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Abstract Background Unnecessary antibiotic prescriptions in primary care are common and contribute to antimicrobial resistance in the population. Audit and feedback (A&F) on antibiotic prescribing to primary care can improve the appropriateness of antibiotic prescribing, but the optimal approach is uncertain. We performed two pragmatic randomized controlled trials of different approaches to audit and feedback. The trial results showed that A&F was associated with significantly reducing antibiotic prescribing. Still, the effect size was small, and the modifications to the A&F interventions tested in the trials were not associated with any change. Herein, we report a theory-informed qualitative process evaluation to explore potential mechanisms underlying the observed effects. Methods Ontario family physicians in the intervention arms of both trials who were sent A&F letters were invited for one-on-one interviews. Purposive sampling was used to seek variation across interested participants in personal and practice characteristics. Qualitative analysis utilized inductive and deductive techniques informed by the Clinical Performance Feedback Intervention Theory. Results Modifications to the intervention design tested in the trial did not alter prescribing patterns beyond the changes made in response to the A&F overall for various reasons. Change in antibiotic prescribing in response to A&F depended on whether it led to the formation of specific intentions and whether those intentions translated to particular behaviours. Those without intentions to change tended to feel that their unique clinical context was not represented in the A&F. Those with intentions but without specific actions taken tended to express a lack of self-efficacy for avoiding a prescription in contexts with time constraints and/or without an ongoing patient relationship. Many participants noted that compared to overall prescribing, A&F on antibiotic prescription duration was perceived as new information and easily actionable. Conclusion Our findings indicate that contextual factors, including the types of patients and the setting where they are seen, affect how clinicians react to audit and feedback. These results suggest a need to test tailored feedback reports that reflect the context of how, where, and why physicians prescribe antibiotics so that they might be perceived as more personal and more actionable. Trial registration Clinical Trial registration IDs: NCT04594200, NCT05044052.

Abstract Objective To examine primary care (PC) team members’ characteristics associated with video use at the Veterans Health Administration (VA). Methods VA electronic data were used to identify PC team characteristics associated with any video-based PC visit, during the three-year study period (3/15/2019-3/15/2022). Multilevel mixed-effects logistic regression models on repeated yearly observations were used, adjusting for patient- and healthcare system-level characteristics, and study year. We included five PC team categories: 1.PC providers (PCP), which includes physicians, nurse practitioners, physician assistants, 2.Nurses (RN/LVN/LPN/other nurses), 3.Mental health (MH) specialists, 4.Social workers (SW), and 5.Clinical pharmacists (PharmD). Population 54,494 PC care team members nationwide (61,728,154 PC visits; 4,916,960 patients), including 14,422 PCPs, 30,273 nurses, 2,721 MH specialists, 4,065 SWs, and 3,013 PharmDs. Results The mean age was 46.1(SD = 11.3) years; 77.1% were women. Percent of video use among PC team members varied from 24 to 84%. In fully adjusted models, older clinicians were more likely to use video compared to the youngest age group (18–29 years old) (example: 50–59 age group: OR = 1.12,95%CI:1.07–1.18). Women were more likely to use video (OR = 1.18, 95%CI:1.14–1.22) compared to men. MH specialists (OR = 7.87,95%CI:7.32–8.46), PharmDs (OR = 1.16,95%CI:1.09–1.25), and SWs (OR = 1.51,95%CI:1.41–1.61) were more likely, whereas nurses (OR = 0.65,95%CI:0.62–0.67) were less likely to use video compared to PCPs. Conclusions This study highlights more video use among MH specialists, SWs, and PharmDs, and less video use among nurses compared to PCPs. Older and women clinicians, regardless of their role, used more video. This study helps to inform the care coordination of video-based delivery among interdisciplinary PC team members.

The frozen elephant trunk (FET) technique can be applied to extensive aortic pathology, including lesions in the aortic arch and proximal descending thoracic aorta. FET is useful for tear-oriented surgery in dissections, managing malperfusion syndrome, and promoting positive aortic remodeling. Despite these benefits, complications such as distal stent-induced new entry and spinal cord ischemia can pose serious problems with the FET technique. To prevent these complications, careful sizing and planning of the FET are crucial. Additionally, since the FET technique involves total arch replacement, meticulous surgical skills are essential, particularly for young surgeons. In this article, we propose several techniques to simplify surgical procedures, which may lead to better outcomes for patients with extensive aortic pathology. In the era of precision medicine, the next-generation FET device could facilitate the treatment of complex aortic diseases through a patient- tailored approach.

Background: Factors contributing to the higher fall risk among people with intellectual disabilities (PIDs) are complex due to their discrete patterns of multimorbidity. Visual impairment, such as cataract, was common at old age and could be a crucial risk factor. Given the insufficient evidence regarding this relationship, the present study aimed at investigating this issue in a hostel setting in Hong Kong. Methods: This study was conducted in four hostels which served people with moderate to severe intellectual disability. Health data of residents collected in the year of 2022-23 was utilized for the current analysis. Data included fall risk, assessed by Morse Fall Scale, as well as other health conditions (osteoporosis, osteoarthritis, cataract) and demographics (age and gender) among residents. Results: The sample consisted of 199 residents (85 were males and 114 females), with an age range of 22 to 76 years. Around 40% (85; 42.7%) of them aged above 45 years old. Among the whole sample, cataract was the most common health condition and its prevalence reached 27.14%. Those who aged 45-year or above were 4.61 times (95%CI 2.09-11.07) more likely to have cataract. Bivariate analysis results showed that presence of fall risk was associated with older age (above 45 years old; OR 2.38; 95%CI 1.28-4.49), diagnosis of cataract (OR 3.3; 95%CI 1.71-6.33) and osteoarthritis (OR 12.68; 95%CI 1.70-564.75). Logistic regression analysis further illustrated that cataract (p = 0.04) remained as a significant predictor of fall risk after controlling age, gender, osteoarthritis and osteoporosis in the model. Conclusion: Our data showed that presence of cataract diagnosis was significantly associated with higher fall risk among PIDs in hostel setting. Given cataract was a prevalent condition especially among aging PIDs, early screening and intervention could be crucial components of fall prevention strategy in a hostel setting.

Abstract Background Glaucoma patients with irreversible visual field loss often experience decreased quality of life, impaired mobility, and mental health challenges. Perceptual learning (PL) and transcranial electrical stimulation (tES) have emerged as promising interventions for vision rehabilitation, showing potential in restoring residual visual functions. The Glaucoma Rehabilitation using ElectricAI Transcranial stimulation (GREAT) project aims to investigate whether combining PL and tES is more effective than using either method alone in maximizing the visual function of glaucoma patients. Additionally, the study will assess the impact of these interventions on brain neural activity, blood biomarkers, mobility, mental health, quality of life, and fear of falling. Methods The study employs a three-arm, double-blind, randomized, superiority-controlled design. Participants are randomly allocated in a 1:1:1 ratio to one of three groups receiving: (1) real PL and real tES, (2) real PL and sham tES, and (3) placebo PL and sham tES. Each participant undergoes 10 sessions per block (~ 1 h each), with a total of three blocks. Assessments are conducted at six time points: baseline, interim 1, interim 2, post-intervention, 1-month post-intervention, and 2-month post-intervention. The primary outcome is the mean deviation of the 24-2 visual field measured by the Humphrey visual field analyzer. Secondary outcomes include detection rate in the suprathreshold visual field, balance and gait functions, and electrophysiological and biological responses. This study also investigates changes in neurotransmitter metabolism, biomarkers, self-perceived quality of life, and psychological status before and after the intervention. Discussion The GREAT project is the first study to assess the effectiveness of PL and tES in the rehabilitation of glaucoma. Our findings will offer comprehensive assessments of the impact of these treatments on a wide range of brain and vision-related metrics including visual field, neural activity, biomarkers, mobility, mental health, fear of falling, and quality of life. Trial registration ClinicalTrials.gov NCT05874258 . Registered on May 15, 2023.

