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Objective: Young-onset colorectal cancer (YCRC) incidence is rising. Scant data exist on YCRC risk after presentation with concerning symptoms such as iron-deficiency anaemia (IDA) or haematochezia. We examined the association between IDA and YCRC, and haematochezia and YCRC., Design: Cohort study of US Veterans aged 18-49 years receiving Veterans Health Administration (VHA) care 1999-2016. IDA analytic cohort was created matching individuals without incident IDA to those with IDA 4:1 based on sex, birth year and first VHA visit date (n=239 000). We used this approach to also create a distinct haematochezia analytic cohort (n=653 740). Incident YCRC was ascertained via linkage to cancer registry and/or cause-specific mortality data. We computed cumulative incidence, risk difference (RD) and HRs using Cox models in each cohort., Results: Five-year YCRC cumulative incidence was 0.45% among individuals with IDA versus 0.05% without IDA (RD: 0.39%, 95% CI: 0.33%-0.46%), corresponding to an HR of 10.81 (95% CI: 8.15-14.33). Comparing IDA versus no IDA, RD was 0.78% for men (95% CI: 0.64%-0.92%) and 0.08% for women (95% CI: 0.03%-0.13%), and RD increased by age from 0.14% for <30 years to 0.53% for 40-49 years. YCRC cumulative incidence was 0.33% among individuals with haematochezia versus 0.03% without haematochezia (RD: 0.30%, 95% CI: 0.26%-0.33%), corresponding to an HR of 10.66 (95% CI: 8.76-12.97). Comparing haematochezia versus no haematochezia, RD increased by age from 0.04% for <30 years to 0.43% for 40-49 years., Conclusion: Colonoscopy should be strongly considered in adults aged <50 years with IDA or haematochezia without a clinically confirmed alternate source., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background & Aims: Colorectal cancer (CRC) incidence and mortality are increasing among persons younger than 50 years old in the United States, but risk factors associated with early-onset CRC (EOCRC) have not been widely studied., Methods: We conducted a case-control study of US veterans 18 to 49 years old who underwent colonoscopy examinations from 1999 through 2014. EOCRC cases were identified from a national cancer registry; veterans who were free of CRC at their baseline colonoscopy through 3 years of follow-up were identified as controls. We collected data on age, sex, race/ethnicity, body weight, body mass index (BMI), diabetes, smoking status, and aspirin use. Multivariate-adjusted EOCRC odds were estimated for each factor, with corresponding 95% confidence interval (CI) values., Results: Our final analysis included 651 EOCRC cases and 67,416 controls. Median age was 45.3 years, and 82.3% were male. Higher proportions of cases were older, male, current smokers, nonaspirin users, and had lower BMIs, compared with controls (P < .05). In adjusted analyses, increasing age and male sex were significantly associated with increased risk of EOCRC, whereas aspirin use and being overweight or obese (relative to normal BMI) were significantly associated with decreased odds of EOCRC. In post hoc analyses, weight loss of 5 kg or more within the 5-year period preceding colonoscopy was associated with higher odds of EOCRC (odds ratio 2.23; 95% CI 1.76-2.83)., Conclusions: In a case-control study of veterans, we found increasing age and male sex to be significantly associated with increased risk of EOCRC, and aspirin use to be significantly associated with decreased risk; these factors also affect risk for CRC onset after age 50. Weight loss may be an early clinical sign of EOCRC. More intense efforts are required to identify the factors that cause EOCRC and signs that can be used to identify individuals at highest risk., (Copyright © 2020 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Background: Potential benefits of screening mammography among women ages 75 years and older remain unclear., Methods: We evaluated 10-year cumulative incidence of breast cancer and death from breast cancer and other causes by Charlson Comorbidity Index (CCI) and age in the Medicare-linked Breast Cancer Surveillance Consortium (1999-2010) cohort of 222 088 women with no less than 1 screening mammogram between ages 66 and 94 years., Results: During median follow-up of 107 months, 7583 were diagnosed with invasive breast cancer and 1742 with ductal carcinoma in situ; 471 died from breast cancer and 42 229 from other causes. The 10-year cumulative incidence of invasive breast cancer did not change with increasing CCI but decreased slightly with age: ages 66-74 years (CCI0 = 4.0% [95% CI = 3.9% to 4.2%] vs CCI  ≥ 2 = 3.9% [95% CI = 3.5% to 4.3%]); ages 75-84 years (CCI0 = 3.7% [95% CI = 3.5% to 3.9%] vs CCI  ≥ 2 = 3.4% [95% CI = 2.9% to 3.9%]); and ages 85-94 years (CCI0 = 2.7% [95% CI = 2.3% to 3.1%] vs CCI  ≥ 2 = 2.1% [95% CI = 1.3% to 3.0%]). The 10-year cumulative incidence of other-cause death increased with increasing CCI and age: ages 66-74 years (CCI0 = 10.4% [95% CI = 10.3 to 10.7%] vs CCI ≥ 2 = 43.4% [95% CI = 42.2% to 44.4%]), ages 75-84 years (CCI0 = 29.8% [95% CI = 29.3% to 30.2%] vs CCI ≥ 2 = 61.7% [95% CI = 60.2% to 63.3%]), and ages 85 to 94 years (CCI0 = 60.3% [95% CI = 59.1% to 61.5%] vs CCI  ≥ 2 = 84.8% [95% CI = 82.5% to 86.9%]). The 10-year cumulative incidence of breast cancer death was small and did not vary by age: ages 66-74 years = 0.2% (95% CI = 0.2% to 0.3%), ages 75-84 years = 0.29% (95% CI = 0.25% to 0.34%), and ages 85 to 94 years = 0.3% (95% CI = 0.2% to 0.4%)., Conclusions: Cumulative incidence of other-cause death was many times higher than breast cancer incidence and death, depending on comorbidity and age. Hence, older women with increased comorbidity may experience diminished benefit from continued screening., (© The Author(s) 2019. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Importance: The American College of Radiology (ACR) has recognized the importance of minimizing radiation doses used for lung cancer screening (LCS) computed tomography (CT). However, without standard protocols, doses could still be unnecessarily high, reducing screening margin of benefit., Objective: To characterize LCS CT radiation doses and identify factors explaining variation., Design, Setting, and Participants: We prospectively collected LCS examination dose metrics, from 2016 to 2017, at US institutions in the University of California, San Francisco International Dose Registry. Institution-level factors were collected through baseline survey. Mixed-effects linear and logistic regression models were estimated using forward variable selection. Results are presented as percentage excess dose and odds ratios (ORs) with 95% confidence intervals (CIs). The analysis was conducted between 2018 and 2019., Main Outcomes and Measures: Log-transformed measures of (1) mean volume CT dose index (CTDIvol, mGy), reflecting the average radiation dose per slice; (2) mean effective dose (ED, mSv), reflecting the total dose received and estimated future cancer risk; (3) proportion of CT scans using radiation doses above ACR benchmarks (CTDIvol >3 mGy, ED >1 mSv); and (4) proportion of CT scans using radiation doses above 75th percentile of registry doses (CTDIvol >2.7 mGy, ED >1.4 mSv)., Results: Data were collected for 12 529 patients undergoing LCS CT scans performed at 72 institutions. Overall, 7232 participants (58%) were men, and the median age was 65 years (interquartile range [IQR], 60-70). Of 72 institutions, 15 (21%) had median CTDIvol and 47 (65%) had median ED above ACR guidelines. Institutions allowing any radiologists to establish protocols had 44% higher mean CTDIvol (mean dose difference [MDD], 44%; 95% CI, 19%-69%) and 27% higher mean ED (MDD, 27%; 95% CI, 5%-50%) vs those limiting who established protocols. Institutions allowing any radiologist to establish protocols had higher odds of examinations exceeding ACR CTDIvol guidelines (OR, 12.0; 95% CI, 2.0-71.4), and 75th percentile of registry CTDIvol (OR, 19.0; 95% CI, 1.9-186.7) or ED (OR, 8.5; 95% CI, 1.7-42.9). Having lead radiologists establish protocols resulted in lower odds of doses exceeding ACR ED guidelines (OR, 0.01; 95% CI, 0.001-0.1). Employing external vs internal medical physicists was associated with increased odds of exceeding ACR CTDIvol guidelines (OR, 6.1; 95% CI, 1.8-20.8). Having medical physicists establish protocols was associated with decreased odds of exceeding 75th percentile of registry CTDIvol (OR, 0.09; 95% CI, 0.01-0.59). Institutions reporting protocol updates as needed had 27% higher mean CTDIvol (MDD, 27%; 95% CI, 8%-45%)., Conclusions and Relevance: Facilities varied in LCS CT radiation dose distributions. Institutions limiting protocol creation to lead radiologists and having internal medical physicists had lower doses.

