The 4AT, a rapid delirium detection tool for use in hospice inpatient units: Findings from a validation study.

BACKGROUND: Delirium is a serious neuropsychiatric syndrome with adverse outcomes, which is common but often undiagnosed in terminally ill people. The 4 'A's test or 4AT (www.the4AT.com), a brief delirium detection tool, is widely used in general settings, but validation studies in terminally ill people are lacking. AIM: To determine the diagnostic accuracy of the 4AT in detecting delirium in terminally ill people, who are hospice inpatients. DESIGN: A diagnostic test accuracy study in which participants underwent the 4AT and a reference standard based on the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders. The reference standard was informed by Delirium Rating Scale Revised-98 and tests assessing arousal and attention. Assessments were conducted in random order by pairs of independent raters, blinded to the results of the other assessment. SETTING/PARTICIPANTS: Two hospice inpatient units in Scotland, UK. Participants were 148 hospice inpatients aged ⩾18 years. RESULTS: A total of 137 participants completed both assessments. Three participants had an indeterminate reference standard diagnosis and were excluded, yielding a final sample of 134. Mean age was 70.3 (SD = 10.6) years. About 33% (44/134) had reference standard delirium. The 4AT had a sensitivity of 89% (95% CI 79%-98%) and a specificity of 94% (95% CI 90%-99%). The area under the receiver operating characteristic curve was 0.97 (95% CI 0.94-1). CONCLUSION: The results of this validation study support use of the 4AT as a delirium detection tool in hospice inpatients, and add to the literature evaluating methods of delirium detection in palliative care settings. TRIAL REGISTRY: ISCRTN 97417474.

Affordability of Canada's Food Guide: Current challenges amid COVID-19, War in Ukraine, and other world events.

Since the 2019 Canada Food Guide was released, there have been concerns raised over the cost of food, with an emphasis on the affordability of nutritious food. In this study, we evaluate the affordability of the 2019 Canada Food Guide in relation to the previous edition from 2007. As a result of the pandemic and other significant world events, many are feeling financial stress as prices in many areas of life rise, including housing, gas, and food. Our results show that it is more cost-effective, on average, for children and teens to follow the 2019 Canada Food Guide, but more expensive for adults, when compared to the 2007 edition.

MK-8353: Discovery of an Orally Bioavailable Dual Mechanism ERK Inhibitor for Oncology.

The emergence and evolution of new immunological cancer therapies has sparked a rapidly growing interest in discovering novel pathways to treat cancer. Toward this aim, a novel series of pyrrolidine derivatives (compound 5) were identified as potent inhibitors of ERK1/2 with excellent kinase selectivity and dual mechanism of action but suffered from poor pharmacokinetics (PK). The challenge of PK was overcome by the discovery of a novel 3(S)-thiomethyl pyrrolidine analog 7. Lead optimization through focused structure-activity relationship led to the discovery of a clinical candidate MK-8353 suitable for twice daily oral dosing as a potential new cancer therapeutic.

Continuous and intermittent dosing of lonafarnib potentiates the therapeutic efficacy of docetaxel on preclinical human prostate cancer models.

Lonafarnib is a potent, selective farnesyltransferase inhibitor (FTI) undergoing clinical studies for the treatment of solid tumors and hematological malignancies. Preclinically, a number of FTIs, including lonafarnib, interact with taxanes to inhibit cancer cell growth in an additive/synergistic manner. These observations provided rationale for investigating the effects of combining lonafarnib and docetaxel on preclinical prostate cancer models. To date, docetaxel is the only chemotherapeutic agent in clinical use for hormone-refractory prostate cancer. In vitro experiments with 22Rv1, LNCaP, DU-145, PC3 and PC3-M prostate cancer cell lines showed significantly enhanced inhibition of cell proliferation and apoptosis when lonafarnib was added to docetaxel. In human tumor xenograft models, continuous coadministration of lonafarnib with docetaxel caused marked tumor regressions (24-47%) in tumors from all of the cell types as well as parental CWR22 xenografts. Intermittent dosing of lonafarnib (5 days on then 5 days off) coadministered with docetaxel produced similar regressions in hormone-refractory 22Rv1 tumors. 22Rv1 tumors progressing on docetaxel treatment also responded to treatment with intermittent lonafarnib (5 days on then 5 days off). Moreover, animals did not exhibit any signs of toxicity during coadministration of lonafarnib and docetaxel. In conclusion, coadministration of continuous and intermittent lonafarnib enhanced the antitumor activity of docetaxel in a panel of prostate cancer models. An intermittent dosing schedule of lonafarnib coadministered with docetaxel may allow enhanced efficacy to that of continuous dosing by improving the tolerability of higher doses of lonafarnib.