Abstract Background Technological burden and medical complexity are significant drivers of clinician burnout. Electronic health record(EHR)-based population health management tools can be used to identify high-risk patient populations and implement prophylactic health practices. Their impact on clinician burnout, however, is not well understood. Our objective was to assess the relationship between ratings of EHR-based population health management tools and clinician burnout. Methods We conducted cross-sectional analyses of 2018 national Veterans Health Administration(VA) primary care personnel survey, administered as an online survey to all VA primary care personnel (n = 4257, response rate = 17.7%), using bivariate and multivariate logistic regressions. Our analytical sample included providers (medical doctors, nurse practitioners, physicians’ assistants) and nurses (registered nurses, licensed practical nurses). The outcomes included two items measuring high burnout. Primary predictors included importance ratings of 10 population health management tools (eg. VA risk prediction algorithm, recent hospitalizations and emergency department visits, etc.). Results High ratings of 9 tools were associated with lower odds of high burnout, independent of covariates including VA tenure, team role, gender, ethnicity, staffing, and training. For example, clinicians who rated the risk prediction algorithm as important were less likely to report high burnout levels than those who did not use or did not know about the tool (OR 0.73; CI 0.61-0.87), and they were less likely to report frequent burnout (once per week or more) (OR 0.71; CI 0.60-0.84). Conclusions Burned-out clinicians may not consider the EHR-based tools important and may not be using them to perform care management. Tools that create additional technological burden may need adaptation to become more accessible, more intuitive, and less burdensome to use. Finding ways to improve the use of tools that streamline the work of population health management and/or result in less workload due to patients with poorly managed chronic conditions may alleviate burnout. More research is needed to understand the causal directional of the association between burnout and ratings of population health management tools.

Abstract Background Alcohol screening and brief intervention (SBI) is an evidence-based intervention recommended by the World Health Organization. This study applied the Consolidated Framework for Implementation Research (CFIR) to understand facilitators and barriers of SBI implementation in primary care settings in Hong Kong, China. Methods This was a sequential mixed-method study. In-depth interviews of 21 physicians and 20 nurses working in the primary care settings from the public and private sectors were first conducted to identify CFIR constructs that were relevant to SBI implementation in the Chinese context and potential factors not covered by the CFIR. A questionnaire was then developed based on the qualitative findings to investigate factors associated with SBI implementation among 282 physicians and 295 nurses. Results The in-depth interviews identified 22 CFIR constructs that were facilitators or barriers of SBI implementation in Hong Kong. In addition, the stigmatization of alcohol dependence was a barrier and the belief that it was important for people to control the amount of alcohol intake in any situation was mentioned as a facilitator to implement SBI. In the survey, 22% of the participants implemented SBI in the past year. Factors associated with the SBI implementation echoed most of the qualitative findings. Among physicians and nurses in both sectors, they were more likely to implement SBI when perceiving stronger evidence supporting SBI, better knowledge and self-efficacy to implement SBI, more available resources, and clearer planning for SBI implementation in the clinics but less likely to do so when perceiving SBI implementation to be complicated and of higher cost, and drinking approved by the Chinese culture. Participants were more likely to implement SBI when perceiving SBI fit better with the existing practice and better leadership engagement in the public sector, but not in the private sector. Perceiving a stronger need and greater importance to implement SBI were associated with higher likelihood of SBI implementation among physicians, but not among nurses. Perceiving better organizational culture supporting SBI was positively associated with SBI implementation among nurses, but not among physicians. Conclusions There was a significant gap between SBI evidence and its implementation. Some strategies to improve SBI implementation may be different between physicians and nurses and between those in the public and private sectors. The CFIR is a useful framework for understanding facilitators and barriers of SBI implementation in primary care settings.

Postpartum maternal sepsis is a leading cause of maternal mortality and morbidity. A single dose of prophylactic antibiotics following assisted vaginal births has been shown to significantly reduce postpartum maternal infection in a landmark multicentre randomised controlled trial, which led to its national recommendation. This project aimed to improve the local implementation of prophylactic antibiotics following assisted vaginal births to reduce postnatal maternal infections.Using a prospectively collated birth register, data were collected retrospectively on prophylactic antibiotics administration and postnatal maternal infection rates after assisted vaginal births at the Sandwell and West Birmingham Hospitals National Health Service Trust in North-West Birmingham of the UK. The data were collected from routinely used electronic health records over three audit cycles (n=287) between 2020 and 2023.A mixed-method approach was used to improve the use of prophylactic antibiotics: (1) evidence-based journal clubs targeting doctors in training, (2) presentations of results after all three audit cycles at our and (3) expedited a formal change of local guidelines to support prophylactic antibiotics use.Prophylactic antibiotic administration increased from 13.2% (December 2021) to 90.7% (July 2023), associated with a reduction in maternal infection rates (18.2% when prophylaxis was given vs 22.2% when no prophylaxis was given). However, we observed a gradual increase in the overall postnatal maternal infection rates during the project period.Our repeat audit identified prophylactic antibiotics were regularly omitted after deliveries in labour ward rooms (59.3%), compared with 100% of those achieved in theatre. After further interventions, prophylactic antibiotics administration rates were comparable between these clinical areas (>90%) in 2023.Together, we have demonstrated a simple set of interventions that induced sustainable changes in practice. Further evaluation of other modifiable risk factors and infection rates following all deliveries is warranted in view of the gradual increase in the overall postnatal maternal infection rates.

Summary: Background: De novo amino acid substitutions (DNS) frequently emerge among immunocompromised patients with chronic SARS-CoV-2 infection. While previous studies have reported these DNS, their significance has not been systematically studied. Methods: We performed a review of DNS that emerged during chronic SARS-CoV-2 infection. We searched PubMed until June 2023 using the keywords “(SARS-CoV-2 or COVID-19) and (mutation or sequencing) and ((prolonged infection) or (chronic infection) or (long term))”. We included patients with chronic SARS-CoV-2 infection who had SARS-CoV-2 sequencing performed for at least 3 time points over at least 60 days. We also included 4 additional SARS-CoV-2 patients with chronic infection of our hospital not reported previously. We determined recurrent DNS that has appeared in multiple patients and determined the significance of these mutations among epidemiologically-significant variants. Findings: A total of 34 cases were analyzed, including 30 that were published previously and 4 from our hospital. Twenty two DNS appeared in ≥3 patients, with 14 (64%) belonging to lineage-defining mutations (LDMs) of epidemiologically-significant variants and 10 (45%) emerging among chronically-infected patients before the appearance of the corresponding variant. Notably, nsp9-T35I substitution (Orf1a T4175I) emerged in all three patients with BA.2.2 infection in 2022 before the appearance of Variants of Interest that carry nsp9-T35I as LDM (EG.5 and BA.2.86/JN.1). Structural analysis suggests that nsp9-T35I substitution may affect nsp9-nsp12 interaction, which could be critical for the function of the replication and transcription complex. Interpretation: DNS that emerges recurrently in different chronically-infected patients may be used as a marker for potential epidemiologically-significant variants. Funding: Theme-Based Research Scheme [T11/709/21-N] of the Research Grants Council (See acknowledgements for full list).

Background: Slum communities face health risks influenced by environmental, human, and animal health factors, particularly antimicrobial resistance (AMR). Tailored, community-driven solutions are needed to address these multifactorial health determinants. This study explores One Health challenges in urban slums using a Patient and Public Involvement (PPI) approach. Objectives: This study aims to use qualitative methods within a PPI framework to examine the social, environmental, and animal health factors contributing to AMR and other health challenges in urban slums. Focusing on One Health, we engaged slum residents in Jaipur, Jakarta, Antofagasta, and Istanbul through participatory approaches like social mapping and transect walks to identify health risks and develop intervention strategies. Methods: A PPI approach was employed to involve communities in the research process, ensuring culturally relevant insights. Data collection included social mapping, transect walks, and key informant interviews in the four cities, highlighting critical health determinants such as environmental contamination, healthcare access, and animal-related risks. Thematic analysis identified common challenges and intervention opportunities within the One Health framework. Conclusion: The study underscores the importance of PPI in addressing One Health challenges in urban slums and reveals interconnected human, environmental, and animal health risks. Engaging communities fostered trust and provided locally relevant solutions to complex health issues like AMR. Future interventions should be co-designed with communities to address social determinants like sanitation and healthcare access for sustainable outcomes.