Introduction: Metformin may be associated with reduced colorectal cancer (CRC) risk, but findings from previous studies have been inconsistent and had insufficient sample sizes to examine whether the association differs by anatomic site. This study examined whether metformin was associated with reduced CRC risk, both overall and stratified by anatomic site, in a large sample of persons with diabetes who underwent colonoscopy., Methods: We performed a case-control study of US Veterans with prevalent diabetes who underwent colonoscopy between 1999 and 2014 using Department of Veterans Affairs electronic health record data. Cases were defined by presence of CRC at colonoscopy, while controls had normal colonoscopy. The primary exposure was metformin use at time of colonoscopy (yes/no). Association of metformin exposure with CRC (further stratified by proximal, distal, or rectal subsite) was examined using multivariable and multinomial logistic regression and summarized by odds ratios (ORs) with 95% confidence intervals (CIs)., Results: We included 6,650 CRC patients and 454,507 normal colonoscopy patients. CRC cases were older and had lower metformin exposure. Metformin was associated with 8% relative reduction in CRC odds (OR: 0.92, 95% CI: 0.87-0.96). By subsite, metformin was associated with a 14% statistically significant reduced rectal cancer odds (OR: 0.86, 95% CI: 0.78-0.94) but no reduced distal or proximal cancer odds., Discussion: Metformin was associated with reduced CRC odds-particularly rectal cancer-in a large sample of persons with diabetes undergoing colonoscopy.

