Opioids are a commonly prescribed and efficacious medication for the treatment of chronic pain but major side effects such as addiction, respiratory depression, analgesic tolerance, and paradoxical pain hypersensitivity make them inadequate and unsafe for patients requiring long‐term pain management. This review summarizes recent advances in our understanding of the outcomes of chronic opioid administration to lay the foundation for the development of novel pharmacological strategies that attenuate opioid tolerance and hypersensitivity; the two main physiological mechanisms underlying the inadequacies of current therapeutic strategies. We also explore mechanistic similarities between the development of neuropathic pain states, opioid tolerance, and hypersensitivity which may explain opioids’ lack of efficacy in certain patients. The findings challenge the current direction of analgesic research in developing non‐opioid alternatives and we suggest that improving opioids, rather than replacing them, will be a fruitful avenue for future research.

Calanolides are tetracyclic 4-substituted dipyranocoumarins. Calanolide A, isolated from the leaves and twigs of Calophyllum lanigerum var. austrocoriaceum (Whitmore) P. F. Stevens, is the first member of this group of compounds with anti-HIV-1 activity mediated by reverse transcriptase inhibition. Calanolides are classified pharmacologically as non-nucleoside reverse transcriptase inhibitors (NNRTI). There are at least 15 naturally occurring calanolides distributed mainly within the genus Calophyllum, but some of them are also present in the genus Clausena. Besides significant anti-HIV properties, which have been exploited towards potential development of new NNRTIs for anti-HIV therapy, calanolides have also been found to possess anticancer, antimicrobial and antiparasitic potential. This review article provides a comprehensive update on all aspects of naturally occurring calanolides, including their chemistry, natural occurrence, biosynthesis, pharmacological and toxicological aspects including mechanism of action and structure activity relationships, pharmacokinetics, therapeutic potentials and available patents.

We read with great interest the study by Siyu Chen and colleagues. The authors evaluated the clinical features and outcomes of five pregnant patients with COVID‐19 at term, whose delivery was uneventful and led to favorable perinatal outcomes for both mother and neonate. We would like to draw attention to a growing body of evidence that now points towards an under‐addressed association between preterm maternal SARS‐CoV‐2 infection, preterm delivery and adverse neonatal outcomes, which is not reflected in Chen et al.'s small cohort. We also stress that vertical transmission, which was not tested for by Chen et al., should not be excluded as a potential mechanism for viral spread. Centers should therefore be meticulous in their approach to a SARS‐CoV‐2+ pregnancy to optimize clinical outcomes for both mother and child.

Purpurogallin (PPG), an orange-red crystalline compound from nutgalls and oak bark, is an exemplar of numerous, ubiquitous natural colorants, biosynthesized through oxidative dimerization-decarboxylation of phenolic compounds. It possesses antioxidant, anticancer, and anti-inflammatory effects. Herein, a robust method is presented to allow students to expediently make this interesting compound that contains a tropolone ring, whose identity initiated a paradigm shift in the understanding of aromaticity. 1D and 2D nuclear magnetic resonance (NMR) spectroscopic data (¹H, ¹³C-DEPT-Q, HSQC, HMBC) were used to identify which protons are connected to carbon atoms. Fourier transform infrared spectroscopy (FT-IR), mass spectrometry, and X-ray diffraction were used to provide complementary information. Importantly, sufficient historical detail is given to provide a useful narrative that highlights the shift from deductive and synthetic proof of structural identity to modern methods of structural elucidation. As a minor, but important, aspect of iron gall inks, PPG links the work of important western historical documents from Da Vinci’s Vitruvian Man to the United States Declaration of Independence. In the experience of the authors, such a pedagogic approach enlivens students with practical exercises which place them within the historical arc and reasoning of notable scientists, adding a sense of scientific discovery.

Background and Aims: Atezolizumab and bevacizumab (A+B) are recommended for treating unresectable hepatocellular carcinoma (HCC). Although highly effective, A+B can lead to potentially life-threatening adverse events including bleeding. We investigated whether albumin-bilirubin (ALBI) grade identifies patients with a higher risk of bleeding and its impact on prognosis than the Child-Pugh (CP) score. Methods: We performed a multicenter retrospective study of 15 tertiary referral centers that consecutively treated patients with A+B. We analyzed the association between the ALBI grade and gastrointestinal bleeding using the χ 2 test. Overall survival (OS) stratified by ALBI was estimated using the Kaplan-Meier method and the predictive value for the 6-months OS landmark with ROC curves. Results: Of the 368 patients included in the analysis, 163 (44.3%), 192 (52.2%) and 13 (3.5%) had ALBI 1, ALBI 2, and ALBI 3, respectively. ALBI grade was associated with a 3-fold increase in bleeding risk (3.1% in ALBI 1 vs 10.2% in ALBI 2/3, p=0.008). Among 192 patients with pre-treatment EGD, G2 and G3 varices were associated with an increased risk of bleeding, whereas G1 varices had a similar risk as no varices. Patients with ALBI 1 achieved a longer median OS (not reached; 95% CI, 24.9– 33.7), than ALBI 2 (9.7 months; 95% CI, 7.0– 12.3) or ALBI 3 (5.6 months; 95% CI, 0.1– 12.0). ALBI outperformed the CP score for predicting 6-month OS with an AUC 0.79 of ALBI versus 0.71 for the CP score (p=0.01). Conclusion: A Higher ALBI grade was associated with an increased risk of gastrointestinal bleeding after receiving A+B, and outperformed the CP score in predicting worse survival.