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Most longitudinal studies of healthcare workers' mental health during COVID-19 end in 2021. We examined trends in hospital workers eight times, ending in 2023. A cohort of healthcare workers at one organization was surveyed at 3-month intervals until Spring 2022 and re-surveyed in Spring 2023 using validated measures of common mental health problems. Of 538 workers in the original cohort, 289 (54%) completed the eighth survey. Repeated-measures ANOVA revealed significant changes in psychological distress (F = 7.4, P < .001), posttraumatic symptoms (F = 14.1, P < .001), and three dimensions of burnout: emotional exhaustion (F = 5.7, P < .001), depersonalization (F = 2.7, P = .01), and personal accomplishment (F = 2.8, P = .008). Over time, psychological distress and depersonalization increased, posttraumatic symptoms and personal accomplishment decreased, and emotional exhaustion fluctuated significantly without net change. Most measures did not improve significantly in the year prior to the declaration of the pandemic's end. The lack of improvement in psychological distress, emotional exhaustion, depersonalization, and personal accomplishment during the period in which COVID-19 case rates declined and public health measures were relaxed is a concerning indication of the chronicity of the impact of the pandemic on healthcare workers., (© 2024. The Author(s).)

Significance: Adaptive optics fluorescence lifetime ophthalmoscopy (AOFLIO) provides a label-free approach to observe functional and molecular changes at cellular scale in vivo . Adding multispectral capabilities improves interpretation of lifetime fluctuations due to individual fluorophores in the retinal pigment epithelium (RPE)., Aim: To quantify the cellular-scale changes in autofluorescence with age and eccentricity due to variations in lipofuscin, melanin, and melanolipofuscin in RPE using multispectral AOFLIO., Approach: AOFLIO was performed on six subjects at seven eccentricities. Four imaging channels ( λ ex / λ em ) were used: 473/SSC, 473/LSC, 532/LSC, and 765/NIR. Cells were segmented and the timing signals of each pixel in a cell were combined into a single histogram, which were then used to compute the lifetime and phasor parameters. An ANOVA was performed to investigate eccentricity and spectral effects on each parameter., Results: A repeatability analysis revealed < 11.8 % change in lifetime parameters in repeat visits for 532/LSC. The 765/NIR and 532/LSC had eccentricity and age effects similar to previous reports. The 473/LSC had a change in eccentricity with mean lifetime and a phasor component. Both the 473/LSC and 473/SSC had changes in eccentricity in the short lifetime component and its relative contribution. The 473/SSC had no trend in eccentricity in phasor. The comparison across the four channels showed differences in lifetime and phasor parameters., Conclusions: Multispectral AOFLIO can provide a more comprehensive picture of changes with age and eccentricity. These results indicate that cell segmentation has the potential to allow investigations in low-photon scenarios such as in older or diseased subjects with the co-capture of an NIR channel (such as 765/NIR) with the desired spectral channel. This work represents the first multispectral, cellular-scale fluorescence lifetime comparison in vivo in the human RPE and may be a useful method for tracking diseases., (© 2024 The Authors.)

This study undertook an exploration of how Adaptive Mentoring Networks focusing on chronic pain, substance use disorders and mental health were supporting primary care providers to engage in compassionate care. The study utilised the Cole-King & Gilbert Compassionate Care Framework to guide qualitative semi-structured interviews of participants in two Adaptive Mentoring Networks in Ontario, Canada. Fourteen physician participants were interviewed including five mentors (psychiatrists) and nine mentees (family physicians) in the Networks. The Cole-King & Gilbert Framework helped provide specific insights on how these mentoring networks were affecting the attributes of compassion such as motivation, distress-tolerance, non-judgement, empathy, sympathy , and sensitivity . The findings of this study focused on the role of compassionate provider communities and the development of skills and attitudes related to compassion that were both being supported in these networks. Adaptive Mentoring Networks can support primary care providers to offer compassionate care to patients with chronic pain, substance use disorders, and mental health challenges. This study also highlights how these networks had an impact on provider resiliency, and compassion fatigue. There is promising evidence these networks can support the "quadruple aim" for healthcare systems (improve patient and provider experience, health of populations and value for money) and play a role in addressing the healthcare provider burnout and associated health workforce crisis., Competing Interests: No potential conflict of interest was reported by the author(s)., (© 2024 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.)