Mailed outreach promoting colorectal cancer (CRC) screening with a stool blood test kit may increase participation, but magnitude and consistency of benefit of this intervention strategy is uncertain. Our aim was to conduct a systematic review and meta-analysis of randomized controlled trials (RCTs) comparing mailed outreach offering stool tests to usual care, clinic-based screening offers on CRC screening uptake in the USA. We performed a systematic literature search of five databases for RCTs of mailed outreach from January 1980 through June 2017. Primary outcome was screening completion, summarized using random-effects meta-analysis as pooled differences in proportion completing the screening and relative risk of achieving screening compared to control. Subgroup analyses by test type offered-fecal immunochemical test (FIT) or guaiac fecal occult blood test (gFOBT), the presence of telephone reminders, and the presence of predominant underserved/minority population within study were performed. Quality of evidence was evaluated using the GRADE framework. Seven RCTs which enrolled 12,501 subjects were included (n = 5703 assigned mailed outreach and n = 6798 usual care). Mailed outreach resulted in a 28% absolute (95% CI 25-30%; I 2  = 47%) and a 2.8-fold relative (RR 2.65, 95% CI 2.03-3.45; I 2  = 92%) increase in screening completion compared to usual care, with a number needed to invite estimated to be 3.6. Similar outcomes were observed across subgroups. Overall body of evidence was at moderate quality. Mailed outreach offering a gFOBT or FIT is associated with a large and consistent increase in CRC screening completion and should be considered for more widespread implementation for improving screening rates nationwide.

Objective: To conduct an anatomic site-specific case-control study of candidate colorectal cancer (CRC) risk factors., Design: Case-control study of US veterans with >1 colonoscopy during 1999-2011. Cases had cancer registry-identified CRC at colonoscopy, while controls were CRC free at colonoscopy and within 3 years of colonoscopy. Primary outcome was CRC, stratified by anatomic site: proximal, distal, or rectal. Candidate risk factors included age, sex, race/ethnicity, body mass index, height, diabetes, smoking status, and aspirin exposure summarised by adjusted ORs and 95% CIs., Results: 21 744 CRC cases (n=7017 rectal; n=7039 distal; n=7688 proximal) and 612 646 controls were included. Males had significantly higher odds relative to females for rectal cancer (OR=2.84, 95% CI 2.25 to 3.58) than distal cancer (OR=1.84, 95% CI 1.50 to 2.24). Relative to whites, blacks had significantly lower rectal cancer odds (OR=0.88, 95% CI 0.82 to 0.95), but increased distal (OR=1.27, 95% CI 1.19 to 1.37) and proximal odds (OR=1.62, 95% CI 1.52 to 1.72). Diabetes prevalence was more strongly associated with proximal (OR=1.29, 95% CI 1.22 to 1.36) than distal (OR=1.15, 95% CI 1.08 to 1.22) or rectal cancer (OR=1.12, 95% CI 1.06 to 1.19). Current smoking was more strongly associated with rectal cancer (OR=1.81, 95% CI 1.68 to 1.95) than proximal cancer (OR=1.53, 95% CI 1.43 to 1.65) or distal cancer (OR=1.46, 95% CI 1.35 to 1.57) compared with never smoking. Aspirin use was significantly more strongly associated with reduced rectal cancer odds (OR=0.71, 95% CI 0.67 to 0.76) than distal (OR=0.85, 95% CI 0.81 to 0.90) or proximal (OR=0.91, 95% CI 0.86 to 0.95)., Conclusion: Candidate CRC risk factor associations vary significantly by anatomic site. Accounting for site may enable better insights into CRC pathogenesis and cancer control strategies., Competing Interests: Competing interests: None declared.

