Considering potential benefits, as well as harms, from the COVID-19 disruption to cancer screening and other healthcare services.

Since 2020, hundreds of thousands of more deaths than expected have been observed across the globe. Amid the coronavirus 2019 (COVID-19) pandemic, current research priorities are to control the spread of infection and minimise loss of life. However, there may be future opportunities to learn from the pandemic to build a better healthcare system that delivers maximum health benefits with minimum harm. So far, much research has focused on foregone benefits of healthcare services such as cancer screening during the pandemic. A more balanced approach is to recognise that all healthcare services have potential harms as well as benefits. In this way, we may be able to use pandemic 'natural experiments' to identify cases where a reduction in a healthcare service has not been harmful to the population and some instances where this may have even been beneficial.

Narcotic administration and fall-related injury in the hospital: implications for patient safety programs and providers.

OBJECTIVE: Identify factors that predict fall-related injury in hospitalized adults. DESIGN: Retrospective records review. SETTING: 435-bed university hospital. PARTICIPANTS: Inpatients with reported falls in 2010. RESULTS: Medical records were available for 286/293 (98%) of reported falls in 251 patients. 25% (63/286) of falls were associated with injury, 4% (11/286) with serious injury. Compared to all fallers, patients with injury did not differ by gender or age. In univariate analysis, patients who reported hitting their head, had pre-fall confusion, or who received narcotics within 24 hours before falling were more likely to suffer injury (estimated odds ratios 6.04, 2.00 and 5.1, respectfully). In multivariate analysis, receiving a narcotic prior to falling was the strongest predictor of injury (estimated odds ratio 5.38; 95% confidence intervals 2.07-13.98, p < 0.001). CONCLUSIONS: In this single-institution study, 25% of patients who fell suffered injury and 4% serious injury. Neither age nor gender predicted fall-related injury. Recent narcotic administration was the strongest predictor of injury. Strategies to prevent fall-related injury in the hospital should target patients receiving narcotics. When evaluating inpatients who have fallen, providers should be especially vigilant about injury in patients who have pre-fall confusion, hit their head, or have received recent narcotics.

Isosteric analogs of lenalidomide and pomalidomide: synthesis and biological activity.

A series of analogs of the immunomodulary drugs lenalidomide (1) and pomalidomide (2), in which the amino group is replaced with various isosteres, was prepared and assayed for immunomodulatory activity and activity against cancer cell lines. The 4-methyl and 4-chloro analogs 4 and 15, respectively, displayed potent inhibition of tumor necrosis factor-α (TNF-α) in LPS-stimulated hPBMC, potent stimulation of IL-2 in a human T cell co-stimulation assay, and anti-proliferative activity against the Namalwa lymphoma cell line. Both of these analogs displayed oral bioavailability in rat.

Aminopurine based JNK inhibitors for the prevention of ischemia reperfusion injury.

In this Letter we describe the optimization of an aminopurine lead (1) with modest potency and poor overall kinase selectivity which led to the identification of a series of potent, selective JNK inhibitors. Improvement in kinase selectivity was enabled by introduction of an aliphatic side chain at the C-2 position. CC-359 (2) was selected as a potential clinical candidate for diseases manifested by ischemia reperfusion injury.

Discovery of CC-930, an orally active anti-fibrotic JNK inhibitor.

In this Letter we describe the discovery of potent, selective, and orally active aminopurine JNK inhibitors. Improving the physico-chemical properties as well as increasing the potency and selectivity of a subseries with rat plasma exposure, led to the identification of four structurally diverse inhibitors. Differentiation based on PK profiles in multiple species as well as activity in a chronic efficacy model led to the identification of 1 (CC-930) as a development candidate, which is currently in Phase II clinical trial for IPF.

Discovery of (S)-N-[2-[1-(3-ethoxy-4-methoxyphenyl)-2-methanesulfonylethyl]-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl] acetamide (apremilast), a potent and orally active phosphodiesterase 4 and tumor necrosis factor-alpha inhibitor.

In this communication, we report the discovery of 1S (apremilast), a novel potent and orally active phosphodiesterase 4 (PDE4) and tumor necrosis factor-alpha inhibitor. The optimization of previously reported 3-(1,3-dioxo-1,3-dihydroisoindol-2-yl)-3-(3,4-dimethoxyphenyl)propionic acid PDE4 inhibitors led to this series of sulfone analogues. Evaluation of the structure-activity relationship of substitutions on the phthalimide group led to the discovery of an acetylamino analogue 1S, which is currently in clinical trials.

