. Here, we find that AIEC can overcome this nutrient limitation by switching the nutrient source from the diet to the host cells in the presence of mucolytic bacteria. During diet-derived L-serine restriction, the mucolytic symbiont Akkermansia muciniphila promotes the encroachment of AIEC to the epithelial niche by degrading the mucus layer. In the epithelial niche, AIEC acquires L-serine from the colonic epithelium and thus proliferates. Our work suggests that the indirect metabolic network between pathobionts and commensal symbionts enables pathobionts to overcome nutritional restriction and thrive in the gut.

Implications of Selection Bias Due to Delayed Study Entry in Clinical Genomic Studies.

IMPORTANCE: Real-world data sets that combine clinical and genomic data may be subject to left truncation (when potential study participants are not included because they have already passed the milestone of interest at the time of study recruitment). The lapse between diagnosis and molecular testing can present analytic challenges and threaten the validity and interpretation of survival analyses. OBSERVATIONS: Effects of ignoring left truncation when estimating overall survival are illustrated using data from the American Association for Cancer Research (AACR) Project Genomics Evidence Neoplasia Information Exchange Biopharma Collaborative (GENIE BPC), and a straightforward risk-set adjustment approach is described. Ignoring left truncation results in overestimation of overall survival: unadjusted median survival estimates from diagnosis among patients with stage IV non-small cell lung cancer or stage IV colorectal cancer were overestimated by more than 1 year. CONCLUSIONS AND RELEVANCE: Clinicogenomic data are a valuable resource for evaluation of real-world cancer outcomes and should be analyzed using appropriate methods to maximize their potential. Analysts must become adept at application of appropriate statistical methods to ensure valid, meaningful, and generalizable research findings.

A Scalable Quality Assurance Process for Curating Oncology Electronic Health Records: The Project GENIE Biopharma Collaborative Approach.

PURPOSE: The American Association for Cancer Research Project Genomics Evidence Neoplasia Information Exchange Biopharma Collaborative is a multi-institution effort to build a pan-cancer repository of genomic and clinical data curated from the electronic health record. For the research community to be confident that data extracted from electronic health record text are reliable, transparency of the approach used to ensure data quality is essential. MATERIALS AND METHODS: Four institutions participating in AACR's Project GENIE created an observational cohort of patients with cancer for whom tumor molecular profiling data, therapeutic exposures, and treatment outcomes are available and will be shared publicly with the research community. A comprehensive approach to quality assurance included assessments of (1) feasibility of the curation model through pressure test cases; (2) accuracy through programmatic queries and comparison with source data; and (3) reproducibility via double curation and code review. RESULTS: Assessments of feasibility resulted in critical modifications to the curation directives. Queries and comparison with source data identified errors that were rectified via data correction and curator retraining. Assessment of intercurator reliability indicated a reliable curation model. CONCLUSION: The transparent quality assurance processes for the GENIE BPC data ensure that the data can be used for analyses that support clinical decision making and advances in precision oncology.

The multimorbidity collaborative medication review and decision making (MyComrade) study: a pilot cluster randomised trial in two healthcare systems.

BACKGROUND: While international guidelines recommend medication reviews as part of the management of multimorbidity, evidence on how to implement reviews in practice in primary care is lacking. The MyComrade (MultimorbiditY Collaborative Medication Review And Decision Making) intervention is an evidence-based, theoretically informed novel intervention which aims to support the conduct of medication reviews for patients with multimorbidity in primary care. AIM: The pilot study aimed to assess the feasibility of a definitive trial of the MyComrade intervention across two healthcare systems (Republic of Ireland (ROI) and Northern Ireland (NI)). DESIGN: A pilot cluster-randomised controlled trial was conducted (clustered at general practice level), using specific progression criteria and a process evaluation framework. SETTING: General practices in the ROI and NI. PARTICIPANTS: Eligible practices were those in defined geographical areas who had GP's and Practice Based Pharmacists (PBP's) (in NI) willing to conduct medication reviews. Eligible patients were those aged 18 years and over, with multi morbidity and on ten or more medications. INTERVENTION: The MyComrade intervention is an evidence-based, theoretically informed novel intervention which aims to support the conduct of medication reviews for patients with multimorbidity in primary care, using a planned collaborative approach guided by an agreed checklist, within a specified timeframe. OUTCOME MEASURES: Feasibility outcomes, using pre-determined progression criteria, assessed practice and patient recruitment and retention and intervention acceptability and fidelity. Anonymised patient-related quantitative data, from practice medical records and patient questionnaires were collected at baseline, 4 and 8 months, to inform potential outcome measures for a definitive trial. These included (i) practice outcomes-completion of medication reviews; (ii) patient outcomes-treatment burden and quality of life; (iii) prescribing outcomes-number and changes of prescribed medications and incidents of potentially inappropriate prescribing; and (iv) economic cost analysis. The framework Decision-making after Pilot and feasibility Trials (ADePT) in conjunction with a priori progression criteria and process evaluation was used to guide the collection and analysis of quantitative and qualitative data. RESULTS: The recruitment of practices (n = 15) and patients (n = 121, mean age 73 years and 51% female), representing 94% and 38% of a priori targets respectively, was more complex and took longer than anticipated; impacted by the global COVID-19 pandemic. Retention rates of 100% of practices and 85% of patients were achieved. Both practice staff and patients found the intervention acceptable and reported strong fidelity to the My Comrade intervention components. Some practice staff highlighted concerns such as poor communication of the reviews to patients, dissatisfaction regarding incentivisation and in ROI the sustainability of two GPs collaboratively conducting the medication reviews. Assessing outcomes from the collected data was found feasible and appropriate for a definitive trial. Two progression criteria met the 'Go' criterion (practice and patient retention), two met the 'Amend' criterion (practice recruitment and intervention implementation) and one indicated a 'Stop - unless changes possible' (patient recruitment). CONCLUSION: The MyComrade intervention was found to be feasible to conduct within two different healthcare systems. Recruitment of participants requires significant time and effort given the nature of this population and the pairing of GP and pharmacist may be more sustainable to implement in routine practice. TRIAL REGISTRATION: Registry: ISRCTN, ISRCTN80017020 ; date of confirmation 4/11/2019; retrospectively registered.