Background The transition from medical student to intern is a recognized educational gap. To help address this, the Association of American Medical Colleges developed the Core Entrustable Professional Activities for entering residency. As these metrics outline expectations for all graduating students regardless of specialty, the described procedural expectations are appropriately basic. However, in procedure-heavy specialties such as emergency medicine, the ability to perform advanced procedures continues to contribute to the disconnect between undergraduate and graduate medical education. To prepare our graduating students for their internship in emergency medicine, we developed a simulation-based mastery learning curriculum housed within a specialty-specific program. Our overall goal was to develop the students’ procedural competency for central venous catheter placement and endotracheal intubation before graduation from medical school.Methods Twenty-five students participated in a simulation-based mastery learning procedures curriculum for ultrasound-guided internal jugular central venous catheter placement and endotracheal intubation. Students underwent baseline assessment, deliberate practice, and post-test assessments. Both the baseline and post-test assessments used the same internally developed checklists with pre-established minimum passing scores.Results Despite completing an emergency medicine rotation and a critical care rotation, none of the students met the competency standard during their baseline assessments. All twenty-five students demonstrated competency on both procedures by the end of the curriculum. A second post-test was required to demonstrate achievement of the central venous catheter and endotracheal intubation minimum passing scores by 16% and 28% of students, respectively.Conclusions Students demonstrated procedural competency for central venous catheter placement and endotracheal intubation by engaging in simulation-based mastery learning procedures curriculum as they completed their medical school training. With three instructional hours, students were able to achieve basic procedural competence for two common, high-risk procedures they will need to perform during emergency medicine residency training.

The COVID-19 pandemic has led to many undergraduate medical programs shifting their preclinical curricula online— reducing access to clinical skills sessions and ultimately causing gaps in students’ knowledge. This study sought to better understand the impact and role of virtual clinical skills training sessions, using point-of-view (POV) livestreaming wearable technology, in supplementing medical students’ learning. 38 University of Ottawa medical students were recruited to participate in a 1.5-hour virtual clinical teaching session. An abdominal physical examination was broadcasted through two views (chest-mounted smartphone, room overview). Participants completed pre- and post-event questionnaires on their overall impression, satisfaction/challenges, and platform efficacy compared to other learning modalities. Improvements were noted in participants’ perspectives towards event engagement (p=0.042, Cohen’s d=0.48), comparability to in-person encounters (p=

Summary: Background: Endovascular therapy (EVT) was demonstrated effective in acute large vessel occlusion (LVO) with large infarction. Revealing subgroups of patients who would or would not benefit from EVT will further inform patient selection for EVT. Methods: This post-hoc analysis of the ANGEL-ASPECT trial, a randomised controlled trial of 456 adult patients with acute anterior-circulation LVO and large infarction, defined by ASPECTS 3–5 or infarct core volume 70–100 mL, enrolled from 46 centres across China, between October 2, 2020 and May 18, 2022. Patients were randomly assigned (1:1) to receiving EVT and medical management or medical management alone. One patient withdrew consent, 455 patients were included in this post-hoc analysis and categorised into 4 subgroups by lower or higher NIHSS (< or ≥16) and smaller or larger infarct core (< or ≥70 mL). Those with lower NIHSS & smaller core, and higher NIHSS & larger core were considered clinical-radiological matched subgroups; otherwise clinical-radiological mismatched subgroups. Primary outcome was 90-day modified Rankin Scale (mRS). ANGEL-ASPECT is registered with ClinicalTrials.gov, NCT04551664. Findings: Overall, 139 (30.5%) patients had lower NIHSS & smaller core, 106 (23.3%) higher NIHSS & larger core, 130 (28.6%) higher NIHSS & smaller core, and 80 (17.6%) lower NIHSS & larger core. There was significant ordinal shift in the 90-day mRS toward a better outcome with EVT in clinical-radiological matched subgroups: lower NIHSS & smaller core (generalised OR, 1.76; 95% CI, 1.18–2.62; p = 0.01) and higher NIHSS & larger core (1.64; 1.06–2.54; 0.01); but not in the two clinical-radiological mismatched subgroups. Interpretation: Our findings suggested that in patients with anterior-circulation LVO and large infarction, EVT was associated with improved 90-day functional outcomes in those with matched clinical and radiological severities, but not in those with mismatched clinical and radiological severities. Simultaneous consideration of stroke severity and infarct core volume may inform patient selection for EVT. Funding: Unrestricted grants from industry [Covidien Healthcare International Trading (Shanghai), Johnson & Johnson MedTech, Genesis MedTech (Shanghai), and Shanghai HeartCare Medical Technology].

Abstract Background In 2016, we developed a pediatric parent advisory group to inform our research program which creates innovative knowledge translation (KT) tools for parents on priority topics related to acute childhood illness. We implemented a mixed methods strategy to evaluate the experiences of group members. The purpose of this paper is to present the findings from parent evaluations over four years and to discuss our experiences collaborating with the group over a multi-year period. Methods We conducted year-end surveys and interviews of group members to understand parents’ perceptions of their experiences, group management, researcher interaction, and other outcomes of advisory group participation from 2018 to 2021. We applied a mixed methods approach, collecting and analyzing both quantitative (survey) and qualitative (survey/interview) data. Survey data were analyzed by term using descriptive statistics (i.e., frequencies, percentages). Open-ended survey responses were analyzed by conventional content analysis. Interview data were analysed thematically. Results Year-end survey response rates and interview participation varied over the years. Responses to evaluation questions were generally positive and most improved over time. Results prompted changes to improve P-PAG operations, such as changes to location of meetings, communications about the group’s purpose, offering sufficient context for discussion items, and providing feedback about how members’ input was used. Themes identified from the qualitative data related to the importance of certain aspects of group functioning, positive views of the group’s current management, and potential areas for improvement. Parents regularly expressed a desire for more diversity in the group’s membership and an interest in hearing more about how the research program’s activities fit into the broader healthcare system and their impacts on health outcomes. Conclusions Our experience in establishing, managing, and evaluating a parent advisory group over many years has resulted in valuable insights regarding patient engagement in health research and sustaining an advisory group over time. We have learned that an intentional and iterative approach with regular evaluations and responsive changes has been essential for fostering meaningful engagement. Significant resources are required to maintain the group; in turn, the group has made substantial and diverse contributions to the research program and its outputs.

As the most common internal modification of mRNA, N6-methyladenosine (m6A) and its regulators modulate gene expression and play critical roles in various biological and pathological processes including tumorigenesis. It was reported previously that m6A methyltransferase (writer), methyltransferase-like 3 (METTL3) adds m6A in primary microRNAs (pri-miRNAs) and facilitates its processing into precursor miRNAs (pre-miRNAs). However, it is unknown whether m6A modification also plays a role in the maturation process of pre-miRNAs and (if so) whether such a function contributes to tumorigenesis. Here, we found that YTHDF2 is aberrantly overexpressed in acute myeloid leukemia (AML) patients, especially in relapsed patients, and plays an oncogenic role in AML. Moreover, YTHDF2 promotes expression of miR-126-3p (also known as miR-126, as it is the main product of precursor miR-126 (pre-miR-126)), a miRNA that was reported as an oncomiRNA in AML, through facilitating the processing of pre-miR-126 into mature miR-126. Mechanistically, YTHDF2 recognizes m6A modification in pre-miR-126 and recruits AGO2, a regulator of pre-miRNA processing, to promote the maturation of pre-miR-126. YTHDF2 positively and negatively correlates with miR-126 and miR-126's downstream target genes, respectively, in AML patients, and forced expression of miR-126 could largely rescue YTHDF2/Ythdf2 depletion-mediated suppression on AML cell growth/proliferation and leukemogenesis, indicating that miR-126 is a functionally important target of YTHDF2 in AML. Overall, our studies not only reveal a previously unappreciated YTHDF2/miR-126 axis in AML and highlight the therapeutic potential of targeting this axis for AML treatment, but also suggest that m6A plays a role in pre-miRNA processing that contributes to tumorigenesis.

