Theranostic Small-Molecule Prodrug Conjugates for Targeted Delivery and Controlled Release of Toll-like Receptor 7 Agonists.

We previously reported the design and synthesis of a small-molecule drug conjugate (SMDC) platform that demonstrated several advantages over antibody-drug conjugates (ADCs) in terms of in vivo pharmacokinetics, solid tumor penetration, definitive chemical structure, and adaptability for modular synthesis. Constructed on a tri-modal SMDC platform derived from 1,3,5-triazine (TZ) that consists of a targeting moiety (Lys-Urea-Glu) for prostate-specific membrane antigen (PSMA), here we report a novel class of chemically identical theranostic small-molecule prodrug conjugates (T-SMPDCs), [18/19F]F-TZ(PSMA)-LEGU-TLR7, for PSMA-targeted delivery and controlled release of toll-like receptor 7 (TLR7) agonists to elicit de novo immune response for cancer immunotherapy. In vitro competitive binding assay of [19F]F-TZ(PSMA)-LEGU-TLR7 showed that the chemical modification of Lys-Urea-Glu did not compromise its binding affinity to PSMA. Receptor-mediated cell internalization upon the PSMA binding of [18F]F-TZ(PSMA)-LEGU-TLR7 showed a time-dependent increase, indicative of targeted intracellular delivery of the theranostic prodrug conjugate. The designed controlled release of gardiquimod, a TLR7 agonist, was realized by a legumain cleavable linker. We further performed an in vivo PET/CT imaging study that showed significantly higher uptake of [18F]F-TZ(PSMA)-LEGU-TLR7 in PSMA+ PC3-PIP tumors (1.9 ± 0.4% ID/g) than in PSMA- PC3-Flu tumors (0.8 ± 0.3% ID/g) at 1 h post-injection. In addition, the conjugate showed a one-compartment kinetic profile and in vivo stability. Taken together, our proof-of-concept biological evaluation demonstrated the potential of our T-SMPDCs for cancer immunomodulatory therapies.

Does pulmonary artery pulsatility index predict mortality in pulmonary arterial hypertension?

AIMS: Pulmonary artery pulsatility index (PAPi), defined as [(pulmonary artery systolic pressure - diastolic pulmonary artery pressure)/mean right atrial pressure], is a novel haemodynamic index that predicts right ventricular failure after myocardial infarction and left ventricular assist device implantation. We analysed if a low PAPi is associated with death in our 14 - â€‹year pulmonary arterial hypertension (PAH) registry. METHODS: Consecutive patients with newly diagnosed PAH and complete haemodynamic data were prospectively enrolled into our standing registry between January 2003 and December 2016. PAPi was calculated from baseline invasive right heart catheterization data. A prognostic cut-off value was determined with a decision tree. Baseline characteristics of 'high' and 'low' PAPi groups based on this cut-off were compared, as well as odds of death and time-to-death. RESULTS: One hundred and two patients were included. Mean age was 53 years, and 77% were women. Our multi-ethnic cohort was 64% Chinese, 23% Malay, and 10% Indian. The aetiologies were idiopathic (33%), connective tissue disease (31%), congenital heart disease (24%), and others (12%). The low PAPi group (<5.3) had a greater age (56 years vs. 49 years), lower pulmonary artery systolic pressure (71 mmHg vs. 85 mmHg), and higher mean right atrial pressure (14 mmHg vs. 6 mmHg). Mortality risk was higher in the low PAPi group (adjusted odds ratio: 2.98 and adjusted hazard ratio: 2.23). Mean right atrial pressure was the strongest predictor (hazard ratio 1.114, P = 0.009) when components of PAPi were analysed. CONCLUSIONS: Pulmonary artery pulsatility index was found to be predictive of mortality in PAH and may be a valuable marker for risk stratification. Its prognostic strength may be driven by mean right atrial pressure.