Purpose: To demonstrate the first near-infrared adaptive optics fluorescence lifetime imaging ophthalmoscopy (NIR-AOFLIO) measurements in vivo of the human retinal pigment epithelial (RPE) cellular mosaic and to visualize lifetime changes at different retinal eccentricities., Methods: NIR reflectance and autofluorescence were captured using a custom adaptive optics scanning light ophthalmoscope in 10 healthy subjects (23-64 years old) at seven eccentricities and in two eyes with retinal abnormalities. Repeatability was assessed across two visits up to 8 weeks apart. Endogenous retinal fluorophores and hydrophobic whole retinal extracts of Abca4-/- pigmented and albino mice were imaged to probe the fluorescence origin of NIR-AOFLIO., Results: The RPE mosaic was resolved at all locations in five of seven younger subjects (<35 years old). The mean lifetime across near-peripheral regions (8° and 12°) was longer compared to near-foveal regions (0° and 2°). Repeatability across two visits showed moderate to excellent correlation (intraclass correlation: 0.88 [τm], 0.75 [τ1], 0.65 [τ2], 0.98 [a1]). The mean lifetime across drusen-containing eyes was longer than in age-matched healthy eyes. Fluorescence was observed in only the extracts from pigmented Abca4-/- mouse., Conclusions: NIR-AOFLIO was repeatable and allowed visualization of the RPE cellular mosaic. An observed signal in only the pigmented mouse extract infers the fluorescence signal originates predominantly from melanin. Variations observed across the retina with intermediate age-related macular degeneration suggest NIR-AOFLIO may act as a functional measure of a biomarker for in vivo monitoring of early alterations in retinal health.

Purpose: Fluorescence lifetime ophthalmoscopy (FLIO) is an emerging clinical modality that could provide biomarkers of retinal health beyond fluorescence intensity. Adaptive optics (AO) ophthalmoscopy provides the confocality to measure fluorescence lifetime (FL) primarily from the retinal pigment epithelium (RPE) whereas clinical FLIO has greater influence from fluorophores in the inner retina and lens. Adaptive optics fluorescence lifetime ophthalmoscopy (AOFLIO) measures of FL in vivo could provide insight into RPE health at different stages of disease. In this study, we assess changes in pentosan polysulfate sodium (PPS) toxicity, a recently described toxicity that has clinical findings similar to advanced age-related macular degeneration., Methods: AOFLIO was performed on three subjects with PPS toxicity (57-67 years old) and six age-matched controls (50-64 years old). FL was analyzed with a double exponential decay curve fit and with phasor analysis. Regions of interest (ROIs) were subcategorized based on retinal features on optical coherence tomography (OCT) and compared to age-matched controls., Results: Twelve ROIs from PPS toxicity subjects met the threshold for analysis by curve fitting and 15 ROIs met the threshold for phasor analysis. Subjects with PPS toxicity had prolonged FL compared to age-matched controls. ROIs of RPE degeneration had the longest FLs, with individual pixels extending longer than 900 ps., Conclusions: Our study shows evidence that AOFLIO can provide meaningful information in outer retinal disease beyond what is obtainable from fluorescence intensity alone. More studies are needed to determine the prognostic value of AOFLIO.

