Online medical student OSCE examinations during the first three years of the COVID-19 pandemic compared to three years pre-pandemic: An Australian experience in psychiatry and addiction medicine.

PURPOSE: We have evaluated the final-year Psychiatry and Addiction Medicine (PAM) summative Objective Structured Clinical Examination (OSCE) examinations in a four-year graduate medical degree program, for the previous three years as a baseline comparator, and during three years of the COVID-19 pandemic (2020-2022). METHODS: A de-identified analysis of medical student summative OSCE examination performance, and comparative review for the 3 years before, and for each year of the pandemic. RESULTS: Internal reliability in test scores as measured by R-squared remained the same or increased following the start of the pandemic. There was a significant increase in mean test scores after the start of the pandemic compared to pre-pandemic for combined OSCE scores for all final-year disciplines, as well as for the PAM role-play OSCEs, but not for the PAM mental state examination OSCEs. CONCLUSIONS: Changing to online OSCEs during the pandemic was related to an increase in scores for some but not all domains of the tests. This is in line with a nascent body of literature on medical teaching and examination following the start of the pandemic. Further research is needed to optimise teaching and examination in a post-pandemic medical school environment.

Increasing Linker Chain Length and Intestinal Stability Enhances Lymphatic Transport and Lymph Node Exposure of Triglyceride Mimetic Prodrugs of a Model Immunomodulator Mycophenolic Acid.

Targeted delivery of immunomodulators to the lymphatic system has the potential to enhance therapeutic efficacy by increasing colocalization of drugs with immune targets such as lymphocytes. A triglyceride (TG)-mimetic prodrug strategy has been recently shown to enhance the lymphatic delivery of a model immunomodulator, mycophenolic acid (MPA), via incorporation into the intestinal TG deacylation-reacylation and lymph lipoprotein transport pathways. In the current study, a series of structurally related TG prodrugs of MPA were examined to optimize structure-lymphatic transport relationships for lymph-directing lipid-mimetic prodrugs. MPA was conjugated to the sn-2 position of the glyceride backbone of the prodrugs using linkers of different chain length (5-21 carbons) and the effect of methyl substitutions at the alpha and/or beta carbons to the glyceride end of the linker was examined. Lymphatic transport was assessed in mesenteric lymph duct cannulated rats, and drug exposure in lymph nodes was examined following oral administration to mice. Prodrug stability in simulated intestinal digestive fluid was also evaluated. Prodrugs with straight chain linkers were relatively unstable in simulated intestinal fluid; however, co-administration of lipase inhibitors (JZL184 and orlistat) was able to reduce instability and increase lymphatic transport (2-fold for a prodrug with a 6-carbon spacer, i.e., MPA-C6-TG). Methyl substitutions to the chain resulted in similar trends in improving intestinal stability and lymphatic transport. Medium- to long-chain spacers (C12, C15) between MPA and the glyceride backbone were most effective in promoting lymphatic transport, consistent with increases in lipophilicity. In contrast, short-chain (C6-C10) linkers appeared to be too unstable in the intestine and insufficiently lipophilic to associate with lymph lipid transport pathways, while very long-chain (C18, C21) linkers were also not preferred, likely as a result of increases in molecular weight reducing solubility or permeability. In addition to more effectively promoting drug transport into mesenteric lymph, TG-mimetic prodrugs based on a C12 linker resulted in marked increases (>40 fold) in the exposure of MPA in the mesenteric lymph nodes in mice when compared to administration of MPA alone, suggesting that optimizing prodrug design has the potential to provide benefit in targeting and modulating immune cells.

Peer-supported physical activity intervention for academic probation freshmen in a physiology-related major: a feasibility study.

