A demonstration of cone function plasticity after gene therapy in achromatopsia.

Recent advances in regenerative therapy have placed the treatment of previously incurable eye diseases within arms' reach. Achromatopsia is a severe monogenic heritable retinal disease that disrupts cone function from birth, leaving patients with complete colour blindness, low acuity, photosensitivity and nystagmus. While successful gene-replacement therapy in non-primate models of achromatopsia has raised widespread hopes for clinical treatment, it was yet to be determined if and how these therapies can induce new cone function in the human brain. Using a novel multimodal approach, we demonstrate for the first time that gene therapy can successfully activate dormant cone-mediated pathways in children with achromatopsia (CNGA3- and CNGB3-associated, 10-15 years). To test this, we combined functional MRI population receptive field mapping and psychophysics with stimuli that selectively measure cone photoreceptor signalling. We measured cortical and visual cone function before and after gene therapy in four paediatric patients, evaluating treatment-related change against benchmark data from untreated patients (n = 9) and normal-sighted participants (n = 28). After treatment, two of the four children displayed strong evidence for novel cone-mediated signals in visual cortex, with a retinotopic pattern that was not present in untreated achromatopsia and which is highly unlikely to emerge by chance. Importantly, this change was paired with a significant improvement in psychophysical measures of cone-mediated visual function. These improvements were specific to the treated eye, and provide strong evidence for successful read-out and use of new cone-mediated information. These data show for the first time that gene replacement therapy in achromatopsia within the plastic period of development can awaken dormant cone-signalling pathways after years of deprivation. This reveals unprecedented neural plasticity in the developing human nervous system and offers great promise for emerging regenerative therapies.

Infant Sex-Specific Associations between Prenatal Food Insecurity and Low Birthweight: A Multistate Analysis.

BACKGROUND: Low birthweight is associated with increased risk of neonatal mortality and adverse outcomes among survivors. As maternal sociodemographic factors do not explain all of the risk in low birthweight, exploring exposures occurring during critical periods, such as maternal food insecurity, should be considered from a life course perspective. OBJECTIVES: To explore the association between prenatal food insecurity and low birthweight, as well as whether or not there may be a sex-specific response using a multistate survey. METHODS: Pregnancy Risk Assessment Monitoring System (PRAMS) data of live births from 11 states during 2009-2017 were used, restricting to women with a singleton birth. Food insecurity was determined by a single question in PRAMS, and low birthweight was defined as a birth <2500 g. Multivariable logistic regression was used, stratified by infant sex and adjusted for maternal sociodemographic and prepregnancy health characteristics. RESULTS: There were n = 50,915 women from 2009 to 2017, with 9.1% experiencing food insecurity. Unadjusted results revealed that food-insecure mothers had an increased odds ratio of delivering a low-birthweight baby (OR: 1.38; 95% CI: 1.25, 1.53). Adjustment for covariates appeared to explain the association among male infants, whereas magnitudes remained greater among female infants (adjusted OR: 1.13; 95% CI: 0.94, 1.35). CONCLUSIONS: Findings suggest a sex-specific response to prenatal food insecurity, particularly among female offspring. Future studies are warranted with more precise measures of food insecurity and to understand the difference by infant sex.

Once daily combined inhaled steroid and ultra long-acting bronchodilator prescribing in pediatric asthma: a dual Center retrospective cohort study.

OBJECTIVE: A high proportion of children and adolescents who have "difficult" or therapy-resistant asthma, are found to have poor adherence to maintenance therapies. Such individuals are thus difficult asthmatics (for reasons of poor adherence) rather than being young people with true difficult asthma. In our centers, once daily ICS/ULABA (Relvar™) is considered if there is an increase in reported interval symptoms, asthma attacks requiring hospital attendance or rescue oral prednisolone, or persistently low lung function despite reported regular use of a twice daily ICS/LABA preparation. In the majority of these young people, a clinical history of overt non-adherence or a clinical suspicion of covert non-adherence will be noted. METHODS: The aim of our retrospective cohort study was to assess the clinical effectiveness of Relvar™ in a selected adolescent asthma population. RESULTS: In a pre-selected group of adolescents with likely poor prior adherence to inhaled therapies, a change to Relvar™ (once daily combined ICS/ULABA) led to improvements in asthma control, as assessed by ED attendances and oral steroid burden. CONCLUSIONS: A prospective study to verify these findings and also explore the effects on quality of life, asthma control, and adherence is warranted.

Visual Population Receptive Fields in People with Schizophrenia Have Reduced Inhibitory Surrounds.