Brain cancer is a substantial factor in the mortality associated with cancer, presenting difficulties in the timely identification of the disease. The precision of diagnoses is significantly dependent on the proficiency of radiologists and neurologists. Although there is potential for early detection with computer-aided diagnosis (CAD) algorithms, the majority of current research is hindered by its modest sample sizes. This meta-analysis aims to comprehensively assess the diagnostic test accuracy (DTA) of computer-aided design (CAD) models specifically designed for the detection of brain cancer utilizing hyperspectral (HSI) technology. We employ Quadas-2 criteria to choose seven papers and classify the proposed methodologies according to the artificial intelligence method, cancer type, and publication year. In order to evaluate heterogeneity and diagnostic performance, we utilize Deeks’ funnel plot, the forest plot, and accuracy charts. The results of our research suggest that there is no notable variation among the investigations. The CAD techniques that have been examined exhibit a notable level of precision in the automated detection of brain cancer. However, the absence of external validation hinders their potential implementation in real-time clinical settings. This highlights the necessity for additional studies in order to authenticate the CAD models for wider clinical applicability.

Medication-related osteonecrosis of the jaw (MRONJ) is a debilitating condition associated with antiresorptive and antiangiogenic medications that are frequently used in treating osteoporosis and cancers. With the ability to produce high-resolution images with a lower radiation dose, cone beam computed tomography (CBCT) is an emerging technology in maxillofacial imaging that offers several advantages in evaluating MRONJ. This review aims to summarise the radiological features of MRONJ as observed via CBCT and highlight its advantages over two-dimensional plain films in assessing MRONJ. CBCT has the capability to detect early MRONJ lesions, characterise the extent and nature of lesions, distinguish MRONJ from other osseous pathologies, and assist in treatment planning. By leveraging the advantages of CBCT, clinicians can enhance their understanding of MRONJ, improve decision making, and ultimately optimize patient care.

Summary: Background: In the post-pandemic era, growing apprehension exists regarding the potential sequelae of COVID-19. However, the risks of respiratory diseases following SARS-CoV-2 infection have not been comprehensively understood. This study aimed to investigate whether COVID-19 increases the long-term risk of respiratory illness in patients with COVID-19. Methods: In this longitudinal, population-based cohort study, we built three distinct cohorts age 37–73 years using the UK Biobank database; a COVID-19 group diagnosed in medical records between January 30th, 2020 and October 30th, 2022, and two control groups, a contemporary control group and a historical control group, with cutoff dates of October 30th, 2022 and October 30th, 2019, respectively. The follow-up period of all three groups was 2.7 years (the median (IQR) follow-up time was 0.8 years). Respiratory outcomes diagnosed in medical records included common chronic pulmonary diseases (asthma, bronchiectasis, chronic obstructive pulmonary disease (COPD), interstitial lung disease (ILD), pulmonary vascular disease (PVD), and lung cancer. For the data analysis, we calculated hazard ratios (HRs) along with their 95% CIs using Cox regression models, following the application of inverse probability weights (IPTW). Findings: A total of 3 cohorts were included in this study; 112,311 individuals in the COVID-19 group with a mean age (±SDs) of 56.2 (8.1) years, 359,671 in the contemporary control group, and 370,979 in the historical control group. Compared with the contemporary control group, those infected with SARS-CoV-2 exhibited elevated risks for developing respiratory diseases. This includes asthma, with a HR of 1.49 and a 95% CI 1.28–1.74; bronchiectasis (1.30; 1.06–1.61); COPD (1.59; 1.41–1.81); ILD (1.81; 1.38–2.21); PVD (1.59; 1.39–1.82); and lung cancer (1.39; 1.13–1.71). With the severity of the acute phase of COVID-19, the risk of pre-described respiratory outcomes increases progressively. Besides, during the 24-months follow-up, we observed an increasing trend in the risks of asthma and bronchiectasis over time. Additionally, the HR of lung cancer for 0–6 month follow-up was 3.07 (CI 1.73–5.44), and the association of lung cancer with COVID-19 disease disappeared at 6–12 month follow-up (1.06; 0.43–2.64) and at 12–24 months (1.02; 0.45–2.34). Compared to those with one SARS-CoV-2 infection, reinfected patients were at a higher risk of asthma (3.0; 1.32–6.84), COPD (3.07; 1.42–6.65), ILD (3.61; 1.11–11.8), and lung cancer (3.20; 1.59–6.45). Similar findings were noted when comparing with a historical cohort serving as a control group, including asthma (1.31; 1.13–1.52); bronchiectasis (1.53; 1.23–1.89); COPD (1.41; 1.24–1.59); ILD (2.53; 2.05–3.13); PVD (2.30; 1.98–2.66); and lung cancer (2.23; 1.78–2.79). Interpretation: Our research suggests that patients with COVID-19 may have an increased risk of developing respiratory diseases, and the risk increases with the severity of infection and reinfection. Even during the 24-month follow-up, the risk of asthma and bronchiectasis continued to increase. Hence, implementing appropriate follow-up strategies for these individuals is crucial to monitor and manage potential long-term respiratory health issues. Additionally, the increased risk in lung cancer in the COVID-19 individuals was probably due to the diagnostic tests conducted and incidental diagnoses. Funding: The National Natural Science Foundation of China of China Regional Innovation and Development Joint Foundation; National Natural Science Foundation of China; Program for High-level Foreign Expert Introduction of China; Natural Science Foundation for Distinguished Young Scholars of Guangdong Province; Guangdong Basic and Applied Basic Research Foundation; Climbing Program of Introduced Talents and High-level Hospital Construction Project of Guangdong Provincial People’s Hospital; VA Clinical Merit and ASGE clinical research funds.

Summary: Background: Diabetic kidney disease (DKD) is a leading cause of end-stage kidney disease and is associated with high mortality rates. The influence of routine clinical parameters on DKD onset in patients with type 2 diabetes mellitus (T2DM) remains uncertain. Methods: In this systematic review and meta-analysis, we searched multiple databases, including PubMed, Embase, Scopus, Web of Science, and Cochrane Library, for studies published from each database inception until January 11, 2024. We included cohort studies examining the association between DKD onset and various clinical parameters, including body mass index (BMI), hemoglobin A1c (HbA1c), systolic blood pressure (SBP), diastolic blood pressure (DBP), total cholesterol (TC), triglycerides (TG), low-density lipoprotein (LDL), high-density lipoprotein (HDL), and serum uric acid (UA). Random-effect dose–response meta-analyses utilizing one-stage and/or cubic spline models, were used to estimate correlation strength. This study is registered in PROSPERO (CRD42022326148). Findings: This analysis of 46 studies involving 317,502 patients found that in patients with T2DM, the risk of DKD onset increased by 3% per 1 kg/m2 increase in BMI (relative risk (RR) = 1.03, confidence interval (CI) [1.01–1.04], I2 = 70.07%; GRADE, moderate); a 12% increased risk of DKD onset for every 1% increase in HbA1c (RR = 1.12, CI [1.07–1.17], I2 = 94.94%; GRADE, moderate); a 6% increased risk of DKD onset for every 5 mmHg increase in SBP (RR = 1.06. CI [1.03–1.09], I2 = 85.41%; GRADE, moderate); a 2% increased risk of DKD onset per 10 mg/dL increase in TG (RR = 1.02, CI [1.01–1.03], I2 = 78.45%; GRADE, low); an 6% decreased risk of DKD onset per 10 mg/dL increase in HDL (RR = 0.94, CI [0.92–0.96], I2 = 0.33%; GRADE, high), and a 11% increased risk for each 1 mg/dL increase in UA (RR = 1.11, CI [1.05–1.17], I2 = 79.46%; GRADE, moderate). Subgroup analysis revealed a likely higher risk association of clinical parameters (BMI, HbA1c, LDL, and UA) in patients with T2DM for less than 10 years. Interpretation: BMI, HbA1c, SBP, TG, HDL and UA are potential predictors of DKD onset in patients with T2DM. Given high heterogeneity between included studies, our findings should be interpreted with caution, but they suggest monitoring of these clinical parameters to identify individuals who may be at risk of developing DKD. Funding: Shenzhen Science and Innovation Fund, the Hong Kong Research Grants Council, and the HKU Seed Funds, and Scientific and technological innovation project of China Academy of Chinese Medical Sciences.

