Pilot Study Assessment of Dynamic Vascular Changes in Breast Cancer with Near-Infrared Tomography from Prospectively Targeted Manipulations of Inspired End-Tidal Partial Pressure of Oxygen and Carbon Dioxide

The dynamic vascular changes in the breast resulting from manipulation of both inspired end-tidal partial pressure of oxygen and carbon dioxide were imaged using a 30 s per frame frequency-domain near-infrared spectral (NIRS) tomography system. By analyzing the images from five subjects with asymptomatic mammography under different inspired gas stimulation sequences, the mixture that maximized tissue vascular and oxygenation changes was established. These results indicate maximum changes in deoxy-hemoglobin, oxygen saturation, and total hemoglobin of 21, 9, and 3%, respectively. Using this inspired gas manipulation sequence, an individual case study of a subject with locally advanced breast cancer undergoing neoadjuvant chemotherapy (NAC) was analyzed. Dynamic NIRS imaging was performed at different time points during treatment. The maximum tumor dynamic changes in deoxy-hemoglobin increased from less than 7% at cycle 1, day 5 (C1, D5) to 17% at (C1, D28), which indicated a complete response to NAC early during treatment and was subsequently confirmed pathologically at the time of surgery

Tissue Oxygen Saturation Predicts Response to Breast Cancer Neoadjuvant Chemotherapy within 10 Days of Treatment

Ideally, neoadjuvant chemotherapy (NAC) assessment should predict pathologic complete response (pCR), a surrogate clinical endpoint for 5-year survival, as early as possible during typical 3- to 6-month breast cancer treatments. We introduce and demonstrate an approach for predicting pCR within 10 days of initiating NAC. The method uses a bedside diffuse optical spectroscopic imaging (DOSI) technology and logistic regression modeling. Tumor and normal tissue physiological properties were measured longitudinally throughout the course of NAC in 33 patients enrolled in the American College of Radiology Imaging Network multicenter breast cancer DOSI trial (ACRIN-6691). An image analysis scheme, employing z-score normalization to healthy tissue, produced models with robust predictions. Notably, logistic regression based on z-score normalization using only tissue oxygen saturation (StO2) measured within 10 days of the initial therapy dose was found to be a significant predictor of pCR (AUC  =  0.92; 95% CI: 0.82 to 1). This observation suggests that patients who show rapid convergence of tumor tissue StO2 to surrounding tissue StO2 are more likely to achieve pCR. This early predictor of pCR occurs prior to reductions in tumor size and could enable dynamic feedback for optimization of chemotherapy strategies in breast cancer

Outdoor Air Pollution Exposure and Inter-relation of Global Cognitive Performance and Emotional Distress in Older Women

The interrelationships among long-term ambient air pollution exposure, emotional distress and cognitive decline in older adulthood remain unclear. Long-term exposure may impact cognitive performance and subsequently impact emotional health. Conversely, exposure may initially be associated with emotional distress followed by declines in cognitive performance. Here we tested the inter-relationship between global cognitive ability, emotional distress, and exposure to PM2.5 (particulate matter with aerodynamic diameter 2 (nitrogen dioxide) in 6118 older women (aged 70.6 ± 3.8 years) from the Women’s Health Initiative Memory Study. Annual exposure to PM2.5 (interquartile range [IQR] = 3.37 μg/m3) and NO2 (IQR = 9.00 ppb) was estimated at the participant’s residence using regionalized national universal kriging models and averaged over the 3-year period before the baseline assessment. Using structural equation mediation models, a latent factor capturing emotional distress was constructed using item-level data from the 6-item Center for Epidemiological Studies Depression Scale and the Short Form Health Survey Emotional Well-Being scale at baseline and one-year follow-up. Trajectories of global cognitive performance, assessed by the Modified-Mini Mental State Examination (3MS) annually up to 12 years, were estimated. All effects reported were adjusted for important confounders. Increases in PM2.5 (β = -0.144 per IQR; 95% CI = −0.261; −0.028) and NO2 (β = −0.157 per IQR; 95% CI = −0.291; −0.022) were associated with lower initial 3MS performance. Lower 3MS performance was associated with increased emotional distress (β = −0.008; 95% CI = −0.015; −0.002) over the subsequent year. Significant indirect effect of both exposures on increases in emotional distress mediated by exposure effects on worse global cognitive performance were present. No statistically significant indirect associations were found between exposures and 3MS trajectories putatively mediated by baseline emotional distress. Our study findings support cognitive aging processes as a mediator of the association between PM2.5 and NO2 exposure and emotional distress in later-life