To retain students on academic probation, physiology and physiology-related programs may offer a variety of academic support initiatives. This pilot research study examined the feasibility and perceptions of implementing a success coach-led physical activity (PA) program for freshmen on academic probation in a physiology-related program. Freshman on academic probation [grade point average (GPA) <2.0] worked with a success coach on academic success strategies and PA. Freshmen completed validated surveys (Academic Self-Efficacy, Self-Efficacy of Regulated Learning, Institutional Integration Scale) before and after intervention and semistructured interviews after intervention. Retention rate was determined at longitudinal follow-up in Fall 2022. Six freshmen participated. Average GPA did not improve between Fall 2021 (1.561 ± 0.285) and Spring 2022 (1.606 ± 0.832) (P = 0.89). All felt that the program improved their study skills, but fewer (40%) felt that their grades improved. Most had positive perceptions of the PA program, including self-reported improvements in health/fitness (60%), mood/mental well-being (100%), and stress management (80%). Although most improved attention when studying (80%), this did not translate to improved academic performance (40%). For the Institutional Integration Scales, only the scale for "Faculty Concern for Student Development and Teaching" improved by the end of the semester (pre: 37 ± 7.6, post: 19 ± 3.4, P < 0.001). Retention rate of participants (83%) was higher than the university's overall retention rate for students on academic probation (37%). By fostering social integration, improving mood and mental well-being, and increasing university retention rates this pilot project confirmed the feasibility of using upperclassmen as success coaches for a physical activity intervention for academic probation freshmen.NEW & NOTEWORTHY Using upperclassmen as success coaches for a physical activity intervention for academic probation freshmen fostered social integration, improved mood and mental well-being, and increased university retention rates.

Commentary on alignment of medical student assessment and vocational training in psychiatry and addiction medicine.

OBJECTIVE: To comment upon the potential for alignment of medical student assessment and vocational specialist training through the RANZCP-CanMEDS model of Entrustable Professional Activities (EPAs) and Workplace-Based Assessments (WBAs). We discuss a specific post hoc example of such an alignment in an Australian graduate medical school in Psychiatry and Addiction Medicine. CONCLUSIONS: Vocational training models of assessment, such as the RANZCP specialist training program for psychiatrists, can potentially be mapped to medical student education in formative and summative assessment through CanMEDs-based EPAs and WBAs, to assist in transition to specialist training.

Final-year medical student Psychiatry and Addiction Medicine synchronous summative tele-assessments during a COVID-19 Delta-variant stay-at-home lockdown.

OBJECTIVE: We describe the planning, process and evaluation of final-year Psychiatry and Addiction Medicine summative assessments in a four-year graduate medical degree program, during a COVID-19 Delta-variant public health stay-at-home lockdown. CONCLUSIONS: We conducted separate written and clinical synchronous (real-time simultaneous) tele-assessments. We used online assessment technology with students, examiners and simulated patients, all in different physical locations. Medical students' examination performance showed a good range. This was comparable to other discipline stations, and performance in previous years. There was no differential performance of students through the day of the assessments.

Maslow's hammer: considering the perils of solutionism in mental healthcare and psychiatric practice.

OBJECTIVE: To discuss narrow pragmatism, manifest as digital and technical solutionism, in mental healthcare and psychiatric practice. Pragmatism is a view of the field of psychiatry as an instrument or tool for the purpose of providing psychiatric care for people with a mental illness. Solutionism, as proposed by Morozov, can be considered a special case of pragmatism that valorises an approach to solving real-world problems based on computation, algorithms and digital technology,1 which we extend to discuss other technical solutions such as medication, non-invasive brain stimulation and psychotherapy. CONCLUSIONS: Digital or technical solutionism may unnecessarily constrain approaches to mental healthcare and psychiatric practice. Psychiatrists can consider, and should advocate for, appropriate adaptation of technology and technical solutions toward collaborative and effective mental healthcare.

Flattening the curve of COVID-19 for medical education in psychiatry and addiction medicine.

