IMPORTANCEIf we assume that women and men exhibit variations of the same fundamental vascular physiology, then conventional analyses of subclinical measures would suggest that women catch up to men by midlife in the extent of potentially important vascular disease. Alternatively, under the assumption that vascular physiology may fundamentally differ between women and men, a sex-specific analysis of existing data could offer new insights and augment our understanding of sex differences in cardiovascular diseases.OBJECTIVE To evaluate whether longitudinal patterns of blood pressure (BP) elevation differ between women and men during the life course when considering baseline BP levels as the reference. DESIGN, SETTING, AND PARTICIPANTSWe conducted sex-specific analyses of longitudinal BP measures (144 599 observations) collected for a period of 43 years (1971 to 2014) in 4 community-based US cohort studies. The combined total included 32 833 participants (54% female) spanning ages 5 to 98 years. Data were analyzed between May 4, 2019, and August 5, 2019.EXPOSURES Age and serially assessed longitudinal BP measures: systolic BP, diastolic BP, mean arterial pressure (MAP), and pulse pressure (PP).MAIN OUTCOMES AND MEASURES Sex-specific change in each primary BP measure compared with baseline BP levels, derived from multilevel longitudinal models fitted over the age span, and new-onset cardiovascular disease events. RESULTSOf the 32 833 participants, 17 733 were women (54%). Women compared with men exhibited a steeper increase in BP that began as early as in the third decade and continued through the life course (likelihood ratio test χ 2 = 531 for systolic BP; χ 2 = 123 for diastolic BP; χ 2 = 325 for MAP; and χ 2 = 572 for PP; P for all <.001). After adjustment for multiple cardiovascular disease risk factors, these between-sex differences in all BP trajectories persisted (likelihood ratio test χ 2 = 314 for systolic BP; χ 2 = 31 for diastolic BP; χ 2 = 129 for MAP; and χ 2 = 485 for PP; P for all <.001). CONCLUSIONS AND RELEVANCEIn contrast with the notion that important vascular disease processes in women lag behind men by 10 to 20 years, sex-specific analyses indicate that BP measures actually progress more rapidly in women than in men, beginning early in life. This early-onset sexual dimorphism may set the stage for later-life cardiovascular diseases that tend to present differently, not simply later, in women compared with men.

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Obesity-induced hyperglycemic and prediabetic/early diabetic conditions caused detrimental impacts on retinal light sensitivities and health. The decrease of the ERG components in early diabetes reflects the decreased neuronal activity of retinal light responses, which may be caused by a decrease in neuronal calcium signaling. Since PI3K-AKT is important in regulating calcium homeostasis and neural survival, maintaining proper PI3K-AKT signaling in early diabetes or at the prediabetic stage might be a new strategy for DR prevention.

Citation: Vaghefi E, Kim A, Donaldson PJ. Active maintenance of the gradient of refractive index is required to sustain the optical properties of the lens. Invest Ophthalmol Vis Sci. 2015;56:7195-7208. DOI:10.1167/ iovs.15-17861 PURPOSE. To determine whether the cellular physiology of the lens actively maintains the optical properties of the lens and whether inhibition of lens transport affects overall visual quality. METHODS.One lens from a pair of bovine lenses was cultured in artificial aqueous humor (AAH), while the other was cultured in either AAH-High-K þ or AAH þ 0.1 mM ouabain for 4 hours. Lens pairs or whole enucleated eyes were then imaged in 4.7 Tesla (T) high-field small animal magnet. Lens surface curvatures, T1 measurements of water content, and T2 measurements of water/protein ratios were extracted from cultured lenses, while the geometrical parameters that define the optical pathway were obtained from whole eyes. Gradients of refractive index (GRIN), calculated from T2 measurements, and the extracted geometric parameters were inputted into optical models of the isolated lens and the whole bovine eye. RESULTS.Inhibiting circulating fluxes by inhibiting the Na/K-ATPase with ouabain or depolarization of the lens potential by High K þ caused changes to lens water content, the water/protein ratio (GRIN) and surface geometry that manifested as an increase in optical power and a decrease in negative spherical aberration in cultured lenses. Changes to optical properties of the lens resulted in a myopic shift that impaired vision quality in the optical model of the bovine eye.CONCLUSIONS. The cellular physiology of the lens actively maintains its optical properties and inhibiting the Na/K/ATPase induces a myopic shift in vision similar to that observed clinically in patients who go on to develop cataract.Keywords: lens physiology, magnetic resonance imaging, gradient of refractive index, physiological optics, optical modeling, cataract O ur sense of sight is critically dependent on the optical properties of the ocular lens that enables light to be focused onto the retina.1 Like a glass window, the lens allows light rays that enter the eye to pass through it with minimal scattering. However, the lens is more than a simple pane of glass, because its curved surfaces enable it to focus light. In addition, the lens needs to correct for positive spherical aberration introduced to the optical pathway via the cornea. This spherical aberration is an optical error caused by the increased refraction of light rays that strike the periphery of the cornea relative to those that strike its center.2 The lens compensates for this optical error by imposing and maintaining a compensating negative spherical aberration through the establishment an inherent gradient of refractive index (GRIN). 3Being a biological tissue, this gradient is generated by over expressing different subtypes of crystallin proteins with varying refractive indices, 4 thereby ensuring that incoming light is accurately focussed on the retina. While ...