Metabolite interference in pharmacokinetic studies.

Our policy of conducting biotransformation studies with extended chromatography prior to pharmacokinetic bioanalyses allowed us to quickly detect an unusual, cis/trans metabolite in rat plasma that was inseparable using a short chromatographic method. We caution investigators that short methods invite unknown isobaric metabolites to cause inaccuracies in plasma concentration measurements.

The synthetic compound CC-5079 is a potent inhibitor of tubulin polymerization and tumor necrosis factor-alpha production with antitumor activity.

We have found that the synthetic compound CC-5079 potently inhibits cancer cell growth in vitro and in vivo by a novel combination of molecular mechanisms. CC-5079 inhibits proliferation of cancer cell lines from various organs and tissues at nanomolar concentrations. Its IC(50) value ranges from 4.1 to 50 nmol/L. The effect of CC-5079 on cell growth is associated with cell cycle arrest in G(2)-M phase, increased phosphorylation of G(2)-M checkpoint proteins, and apoptosis. CC-5079 prevents polymerization of purified tubulin in a concentration-dependent manner in vitro and depolymerizes microtubules in cultured cancer cells. In competitive binding assays, CC-5079 competes with [(3)H]colchicine for binding to tubulin; however, it does not compete with [(3)H]paclitaxel (Taxol) or [(3)H]vinblastine. Our data indicate that CC-5079 inhibits cancer cell growth with a mechanism of action similar to that of other tubulin inhibitors. However, CC-5079 remains active against multidrug-resistant cancer cells unlike other tubulin-interacting drugs, such as Taxol and colchicine. Interestingly, CC-5079 also inhibits tumor necrosis factor-alpha (TNF-alpha) secretion from lipopolysaccharide-stimulated human peripheral blood mononuclear cells (IC(50), 270 nmol/L). This inhibitory effect on TNF-alpha production is related to its inhibition of phosphodiesterase type 4 enzymatic activity. Moreover, in a mouse xenograft model using HCT-116 human colorectal tumor cells, CC-5079 significantly inhibits tumor growth in vivo. In conclusion, our data indicate that CC-5079 represents a new chemotype with novel mechanisms of action and that it has the potential to be developed for neoplastic and inflammatory disease therapy.

Orally administered lenalidomide (CC-5013) is anti-angiogenic in vivo and inhibits endothelial cell migration and Akt phosphorylation in vitro.

The thalidomide analogue and immunomodulatory drug (IMiD) lenalidomide (CC-5013, REVLIMID) is emerging as a useful treatment for a number of cancers and has recently entered phase III trials for multiple myeloma. It has been suggested that the anti-tumor effect of lenalidomide is related to its anti-angiogenic potency. In this regard, we have previously shown that lenalidomide inhibits angiogenesis in both rat and human in vitro models but does not affect endothelial cell proliferation. We now show that oral administration of lenalidomide attenuates growth factor-induced angiogenesis in vivo; the rat mesenteric window assay was utilized to show that lenalidomide significantly inhibits vascularization in a dose-dependent manner. We also found that lenalidomide significantly inhibits growth factor-induced endothelial cell migration. This correlates with the inhibitory effect of lenalidomide on growth factor-induced Akt phosphorylation, thereby providing a potential mechanism for its anti-migratory and subsequent anti-angiogenic effects. These data further support the use of lenalidomide as an orally administered drug for the effective treatment of angiogenesis-dependent conditions, including cancer, and suggest a potential mechanism of action.

Ground deposition impact of aerially applied fenthion on the fiddler crabs, Uca pugilator.

Caged fiddler crabs, Uca pugilator, were exposed to field ULV applications to measure the impact of fenthion. Two nozzle systems, conventional flat-fan nozzles (Tee Jet 8002SS) and high-pressure hydraulic nozzles (1/8 MIS), were compared using single spray swaths. Fenthion residues were detected throughout the 4.83-km test zone for both systems. Heavy ground deposits (650-1,670 microg/m2) of fenthion were found within 1 km using the flat-fan nozzle systems, which resulted in 80% fiddler crab mortality. Less than 100 microg/m2 fenthion ground deposits were detected during the high-pressure nozzle trials. No fiddler crab mortality was observed within the first 1-km zone following 3 single swath applications repeated during 3 consecutive nights. We found also that when the fiddler crabs were exposed to 700-800 microg/m2 fenthion, mortality occurred. Significant crab mortality (>50%) was observed when residues exceeded 1,000 microg/m2.