People with schizophrenia (SZ) experience abnormal visual perception on a range of visual tasks, which have been linked to abnormal synaptic transmission and an imbalance between cortical excitation and inhibition. However, differences in the underlying architecture of visual cortex neurons, which might explain these visual anomalies, have yet to be reported in vivo Here, we probed the neural basis of these deficits using fMRI and population receptive field (pRF) mapping to infer properties of visually responsive neurons in people with SZ. We employed a difference-of-Gaussian model to capture the center-surround configuration of the pRF, providing critical information about the spatial scale of the pRFs inhibitory surround. Our analysis reveals that SZ is associated with reduced pRF size in early retinotopic visual cortex, as well as a reduction in size and depth of the inhibitory surround in V1, V2, and V4. We consider how reduced inhibition might explain the diverse range of visual deficits reported in SZ.SIGNIFICANCE STATEMENT People with schizophrenia (SZ) experience abnormal perception on a range of visual tasks, which has been linked to abnormal synaptic transmission and an imbalance between cortical excitation/inhibition. However, associated differences in the functional architecture of visual cortex neurons have yet to be reported in vivo We used fMRI and population receptive field (pRF) mapping to demonstrate that the fine-grained functional architecture of visual cortex in people with SZ differs from unaffected controls. SZ is associated with reduced pRF size in early retinotopic visual cortex largely due to reduced inhibitory surrounds. An imbalance between cortical excitation and inhibition could drive such a change in the center-surround pRF configuration and ultimately explain the range of visual deficits experienced in SZ.

Retrospective cohort study of breast cancer incidence, health service use and outcomes in Europe: a study of feasibility.

Background: Comparisons of outcomes of health care in different systems can be used to inform health policy. The EuroHOPE (European Healthcare Outcomes, Performance and Efficiency) project investigated the feasibility of comparing routine data on selected conditions including breast cancer across participating European countries. Methods: Routine data on incidence, treatment and mortality by age and clinical characteristics for breast cancer in women over 24 years of age were obtained (for a calendar year) from linked hospital discharge records, cancer and death registers from Finland, the Turin metropolitan area, Scotland and Sweden (all 2005), Hungary (2006) and Norway (2009). Age-adjusted breast cancer incidence and 1-year survival were estimated for each country/region. Results: In total, 24 576 invasive breast cancer cases were identified from cancer registries from over 13 million women. Age-adjusted incidence ranged from 151.1 (95%CI 147.2-155.0) in Hungary to 234.7 (95%CI 227.4-242.0)/100 000 in Scotland. One-year survival ranged from 94.1% (95%CI 93.5-94.7%) in Scotland to 97.1% (95%CI 96.2-98.1%) in Italy. Scotland had the highest proportions of poor prognostic factors in terms of tumour size, nodal status and metastases. Significant variations in data completeness for prognostic factors prevented adjustment for case mix. Conclusion: Incidence of and survival from breast cancer showed large differences between countries. Substantial improvements in the use of internationally recognised common terminology, standardised data coding and data completeness for prognostic indicators are required before international comparisons of routine data can be used to inform health policy.

Larger extrastriate population receptive fields in autism spectrum disorders.

Previous behavioral research suggests enhanced local visual processing in individuals with autism spectrum disorders (ASDs). Here we used functional MRI and population receptive field (pRF) analysis to test whether the response selectivity of human visual cortex is atypical in individuals with high-functioning ASDs compared with neurotypical, demographically matched controls. For each voxel, we fitted a pRF model to fMRI signals measured while participants viewed flickering bar stimuli traversing the visual field. In most extrastriate regions, perifoveal pRFs were larger in the ASD group than in controls. We observed no differences in V1 or V3A. Differences in the hemodynamic response function, eye movements, or increased measurement noise could not account for these results; individuals with ASDs showed stronger, more reliable responses to visual stimulation. Interestingly, pRF sizes also correlated with individual differences in autistic traits but there were no correlations with behavioral measures of visual processing. Our findings thus suggest that visual cortex in ASDs is not characterized by sharper spatial selectivity. Instead, we speculate that visual cortical function in ASDs may be characterized by extrastriate cortical hyperexcitability or differential attentional deployment.

fMRI and gene therapy in adults with CNGB3 mutation.