Purpose: RPE disruption with light exposures below or close to the American National Standards Institute (ANSI) photochemical maximum permissible exposure (MPE) have been observed, but these findings were limited to two wavelengths. We have extended the measurements across the visible spectrum., Methods: Retinal imaging with fluorescence adaptive optics scanning light ophthalmoscopy (FAOSLO) was used to provide an in vivo measure of RPE disruption at a cellular level. The threshold retinal radiant exposures (RREs) for RPE disruption (localized detectable change in the fluorescence image) were determined at 460, 476, 488, 530, 543, 561, 594, 632, and 671 nm (uniform 0.5° square exposure) using multiples locations in 4 macaques., Results: FAOSLO is sensitive in detecting RPE disruption. The visible light action spectrum dependence for RPE disruption with continuous wave (CW) extended field exposures was determined. It has a shallower slope than the current ANSI blue-light hazard MPE. At all wavelengths beyond 530 nm, the disruption threshold is below the ANSI blue-light hazard MPE. There is reciprocity of exposure irradiance and duration for exposures at 460 and 594 nm., Conclusions: We measured with FAOSLO the action spectrum dependence for photochemical RPE disruption across the visible light spectrum. Using this in vivo measure of phototoxicity provided by FAOSLO, we find that thresholds are lower than previously measured. The wavelength dependence in our data is considerably shallower than the spectral dependence of the traditional ANSI blue-light hazard, emphasizing the need for more caution with increasing wavelength than expected.

Objective: We tested if automated Personalized Self-Awareness Feedback (PSAF) from an online survey or in-person Peer Resilience Champion support (PRC) reduced emotional exhaustion among hospital workers during the COVID-19 pandemic., Method: Among a single cohort of participating staff from one hospital organization, each intervention was evaluated against a control condition with repeated measures of emotional exhaustion at quarterly intervals for 18 months. PSAF was tested in a randomized controlled trial compared to a no-feedback condition. PRC was tested in a group-randomized stepped-wedge design, comparing individual-level emotional exhaustion before and after availability of the intervention. Main and interactive effects on emotional exhaustion were tested in a linear mixed model., Results: Among 538 staff, there was a small but significant beneficial effect of PSAF over time (p = .01); the difference at individual timepoints was only significant at timepoint three (month six). The effect of PRC over time was non-significant with a trend in the opposite direction to a treatment effect (p = .06)., Conclusions: In a longitudinal assessment, automated feedback about psychological characteristics buffered emotional exhaustion significantly at six months, whereas in-person peer support did not. Providing automated feedback is not resource-intensive and merits further investigation as a method of support., (Copyright © 2023. Published by Elsevier Inc.)

Background: Previous research suggests that moral distress contributes to burnout in nurses and other healthcare workers. We hypothesized that burnout both contributed to moral distress and was amplified by moral distress for hospital workers in the COVID-19 pandemic. This study also aimed to test if moral distress was related to considering leaving one's job., Methods: A cohort of 213 hospital workers completed quarterly surveys at six time-points over fifteen months that included validated measures of three dimensions of professional burnout and moral distress. Moral distress was categorized as minimal, medium, or high. Analyses using linear and ordinal regression models tested the association between burnout and other variables at Time 1 (T1), moral distress at Time 3 (T3), and burnout and considering leaving one's job at Time 6 (T6)., Results: Moral distress was highest in nurses. Job type (nurse (co-efficient 1.99, p < .001); other healthcare professional (co-efficient 1.44, p < .001); non-professional staff with close patient contact (reference group)) and burnout-depersonalization (co-efficient 0.32, p < .001) measured at T1 accounted for an estimated 45% of the variance in moral distress at T3. Moral distress at T3 predicted burnout-depersonalization (Beta = 0.34, p < .001) and burnout-emotional exhaustion (Beta = 0.38, p < .008) at T6, and was significantly associated with considering leaving one's job or healthcare., Conclusion: Aspects of burnout that were associated with experiencing greater moral distress occurred both prior to and following moral distress, consistent with the hypotheses that burnout both amplifies moral distress and is increased by moral distress. This potential vicious circle, in addition to an association between moral distress and considering leaving one's job, suggests that interventions for moral distress may help mitigate a workforce that is both depleted and burdened with burnout., (© 2023. The Author(s).)