Abstract Background Gastric cancer (GC) is one of the most common tumours in East Asia countries and is associated with Helicobacter pylori infection. H. pylori utilizes virulence factors, CagA and VacA, to up‐regulate pro‐inflammatory cytokines and activate NF‐κB signaling. Meanwhile, the PIEZO1 upregulation and cancer‐associated fibroblast (CAF) enrichment were found in GC progression. However, the mechanisms of PIEZO1 upregulation and its involvement in GC progression have not been fully elucidated. Methods The CAF enrichment and clinical significance were investigated in animal models and primary samples. The expression of NF‐κB and PIEZO1 in GC was confirmed by immunohistochemistry staining, and expression correlation was analysed in multiple GC datasets. GSEA and Western blot analysis revealed the YAP1‐CTGF axis regulation by PIEZO1. The stimulatory effects of CTGF on CAFs were validated by the co‐culture system and animal studies. Patient‐derived organoid and peritoneal dissemination models were employed to confirm the role of the PIEZO1‐YAP1‐CTGF cascade in GC. Results Both CAF signature and PIEZO1 were positively correlated with H. pylori infection. PIEZO1, a mechanosensor, was confirmed as a direct downstream of NF‐κB to promote the transformation from intestinal metaplasia to GC. Mechanistic studies revealed that PIEZO1 transduced the oncogenic signal from NF‐κB into YAP1 signaling, a well‐documented oncogenic pathway in GC progression. PIEZO1 expression was positively correlated with the YAP1 signature (CTGF, CYR61, and c‐Myc, etc.) in primary samples. The secreted CTGF by cancer cells stimulated the CAF infiltration to form a stiffened collagen‐enrichment microenvironment, thus activating PIEZO1 to form a positive feedback loop. Both PIEZO1 depletion by shRNA and CTGF inhibition by Procyanidin C1 enhanced the efficacy of 5‐FU in suppressing the GC cell peritoneal metastasis. Conclusion This study elucidates a novel driving PIEZO1‐YAP1‐CTGF force, which opens a novel therapeutic avenue to block the transformation from precancerous lesions to GC. H. pylori‐NF‐κB activates the PIEZO1‐YAP1‐CTGF axis to remodel the GC microenvironment by promoting CAF infiltration. Targeting PIEZO1‐YAP1‐CTGF plus chemotherapy might serve as a potential therapeutic option to block GC progression and peritoneal metastasis.

The NG-Test CARBA 5 and Carbapenem-resistant K.N.I.V.O. Detection K-Set are lateral flow assays (LFAs) that rapidly detect five carbapenemases (KPC, NDM, IMP, VIM and OXA-48-like). We evaluated the effect of inoculum size on the performance of these two assays using 27 Enterobacterales isolates. Whole-genome sequencing (WGS) was used as the reference method. Using the NG-Test CARBA 5, eight Serratia spp. and six M. morganii isolates showed false-positive NDM results with a high inoculum. Using the Carbapenem-resistant K.N.I.V.O. Detection K-Set, eight M. morganii, four Serratia spp. and one K. pneumoniae isolates showed false-positive NDM and/or OXA-48-like bands at large inoculum sizes, while the other two M. morganii isolates demonstrated false-positive NDM and OXA-48-like results at all inoculum sizes. The false-positive bands varied in intensity. WGS confirmed that no carbapenemase gene was present. No protein sequence with a ≥50% identity to NDM or OXA-48-like enzymes was found. This study emphasizes the importance of assessing inoculum size in the diagnostic evaluation of LFAs.

Abstract Background Optimal carbohydrate intake is an important and controversial area in the nutritional management of type 2 diabetes. Some evidence indicates that reducing overall carbohydrate intake with a low- or very low-carbohydrate eating plan can improve glycemic control compared to following eating plans that involve greater carbohydrate intake. However, critical knowledge gaps currently prevent clear recommendations about carbohydrate intake levels. Methods The LEGEND (Lifestyle Education about Nutrition for Diabetes) Trial aims to compare a very low-carbohydrate diet to a moderate-carbohydrate plate-method diet for glycemic control in adults with type 2 diabetes. This two-site trial plans to recruit 180 adults with type 2 diabetes. We will randomize participants to either a 20-session group-based diet and lifestyle intervention that teaches either a very low-carbohydrate diet or a moderate-carbohydrate plate-method diet. We will assess participants at study entry and 4 and 12 months later. The primary outcome is HbA1c, and secondary outcomes include inflammation (high sensitivity C-reactive protein), body weight, changes in diabetes medications, lipids (small particle LDL, HDL, triglycerides), skeletal metabolism (bone mineral density from dual-energy x-ray absorptiometry and bone turnover markers serum procollagen type I N propeptide and serum C-terminal telopeptide of type I collagen), and body composition (percent body fat, percent lean body mass). Discussion The LEGEND trial is a randomized controlled trial to assess optimal carbohydrate intake in type 2 diabetes by evaluating the effects of a very low-carbohydrate diet vs. a moderate-carbohydrate plate-method diet over a year-long period. The research addresses important gaps in the evidence base for the nutritional management of type 2 diabetes by providing data on potential benefits and adverse effects of different levels of carbohydrate intake. Trial registration ClinicalTrials.gov NCT05237128. Registered on February 11, 2022

Here, we report the first adult case of pancreatic yolk sac tumor with ectopic adrenocorticotropic hormone (ACTH) syndrome. The patient was a 27-year-old woman presenting with abdominal distension, Cushingoid features, and hyperpigmentation. Endogenous Cushing’s syndrome was biochemically confirmed. The ACTH level was in the normal range, which raised the suspicion of ACTH precursor-dependent disease. Elevated ACTH precursors were detected, supporting the diagnosis of ectopic ACTH syndrome. Functional imaging followed by tissue sampling revealed a pancreatic yolk sac tumor. The final diagnosis was Cushing’s syndrome due to a yolk sac tumor. The patient received a steroidogenesis inhibitor and subsequent bilateral adrenalectomy for control of hypercortisolism. Her yolk sac tumor was treated with chemotherapy and targeted therapy. Cushing’s syndrome secondary to a yolk sac tumor is extremely rare. This case illustrated the utility of ACTH precursor measurement in confirming an ACTH-related pathology and distinguishing an ectopic from a pituitary source for Cushing’s syndrome.