Achromatopsia is an inherited retinal disease that affects 1 in 30,000-50,000 individuals and is characterised by an absence of functioning cone photoreceptors from birth. This results in severely reduced visual acuity, no colour vision, marked sensitivity to light and involuntary oscillations of the eyes (nystagmus). In most cases, a single gene mutation prevents normal development of cone photoreceptors, with mutations in the CNGB3 or CNGA3 gene being responsible for ∼80 % of all patients with achromatopsia. There are a growing number of studies investigating recovery of cone function after targeted gene therapy. These studies have provided some promise for patients with the CNGA3 mutation, but thus far have found limited or no recovery for patients with the CNGB3 mutation. Here, we developed colour-calibrated visual stimuli designed to isolate cone photoreceptor responses. We combined these with adapted fMRI techniques and pRF mapping to identify if cortical responses to cone-driven signals could be detected in 9 adult patients with the CNGB3 mutation after receiving gene therapy. We did not detect any change in brain activity after gene therapy when the 9 patients were analysed as a group. However, on an individual basis, one patient self-reported a change in colour perception, corroborated by improved performance on a psychophysical task designed to selectively identify cone function. This suggests a level of cone sensitivity that was lacking pre-treatment, further supported by a subtle but reliable change in cortical activity within their primary visual cortex.

The Association Between Prenatal Food Insecurity and Breastfeeding Initiation and Exclusive Breastfeeding Duration: A Longitudinal Study Using Oregon PRAMS and PRAMS-2, 2008-2015.

Background: In the United States, 11.1% of households experience food insecurity; however, pregnant women are disproportionately affected. Maternal food insecurity may affect infant feeding practices, for example, through being a source of chronic stress that may alter the decision to initiate and continue breastfeeding. Thus, we sought to determine whether prenatal food insecurity was associated with breastfeeding (versus not) and exclusive breastfeeding duration among Oregon women. Method: The Oregon Pregnancy Risk Assessment Monitoring System (PRAMS) data of live births from 2008 to 2015 and the Oregon PRAMS-2 follow-up survey were used (n = 3,624) in this study. Associations with breastfeeding initiation and duration were modeled with multivariable logistic regression and accelerated failure time (AFT), respectively. Models were adjusted for maternal sociodemographic and pre-pregnancy health characteristics. Results: Nearly 10% of women experienced prenatal food insecurity. For breastfeeding initiation, unadjusted models suggested non-significant decreased odds (odds ratio (OR) 0.88 [confidence intervals (CI): 0.39, 1.99]), whereas adjusted models revealed a non-significant increased odds (OR 1.41 [CI: 0.58, 3.47]). Unadjusted AFT models suggested that food-insecure mothers had a non-significant decrease in exclusive breastfeeding duration (OR 0.76 [CI: 0.50, 1.17]), but adjustment for covariates attenuated results (OR 0.89 [CI: 0.57, 1.39]). Conclusions: Findings suggest minimal differences in breastfeeding practices when exploring food security status in the prenatal period, though the persistence of food insecurity may affect exclusive breastfeeding duration. Lower breastfeeding initiation may be due to other explanatory factors correlated with food insecurity and breastfeeding, such as education and marital status.

Cortical network for gaze control in humans revealed using multimodal MRI.

Functional magnetic resonance imaging (fMRI) techniques allow definition of cortical nodes that are presumed to be components of large-scale distributed brain networks involved in cognitive processes. However, very few investigations examine whether such functionally defined areas are in fact structurally connected. Here, we used combined fMRI and diffusion MRI-based tractography to define the cortical network involved in saccadic eye movement control in humans. The results of this multimodal imaging approach demonstrate white matter pathways connecting the frontal eye fields and supplementary eye fields, consistent with the known connectivity of these regions in macaque monkeys. Importantly, however, these connections appeared to be more prominent in the right hemisphere of humans. In addition, there was evidence of a dorsal frontoparietal pathway connecting the frontal eye field and the inferior parietal lobe, also right hemisphere dominant, consistent with specialization of the right hemisphere for directed attention in humans. These findings demonstrate the utility and potential of using multimodal imaging techniques to define large-scale distributed brain networks, including those that demonstrate known hemispheric asymmetries in humans.

Expert cognitive control and individual differences associated with frontal and parietal white matter microstructure.

Although many functional imaging studies have reported frontal activity associated with "cognitive control" tasks, little is understood about factors underlying individual differences in performance. Here we compared the behavior and brain structure of healthy controls with fighter pilots, an expert group trained to make precision choices at speed in the presence of conflicting cues. Two different behavioral paradigms--Eriksen Flanker and change of plan tasks--were used to assess the influence of distractors and the ability to update ongoing action plans. Fighter pilots demonstrated superior cognitive control as indexed by accuracy and postconflict adaptation on the Flanker task, but also showed increased sensitivity to irrelevant, distracting choices. By contrast, when pilots were examined on their ability to inhibit a current action plan in favor of an alternative response, their performance was no better than the control group. Diffusion weighted imaging revealed differences in white matter radial diffusivity between pilots and controls not only in the right dorsomedial frontal region but also in the right parietal lobe. Moreover, analysis of individual differences in reaction time costs for conflict trials on the Flanker task demonstrated significant correlations with radial diffusivity at these locations, but in different directions. Postconflict adaptation effects, however, were confined to the dorsomedial frontal locus. The findings demonstrate that in humans expert cognitive control may surprisingly be mediated by enhanced response gain to both relevant and irrelevant stimuli, and is accompanied by structural alterations in the white matter of the frontal and parietal lobe.