More than Pus - Primary Hepatic Epithelioid Angiomyolipoma Masquerading as Liver Abscess.

Hepatic angiomyolipomas (AML) are rare mesenchymal tumours of which the epithelioid type is a rare type with malignant potential. We report a case of primary hepatic epithelioid angiomyolipoma masquerading as liver abscess. A 46-year-old man presented with a 5-day history of fever with epigastric pain and nausea. On the night of admission, his temperature spiked to 39°C, his blood pressure was 135/79, his heart rate 98, his liver function test revealed albumin 37 g/L, bilirubin 25 µmol/L, ALP 298 U/L, ALT 247 U/L, and AST 344 U/L. The clinical suspicion was hepatobiliary sepsis and intravenous ceftriaxone was commenced. CT of the abdomen showed an ill-defined hypodense focus in segment 4A/8 (4.5 × 3.5 cm) with a minimal fluid component implying a developing abscess or phlegmon. The images were reviewed by a radiologist and showed minimal fluid for percutaneous drainage. MRI of the liver was performed to further characterize the lesion and revealed a solid mass with nodular areas of arterial enhancement and washout, suspicious of neoplasm. Ultrasound-guided liver biopsy of the lesion was performed. Histology showed a histiocyte-rich epithelioid neoplasm consistent with the epithelioid variant of AML. Immunohistochemical staining was positive for human melanoma black 45, melan-A and cluster of differentiation 68. He successfully underwent liver resection of segment 4A/8 after 6 weeks of antibiotics. To our knowledge, this is the first reported case in the literature of primary hepatic epithelioid angiomyolipoma masquerading as liver abscess.

Characterisation of serum progesterone and progesterone-induced blocking factor (PIBF) levels across trimesters in healthy pregnant women.

Progesterone-induced blocking factor (PIBF), which plays an important role in maintaining healthy pregnancies, has shown great promise as a prognostic biomarker for threatened miscarriage. To better characterise the physiological trends of progesterone and PIBF, we analysed serum progesterone and PIBF concentrations in healthy non-pregnant and pregnant women across trimesters. We saw increasing concentrations of progesterone and PIBF in pregnant women with advancing trimesters. The serum progesterone and PIBF percentiles across gestational age in healthy pregnancies can be used as a guide for the formulation of reference ranges. We also demonstrated a significant positive correlation between progesterone and PIBF levels. This study demonstrates increasing progesterone and PIBF concentrations in later trimesters and underscores the importance of progesterone and PIBF in healthy pregnancies. Characterisation of progesterone and PIBF across gestational age in healthy pregnant women may help to prognosticate pregnancy viability and support further research into the importance of progesterone and PIBF in the maintenance of healthy pregnancies.

Pulmonary arterial hypertension in a multi-ethnic Asian population: Characteristics, survival and mortality predictors from a 14-year follow-up study.

BACKGROUND AND OBJECTIVE: Pulmonary arterial hypertension (PAH) is a rare and fatal disease. Data from Asia are lacking compared with the West. We aim to describe disease characteristics in an ethnically diverse South-East Asian population and assess predictors for survival. METHODS: We consecutively enrolled patients with PAH referred to our pulmonary hypertension specialty centre from January 2003 to December 2016. Baseline characteristics and survival were analysed. Based on a forward predictor selection procedure, a multi-level structural equation model was applied to identify predictors associated with mortality. RESULTS: Out of 148 patients enrolled, 77% were females and mean age was 50.8 ± 15.9 years. Racial distribution was consistent with our population census. The most common aetiologies were congenital heart disease-associated PAH (35.8%), idiopathic PAH (29.7%) and then connective tissue disease-associated PAH (24.3%). Most patients presented in World Health Organization (WHO) Functional Class (FC) II (48.6%), followed by FC III (28.8%). Majority of patients (54.1%) were on phosphodiesterase type 5 (PDE5) inhibitor monotherapy. Survival rates were 85.8% at the end of the first year, 70.9% at 3 years, 66.9% at 5 years, 61.5% at 7 years and 55.4% at 10 years. The Registry to Evaluate Early And Long-term PAH Disease Management (REVEAL) score (RS) was found to be the best predictor of mortality. A score > 6 was identified as a cut-off. Other predictors include mean right atrial pressure, heart rate, aetiology, age and N-terminal pro-brain natriuretic peptide. CONCLUSION: In this first registry study from a South-East Asian population, our survival rates are comparable with other national registries. The RS is validated in our population to be a good predictor of mortality.