Background: The term resilience is used to refer to multiple related phenomena, including: (i) characteristics that promote adaptation to stressful circumstances, (ii) withstanding stress, and (iii) bouncing back quickly. There is little evidence to understand how these components of resilience are related to one another. Skills-based adaptive characteristics that can respond to training (as opposed to personality traits) have been proposed to include living authentically, finding work that aligns with purpose and values, maintaining perspective in the face of adversity, managing stress, interacting cooperatively, staying healthy, and building supportive networks. While these characteristics can be measured at a single time-point, observing responses to stress (withstanding and bouncing back) require multiple, longitudinal observations. This study's aim is to determine the relationship between these three aspects of resilience in hospital workers during the prolonged, severe stress of the COVID-19 pandemic., Methods: We conducted a longitudinal survey of a cohort of 538 hospital workers at seven time-points between the fall of 2020 and the spring of 2022. The survey included a baseline measurement of skills-based adaptive characteristics and repeated measures of adverse outcomes (burnout, psychological distress, and posttraumatic symptoms). Mixed effects linear regression assessed the relationship between baseline adaptive characteristics and the subsequent course of adverse outcomes., Results: The results showed significant main effects of adaptive characteristics and of time on each adverse outcome (all p < .001). The size of the effect of adaptive characteristics on outcomes was clinically significant. There was no significant relationship between adaptive characteristics and the rate of change of adverse outcomes over time (i.e., no contribution of these characteristics to bouncing back)., Conclusions: We conclude that training aimed at improving adaptive skills may help individuals to withstand prolonged, extreme occupational stress. However, the speed of recovery from the effects of stress depends on other factors, which may be organizational or environmental., (© 2023. The Author(s).)

Background: Following 14 years of civil war in Liberia, war exposure, gender-based violence, and extreme poverty have been identified as key challenges affecting the mental and sexual health of young pregnant women and the health of their unborn children. Despite ongoing efforts to rebuild the country's healthcare infrastructure, empirical and culturally tailored interventions to address the consequences of war are severely limited. To address these concerns, we developed Project POWER (Progressing Our Well-being, Emotions, and Relationships), a mindfulness-infused, cognitive-behavioral intervention for young adult pregnant women. This study sought to 1) assess the feasibility and acceptability of POWER and 2) determine the preliminary efficacy of POWER for improving mental and sexual health outcomes among Liberian war-exposed young adult pregnant women., Methods: Eighty-seven women aged 18-25 were recruited from three catchment areas in Monrovia, Liberia to participate in a two-condition, pre-post design quasi-experimental pilot trial. Participants were allocated to the intervention (POWER) or the control condition (a health education program) based on where they resided relative to the catchment areas. Each condition completed a ten-session program delivered over 5-weeks. Feasibility and acceptability of POWER were examined using program logs (e.g., the number of participants screened and enrolled, facilitator satisfaction, etc.) and data from an end-of-program exit interview. The preliminary efficacy of POWER on mental and sexual health outcomes was assessed using repeated measures ANOVA with time and condition as factors., Results: Analyses provided preliminary support for the feasibility and acceptability of POWER. Participants attended an average of 8.99 sessions out of 10 and practiced material outside the sessions at least 2.77 times per week. Women in both conditions showed significant reductions in the level of prenatal distress (baseline, M = 16.84, 3-month assessment, M = 12.24), severity of post-traumatic stress disorder (PTSD) symptoms (baseline, M = 11.97, 3-month assessment, M = 9.79),), and the number of transactional sexual behaviors (baseline, M = 1.37, 3-month assessment, M = .94) over time. Participants who received POWER showed significant reductions in the frequency of depressive symptoms (baseline, M = 5.09, 3-month assessment, M = 2.63) over women in the control condition., Conclusions: Findings suggest that POWER may be a feasible and acceptable intervention to promote mental and sexual health for young adult pregnant women in Liberia. However, fully powered clinical trials are still needed to determine the efficacy and effectiveness of POWER before recommending its use on a larger scale in Liberia., (© 2023. The Author(s).)