Neural correlates of spatial orienting in the human superior colliculus.

A natural visual scene contains more information than the visual system has the capacity to simultaneously process, requiring specific items to be selected for detailed analysis at the expense of others. Such selection and inhibition are fundamental in guiding search behavior, but the neural basis of these mechanisms remains unclear. Abruptly appearing visual items can automatically capture attention, but once attention has been directed away from the salient event, return to that same location is slowed. In non-human primates, signals associated with attentional capture (AC) and subsequent inhibition of return (IOR) have been recorded from the superior colliculus (SC)--a structure known to play a pivotal role in reflexive spatial orienting. Here, we sought to establish whether similar signals could be recorded from the human SC, as well as early retinotopic cortical visual areas, where signals associated with AC and IOR have yet to be investigated with respect to oculomotor responses. Using an optimized oculomotor paradigm together with high-field, high-spatial resolution functional magnetic resonance imaging and high-speed eye tracking, we demonstrate that BOLD signal changes recorded from the human SC correlate strongly with our saccadic measures of AC and IOR. A qualitatively similar pattern of responses was found for V1, but only the inhibitory response associated with IOR persisted through V2 and V3. Although the SC plays a role in mediating these automatic attentional biasing signals, the source of these signals is likely to lie in higher cortical areas.

Overlapping functional anatomy for working memory and visual search.

Recent behavioural findings using dual-task paradigms demonstrate the importance of both spatial and non-spatial working memory processes in inefficient visual search (Anderson et al. in Exp Psychol 55:301-312, 2008). Here, using functional magnetic resonance imaging (fMRI), we sought to determine whether brain areas recruited during visual search are also involved in working memory. Using visually matched spatial and non-spatial working memory tasks, we confirmed previous behavioural findings that show significant dual-task interference effects occur when inefficient visual search is performed concurrently with either working memory task. Furthermore, we find considerable overlap in the cortical network activated by inefficient search and both working memory tasks. Our findings suggest that the interference effects observed behaviourally may have arisen from competition for cortical processes subserved by these overlapping regions. Drawing on previous findings (Anderson et al. in Exp Brain Res 180:289-302, 2007), we propose that the most likely anatomical locus for these interference effects is the inferior and middle frontal cortex of the right hemisphere. These areas are associated with attentional selection from memory as well as manipulation of information in memory, and we propose that the visual search and working memory tasks used here compete for common processing resources underlying these mechanisms.

Monocular signals in human lateral geniculate nucleus reflect the Craik-Cornsweet-O'Brien effect.

The human visual system has a remarkable ability to accurately estimate the relative brightness of adjacent objects despite large variations in illumination. However, the lightness of two identical equiluminant gray regions can appear quite different when a light-dark luminance transition falls between them. This illusory brightness "filling-in" phenomenon, the Craik-Cornsweet-O'Brien (CCOB) illusion, exposes fundamental assumptions made by the visual system in estimating lightness, but its neural basis remains unclear. While the responses of high-level visual cortex can be correlated with perception of the CCOB, simple computational models suggest that the effect may originate from a much lower level, possibly subcortical. Here, we used high spatial resolution functional magnetic resonance imaging to show that the CCOB illusion is strongly correlated with signals recorded from the human lateral geniculate nucleus. Moreover, presenting the light and dark luminance transitions that induce the CCOB effect separately to each eye abolishes the illusion, suggesting that it depends on eye-specific signals. Our observations suggest that the CCOB effect arises from signals in populations of monocular neurons very early in the human geniculostriate visual pathway.

Correction: Local and Global Limits on Visual Processing in Schizophrenia.

[This corrects the article DOI: 10.1371/journal.pone.0117951.].

Correction: Reduced Crowding and Poor Contour Detection in Schizophrenia Are Consistent with Weak Surround Inhibition.

[This corrects the article DOI: 10.1371/journal.pone.0060951.].

Corrigendum: Visual surround suppression in schizophrenia.

[This corrects the article DOI: 10.3389/fpsyg.2013.00088.].

Predicting breast cancer risk: implications of a "weak" family history.