Impact of financial background and student debt on postgraduate residency choices of medical students in Singapore.

INTRODUCTION: Medical school fees are rising globally. Student debt and financial background may affect residency choices, but few studies have been conducted in Asia. This study aimed to explore the relationship between financial background, student debt and postgraduate residency choices among medical students in Singapore. METHODS: An anonymised survey of all medical students in Singapore was conducted and had a response rate of 67.9%. RESULTS: 40.5% of our study population would graduate with debt. Medical students with monthly per capita household income < SGD 1,000 were more likely to graduate with debt (unadjusted odds ratio [OR] 2.0, 95% confidence interval [CI] 1.6-2.7; p < 0.001) and feel burdened by the cost of medical education (unadjusted OR 2.8, 95% CI 2.0-3.9; p < 0.001). Students with monthly per capita household income < SGD 1,000 (unadjusted OR 1.818, 95% CI 1.338-2.470, p < 0.001; adjusted OR 1.692, 95% CI 1.202-2.381, p = 0.003) and those with debt (unadjusted OR 1.623, 95% CI 1.261-2.090, p < 0.001; adjusted OR 1.393, 95% CI 1.048-1.851, p = 0.022) were more likely to rank at least one economic factor as 'very significant' in influencing their postgraduate training choices. CONCLUSION: It is concerning that despite financial aid schemes, the cost of medical education remains a burden to students from lower-income households in Singapore. Student debt and financial background may distort postgraduate career choices, creating an undue push towards high-paying specialties.

Impact of financial background and student debt on postgraduate residency choices of medical students in Singapore

INTRODUCTION@#Medical school fees are rising globally. Student debt and financial background may affect residency choices, but few studies have been conducted in Asia. This study aimed to explore the relationship between financial background, student debt and postgraduate residency choices among medical students in Singapore.@*METHODS@#An anonymised survey of all medical students in Singapore was conducted and had a response rate of 67.9%.@*RESULTS@#40.5% of our study population would graduate with debt. Medical students with monthly per capita household income < SGD 1,000 were more likely to graduate with debt (unadjusted odds ratio [OR] 2.0, 95% confidence interval [CI] 1.6-2.7; p < 0.001) and feel burdened by the cost of medical education (unadjusted OR 2.8, 95% CI 2.0-3.9; p < 0.001). Students with monthly per capita household income < SGD 1,000 (unadjusted OR 1.818, 95% CI 1.338-2.470, p < 0.001; adjusted OR 1.692, 95% CI 1.202-2.381, p = 0.003) and those with debt (unadjusted OR 1.623, 95% CI 1.261-2.090, p < 0.001; adjusted OR 1.393, 95% CI 1.048-1.851, p = 0.022) were more likely to rank at least one economic factor as 'very significant' in influencing their postgraduate training choices.@*CONCLUSION@#It is concerning that despite financial aid schemes, the cost of medical education remains a burden to students from lower-income households in Singapore. Student debt and financial background may distort postgraduate career choices, creating an undue push towards high-paying specialties.

An update on finances and financial support for medical students in Yong Loo Lin School of Medicine.

