Presenting statistical uncertainty in trends and dose-response relations.

When one estimates the effects of a polytomous exposure, it is common practice to express all effects relative to a baseline or reference level. Certain authors have challenged this practice and proposed alternatives, which we review here. One alternative, the "floating absolute risk" method, can supply useful statistics and trend graphs, but it does not yield valid confidence intervals for relative risks. All categorical methods have further shortcomings when the exposure is continuous, however. These shortcomings can be addressed by plotting or tabulating confidence limits for points on a flexible curve fitted to the uncategorized data.     

Responses of movement-sensitive visual interneurons to prey-like stimuli in the praying mantis Sphodromantis lineola (Burmeister)

Previous behavioral work using both mechanical and computer-generated visual stimuli has demonstrated that mantids use a computational algorithm to recognize prey similar to that used by some amphibian predators: A stimulus elicits prey capture behavior if it falls within a perceptual envelope defined by five fundamental stimulus parameters: (1) overall size, (2) length of the leading edge, (3) contrast to the background, (4) location in the visual field, and (5) apparent speed. In this study, we recorded simultaneously from both cervical nerve cords of monocular Sphodromantis lineola while they viewed the same visual stimuli successfully used in the behavioral studies. Extracellular recordings showed three consistently proportioned amplitude classes of movement-elicited spikes in each cord and these were repeatedly and reliably identifiable across mantids. Overall, the movement-elicited activity in both cords was dominated by very large spikes suggesting the existence of several large, descending movement-sensitive interneurons projecting both ipsilaterally and contralaterally from the optic lobes. However, only the largest contralateral spikes occurred preferentially to prey-like stimuli, mirrored the behavioral response curves generated by S. lineola to the same visual stimuli, and displayed activity peaks that were correlated with the times at which the mantid emitted predatory strikes. Copyright (R) 2000 S.Karger AG, Basel     

Sequestration of type VI collagen in the pericellular microenvironment of adult chrondrocytes cultured in agarose

The chondron represents the chondrocyte and its pericellular microenvironment and plays an important role in the progression of osteoarthritis. Type VI collagen is preferentially localized in the pericellular microenvironment of adult articular cartilage and increases during osteoarthritis. In this study, we characterized the pericellular sequestration of type VI collagen in long-term chondrocyte-agarose cultures, and assessed the action of interleukin-1 on type VI collagen deposition and assembly. Immunohistochemical and biochemical analysis showed that cultured chondrocytes initiate type VI collagen sequestration immediately upon plating and continue pericellular matrix sequestration in a time dependent manner. Confocal microscopy confirmed the cell surface localization and pericellular accumulation of type VI collagen, while image analysis identified a 'cargo-net like' organization of type VI collagen around each chondrocyte. Quantitative analysis revealed a primary phase of rapid cell division and low levels of type VI collagen sequestration, followed by a secondary phase of relative growth stability and high levels of type VI collagen deposition. Interleukin-1 treated cultures showed increased sequestration and retention of type VI collagen in an expanded microenvironment surrounding the chondrocytes. The data suggests a role for type VI collagen in the differentiation of the pericellular microenvironment in vitro. The increased type VI collagen sequestration promoted by interleukin-1 was consistent with previous studies on osteoarthritic cartilage, and implies a functional role for type VI collagen in the chondron remodeling associated with cartilage degradation.     

The diagnosis of aortoiliac disease. A noninvasive femoral cuff technique.

An inexpensive femoral "cuff" developed in this noninvasive vascular laboratory allows pulse volume recordings and systolic pressure measurements of the femoral arteries. Using the parameters 1) femoral/brachial systolic pressure ratio, 2) wave amplitude, and 3) status of the dicrotic notch for assessment of results, it was found that the cuff correctly identified 59 of 62 limbs with at least 50% aortoiliac stenosis, with only two false-positive results, for an accuracy of 97%. The high, wide thigh cuff identified 57 of the 62 limbs, but had 45 false-positive results (77% accuracy). Use of the femoral "cuff" has refined the ability to identify the anatomic location of significant arterial stenoses in the lower extremities.     