Microwave Imaging for Neoadjuvant Chemotherapy Monitoring: Initial Clinical Experience

Introduction: Microwave tomography recovers images of tissue dielectric properties, which appear to be specific for breast cancer, with low-cost technology that does not present an exposure risk, suggesting the modality may be a good candidate for monitoring neoadjuvant chemotherapy. Methods: Eight patients undergoing neoadjuvant chemotherapy for locally advanced breast cancer were imaged longitudinally five to eight times during the course of treatment. At the start of therapy, regions of interest (ROIs) were identified from contrast-enhanced magnetic resonance imaging studies. During subsequent microwave examinations, subjects were positioned with their breasts pendant in a coupling fluid and surrounded by an immersed antenna array. Microwave property values were extracted from the ROIs through an automated procedure and statistical analyses were performed to assess short term (30 days) and longer term (four to six months) dielectric property changes. Results: Two patient cases (one complete and one partial response) are presented in detail and demonstrate changes in microwave properties commensurate with the degree of treatment response observed pathologically. Normalized mean conductivity in ROIs from patients with complete pathological responses was significantly different from that of partial responders (P value = 0.004). In addition, the normalized conductivity measure also correlated well with complete pathological response at 30 days (P value = 0.002). Conclusions: These preliminary findings suggest that both early and late conductivity property changes correlate well with overall treatment response to neoadjuvant therapy in locally advanced breast cancer. This result is consistent with earlier clinical outcomes that lesion conductivity is specific to differentiating breast cancer from benign lesions and normal tissue

Air Pollution and the Dynamic Association Between Depressive Symptoms and Memory in Oldest-Old Women

BACKGROUND/OBJECTIVES Exposure to air pollution may contribute to both increasing depressive symptoms and decreasing episodic memory in older adulthood, but few studies have examined this hypothesis in a longitudinal context. Accordingly, we examined the association between air pollution and changes in depressive symptoms (DS) and episodic memory (EM) and their interrelationship in oldest-old (aged 80 and older) women. DESIGN Prospective cohort data from the Women\u27s Health Initiative Memory Study-Epidemiology of Cognitive Health Outcomes. SETTING Geographically diverse community-dwelling population. PARTICIPANTS A total of 1,583 dementia-free women aged 80 and older. MEASUREMENTS Women completed up to six annual memory assessments (latent composite of East Boston Memory Test and Telephone Interview for Cognitive Status) and the 15-item Geriatric Depression Scale (GDS-15). We estimated 3-year average exposures to regional particulate matter with aerodynamic diameter below 2.5 μm (PM2.5) (interquartile range [IQR] = 3.35 μg/m3) and gaseous nitrogen dioxide (NO2) (IQR = 9.55 ppb) at baseline and during a remote period 10 years earlier, using regionalized national universal kriging. RESULTS Latent change structural equation models examined whether residing in areas with higher pollutant levels was associated with annual changes in standardized EM and DS while adjusting for potential confounders. Remote NO2 (β = .287 per IQR; P = .002) and PM2.5 (β = .170 per IQR; P = .019) exposure was significantly associated with larger increases in standardized DS, although the magnitude of the difference, less than 1 point on the GDS-15, is of questionable clinical significance. Higher DS were associated with accelerated EM declines (β = −.372; P = .001), with a significant indirect effect of remote NO2 and PM2.5 exposure on EM declines mediated by DS. There were no other significant indirect exposure effects. CONCLUSION These findings in oldest-old women point to potential adverse effects of late-life exposure to air pollution on subsequent interplay between DS and EM, highlighting air pollution as an environmental health risk factor for older women