ABSTRACTContext Bedside clinical teaching is the backbone of clerkship education. Data-driven methods for supplementing bedside encounters with standardized content from vetted resources are needed.Objective To compare a flipped-classroom versus an interactive online-only instruction for improving knowledge, skills, self-directed learning (SDL) behaviors, and satisfaction in a medical school clerkship.Methods An IRB-approved prospective study employing a peer-reviewed clinical reasoning curriculum in neurology was conducted; 2nd-4th year medical students rotating through a required clerkship were enrolled. Students were randomized to flipped-classroom (i.e., flipped) or interactive asynchronous online instruction (i.e., online-only), which supplemented existing bedside teaching. Baseline and end-of-course knowledge, skill development, SDL behaviors, satisfaction, and long-term retention were assessed by peer-reviewed clinical reasoning exam, NBME scores, faculty/resident clinical evaluations, non-compulsory assignment completion, end-of-clerkship surveys, and objective structured clinical exam (OSCE).Results 104 students (49 flipped, 55 online-only) were enrolled. Age, gender, and training level did not differ by group (all p > 0.43); baseline knowledge was higher in the flipped group (p = 0.003). Knowledge-based exam scores did not differ by group even after adjusting for differences in baseline knowledge (2.3-points higher in flipped group, 95%CI −0.4–4.8, p = 0.07). Clinical skills were significantly higher in the flipped group, including examination skills (4.2 ± 0.5 vs. 3.9 ± 0.7, p = 0.03) and future housestaff potential (4.8 ± 0.3 vs 4.5 ± 0.6, p = 0.03). Students in the online-only group were more likely to engage in SDL (42 vs. 12%, p = 0.001) and reported more hours studying (6.1 vs. 3.8 hours, p = 0.03). Satisfaction (p = 0.51) and OSCE scores (p = 0.28) were not different by group.Conclusions In this comparative study of two evidence-based curricular delivery approaches, we observed no difference in knowledge acquired. Greater clinical skills were observed with flipped instruction, while more SDL was observed with online-only instruction. Supplementing bedside teaching with blended instruction that balances live skill development with vetted online resources is optimal for clerkship education.

Background: Community-based service learning (CBSL) is a core component of the Canadian medical education system. However, the unique role of community partner organizations (CPOs) in supporting CBSL remains unclear. This qualitative study evaluates the perspective of CPOs as co-educators in the undergraduate medical curriculum. Methods: We conducted eight semi-structured, one-on-one interviews with CPOs at a medical school in Toronto, Ontario between 2020-2021. Interviews were conducted following a pre-determined interview guide and then recorded, de-identified, and transcribed. Three reviewers independently performed an inductive thematic analysis of codes followed by a group review of discrepancies. Results: Five main findings were identified: 1) CPOs share a common interest in serving as co-educators; 2) considerable heterogeneity in the understanding of co-education exists; 3) there is an opportunity for increased partnerships between CPOs and faculty; 4) the role of co-educators is limited by curriculum structure; and 5) co-educators facilitate unique teachings of social determinants of health otherwise not available through traditional didactic teaching. Conclusions: There is an emerging, unique role for community co-educators in the undergraduate medical curriculum, supported by interest from CPOs. Its emphasis may contribute to future cohorts of medical students capable of understanding and addressing the needs of the populations they serve.

Summary: Background: COVID-19 and antimicrobial resistance (AMR) are two intersecting public health crises. Antimicrobial overuse in patients with COVID-19 threatens to worsen AMR. Guidelines are fundamental in encouraging antimicrobial stewardship. We sought to assess the quality of antibiotic prescribing guidelines and recommendations in the context of COVID-19, and whether they incorporate principles of antimicrobial stewardship. Methods: We performed a systematic survey which included a search using the concepts “antibiotic/antimicrobial” up to November 15, 2022 of the eCOVID-19 living map of recommendations (RecMap) which aggregates guidelines across a range of international sources and all languages. Guidelines providing explicit recommendations regarding antibacterial use in COVID-19 were eligible for inclusion. Guideline and recommendation quality were assessed using the AGREE II and AGREE-REX instruments, respectively. We extracted guideline characteristics including panel representation and the presence or absence of explicit statements related to antimicrobial stewardship (i.e., judicious antibiotic use, antimicrobial resistance or adverse effects as a consequence of antibiotic use). We used logistic regression to evaluate the relationship between guideline characteristics including quality and incorporation of antimicrobial stewardship principles. Protocol registration (OSF): https://osf.io/4pgtc. Findings: Twenty-eight guidelines with 63 antibiotic prescribing recommendations were included. Recommendations focused on antibiotic initiation (n = 52, 83%) and less commonly antibiotic selection (n = 13, 21%), and duration of therapy (n = 15, 24%). Guideline and recommendation quality varied widely. Twenty (71%) guidelines incorporated at least one concept relating to antimicrobial stewardship. Including infectious diseases expertise on the guideline panel (OR 9.44, 97.5% CI: 1.09–81.59) and AGREE-REX score (OR 3.26, 97.5% CI: 1.14–9.31 per 10% increase in overall score) were associated with a higher odds of guidelines addressing antimicrobial stewardship. Interpretation: There is an opportunity to improve antibiotic prescribing guidelines in terms of both quality and incorporation of antimicrobial stewardship principles. These findings can help guideline developers better address antibiotic stewardship in future recommendations beyond COVID-19. Funding: This project was funded by Michael G. DeGroote Cochrane Canada and McMaster GRADE centres.

Abstract Background Service gaps exist in oral anticoagulant (OAC) use among patients with atrial fibrillation (AF) in primary care. The purpose of this study was to explore the clinical effectiveness of a community dwelling Atrial Fibrillation Special Clinic (AFSC) run by primary care physicians by evaluating its impact on OAC use and the control of modifiable cardiovascular disease (CVD) risk factors in high risk AF patients. Method Quasi-experimental study was conducted in AFSC run by public primary care physicians in Hong Kong. Study subjects were high risk AF patients with CHA2DS2-VASc scores ≥ 2, who had been followed up (FU) at AFSC for at least one year from 01 August, 2019 to 31 October, 2020. OAC usage and modifiable CVD risk factor control were compared before and after one year of FU at AFSC. Drug-related adverse events, emergency attendance or hospitalisation episodes, survival and mortality rates after one year FU at AFSC were also reviewed. Results Among the 299 high risk AF patients included in the study, significant increase in OAC use was observed from 58.5% at baseline to 82.6% after one year FU in AFSC (P

Abstract Background Many foreign studies investigated glycemic control and fall risk. However, there was insufficient study on this topic in Hong Kong. This study aims to find out the association of glycemic control and fall risk in the diabetic elderly in a general outpatient clinic in the North District of Hong Kong. Their frequency of falls and other associated risk factors of fall were also studied. Methods A cross-sectional questionnaire survey was conducted on 442 diabetic patients aged 65 years-old or above with regular follow-up in a general outpatient clinic. Main outcome measure was the number of falls in the past one year from the interview date. Recurrent falls was defined as two or more falls in the past one year from the interview date. Subjects were asked about experience of hypoglycemic symptoms. HbA1c level, chronic illness, retinopathy etc. were obtained through computerized medical record review. Chi square test and logistic regression were used to assess the association between outcomes and the explanatory variables. Results In the past one year, 23.3% participants experienced at least one fall and 8.6% had recurrent falls. Hypoglycemic symptoms, and lower visual acuity

The performance of the Xpert Xpress CoV-2/Flu/RSV plus and Alinity m Resp-4-Plex Assays were evaluated using 167 specimens, including 158 human respiratory specimens and 9 external quality assessment program (EQAP) samples. For respiratory specimens, CoV-2/Flu/RSV plus exhibited perfect agreement with the standard-of-care (SOC) methods (Cohen’s κ: 1, 100% agreement). The overall positive and negative percent agreement (PPA and NPA) were 100%, with 95% confidence intervals of 96.50 to 100% and 85.70 to 100%, respectively. On the other hand, Resp-4-Plex revealed an almost perfect agreement with the SOC methods (Cohen’s κ: 0.92, 97.71% agreement). The overall PPA and NPA were 100% (95.76 to 100%) and 88.46% (70.20 to 96.82%), respectively. For EQAP samples, the results of CoV-2/Flu/RSV plus (9/9) and Resp-4-Plex (4/4) were concordant with the expected results. The experimental limit of detection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was the lowest (25 copies/mL for both methods), and that of the respiratory syncytial virus was the highest (400 copies/mL for CoV-2/Flu/RSV plus and 100 copies/mL for Resp-4-Plex). Threshold cycle (Ct) value correlation showed a large positive linear association between CoV-2/Flu/RSV plus and Resp-4-Plex, with R-squared values of 0.92–0.97, and on average, the Ct values of CoV-2/Flu/RSV plus were higher than that of Resp-4-Plex by 1.86–2.78, except for Flu A1 target (−0.66). To conclude, the performance of both assay was comparable to the SOC methods for both upper and lower respiratory specimens. Implementation of these rapid assay may reinforce the diagnostic capacity for the post-pandemic co-circulation of SARS-CoV-2 and other respiratory viruses.