OBJECTIVE: To describe the context, challenges and responses to COVID-19 public health measures for medical education in psychiatry, with an emphasis on sharing strategies for ongoing COVID-19 challenges. CONCLUSION: The rapidity of COVID-19 public health measures instituted in Australia required swift action for medical education to address lockdowns of student clinical placements. The responses included a transition to interim online learning followed by a return to truncated clinical placements renegotiated to conform to public health measures. Adjustment of formative and summative assessment has been necessary. However, further contingencies may emerge depending upon the overall progress of the COVID-19 pandemic.

Conduct and evaluation of final-year medical student summative assessments in Psychiatry and Addiction Medicine during COVID-19: an Australian University Medical School experience.

OBJECTIVE: To describe and share with the medical education community, the conduct and evaluation of summative graduate medical student assessments in Psychiatry and Addiction Medicine during COVID-19 at an Australian university. METHODS: Summative assessments were redesigned as follows: written assessments were administered via an online platform (WATTLE), while the Objective Structured Clinical Examinations (OSCE) were conducted via a secure video-conferencing software (Zoom). RESULTS: Our preliminary analysis of the summative assessments indicated that both examiners and students adapted to the format, with overall performance of the students showing no variation due to timing of the assessment (earlier versus later in the day) and performances similar to face-to-face assessments in previous years. Examiners also expressed positive feedback on the assessment process. CONCLUSIONS: Our graduate fourth-year medical student summative assessments were effectively conducted using online and video-conferencing software in accordance with existing COVID-19 pandemic public health measures for physical distancing and hygiene.

Student evaluations of teaching (SET): implications for medical education in psychiatry and an approach to evaluating SET and student performance.

OBJECTIVE: We present reflections on student evaluation of teaching (SET) in the context of recent higher educational research that assesses SET, as well as concurrent and/or subsequent student performance. CONCLUSIONS: In a sense, there is in-built cynicism in SET, with more favourable SET for easier assessment. There is emerging evidence that SET is inversely proportional to the performance of students in subsequent courses, i.e. the higher the ratings, the poorer the students perform in subsequent studies. It is proposed that SET should be combined with contemporaneous formative and summative assessments of student performance in medical school settings, especially in psychiatry education.

Toll-like receptor 8 agonist nanoparticles mimic immunomodulating effects of the live BCG vaccine and enhance neonatal innate and adaptive immune responses.

BACKGROUND: Newborns display distinct immune responses, leaving them vulnerable to infections and impairing immunization. Targeting newborn dendritic cells (DCs), which integrate vaccine signals into adaptive immune responses, might enable development of age-specific vaccine formulations to overcome suboptimal immunization. OBJECTIVE: Small-molecule imidazoquinoline Toll-like receptor (TLR) 8 agonists robustly activate newborn DCs but can result in reactogenicity when delivered in soluble form. We used rational engineering and age- and species-specific modeling to construct and characterize polymer nanocarriers encapsulating a TLR8 agonist, allowing direct intracellular release after selective uptake by DCs. METHODS: Chemically similar but morphologically distinct nanocarriers comprised of amphiphilic block copolymers were engineered for targeted uptake by murine DCs in vivo, and a range of TLR8 agonist-encapsulating polymersome formulations were then synthesized. Novel 96-well in vitro assays using neonatal human monocyte-derived DCs and humanized TLR8 mouse bone marrow-derived DCs enabled benchmarking of the TLR8 agonist-encapsulating polymersome formulations against conventional adjuvants and licensed vaccines, including live attenuated BCG vaccine. Immunogenicity of the TLR8 agonist adjuvanted antigen 85B (Ag85B)/peptide 25-loaded BCG-mimicking nanoparticle formulation was evaluated in vivo by using humanized TLR8 neonatal mice. RESULTS: Although alum-adjuvanted vaccines induced modest costimulatory molecule expression, limited TH-polarizing cytokine production, and significant cell death, BCG induced a robust adult-like maturation profile of neonatal DCs. Remarkably, TLR8 agonist polymersomes induced not only newborn DC maturation profiles similar to those induced by BCG but also stronger IL-12p70 production. On subcutaneous injection to neonatal mice, the TLR8 agonist-adjuvanted Ag85B peptide 25 formulation was comparable with BCG in inducing Ag85B-specific CD4+ T-cell numbers. CONCLUSION: TLR8 agonist-encapsulating polymersomes hold substantial potential for early-life immunization against intracellular pathogens. Overall, our study represents a novel approach for rational design of early-life vaccines.