Objectives: We examined the association between three inflammatory markers (Interleukin (IL)-6, C-reactive protein (CRP), tumor necrosis factor (TNF)-α) and incident lung cancer using baseline, updated, and averaged inflammatory measures in older adults., Methods: We fitted multivariable Cox models to assess whether circulating levels of inflammation markers were associated with incident lung cancers in the Health Aging, Body and Composition (HealthABC) prospective cohort of 3075 older adults aged 70-79 years at baseline. IL-6 and CRP were measured biennially, whereas TNF-α was measured at baseline., Results: Baseline levels of IL-6 were significantly associated with incident lung cancer risk in a model that adjusted for age, gender, race, and site (Model 1) (Hazard Ratio T3 vs. T1 : 3.34, 95% Confidence Interval: 1.91, 5.85) and in a model adjusted for health factors linked to chronic inflammation (Model 2) (HR T3 vs. T1 : 2.57, 95% CI: 1.41, 4.65). The associations observed in time-updated IL-6 (HR T3 vs. T1 : 2.47, 95% CI: 1.43, 4.28), cumulatively averaged IL-6 (HR T3 vs. T1 : 2.47, 95% CI: 1.43, 4.35), and baseline CRP levels (HR T3 vs. T1 : 1.85, 95% CI: 1.11, 3.08) with incident lung cancer in Model 1 were not statistically significant in Model 2., Conclusions: Baseline CRP and IL-6 levels were associated with increased risk of lung cancer in Model 1 and both models, respectively. Chronic IL-6 inflammation, as quantified by repeated measures was associated with incident lung cancer in Model 1, but not Model 2. Further research is needed to understand the role of CRP and IL-6 in lung carcinogenesis., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Objectives: We conducted a systematic review of the literature relating early life socioeconomic position (SEP) to breast cancer incidence and mortality from a critical period and life-course trajectory perspective., Methods: PubMed, EMBASE and Web of Science were searched to identify cohort studies that evaluated the impact of early life SEP indicators on the incidence and/or mortality from breast cancer in adulthood., Results: Nine distinct studies evaluated the relationship between early life SEP and breast cancer between 1990 and 2016. Five reports assessed breast cancer incidence and five assessed breast cancer mortality as outcomes; one study assessed both incidence and mortality. While lower early life SEP was associated with reduced breast cancer incidence and increased breast cancer mortality in the US, studies conducted in Europe were unable to establish a consistent association., Conclusions: We found moderate support for the association between early life SEP and incidence and mortality from breast cancer. The impact of early life SEP on breast cancer incidence and mortality appeared to vary between countries. We urge further investigation of the role of lifelong SEP trajectories in breast cancer outcomes.

Importance: First-degree family history is a strong risk factor for breast cancer, but controversy exists about the magnitude of the association among older women., Objective: To determine whether first-degree family history is associated with increased risk of breast cancer among older women, and identify whether the association varies by breast density., Design, Setting, and Participants: Prospective cohort study between 1996 and 2012 from 7 Breast Cancer Surveillance Consortium (BCSC) registries located in New Hampshire, North Carolina, San Francisco Bay area, western Washington state, New Mexico, Colorado, and Vermont. During a mean (SD) follow-up of 6.3 (3.2) years, 10 929 invasive breast cancers were diagnosed in a cohort of 403 268 women 65 years and older with data from 472 220 mammography examinations. We estimated the 5-year cumulative incidence of invasive breast cancer by first-degree family history, breast density, and age groups. Cox proportional hazards models were fit to estimate the association of first-degree family history with risk of invasive breast cancer (after adjustment for breast density, BCSC registry, race/ethnicity, body mass index, postmenopausal hormone therapy use, and benign breast disease for age groups 65 to 74 years and 75 years and older, separately). Data analyses were performed between June 2016 and June 2017., Exposure: First-degree family history of breast cancer., Main Outcomes and Measures: Incident breast cancer., Results: In 403 268 women 65 years and older, first-degree family history was associated with an increased risk of breast cancer among women ages 65 to 74 years (hazard ratio [HR], 1.48; 95% CI, 1.35-1.61) and 75 years and older (HR, 1.44; 95% CI, 1.28-1.62). Estimates were similar for women 65 to 74 years with first-degree relative's diagnosis age younger than 50 years (HR, 1.47; 95% CI, 1.25-1.73) vs 50 years and older (HR, 1.33; 95% CI, 1.17-1.51) and for women ages 75 years and older with the relative's diagnosis age younger than 50 years (HR, 1.31; 95% CI, 1.05-1.63) vs 50 years and older (HR, 1.55; 95% CI, 1.33-1.81). Among women ages 65 to 74 years, the risk associated with first-degree family history was highest among those with fatty breasts (HR, 1.67; 95% CI, 1.27-2.21), whereas in women 75 years and older the risk associated with family history was highest among those with dense breasts (HR, 1.55; 95% CI, 1.29-1.87)., Conclusions and Relevance: First-degree family history was associated with increased risk of invasive breast cancer in all subgroups of older women irrespective of a relative's age at diagnosis.