Multi-criteria optimization (MCO) function has been available on commercial radiotherapy (RT) treatment planning systems to improve plan quality; however, no study has compared Eclipse and RayStation MCO functions for prostate RT planning. The purpose of this study was to compare prostate RT MCO plan qualities in terms of discrepancies between Pareto optimal and final deliverable plans, and dosimetric impact of final deliverable plans. In total, 25 computed tomography datasets of prostate cancer patients were used for Eclipse (version 16.1) and RayStation (version 12A) MCO-based plannings with doses received by 98% of planning target volume having 76 Gy prescription (PTV76D98%) and 50% of rectum (rectum D50%) selected as trade-off criteria. Pareto optimal and final deliverable plan discrepancies were determined based on PTV76D98% and rectum D50% percentage differences. Their final deliverable plans were compared in terms of doses received by PTV76 and other structures including rectum, and PTV76 homogeneity index (HI) and conformity index (CI), using a t-test. Both systems showed discrepancies between Pareto optimal and final deliverable plans (Eclipse: −0.89% (PTV76D98%) and −2.49% (Rectum D50%); RayStation: 3.56% (PTV76D98%) and −1.96% (Rectum D50%)). Statistically significantly different average values of PTV76D98%,HI and CI, and mean dose received by rectum (Eclipse: 76.07 Gy, 0.06, 1.05 and 39.36 Gy; RayStation: 70.43 Gy, 0.11, 0.87 and 51.65 Gy) are noted, respectively (p < 0.001). Eclipse MCO-based prostate RT plan quality appears better than that of RayStation.

Digitalizing all aspects of dental care is a contemporary approach to ensuring the best possible clinical outcomes. Ongoing advancements in 3D face acquisition have been driven by continuous research on craniofacial structures and treatment effects. An array of 3D surface-imaging systems are currently available for generating photorealistic 3D facial images. However, choosing a purpose-specific system is challenging for clinicians due to variations in accuracy, reliability, resolution, and portability. Therefore, this review aims to provide clinicians and researchers with an overview of currently used or potential 3D surface imaging technologies and systems for 3D face acquisition in craniofacial research and daily practice. Through a comprehensive literature search, 71 articles meeting the inclusion criteria were included in the qualitative analysis, investigating the hardware, software, and operational aspects of these systems. The review offers updated information on 3D surface imaging technologies and systems to guide clinicians in selecting an optimal 3D face acquisition system. While some of these systems have already been implemented in clinical settings, others hold promise. Furthermore, driven by technological advances, novel devices will become cost-effective and portable, and will also enable accurate quantitative assessments, rapid treatment simulations, and improved outcomes.

BackgroundThe understanding of Post-acute sequelae of SARS-CoV-2 infection (PASC) can be improved by longitudinal assessment of symptoms encompassing the acute illness period. To gain insight into the various disease trajectories of PASC, we assessed symptom evolution and clinical factors associated with the development of PASC over 3 months, starting with the acute illness period.MethodsWe conducted a prospective cohort study to identify parameters associated with PASC. We performed cluster and case control analyses of clinical data, including symptomatology collected over 3 months following infection.ResultsWe identified three phenotypic clusters associated with PASC that could be characterized as remittent, persistent, or incident based on the 3-month change in symptom number compared to study entry: remittent (median; min, max: −4; −17, 3), persistent (−2; −14, 7), or incident (4.5; −5, 17) (p = 0.041 remittent vs. persistent, p < 0.001 remittent vs. incident, p < 0.001 persistent vs. incident). Despite younger age and lower hospitalization rates, the incident phenotype had a greater number of symptoms (15; 8, 24) and a higher proportion of participants with PASC (63.2%) than the persistent (6; 2, 9 and 52.2%) or remittent clusters (1; 0, 6 and 18.7%). Systemic corticosteroid administration during acute infection was also associated with PASC at 3 months [OR (95% CI): 2.23 (1.14, 4.36)].ConclusionAn incident disease phenotype characterized by symptoms that were absent during acute illness and the observed association with high dose steroids during acute illness have potential critical implications for preventing PASC.

Summary: Background: Case reports suggest that SARS-CoV-2 infection could lead to immune dysregulation and trigger autoimmunity while COVID-19 vaccination is effective against severe COVID-19 outcomes. We aim to examine the association between COVID-19 and development of autoimmune diseases (ADs), and the potential protective effect of COVID-19 vaccination on such an association. Methods: A retrospective cohort study was conducted in Hong Kong between 1 April 2020 and 15 November 2022. COVID-19 was confirmed by positive polymerase chain reaction or rapid antigen test. Cox proportional hazard regression with inverse probability of treatment weighting was applied to estimate the risk of incident ADs following COVID-19. COVID-19 vaccinated population was compared against COVID-19 unvaccinated population to examine the protective effect of COVID-19 vaccination on new ADs. Findings: The study included 1,028,721 COVID-19 and 3,168,467 non-COVID individuals. Compared with non-COVID controls, patients with COVID-19 presented an increased risk of developing pernicious anaemia [adjusted Hazard Ratio (aHR): 1.72; 95% Confidence Interval (CI): 1.12–2.64]; spondyloarthritis [aHR: 1.32 (95% CI: 1.03–1.69)]; rheumatoid arthritis [aHR: 1.29 (95% CI: 1.09–1.54)]; other autoimmune arthritis [aHR: 1.43 (95% CI: 1.33–1.54)]; psoriasis [aHR: 1.42 (95% CI: 1.13–1.78)]; pemphigoid [aHR: 2.39 (95% CI: 1.83–3.11)]; Graves' disease [aHR: 1.30 (95% CI: 1.10–1.54)]; anti-phospholipid antibody syndrome [aHR: 2.12 (95% CI: 1.47–3.05)]; immune mediated thrombocytopenia [aHR: 2.1 (95% CI: 1.82–2.43)]; multiple sclerosis [aHR: 2.66 (95% CI: 1.17–6.05)]; vasculitis [aHR: 1.46 (95% CI: 1.04–2.04)]. Among COVID-19 patients, completion of two doses of COVID-19 vaccine shows a decreased risk of pemphigoid, Graves' disease, anti-phospholipid antibody syndrome, immune-mediated thrombocytopenia, systemic lupus erythematosus and other autoimmune arthritis. Interpretation: Our findings suggested that COVID-19 is associated with an increased risk of developing various ADs and the risk could be attenuated by COVID-19 vaccination. Future studies investigating pathology and mechanisms would be valuable to interpreting our findings. Funding: Supported by RGC Collaborative Research Fund (C7154-20GF).