Published guidelines adopted in many countries recommend that women whose family history of breast cancer places them at a risk>or=1.7 times that of the age-matched general population, should be considered for inclusion in special surveillance programmes. However validation of risk assessment models has been called for as a matter of urgency. The databases of the four Scottish Familial Breast Cancer clinics and the Scottish Cancer Registry have been searched to identify breast cancers occurring among 1,125 women aged 40-56, with family histories placing them below the "moderate" level of genetic risk. The observed incidence over 6 years was compared with age-specific data for the Scottish population. Our findings confirm that when there are two affected relatives (one first degree) the relative risk (RR) exceeds 1.7 regardless of their ages at diagnosis. When only one (first degree) relative was affected at any age from 40 to 55, the RR does not reach 1.7 if that relative was a mother but exceeds it if the relative was a sister. The probable explanation is that sisters are more likely than mother/daughter pairs to share homozygosity for a risk allele. Surveillance programmes might therefore accommodate sisters of women affected before age 55. Evidence that "low penetrance" alleles contributing to breast cancer risk may be recessive should be taken into account in strategies for identifying them.

Does a short cessation of HRT decrease mammographic density?

BACKGROUND: Hormone replacement therapy (HRT) is known to increase breast density, thus decreasing the sensitivity of cancer screening by mammography. Some authors recommend short cessation of HRT before mammography, but evidence showing the effect of such short cessation is limited. The purpose of this study is to examine whether a short cessation of HRT changes mammographic density. METHODS: Forty-eight women taking HRT agreed to have mammograms taken before and after stopping HRT for 4 weeks. Mammographic density was measured by Wolfe's four-point classification, six-categorical visual scale and two different computer methods (interactive-thresholding and SMF). Density values of mammography before and after the cessation of HRT were compared using Wilcoxon signed-rank test for categorical variables and paired t-test for continuous variables. Changes in breast pain and tenderness during mammography, radiation dose, compression force, and breast thickness were also recorded. RESULTS: No significant changes in mammographic density were observed by either visual or computer methods. There were no significant changes in breast pain or in tenderness on mammograms before and after the month's cessation of HRT. Radiographic measurements were not significantly altered by the 4-week cessation of HRT. CONCLUSION: In this screening population, a 4-week cessation of HRT before mammograms did not significantly alter mammographic density.

Long-term attendance at follow-up of women assessed as being at increased risk of developing breast cancer in south-east Scotland.

BACKGROUND: Women with a family history of breast cancer increasingly seek genetic advice and screening. In the present study we investigated referral rates and factors associated with long-term attendance for screening in Scotland. METHODS: We investigated referral rates to the genetic service over a 21-month period and long-term attendance for screening amongst the 226 women at increased risk of developing breast cancer. RESULTS: The overall annual referral rate was 0.31 per 1,000 patients on general practitioners' lists. Some 98% of women for whom it was appropriate attended at least one screening appointment and 88% were continuing to attend appointments for surveillance up to 5 years later. Attendance was significantly lower among more socially deprived patients (p < 0.01). CONCLUSIONS: These results suggest that as increasing numbers of women with a positive family history seek risk assessment and screening, current facilities may be inadequate.

Binocular Therapy for Childhood Amblyopia Improves Vision Without Breaking Interocular Suppression.

Purpose: Amblyopia is a common developmental visual impairment characterized by a substantial difference in acuity between the two eyes. Current monocular treatments, which promote use of the affected eye by occluding or blurring the fellow eye, improve acuity, but are hindered by poor compliance. Recently developed binocular treatments can produce rapid gains in visual function, thought to be as a result of reduced interocular suppression. We set out to develop an effective home-based binocular treatment system for amblyopia that would engage high levels of compliance but that would also allow us to assess the role of suppression in children's response to binocular treatment. Methods: Balanced binocular viewing therapy (BBV) involves daily viewing of dichoptic movies (with "visibility" matched across the two eyes) and gameplay (to monitor compliance and suppression). Twenty-two children (3-11 years) with anisometropic (n = 7; group 1) and strabismic or combined mechanism amblyopia (group 2; n = 6 and 9, respectively) completed the study. Groups 1 and 2 were treated for a maximum of 8 or 24 weeks, respectively. Results: The treatment elicited high levels of compliance (on average, 89.4% ± 24.2% of daily dose in 68.23% ± 12.2% of days on treatment) and led to a mean improvement in acuity of 0.27 logMAR (SD 0.22) for the amblyopic eye. Importantly, acuity gains were not correlated with a reduction in suppression. Conclusions: BBV is a binocular treatment for amblyopia that can be self-administered at home (with remote monitoring), producing rapid and substantial benefits that cannot be solely mediated by a reduction in interocular suppression.