Agency Rescues Competition for Credit Assignment Among Predictive Cues from Adverse Learning Conditions

A fundamental assumption of learning theories is that the credit assigned to predictive cues is not simply determined by their probability of reinforcement, but by their ability to compete with other cues present during learning. This assumption has guided behavioral and neural science research for decades, and tremendous empirical and theoretical advances have been made identifying the mechanisms of cue competition. However, when learning conditions are not optimal (e.g., when training is massed), cue competition is attenuated. This failure of the learning system exposes the individual’s vulnerability to form spurious associations in the real world. Here, we uncover that cue competition in rats can be rescued when conditions are suboptimal provided that the individual has agency over the learning experience. Our findings reveal a new effect of agency over learning on credit assignment among predictive cues, and open new avenues of investigation into the underlying mechanisms

Cross‐cultural assessment of HIV‐associated cognitive impairment using the Kaufman assessment battery for children: a systematic review

Introduction: Despite improved efficacy of, and access to, combination antiretroviral therapy (cART), HIV‐associated cognitive impairments remain prevalent in both children and adults. Neuropsychological tests that detect such impairment can help clinicians formulate effective treatment plans. The Kaufman Assessment Battery for Children (KABC), although developed and standardized in the United States, is used frequently in many different countries and cultural contexts to assess paediatric performance across various cognitive domains. This systematic review investigated the cross‐cultural utility of the original KABC, and its 2nd edition (KABC‐II), in detecting HIV‐associated cognitive impairment in children and adolescents.Methods: We entered relevant keywords and MeSH terms into the PubMed, PsycInfo, EBSCOHost, ProQuest, and Scopus databases, with search limits set from 1983–2017. Two independent reviewers evaluated the retrieved abstracts and manuscripts. Studies eligible for inclusion in the review were those that (a) used the KABC/KABC‐II to assess cognitive function in children/adolescents aged 2–18 years, (b) featured a definition of cognitive impairment (e.g. >2 SD below the mean) or compared the performance of HIV‐infected and uninfected control groups, and (c) used a sample excluded from population on which the instruments were normed.Results and discussion: We identified nine studies (eight conducted in African countries, and one in the United Kingdom) to comprise the review’s sample. All studies detected cognitive impairment in HIV‐infected children, including those who were cART‐naïve or who were cART treated and clinically stable. KABC/KABC‐II subtests assessing simultaneous processing appeared most sensitive. Evaluation of the methodological quality of the selected studies by two independent reviews suggested that shortcomings included reporting and selection biases.Conclusions: This systematic review provides evidence for the cross‐cultural utility of the KABC/KABC‐II, particularly the simultaneous processing subtests, in detecting cognitive impairment in HIV‐infected children (including those who are clinically stable). Although the current results suggest there is justification for using the KABC/KABC‐II primarily in East Africa, further investigation is required to explore the instrument’s utility in other HIV‐prevalent regions of the globe.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/138351/1/jia21412.pd

Safety and tolerability of sitagliptin in patients with type 2 diabetes: a pooled analysis