Importance: Radiation doses for computed tomography (CT) vary substantially across institutions., Objective: To assess the impact of institutional-level audit and collaborative efforts to share best practices on CT radiation doses across 5 University of California (UC) medical centers., Design, Setting, and Participants: In this before/after interventional study, we prospectively collected radiation dose metrics on all diagnostic CT examinations performed between October 1, 2013, and December 31, 2014, at 5 medical centers. Using data from January to March (baseline), we created audit reports detailing the distribution of radiation dose metrics for chest, abdomen, and head CT scans. In April, we shared reports with the medical centers and invited radiology professionals from the centers to a 1.5-day in-person meeting to review reports and share best practices., Main Outcomes and Measures: We calculated changes in mean effective dose 12 weeks before and after the audits and meeting, excluding a 12-week implementation period when medical centers could make changes. We compared proportions of examinations exceeding previously published benchmarks at baseline and following the audit and meeting, and calculated changes in proportion of examinations exceeding benchmarks., Results: Of 158 274 diagnostic CT scans performed in the study period, 29 594 CT scans were performed in the 3 months before and 32 839 CT scans were performed 12 to 24 weeks after the audit and meeting. Reductions in mean effective dose were considerable for chest and abdomen. Mean effective dose for chest CT decreased from 13.2 to 10.7 mSv (18.9% reduction; 95% CI, 18.0%-19.8%). Reductions at individual medical centers ranged from 3.8% to 23.5%. The mean effective dose for abdominal CT decreased from 20.0 to 15.0 mSv (25.0% reduction; 95% CI, 24.3%-25.8%). Reductions at individual medical centers ranged from 10.8% to 34.7%. The number of CT scans that had an effective dose measurement that exceeded benchmarks was reduced considerably by 48% and 54% for chest and abdomen, respectively. After the audit and meeting, head CT doses varied less, although some institutions increased and some decreased mean head CT doses and the proportion above benchmarks., Conclusions and Relevance: Reviewing institutional doses and sharing dose-optimization best practices resulted in lower radiation doses for chest and abdominal CT and more consistent doses for head CT.

Background: Approximately half of new invasive breast cancer cases diagnosed each year in the United States occur among women aged 65 years and older. The increasing life expectancy coupled with the attendant rise in breast cancer incidence and elimination of out-of-pocket expenses for screening mammography as a result of the Affordable Care Act could lead to higher utilization rates of screening mammography. Although research indicates that life expectancy should be a strong consideration when making screening decisions among older women, the extent to which screening mammography utilization is tailored to comorbidity and life expectancy is not well established., Methods/design: To identify relevant studies, a systematic search of the literature will be conducted using PubMed and EMBASE between January 1, 1991, and March 1, 2016. Additional studies will be found through citation review or by contacting experts in the field. The inclusion criteria will be any study design comprised of women aged 65 and older, assessing women's comorbidity, functional impairments, and/or health status, and reporting outcome measures that addressed mammography utilization within the last 1-5 years. For each study, two authors will independently abstract data regarding study eligibility and outcomes to determine relevance. Quantitative results will be extracted from text and tables, choosing preferably those adjusted for important confounders., Discussion: The review will provide evidence on the impact of comorbidity, functional limitations, and health status on screening mammography utilization in older women and inform decision aids in this area., Systematic Review Registration: PROSPERO CRD42016032661.