A new graduate medical school curriculum in Psychiatry and Addiction Medicine: reflections on a decade of development.

OBJECTIVES: The aim of this study is to reflect upon the rationale, design and development of the Psychiatry and Addiction Medicine curriculum at the Australian National University Medical School, Canberra, Australian Capital Territory, Australia. CONCLUSIONS: We conclude that the development of the fourth-year curriculum of a four-year graduate medical degree was a complex evolutionary process.

Salt in the soul, steel in the eye and caution towards the winds: a mariner's guide for navigating a new academic psychiatry department.

OBJECTIVES: This paper describes principles and advice regarding the development of a new academic psychiatry department within a medical school for aspiring academic psychiatrists. We describe general principles based on the experience of the foundation of the Academic Unit of Psychiatry and Addiction Medicine at the Australian National University Medical School. CONCLUSIONS: Perspicacious leadership and organisation are the foundation for an academic psychiatry department which delivers teaching, research and broader intellectual engagement with the medical and broader community.

Exercise and dietary advice intervention for survivors of triple-negative breast cancer: effects on body fat, physical function, quality of life, and adipokine profile.

PURPOSE: Regular exercise and healthy eating are routinely recommended for breast cancer survivors, and past studies show benefits in quality of life and decreased inflammation. However, this has not been tested specifically in triple-negative breast cancer survivors. Increasing physical activity and losing body fat are thought to positively affect inflammatory biomarkers that have been associated with breast cancer. Therefore, the primary purpose of this study was to determine if participation in an exercise and dietary counseling program can improve body fat, physical function, and quality of life in survivors of this aggressive breast cancer. Secondarily, we sought to determine if participation in the program had beneficial effects on obesity-related markers of the adipokine profile. METHODS: Sixty-six survivors of triple-negative breast cancer with BMI >25 were invited to participate. Twenty-eight enrolled and 23 completed the randomized, controlled trial (13 intervention, 10 control). Moderate-intensity aerobic exercise (150 min per week, for 12 weeks) and diet counseling were compared to usual care, education only. The primary outcome of interest was weight loss (body mass, BMI, % fat), and secondary outcomes included physical function (exercise capacity), quality of life (Function After Cancer Therapy-Breast (FACT-B)), cytokines (C-reactive protein (CRP), TNF-α, IL-6), and adipokine profile (leptin, adiponectin, insulin). RESULTS: Participants in the program lost more body fat (2.4 % loss vs. 0.4 % gain, p < 0.05) than the control group. The intervention group also improved quality of life (FACT-B total score +14 pts) and decreased sedentary time but did not improve peak exercise capacity. The intervention had no effect on serum cytokines and adipokines after 12 weeks in the program. However, serum leptin and adiponectin and their ratio were significantly correlated with BMI in the intervention group (p < 0.05). CONCLUSIONS: Exercise and dietary counseling led to loss of body fat and improved quality of life in survivors of triple-negative breast cancer. BMI was associated with favorable changes in leptin and adiponectin which may reflect a change in adiposity with intervention. Exercise and healthy eating may be equally effective in this high-risk population as in other breast cancer survivors and should be encouraged as a part of a cancer survivorship program.

Exercise reveals impairments in left ventricular systolic function in patients with metabolic syndrome.