<p>Abstract</p> <p>Background</p> <p>Sitagliptin, a highly selective dipeptidyl peptidase-4 inhibitor, is the first in a new class of oral antihyperglycemic agents (AHAs) for the treatment of patients with type 2 diabetes. Type 2 diabetes is a life-long disease requiring chronic treatment and management. Therefore, robust assessment of the long-term safety and tolerability of newer therapeutic agents is of importance. The purpose of this analysis was to assess the safety and tolerability of sitagliptin by pooling 12 large, double-blind, Phase IIb and III studies up to 2 years in duration. Methods: This analysis included 6139 patients with type 2 diabetes receiving either sitagliptin 100 mg/day (N = 3415) or a comparator agent (placebo or an active comparator) (N = 2724; non-exposed group). The 12 studies from which this pooled population was drawn represent the double-blind, randomized, Phase IIB and III studies that included patients treated with the clinical dose of sitagliptin (100 mg/day) for at least 18 weeks up to 2 years and that were available in a single safety database as of November 2007. These 12 studies assessed sitagliptin as monotherapy, initial combination therapy with metformin, or add-on combination therapy with other oral AHAs (metformin, pioglitazone, sulfonylurea, sulfonylurea + metformin, or metformin + rosiglitazone). Patients in the non-exposed group were taking placebo, pioglitazone, metformin, sulfonylurea, sulfonylurea + metformin, or metformin + rosiglitazone. This safety analysis used patient-level data from each study to evaluate clinical and laboratory adverse experiences.</p> <p>Results</p> <p>For clinical adverse experiences, the incidence rates of adverse experiences overall, serious adverse experiences, and discontinuations due to adverse experiences were similar in the sitagliptin and non-exposed groups. The incidence rates of specific adverse experiences were also generally similar in the two groups, with the exception of an increased incidence rate of hypoglycemia observed in the non-exposed group. The incidence rates of drug-related adverse experiences overall and discontinuations due to drug-related adverse experiences were higher in the non-exposed group, primarily due to the increased incidence rate of hypoglycemia in this group. For cardiac- and ischemia-related adverse experiences (including serious events), there were no meaningful between-group differences. No meaningful differences between groups in laboratory adverse experiences, either summary measures or specific adverse experiences, were observed.</p> <p>Conclusion</p> <p>In patients with type 2 diabetes, sitagliptin 100 mg/day was well tolerated in clinical trials up to 2 years in duration.</p

Safety and tolerability of sitagliptin in clinical studies: a pooled analysis of data from 10,246 patients with type 2 diabetes

<p>Abstract</p> <p>Background</p> <p>In a previous pooled analysis of 12 double-blind clinical studies that included data on 6,139 patients with type 2 diabetes, treatment with sitagliptin, a dipeptidyl peptidase-4 (DPP-4) inhibitor, was shown to be generally well tolerated compared with treatment with control agents. As clinical development of sitagliptin continues, additional studies have been completed, and more patients have been exposed to sitagliptin. The purpose of the present analysis is to update the safety and tolerability assessment of sitagliptin by pooling data from 19 double-blind clinical studies.</p> <p>Methods</p> <p>The present analysis included data from 10,246 patients with type 2 diabetes who received either sitagliptin 100 mg/day (N = 5,429; sitagliptin group) or a comparator agent (placebo or an active comparator) (N = 4,817; non-exposed group). The 19 studies from which this pooled population was drawn represent the double-blind, randomized studies that included patients treated with the usual clinical dose of sitagliptin (100 mg/day) for between 12 weeks and 2 years and for which results were available as of July 2009. These 19 studies assessed sitagliptin taken as monotherapy, initial combination therapy with metformin or pioglitazone, or as add-on combination therapy with other antihyperglycemic agents (metformin, pioglitazone, a sulfonylurea ± metformin, insulin ± metformin, or rosiglitazone + metformin). Patients in the non-exposed group were taking placebo, metformin, pioglitazone, a sulfonylurea ± metformin, insulin ± metformin, or rosiglitazone + metformin. The analysis used patient-level data from each study to evaluate between-group differences in the exposure-adjusted incidence rates of adverse events.</p> <p>Results</p> <p>Summary measures of overall adverse events were similar in the sitagliptin and non-exposed groups, except for an increased incidence of drug-related adverse events in the non-exposed group. Incidence rates of specific adverse events were also generally similar between the two groups, except for increased incidence rates of hypoglycemia, related to the greater use of a sulfonylurea, and diarrhea, related to the greater use of metformin, in the non-exposed group and constipation in the sitagliptin group. Treatment with sitagliptin was not associated with an increased risk of major adverse cardiovascular events.</p> <p>Conclusions</p> <p>In this updated pooled safety analysis of data from 10,246 patients with type 2 diabetes, sitagliptin 100 mg/day was generally well tolerated in clinical trials of up to 2 years in duration.</p