Combining the farnesyltransferase inhibitor lonafarnib with paclitaxel results in enhanced growth inhibitory effects on human ovarian cancer models in vitro and in vivo.

OBJECTIVES: To determine the effects of combining lonafarnib with paclitaxel on the growth of human ovarian cancer cells and tumor xenografts as well as to monitor a pharmacodynamic marker of farnesyltransferase inhibition (HDJ-2) in peripheral blood mononuclear cells (PBMCs) isolated from tumor-bearing animals after treatment with this combination. METHODS: Proliferation of A2780, PA-1, IGROV-1, and TOV-112D cells was assessed after treatment with lonafarnib and paclitaxel. Cell cycle progression was determined by flow cytometry, and apoptosis was evaluated by assaying for caspase-3 and cleaved PARP. The effects of lonafarnib and paclitaxel on the tumor growth of each model were determined in immunocompromised mice. Proteins extracted from cells, tumors, and PBMCs were assayed for HDJ-2 mobility shifts by Western blotting as well as for farnesyl protein transferase (FTase) enzyme activity by biochemical analyses. RESULTS: In A2780, PA-1, IGROV-1, and TOV-112D cells lonafarnib potentiated the growth inhibitory effects of paclitaxel. In each of the models lonafarnib enhanced paclitaxel-induced mitotic arrest and apoptosis. The combination of lonafarnib plus paclitaxel resulted in marked tumor regressions in A2780, TOV-112D, PA-1, and IGROV-1 tumor xenografts. Western blotting demonstrated that in PBMCs isolated from the animals, paclitaxel treatment suppressed lonafarnib-induced HDJ-2 mobility shifts. Paclitaxel did not affect lonafarnib inhibition of FTase enzyme activity levels in these PBMCs. CONCLUSIONS: Lonafarnib enhances the antiproliferative effects of paclitaxel on ovarian cancer cells in vitro and ovarian tumor xenografts in vivo. Measuring FTase enzyme activity levels rather than HDJ-2 shifts in PBMCs may be a more accurate biomarker to predict levels of farnesyltransferase inhibition in patients who are also receiving paclitaxel chemotherapy.

Enhancement of the antitumor activity of tamoxifen and anastrozole by the farnesyltransferase inhibitor lonafarnib (SCH66336).

Lonafarnib is an orally bioavailable farnesyltransferase inhibitor. Originally developed to block the membrane localization of Ras, subsequent work suggested that farnesyltransferase inhibitors mediate their antitumor activities by altering the biological activities of additional farnesylated proteins. Breast tumor models that express wild-type Ras have been shown to be sensitive to farnesyltransferase inhibitors. We have determined the effects of combining lonafarnib with the antiestrogen 4-hydroxy tamoxifen on hormone-dependent breast cancer cell lines in vitro. The effects of combining lonafarnib with tamoxifen or the aromatase inhibitor anastrozole on the growth of two different MCF-7 breast tumor xenograft models were also evaluated. In four of five human breast cancer cell lines, lonafarnib enhanced the antiproliferative effects of 4-hydroxy tamoxifen. The combination prevented MCF-7 cells from transitioning through the G1 to S phase of the cell cycle and augmented apoptosis. This was associated with reduced expression of E2F-1 and a reduction in hyperphosphorylated retinoblastoma protein. Lonafarnib plus 4-hydroxy tamoxifen also inhibited the mammalian target of rapamycin signal transduction pathway. In nude mice bearing parental MCF-7 or aromatase-transfected MCF-7Ca breast tumor xenografts, lonafarnib enhanced the antitumor activity of both tamoxifen and anastrozole. These studies indicate that lonafarnib enhances the efficacy of endocrine agents clinically used for treating hormone-dependent breast cancer.

SNP allele frequency estimation in DNA pools and variance components analysis.

The estimation of single nucleotide polymorphism (SNP) allele frequency in pooled DNA samples has been proposed as a cost-effective approach to whole genome association studies. However, the key issue is the allele frequency window in which a genotyping method operates and provides a statistically reliable answer. We assessed the homogeneous mass extend assay and estimated the variance associated with each experimental stage. We report that a relationship between estimated allele frequency and variance might exist, suggesting that high statistical power can be retained at low, as well as high, allele frequencies. Assuming this relationship, the formation of subpools consisting of 100 samples retains an effective sample size greater than 70% of the true sample size, with a savings of 11-fold the cost of an individual genotyping study, regardless of allele frequency.