Metabolic syndrome (MetS) is the manifestation of a cluster of cardiovascular risk factors and is associated with a threefold increase in the risk of cardiovascular morbidity and mortality, which is suggested to be mediated, in part, by resting left ventricular (LV) systolic dysfunction. However, to what extent resting LV systolic function is impaired in MetS is controversial, and there are no data indicating whether LV systolic function is impaired during exercise. Accordingly, the objective of this study was to examine comprehensively the LV and arterial responses to exercise in individuals with MetS without diabetes and/or overt cardiovascular disease in comparison to a healthy control population. Cardiovascular function was characterized using Doppler echocardiography and gas exchange in individuals with MetS (n = 27) versus healthy control subjects (n = 20) at rest and during peak exercise. At rest, individuals with MetS displayed normal LV systolic function but reduced LV diastolic function compared with healthy control subjects. During peak exercise, individuals with MetS had impaired contractility, pump performance and vasodilator reserve capacity versus control subjects. A blunted contractile reserve response resulted in diminished arterial-ventricular coupling reserve and limited aerobic capacity in individuals with MetS versus control subjects. These findings are of clinical importance, because they provide insight into the pathophysiological changes in MetS that may predispose this population of individuals to an increased risk of cardiovascular morbidity and mortality.

Self-assembled RNA interference microsponges for efficient siRNA delivery.

The encapsulation and delivery of short interfering RNA (siRNA) has been realized using lipid nanoparticles, cationic complexes, inorganic nanoparticles, RNA nanoparticles and dendrimers. Still, the instability of RNA and the relatively ineffectual encapsulation process of siRNA remain critical issues towards the clinical translation of RNA as a therapeutic. Here we report the synthesis of a delivery vehicle that combines carrier and cargo: RNA interference (RNAi) polymers that self-assemble into nanoscale pleated sheets of hairpin RNA, which in turn form sponge-like microspheres. The RNAi-microsponges consist entirely of cleavable RNA strands, and are processed by the cell's RNA machinery to convert the stable hairpin RNA to siRNA only after cellular uptake, thus inherently providing protection for siRNA during delivery and transport to the cytoplasm. More than half a million copies of siRNA can be delivered to a cell with the uptake of a single RNAi-microsponge. The approach could lead to novel therapeutic routes for siRNA delivery.

Enhanced stability of polymeric micelles based on postfunctionalized poly(ethylene glycol)-b-poly(γ-propargyl L-glutamate): the substituent effect.

One of the major obstacles that delay the clinical translation of polymeric micelle drug delivery systems is whether these self-assembled micelles can retain their integrity in blood following intravenous (IV) injection. The objective of this study was to evaluate the impact of core functionalization on the thermodynamic and kinetic stability of polymeric micelles. The combination of ring-opening polymerization of N-carboxyanhydride (NCA) with highly efficient "click" coupling has enabled easy and quick access to a family of poly(ethylene glycol)-block-poly(γ-R-glutamate)s with exactly the same block lengths, for which the substituent "R" is tuned. The structures of these copolymers were carefully characterized by (1)H NMR, FT-IR, and GPC. When pyrene is used as the fluorescence probe, the critical micelle concentrations (CMCs) of these polymers were found to be in the range of 10(-7)-10(-6) M, which indicates good thermodynamic stability for the self-assembled micelles. The incorporation of polar side groups in the micelle core leads to high CMC values; however, micelles prepared from these copolymers are kinetically more stable in the presence of serum and upon SDS disturbance. It was also observed that these polymers could effectively encapsulate paclitaxel (PTX) as a model anticancer drug, and the micelles possessing better kinetic stability showed better suppression of the initial "burst" release and exhibited more sustained release of PTX. These PTX-loaded micelles exerted comparable cytotoxicity against HeLa cells as the clinically approved Cremophor PTX formulation, while the block copolymers showed much lower toxicity compared to the cremophor-ethanol mixture. The present work demonstrated that the PEG-b-PPLG can be a uniform block copolymer platform toward development of polymeric micelle delivery systems for different drugs through the facile modification of the PPLG block.