Objective: To determine the association of prediagnostic alcohol consumption with long-term mortality from breast cancer and other causes in a cohort of women with breast cancer., Methods: We studied a Michigan-based cohort of 939 women aged 40-84 years, who provided complete information about the type, amount and intensity of prediagnostic alcohol consumption. Associations of alcohol consumption, based on weekly volume of alcohol consumption during the year prior to breast cancer diagnosis, with mortality were evaluated in Cox proportional hazards models, with adjustment for sociodemographic factors, body mass index, smoking, comorbidity, tumor characteristics, and treatment. Differences among covariates were assessed with Pearson χ2 , Student t -tests and Wilcoxon Rank Sum tests. All statistical tests were two-sided., Results: During a median follow-up of 11 years, 724 deaths occurred overall, with 303 from breast cancer. Fifty-five percent of the women were categorized as drinkers with volume of alcohol consumption ranging from 0.75 to 36.00 drinks/week. In multivariable models, a decreased risk of other-cause mortality was associated with low alcohol drinking (0.75-3.75 drinks/week; HR = 0.61, 95% CI = 0.47-0.78), moderate volume alcohol drinking (4.00-9.75 drinks/week; HR = 0.57, 95% CI = 0.39-0.85) and low frequency (0.75-3.75 drinks/week) beer and wine intake (HR = 0.69, 95% CI = 0.50-0.96 and HR = 0.68, 95% CI = 0.52-0.88 respectively). Although the risk of breast cancer-specific mortality was not statistically significantly associated with moderate (4.00-9.75 drinks/week) and high volume (10.00-36.00 drinks/week) alcohol drinking in the overall cohort (HR = 1.43, 95% CI = 95% 0.97-2.12 and HR = 1.53, 95% CI = 0.87-2.70 respectively), there was a positive association of alcohol consumption with breast cancer-specific mortality among current smokers (HR = 1.92, 95% CI = 1.03-3.57; Pinteraction = 0.04)., Conclusion: In this prospective cohort study, regular consumption of 0.75-36.00 alcoholic drinks per week during the year prior to breast cancer diagnosis was associated with a reduction in other-cause mortality and with an increase in breast cancer-specific mortality among current smokers, after taking into account clinical and sociodemographic factors.

We perceive motion when presented with spatiotemporal changes in contrast (second-order cue). This requires linear signals to be rectified and then summed in temporal order to compute direction. Although both operations have been attributed to cortex, rectification might occur in retina, prior to the ganglion cell. Here we show that the Y ganglion cell does indeed respond to spatiotemporal contrast modulations of a second-order motion stimulus. Responses in an OFF ganglion cell are caused by an EPSP/IPSP sequence evoked from within the dendritic field; in ON cells inhibition is indirect. Inhibitory effects, which are blocked by tetrodotoxin, clamp the response near resting potential thus preventing saturation. Apparently the computation for second-order motion can be initiated by Y cells and completed by cortical cells that sum outputs of multiple Y cells in a directionally selective manner.

The receptive field of the Y-ganglion cell comprises two excitatory mechanisms: one integrates linearly over a narrow field, and the other integrates nonlinearly over a wide field. The linear mechanism has been attributed to input from bipolar cells, and the nonlinear mechanism has been attributed to input from a class of amacrine cells whose nonlinear "subunits" extend across the linear receptive field and beyond. However, the central component of the nonlinear mechanism could in theory be driven by bipolar input if that input were rectified. Recording intracellularly from the Y-cell in guinea pig retina, we blocked the peripheral component of the nonlinear mechanism with tetrodotoxin and found the remaining nonlinear receptive field to be precisely co-spatial with the central component of the linear receptive field. Both linear and nonlinear mechanisms were caused by an excitatory postsynaptic potential that reversed near 0 mV. The nonlinear mechanism depended neither on acetylcholine nor on feedback involving GABA or glycine. Thus the central components of the ganglion cell's linear and nonlinear mechanisms are apparently driven by synapses from the same rectifying bipolar cell.

A retinal ganglion cell commonly expresses two spatially overlapping receptive field mechanisms. One is the familiar "center/surround," which sums excitation and inhibition across a region somewhat broader than the ganglion cell's dendritic field. This mechanism responds to a drifting grating by modulating firing at the drift frequency (linear response). Less familiar is the "nonlinear" mechanism, which sums the rectified output of many small subunits that extend for millimeters beyond the dendritic field. This mechanism responds to a contrast-reversing grating by modulating firing at twice the reversal frequency (nonlinear response). We investigated this nonlinear mechanism by presenting visual stimuli to the intact guinea pig retina in vitro while recording intracellularly from large brisk and sluggish ganglion cells. A contrast-reversing grating modulated the membrane potential (in addition to the firing rate) at twice the reversal frequency. This response was initially hyperpolarizing for some cells (either ON or OFF center) and initially depolarizing for others. Experiments in which responses to bars were summed in-phase or out-of-phase suggested that the single class of bipolar cells (either ON or OFF) that drives the center/surround response also drives the nonlinear response. Consistent with this, nonlinear responses persisted in OFF ganglion cells when ON bipolar cell responses were blocked by L-AP-4. Nonlinear responses evoked from millimeters beyond the ganglion cell were eliminated by tetrodotoxin. Thus, to relay the response from distant regions of the receptive field requires a spiking interneuron. Nonlinear responses from different regions of the receptive field added linearly.