Background: In the EPIC-HR trial, nirmatrelvir plus ritonavir led to an 88% reduction in hospitalization or death among unvaccinated outpatients with early COVID-19. Clinical impact of nirmatrelvir plus ritonavir among vaccinated populations is uncertain. Objective: To assess whether nirmatrelvir plus ritonavir reduces risk of hospitalization among outpatients with early COVID-19 in the setting of prevalent SARS-CoV-2 immunity and immune evasive SARS-CoV-2 lineages. Design: Population-based cohort study analyzed to emulate a clinical trial utilizing two-stage, inverse-probability weighted models to account for anticipated bias in testing and treatment. Setting: A large healthcare system providing care for 1.5 million patients in Massachusetts and New Hampshire during Omicron wave (January 1 to May 15, 2022) with staged access and capacity to prescribe nirmatrelvir plus ritonavir. Patients: 30,322 non-hospitalized adults (87.2% vaccinated) aged 50 and older with COVID-19 and without contraindications to nirmatrelvir plus ritonavir. Measurement: Primary outcome was hospitalization within 14 days of COVID-19 diagnosis. Results: During the study period, 6036 (19.9%) patients were prescribed nirmatrelvir plus ritonavir and 24,286 (80.1%) patients were not. Patients prescribed nirmatrelvir were more likely to be older, have more comorbidities, and be unvaccinated. Hospitalization occurred in 40 (0.66%) and 232 (0.96%) patients prescribed and not prescribed nirmatrelvir plus ritonavir, respectively. The adjusted risk ratio was 0.55 (95% confidence interval 0.38 to 0.80, p = 0.002). Observed risk reduction was greater among unvaccinated patients and obese patients. Limitations: Potential for residual confounding due to differential access and uptake of COVID-19 vaccines, diagnostics, and treatment. Conclusions: The overall risk of hospitalization was already low (<1%) following an outpatient diagnosis of COVID-19, but this risk was 45% lower among patients prescribed nirmatrelvir plus ritonavir. Funding: National Institutes of Health (P30 AI060354 and R01 CA236546).

Our attention is strongly influenced by reward learning. Stimuli previously associated with monetary reward have been shown to automatically capture attention in both behavioral and neurophysiological studies. Stimuli previously associated with positive social feedback similarly capture attention; however, it is unknown whether such social facilitation of attention relies on similar or dissociable neural systems. Here, we used the value-driven attentional capture paradigm in an fMRI study to identify the neural correlates of attention to stimuli previously associated with social reward. The results reveal learning-dependent priority signals in the contralateral visual cortex, posterior parietal cortex, and caudate tail, similar to studies using monetary reward. An additional priority signal was consistently evident in the right middle frontal gyrus (MFG). Our findings support the notion of a common neural mechanism for directing attention on the basis of selection history that generalizes across different types of reward.

What we direct our attention to is strongly influenced by both bottom-up and top-down processes. Moreover, the control of attention is biased by prior learning, such that attention is automatically captured by stimuli previously associated with either reward or threat. It is unknown whether value-oriented and threat-oriented mechanisms of selective information processing function independently of one another, or whether they interact with each other in the selection process. Here, we introduced the threat of electric shock into the value-driven attentional capture paradigm to examine whether the experience of threat influences the attention capturing quality of previously reward-associated stimuli. The results showed that value-driven attentional capture was blunted by the experience of threat. This contrasts with previous reports of threat potentiating attentional capture by physically salient stimuli, which we replicate here. Our findings demonstrate that threat selectively interferes with value-based but not salience-based attentional priority, consistent with a competitive relationship between value-based and threat-based information processing.

Anxiety is an adaptive neural state that promotes rapid responses under heightened vigilance when survival is threatened. Anxiety has consistently been found to potentiate the attentional processing of physically salient stimuli. However, a recent study demonstrated that a threat manipulation reduces attentional capture by reward-associated stimuli, suggesting a more complex relationship between anxiety and the control of attention. The mechanisms by which threat can reduce the distracting quality of stimuli are unknown. In this study, using functional magnetic resonance imaging (fMRI) on human subjects, we examined the neural correlates of attention to previously reward-associated stimuli with and without the threat of unpredictable electric shock. We replicate enhanced distractor-evoked activity throughout the value-driven attention network (VDAN) in addition to enhanced stimulus-evoked activity generally under threat. Importantly, these two factors interacted such that the representation of previously reward-associated distractors was particularly pronounced under threat. Our results from neuroimaging fit well with the principle of arousal-biased competition (ABC), although such effects are typically associated with behavioral measures of increased attention to stimuli that already possess elevated attentional priority. The findings of our study suggest that ABC can be leveraged to support more efficient ignoring of reward cues, revealing new insights into the functional significance of ABC as a mechanism of attentional control, and provide a mechanistic explanation of how threat reduces attention to irrelevant reward information.