Summary: Background: Dolutegravir (DTG) is a recommended first-line regimen for all people with Human Immunodeficiency Virus (HIV) infection. Initial findings from Botswana, a country with no folate fortification program, showed an elevated prevalence of neural tube defects (NTDs) with peri-conceptional exposure to DTG. Here we explore whether a low folate diet influences the risk of DTG-associated foetal anomalies in a mouse model. Methods: C57BL/6 mice fed a folate-deficient diet for 2 weeks, were mated and then randomly allocated to control (water), or 1xDTG (2.5 mg/kg), or 5xDTG (12.5 mg/kg) both administered orally with 50 mg/kg tenofovir disoproxil fumarate 33.3 mg/kg emtricitabine. Treatment was administered once daily from gestational day (GD) 0.5 to sacrifice (GD15.5). Foetuses were assessed for gross anomalies. Maternal and foetal folate levels were quantified. Findings: 313 litters (103 control, 106 1xDTG, 104 5xDTG) were assessed. Viability, placental weight, and foetal weight did not differ between groups. NTDs were only observed in the DTG groups (litter rate: 0% control; 1.0% 1xDTG; 1.3% 5xDTG). Tail, abdominal wall, limb, craniofacial, and bleeding defects all occurred at higher rates in the DTG groups versus control. Compared with our previous findings on DTG usage in folate-replete mouse pregnancies, folate deficiency was associated with higher rates of several defects, including NTDs, but in the DTG groups only. We observed a severe left-right asymmetry phenotype that was more frequent in DTG groups than controls. Interpretation: Maternal folate deficiency may increase the risk for DTG-associated foetal defects. Periconceptional folic acid supplementation could be considered for women with HIV taking DTG during pregnancy, particularly in countries lacking folate fortification programs. Funding: This project has been funded by Federal funds from the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Department of Health and Human Services, under Contract No. HHSN275201800001I and award #R01HD104553. LS is supported by a Tier 1 Canada Research Chair in Maternal-Child Health and HIV. HM is supported by a Junior Investigator award from the Ontario HIV Treatment Network.

Letters of recommendation play a significant role in higher education and career progression, particularly for women and underrepresented groups in medicine and science. Already, there is evidence to suggest that written letters of recommendation contain language that expresses implicit biases, or unconscious biases, and that these biases occur for all recommenders regardless of the recommender’s sex. Given that all individuals have implicit biases that may influence language use, there may be opportunities to apply contemporary technologies, such as large language models or other forms of generative artificial intelligence (AI), to augment and potentially reduce implicit biases in the written language of letters of recommendation. In this editorial, we provide a brief overview of existing literature on the manifestations of implicit bias in letters of recommendation, with a focus on academia and medical education. We then highlight potential opportunities and drawbacks of applying this emerging technology in augmenting the focused, professional task of writing letters of recommendation. We also offer best practices for integrating their use into the routine writing of letters of recommendation and conclude with our outlook for the future of generative AI applications in supporting this task.

Abstract Introduction Blood loss and red blood cell (RBC) transfusion in liver surgery are areas of concern for surgeons, anesthesiologists, and patients alike. While various methods are employed to reduce surgical blood loss, the evidence base surrounding each intervention is limited. Hypovolemic phlebotomy, the removal of whole blood from the patient without volume replacement during liver transection, has been strongly associated with decreased bleeding and RBC transfusion in observational studies. This trial aims to investigate whether hypovolemic phlebotomy is superior to usual care in reducing RBC transfusions in liver resection. Methods This study is a double-blind multicenter randomized controlled trial. Adult patients undergoing major hepatic resections for any indication will be randomly allocated in a 1:1 ratio to either hypovolemic phlebotomy and usual care or usual care alone. Exclusion criteria will be minor resections, preoperative hemoglobin

Abstract Background Accurately estimating elderly patients’ rehospitalisation risk benefits clinical decisions and service planning. However, research in rehospitalisation and repeated hospitalisation yielded only models with modest performance, and the model performance deteriorates rapidly as the prediction timeframe expands beyond 28 days and for older participants. Methods A temporal zero-inflated Poisson (tZIP) regression model was developed and validated retrospectively and prospectively. The data of the electronic health records (EHRs) contain cohorts (aged 60+) in a major public hospital in Hong Kong. Two temporal offset functions accounted for the associations between exposure time and parameters corresponding to the zero-inflated logistic component and the Poisson distribution’s expected count. tZIP was externally validated with a retrospective cohort’s rehospitalisation events up to 12 months after the discharge date. Subsequently, tZIP was validated prospectively after piloting its implementation at the study hospital. Patients discharged within the pilot period were tagged, and the proposed model’s prediction of their rehospitalisation was verified monthly. Using a hybrid machine learning (ML) approach, the tZIP-based risk estimator’s marginal effect on 28-day rehospitalisation was further validated, competing with other factors representing different post-acute and clinical statuses. Results The tZIP prediction of rehospitalisation from 28 days to 365 days was achieved at above 80% discrimination accuracy retrospectively and prospectively in two out-of-sample cohorts. With a large margin, it outperformed the Cox proportional and linear models built with the same predictors. The hybrid ML revealed that the risk estimator’s contribution to 28-day rehospitalisation outweighed other features relevant to service utilisation and clinical status. Conclusions A novel rehospitalisation risk model was introduced, and its risk estimators, whose importance outweighed all other factors of diverse post-acute care and clinical conditions, were derived. The proposed approach relies on four easily accessible variables easily extracted from EHR. Thus, clinicians could visualise patients’ rehospitalisation risk from 28 days to 365 days after discharge and screen high-risk older patients for follow-up care at the proper time.

Abstract Background Prognostic information for patients with hypertension is largely based on population averages. The purpose of this study was to compare the performance of four machine learning approaches for personalized prediction of incident hospitalization for cardiovascular disease among newly diagnosed hypertensive patients. Methods Using province-wide linked administrative health data in Alberta, we analyzed a cohort of 259,873 newly-diagnosed hypertensive patients from 2009 to 2015 who collectively had 11,863 incident hospitalizations for heart failure, myocardial infarction, and stroke. Linear multi-task logistic regression, neural multi-task logistic regression, random survival forest and Cox proportional hazard models were used to determine the number of event-free survivors at each time-point and to construct individual event-free survival probability curves. The predictive performance was evaluated by root mean squared error, mean absolute error, concordance index, and the Brier score. Results The random survival forest model has the lowest root mean squared error value at 33.94 and lowest mean absolute error value at 28.37. Machine learning methods provide similar discrimination and calibration in the personalized survival prediction of hospitalizations for cardiovascular events in patients with hypertension. Neural multi-task logistic regression model has the highest concordance index at 0.8149 and lowest Brier score at 0.0242 for the personalized survival prediction. Conclusions This is the first personalized survival prediction for cardiovascular diseases among hypertensive patients using administrative data. The four models tested in this analysis exhibited a similar discrimination and calibration ability in predicting personalized survival prediction of hypertension patients.

Triple-negative breast cancer (TNBC) is a highly aggressive and metastasizing cancer that has the worst prognosis out of all breast cancer subtypes. The epithelial–mesenchymal transition (EMT) and cancer stem cells (CSCs) have been proposed as important mechanisms underlying TNBC metastasis. CDK9 is highly expressed in breast cancer, including TNBC, where it promotes EMT and induces cancer cell stemness. In this study, we have identified a tetrahydroisoquinoline derivative (compound 1) as a potent and selective CDK9-cyclin T1 inhibitor via virtual screening. Interestingly, by targeting the ATP binding site, compound 1 not only inhibited CDK9 activity but also disrupted the CDK9-cyclin T1 protein–protein interaction (PPI). Mechanistically, compound 1 reversed EMT and reduced the ratio of CSCs by blocking the CDK9-cyclin T1 interaction, leading to reduced TNBC cell proliferation and migration. To date, compound 1 is the first reported tetrahydroisoquinoline-based CDK9-cyclin T1 ATP-competitive inhibitor that also interferes with the interaction between CDK9 and cyclin T1. Compound 1 may serve as a promising scaffold for developing more selective and potent anti-TNBC agents. Our work also provides insight into the role of the CDK9-cyclin T1 PPI on EMT and CSCs and highlights the feasibility and significance of targeting CDK9 for the treatment of TNBC.