Intracellular trafficking of polyamidoamine-poly(ethylene glycol) block copolymers in DNA delivery.

The delivery of nucleic acids has the potential to revolutionize medicine by allowing previously untreatable diseases to be clinically addressed. Viral delivery systems have shown immunogenicity and toxicity dangers, but synthetic vectors have lagged in transfection efficiency. Previously, we developed a modular, linear-dendritic block copolymer architecture with high gene transfection efficiency compared to commercial standards. This rationally designed system makes use of a cationic dendritic block to condense the anionic DNA and forms complexes with favorable endosomal escape properties. The linear block provides biocompatibility and protection from serum proteins, and can be functionalized with a targeting ligand. In this work, we quantitate performance of this system with respect to intracellular barriers to gene delivery using both high-throughput and traditional approaches. An image-based, high-throughput assay for endosomal escape is described and applied to the block copolymer system. Nuclear entry is demonstrated to be the most significant barrier to more efficient delivery and will be addressed in future versions of the system.

Targeted delivery of mycophenolic acid to the mesenteric lymph node using a triglyceride mimetic prodrug approach enhances gut-specific immunomodulation in mice.

The mesenteric lymph nodes (MLN) are a key site for the generation of adaptive immune responses to gut-derived antigenic material and immune cells within the MLN contribute to the pathophysiology of a range of conditions including inflammatory and autoimmune diseases, viral infections, graft versus host disease and cancer. Targeting immunomodulating drugs to the MLN may thus be beneficial in a range of conditions. This paper investigates the potential benefit of targeting a model immunosuppressant drug, mycophenolic acid (MPA), to T cells in the MLN, using a triglyceride (TG) mimetic prodrug approach. We confirmed that administration of MPA in the TG prodrug form (MPA-TG), increased lymphatic transport of MPA-related species 83-fold and increased MLN concentrations of MPA >20 fold, when compared to MPA alone, for up to 4 h in mice. At the same time, the plasma exposure of MPA and MPA-TG was similar, limiting the opportunity for systemic side effects. Confocal microscopy and flow cytometry studies with a fluorescent model prodrug (Bodipy-TG) revealed that the prodrug accumulated in the MLN cortex and paracortex at 5 and 10 h following administration and was highly associated with B cells and T cells that are found in these regions of the MLN. Finally, we demonstrated that MPA-TG was significantly more effective than MPA at inhibiting CD4+ and CD8+ T cell proliferation in the MLN of mice in response to an oral ovalbumin antigen challenge. In contrast, MPA-TG was no more effective than MPA at inhibiting T cell proliferation in peripheral LN when mice were challenged via SC administration of ovalbumin. This paper provides the first evidence of an in vivo pharmacodynamic benefit of targeting the MLN using a TG mimetic prodrug approach. The TG mimetic prodrug technology has the potential to benefit the treatment of a range of conditions where aberrant immune responses are initiated in gut-associated lymphoid tissues.

Relative quantum yield measurements of coumarin encapsulated in core-shell silica nanoparticles.

Fluorescent silica nanoparticles encapsulating organic fluorophores provide an attractive materials platform for a wide array of applications where high fluorescent brightness is required. We describe a class of fluorescent silica nanoparticles with a core-shell architecture and narrow particle size distribution, having a diameter of less than 20 nm and covalently incorporating a blue-emitting coumarin dye. A quantitative comparison of the scattering-corrected relative quantum yield of the particles to free dye in water yields an enhancement of approximately an order of magnitude. This enhancement of quantum efficiency is consistent with previous work on rhodamine dye-based particles. It provides support for the argument that improved brightness over free dye in aqueous solution is a more general effect of covalent incorporation of fluorescent organic dyes within rigid silica nanoparticle matrices. These results indicate a synthetic route towards highly fluorescent silica nanoparticles that produces excellent probes for imaging, security, and sensing applications.