Cerebrospinal fluid shunt function and hydrocephalus in the pediatric age group: a radiographic/clinical correlation.

Eighty-four pediatric patients were evaluated clinically and radiographically on 112 separate admissions for suspected increased intracranial pressure and possible shunt malfunction. The shunt system was tested clinically in each patient and correlated with the ventricular size as determined by CT. Of the patients with enlarged ventricles, 87% had an improperly functioning shunt and 13% had a normally functioning shunt. Of the patients with normal or small ventricles, 93% had a normally functioning shunt. Thus the "false negative" rate was 4% (small ventricles with a nonfunctioning shunt) and the "false positive" rate was 13% (large ventricles with a functioning shunt).     

Erk activation is required for Nrf2 nuclear localization during pyrrolidine dithiocarbamate induction of glutamate cysteine ligase modulatory gene expression in HepG2 cells.

Pyrrolidine dithiocarbamate (PDTC) induction of the human glutamate cysteine ligase modulatory (GCLM) gene is dependent on activation of the mitogen-activated protein kinases (MAPKs) extracellular regulated kinase (Erk) and p38, and is not affected by protein kinase C (PKC) or PI3K inhibitors. Nrf2 binding to the electrophile response element (EpRE) located within the GCLM promoter is decreased after MAPK inhibition, suggesting that Nrf2 could be a downstream target of activated MAPK. To evaluate this hypothesis, a series of Nrf2 proteins harboring mutations in conserved consensus MAPK phosphorylation sites were developed and used in multiple functional assays. All mutated Nrf2 proteins tested interacted with the cytoplasmic repressor Keap1 in a manner indistinguishable from wild-type Nrf2. Furthermore, the mutant and wild-type Nrf2 proteins were similarly capable of transactivating an EpRE-containing GCLM/luciferase reporter transgene. Collectively these functional assays suggest that Nrf2 is not likely to be a direct downstream target of activated MAPK in vivo. However, treatment of HepG2 cells with MAPK inhibitors PD98059 and/or SB202190 prior to exposure to PDTC, reduced Nrf2 translocation to the nucleus, suggesting that MAPK-directed phosphorylation is a requirement for nuclear localization during PDTC induction of GCLM gene expression.     

RSR13 plus cranial radiation therapy in patients with brain metastases: comparison with the Radiation Therapy Oncology Group Recursive Partitioning Analysis Brain Metastases Database.

PURPOSE: This phase II, open-label, multicenter study assessed the efficacy and safety of the potential radiation enhancer RSR13 plus cranial radiation therapy (RT) in patients with brain metastases. The primary end point was patient survival in comparison with the Radiation Therapy Oncology Group Recursive Partitioning Analysis Brain Metastases Database (RTOG RPA BMD). PATIENTS AND METHODS: Eligibility criteria were age > or = 18 years, Karnofsky performance score > or = 70, and brain metastases with solid tumor histology. Patients received cranial RT, 30 Gy in 10 fractions of 3 Gy each, preceded by RSR13, 50 to 100 mg/kg intravenously over 30 minutes. Univariate and multivariate comparisons of survival and cause of death were made between class II study patients and RTOG BMD patients. RESULTS: Fifty-seven RPA class II patients were enrolled. With a minimum follow-up of 24 months, the median survival time and 1- and 2-year survival rates were 6.4 months, 23%, and 11% for the RSR13-treated patients compared with 4.1 months, 15%, and 3% for the RTOG BMD patients (P =.0174). In an exact-matched case analysis (n = 38), median survival time for RSR13 patients was 7.3 months versus 3.4 months for the RTOG BMD patients (P =.006). There was a 54% reduction in the risk of death for RSR13 patients (P =.0267). RSR13-related adverse events of greater than or equal to grade 3 toxicity that occurred in more than one patient included hypoxia, headache, anemia, fatigue, hypertension, and intracranial hypertension. CONCLUSION: RSR13 plus cranial RT resulted in a significant improvement in survival, as well as a reduction in death due to brain metastases, compared with class II patients in the RTOG BMD.     