Perceptual studies suggest that visual motion perception is mediated by opponent mechanisms that correspond to mutually suppressive populations of neurons sensitive to motions in opposite directions. We tested for a neuronal correlate of motion opponency using functional magnetic resonance imaging (fMRI) to measure brain activity in human visual cortex. There was strong motion opponency in a secondary visual cortical area known as the human MT complex (MT+), but there was little evidence of motion opponency in primary visual cortex. To determine whether the level of opponency in human and monkey are comparable, a variant of these experiments was performed using multiunit electrophysiological recording in areas MT and MST of the macaque monkey brain. Although there was substantial variability in the degree of opponency between recording sites, the monkey and human data were qualitatively similar on average. These results provide further evidence that: (1) direction-selective signals underly human MT+ responses, (2) neuronal signals in human MT+ support visual motion perception, (3) human MT+ is homologous to macaque monkey MT and adjacent motion sensitive brain areas, and (4) that fMRI measurements are correlated with average spiking activity.

Developmental dyslexia has been associated with both abnormal hemispheric symmetry of the planum temporale (PT) and a deficit in the magnocellular visual pathway. We examined the relationship between these two abnormalities. Using sagittal magnetic resonance images and three methods, we measured the PT in dyslexic subjects with a documented magnocellular deficit and controls. Dyslexic subjects did not deviate from normal leftward PT asymmetry, but both groups became less left-lateralized with methods that excluded sulcul tissue. Results suggest that dyslexic subjects with a magnocellular deficit do not always have abnormal symmetry of the PT. PT symmetry may instead be related to a different subtype of dyslexia. In addition, PT asymmetry in any subject group depends on the measurement method.

Psychophysical contrast increment thresholds were compared with neuronal responses, inferred from functional magnetic resonance imaging (fMRI) to test the hypothesis that contrast discrimination judgements are limited by neuronal signals in early visual cortical areas. FMRI was used to measure human brain activity as a function of stimulus contrast, in each of several identifiable visual cortical areas. Contrast increment thresholds were measured for the same stimuli across a range of baseline contrasts using a temporal 2AFC paradigm. FMRI responses and psychophysical measurements were compared by assuming that: (1) fMRI responses are proportional to local average neuronal activity; (2) subjects choose the stimulus interval that evoked the greater average neuronal activity; and (3) variability in the observer's psychophysical judgements was due to additive (IID) noise. With these assumptions, FMRI responses in visual areas V1, V2d, V3d and V3A were found to be consistent with the psychophysical judgements, i.e. a contrast increment was detected when the fMRI responses in each of these brain areas increased by a criterion amount. Thus, the pooled activity of large numbers of neurons can reasonably well predict behavioral performance. The data also suggest that contrast gain in early visual cortex depends systematically on spatial frequency.

We measured brain activity, perceptual thresholds, and reading performance in a group of dyslexic and normal readers to test the hypothesis that dyslexia is associated with an abnormality in the magnocellular (M) pathway of the early visual system. Functional magnetic resonance imaging (fMRI) was used to measure brain activity in conditions designed to preferentially stimulate the M pathway. Speed discrimination thresholds, which measure the minimal increase in stimulus speed that is just noticeable, were acquired in a paradigm modeled after a previous study of M pathway-lesioned monkeys. Dyslexics showed reduced brain activity compared with controls both in primary visual cortex (V1) and in several extrastriate areas, including area MT and adjacent motion-sensitive areas (MT+) that are believed to receive a predominant M pathway input. There was a strong three-way correlation between brain activity, speed discrimination thresholds, and reading speed. Subjects with higher V1 and MT+ responses had lower perceptual thresholds (better performance) and were faster readers. These results support the hypothesis for an M pathway abnormality in dyslexia and imply strong relationships between the integrity of the M pathway, visual motion perception, and reading ability.

The relationship between reading ability and psychophysical performance was examined to test the hypothesis that dyslexia is associated with a deficit in the magnocellular (M) pathway. Speed discrimination thresholds and contrast detection thresholds were measured under conditions (low mean luminance, low spatial frequency, high temporal frequency) for which psychophysical performance presumably depends on M pathway integrity. Dyslexic subjects had higher psychophysical thresholds than controls in both the speed discrimination and contrast detection tasks, but only the differences in speed thresholds were statistically significant. In addition, there was a strong correlation between individual differences in speed thresholds and reading rates. These results support the hypothesis for an M pathway abnormality in dyslexia, and suggest that motion discrimination may be a more sensitive psychophysical predictor of dyslexia than contrast sensitivity.