INTRODUCTION: Increasing financial challenges have resulted in great debt among medical graduates worldwide. In Singapore, more scholarships and bursaries have been disbursed in recent years to support students who are financially challenged. We aimed to study the financial status of medical students in National University of Singapore (NUS) Yong Loo Lin School of Medicine (i.e. NUS Medicine), Singapore, and the financial support available to them. METHODS: A cross-sectional quantitative study was performed. Surveys were distributed and completed by medical students of NUS Medicine. Information regarding household income, financial assistance, monthly allowance and expense, and concurrent occupations was collected. We compared our findings with the results of a similar study performed in 2007 and national income data. RESULTS: A total of 956 (66.2%) out of 1,445 medical students completed the survey. 19.5% and 58.5% of respondents came from households with monthly incomes < SGD 3,000 and > SGD 7,000, respectively. 20.6% of students had loans, 18.9% had scholarships and bursaries, and 14.4% worked to support themselves. CONCLUSION: Medical school fees have risen by more than 50% over the past ten years. Our study found that there were increases in the proportion of students from both the lower- and higher-income segments, with proportionally fewer students from the middle-income segment. A large number of students were working and/or had some form of financial support. More should be done to meet the needs of financially challenged medical students to ensure equal access to quality medical education.

An update on finances and financial support for medical students in Yong Loo Lin School of Medicine

<p><b>INTRODUCTION</b>Increasing financial challenges have resulted in great debt among medical graduates worldwide. In Singapore, more scholarships and bursaries have been disbursed in recent years to support students who are financially challenged. We aimed to study the financial status of medical students in National University of Singapore (NUS) Yong Loo Lin School of Medicine (i.e. NUS Medicine), Singapore, and the financial support available to them.</p><p><b>METHODS</b>A cross-sectional quantitative study was performed. Surveys were distributed and completed by medical students of NUS Medicine. Information regarding household income, financial assistance, monthly allowance and expense, and concurrent occupations was collected. We compared our findings with the results of a similar study performed in 2007 and national income data.</p><p><b>RESULTS</b>A total of 956 (66.2%) out of 1,445 medical students completed the survey. 19.5% and 58.5% of respondents came from households with monthly incomes < SGD 3,000 and > SGD 7,000, respectively. 20.6% of students had loans, 18.9% had scholarships and bursaries, and 14.4% worked to support themselves.</p><p><b>CONCLUSION</b>Medical school fees have risen by more than 50% over the past ten years. Our study found that there were increases in the proportion of students from both the lower- and higher-income segments, with proportionally fewer students from the middle-income segment. A large number of students were working and/or had some form of financial support. More should be done to meet the needs of financially challenged medical students to ensure equal access to quality medical education.</p>

Conceptualizing workplace based assessment in Singapore: Undergraduate Mini-Clinical Evaluation Exercise experiences of students and teachers.

OBJECTIVES: The Mini-Clinical Evaluation Exercise (mini-CEX) is one of the most commonly used clinical assessment tools to provide learner feedback to drive learning. High quality constructive feedback promotes development and improves clinical competency. However, the effectiveness of feedback has not been objectively evaluated from the learners' and assessors' points of view, especially in Asia, where the nature of the student-tutor relationship is relatively hierarchical. This study seeks to compare the strengths, limitations, and feedback of the mini-CEX between assessors and students. MATERIALS AND METHODS: A cross-sectional study was conducted among 275 senior medical undergraduates at the National University of Singapore and 121 clinical tutors from seven restructured hospitals in Singapore. Data was collected via a self-administered questionnaire. Univariate analysis was used to determine the prevalence of responses, as well as differences between tutors and students. RESULTS: The mini-CEX provided immediate feedback and timely correction of mistakes. However, effective administration was limited by inter-tutor variability and lack of time. Students reported being receptive to feedback, but tutors disagreed and felt that students were resistant to negative feedback. Additionally, students felt that their performance was compared unfairly against more senior students, although the tutors felt otherwise. CONCLUSION: The mini-CEX is an effective assessment tool, but is limited by barriers to administration and evaluation. Differing opinions and expectations between tutors and students could provide an interesting focal point for future studies.