Randomized trial of two intravenous schedules of the topoisomerase I inhibitor liposomal lurtotecan in women with relapsed epithelial ovarian cancer: a trial of the national cancer institute of Canada clinical trials group.

PURPOSE: Liposomal lurtotecan (OSI-211) is a liposomal formulation of the water-soluble topoisomerase I inhibitor lurtotecan (GI147211), which demonstrated superior levels of activity compared with topotecan in preclinical models. We studied two schedules of OSI-211 in a randomized design in relapsed ovarian cancer to identify the more promising of the two schedules for further study. PATIENTS AND METHODS: Eligible patients had measurable epithelial ovarian, fallopian, or primary peritoneal cancer that was recurrent after one or two prior regimens of chemotherapy. Patients were randomly assigned to receive either arm A (OSI-211 1.8 mg/m(2)/d administered by 30-minute intravenous infusion on days 1, 2, and 3 every 3 weeks) or arm B (OSI-211 2.4 mg/m(2)/d administered by 30-minute intravenous infusion on days 1 and 8 every 3 weeks). The primary outcome measure was objective response, which was confirmed by independent radiologic review, and a pick the winner statistical design was used to identify the schedule most likely to be superior. RESULTS: Eighty-one patients were randomized between October 2000 and September 2001. The hematologic toxic effects were greater on arm A than on arm B (grade 4 neutropenia, 51% v 22%, respectively), as was febrile neutropenia (26% v 2.4%, respectively). Of the 80 eligible patients, eight patients (10%) had objective responses; six responders (15.4%; 95% CI, 6% to 30%) were in arm A and two responders (4.9%; 95% CI, 1% to 17%) were in arm B. CONCLUSION: The OSI-211 daily for 3 days intravenous schedule met the statistical criteria to be declared the winner in terms of objective response. This schedule was also associated with more myelosuppression than the schedule of OSI-211 administered in arm B.     

Factors associated with intention to receive vaccines for bacterial sexually transmitted infections among young HPV-vaccinated Canadian women

ObjectiveThe aim of this study was to explore the acceptability of bacterial STI vaccines among young HPV-vaccinated Canadian women to inform future vaccine program implementation.MethodsA 20-item cross-sectional questionnaire was administered from June 2019 to June 2020 to HPV-vaccinated participants of the pan-Canadian QUEST cohort. Multivariable logistic regression models assessed interest in chlamydia, syphilis, and gonorrhea vaccines using a priori variables and factors significant in bivariate analysis.ResultsOf the 1092 respondents analyzed, 82% indicated interest in receiving one or more future STI vaccines. Respondents had a median age of 19.6 years (range 16.9–23.4), and 75% of respondents identified as white/European descent. In adjusted analyses, intent to engage in positive health behaviours was associated with vaccine interest for syphilis (OR = 5.76, 95% CI 4.03–8.27), chlamydia (OR = 5.27, 95% CI 3.66–7.63), and gonorrhea (OR = 5.96, 95% CI 4.15–8.60). Willingness to pay for an STI vaccine was also associated with vaccine interest for syphilis (OR = 2.02, 95% CI 1.29–3.19), chlamydia (OR = 2.41, 95% CI 1.50–3.90), and gonorrhea (OR = 2.29, 95% CI 1.44–3.63). Ever having sexual intercourse and identifying as LGBTQ were significantly associated with vaccine interest for all infections, while age and ever being immunosuppressed were not significant in any adjusted models.ConclusionFindings indicate over 80% of participants in a cohort of young HPV-vaccinated Canadian women are interested in receiving future bacterial STI vaccines. Further exploration of STI vaccine acceptability among diverse populations is required to inform future bacterial STI vaccine program implementation.Supplementary InformationThe online version contains supplementary material available at 10.17269/s41997-022-00648-2.