The relationship between brain activity and reading performance was examined to test the hypothesis that dyslexia involves a deficit in a specific visual pathway known as the magnocellular (M) pathway. Functional magnetic resonance imaging was used to measure brain activity in dyslexic and control subjects in conditions designed to preferentially stimulate the M pathway. Dyslexics showed reduced activity compared with controls both in the primary visual cortex and in a secondary cortical visual area (MT+) that is believed to receive a strong M pathway input. Most importantly, significant correlations were found between individual differences in reading rate and brain activity. These results support the hypothesis for an M pathway abnormality in dyslexia and imply a strong relationship between the integrity of the M pathway and reading ability.

Functional neuroimaging studies of single-word processing have demonstrated decreased activation in left inferior prefrontal cortex (LIPC) during repeated semantic processing relative to initial semantic processing. This item-specific memory effect occurs under implicit test instructions and represents word-toword semantic repetition priming. The present study examined the stimulus generality of LIPC function by measuring prefrontal cortical activation during repeated relative to initial semantic processing of words (word-to-word semantic repetition priming) and of pictures (picture-to-picture semantic repetition priming). For both words and pictures, LIPC activation decreased with repetition, suggesting that this area subserves semantic analysis of stimuli regardless of perceptual form. Decreased activation was greater in extent for words than for pictures. The LIPC area may act as a semantic executive system that mediates on-line retrieval of long-term conceptual knowledge necessary for guiding task performance.

Prefrontal cortical function was examined during semantic encoding and repetition priming using functional magnetic resonance imaging (fMRI), a noninvasive technique for localizing regional changes in blood oxygenation, a correlate of neural activity. Words studied in a semantic (deep) encoding condition were better remembered than words studied in both easier and more difficult nonsemantic (shallow) encoding conditions, with difficulty indexed by response time. The left inferior prefrontal cortex (LIPC) (Brodmann's areas 45, 46, 47) showed increased activation during semantic encoding relative to nonsemantic encoding regardless of the relative difficulty of the nonsemantic encoding task. Therefore, LIPC activation appears to be related to semantic encoding and not task difficulty. Semantic encoding decisions are performed faster the second time words are presented. This represents semantic repetition priming, a facilitation in semantic processing for previously encoded words that is not dependent on intentional recollection. The same LIPC area activated during semantic encoding showed decreased activation during repeated semantic encoding relative to initial semantic encoding of the same words. This decrease in activation during repeated encoding was process specific; it occurred when words were semantically reprocessed but not when words were nonsemantically reprocessed. The results were apparent in both individual and averaged functional maps. These findings suggest that the LIPC is part of a semantic executive system that contributes to the on-line retrieval of semantic information.

Subjects studied visually presented compound words (e.g., TOOTHPASTE, HEARTACHE) and then received a recognition, perceptual identification, or word-fragment completion test that contained old, recombined (e.g., TOOTHACHE), and partially and completely new words. False recognitions increased with the increasing number of previously studied components; however, priming in perceptual identification occurred only for old words. Priming in word-fragment completion occurred for old and recombined words. Reducing the time available to solve word fragments, from 20 sec to 5 sec, did not affect the pattern of results; it is therefore unlikely that priming for recombined words resulted from the use of a recollection-based strategy. Memory tasks that involve a conceptual component access memories that are constructed from parts; memory tasks that are primarily perceptual do not access such memories.

Play therapy is the treatment of choice with young children, while "talking" therapy is used with older children and adults. There have been reports of written communication being employed in therapy both with children (e.g., diaries and stories) and with adults (e.g., letters and contracts), but little has been reported about the use of the exchange of written words during therapy sessions with "literate" children. The author presents segments of the treatment of a latency age girl to illustrate how the exchange of written language can allow treatment to proceed when children are too distressed to play or to talk at certain points in therapy. Samples of this communication are offered.

There is a popular perception that gay men are artistic. Although art historians and others have documented the substantial contribution to art made by gay men, the existence of a unique gay sensibility remains controversial. Mental health practitioners who work with gay men have addressed aesthetic sensibility in the childhood of gay men, but not the role of art in their adult lives. A literature search on the relationship between homosexuality and artistic ability and/or achievement shows that there is little scientific data addressing this subject. Reasons for the lack of literature as well as suggestions for future research are offered.

In evaluating a large group of foster children from biological families with a high incidence of alcohol and/or drug abuse, there emerges a subsample of children with both atypical eating patterns as well as atypical behavior patterns. Their physical and behavioral characteristics are described. These children are neither obese nor "failure to thrive." They display an excessive appetite for food, a driven quality to their eating, an apparent lack of satiety, and frequent eating to the point of vomiting or gastric pain if food intake is not limited externally. All of these children have psychiatric disorders. Hyperphagia appears to be a marker for significant psychopathology.