In the retina, several molecules involved in metabolism, the visual cycle, and other roles exhibit intrinsic fluorescence. The overall properties of retinal fluorescence depend on changes to the composition of these molecules and their environmental interactions due to transient functional shifts, especially in disease. This behooves the understanding of the origins and deviations of these properties within the multilayered retina at high lateral and axial resolution. Of particular interest is the fluorescence lifetime, a potential biomarker of function and disease independent of fluorescence intensity that can be measured in the retina with adaptive optics fluorescence lifetime ophthalmoscopy (AOFLIO). This work demonstrates the utility of the phasor method of analysis, an alternate approach to traditional multiexponential fitting, to evaluate photoreceptor two-photon excited AOFLIO data and separate them based on functional differences. Phasor analysis on fluorescence lifetime decay data allowed the repeatable segregation of S from M/L cones, likely from differences in functional or metabolic demands. Furthermore, it is possible to track the lifetime changes in S cones after photodamage. Phasor analysis increases the sensitivity of AOFLIO to functional differences between cells and has the potential to improve our understanding of pathways involved in normal and diseased conditions at the cellular scale throughout the retina., (© 2023. The Author(s).)

Background: The stress response includes appraisal of the threat and one's resources, coping (including interpersonal interactions), distress, and recovery. Relationships between patterns of adult attachment and stress response have received little study in the context of prolonged, severe occupational stress, limiting knowledge about how attachment patterns contribute to occupational burnout and recovery., Aim: This study aimed to assess the relationship of adult attachment to aspects of the stress response over time in hospital workers during a pandemic., Methods: This study included 538 hospital workers within a general and a rehabilitation hospital in Toronto, Canada between September 2020 and November 2021. Half, selected at random, completed validated measures of adult attachment, resilience, self-efficacy, coping, interpersonal problems, and various stress outcomes. Attachment insecurity severity was calculated as the vector addition of attachment anxiety and attachment avoidance. Correlations between these measures were determined at individual time-points and temporal patterns of adverse outcomes using repeated-measures ANOVA., Results: All correlations between measures of attachment and resilience or self-efficacy were significant and moderately strong ( r  = .30-.48), while most correlations with coping strategies were weak (<.20). Attachment avoidance was more strongly correlated with interpersonal problems related to being cold, whereas attachment anxiety was more strongly correlated with problems related to being intrusive, overly-nurturant, exploitable and non-assertive. Attachment insecurity severity was moderately correlated with every dimension of interpersonal problems. A significant main effect of each attachment measure on each stress outcome was found (effects sizes: .18-.26). Attachment insecurity severity was significantly associated with outcome X time interactions for burnout, consistent with greater resilience for those with lower attachment insecurity., Conclusions: Severity of insecure attachment was correlated with each measure of self-appraisal, interpersonal problems, and all measured stress outcomes. Severity of attachment insecurity performed well as a summary attachment measure. Greater security is associated with patterns of recovery that indicate resilience., Competing Interests: No potential conflict of interest was reported by the author(s)., (© 2022 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.)

Childhood adversity alters the relational world of the child and inhibits the development of secure attachment bonds. The purpose of this article is to survey recent evidence that attachment insecurity has the potential to impair physical health throughout the lifespan. It is proposed that attachment insecurity contributes to disease risk through a range of mechanisms which include (1) disturbances in arousal and recovery within physiological systems that respond to stress; (2) physiological links between the mediators of social relationships, stress, and immunity; (3) links between relationship style and various health behaviors; and (4) disease risk factors that serve as external regulators of dysphoric affect, such as nicotine and alcohol. The evidence for these mechanisms, particularly the evidence that has accumulated since the model was first proposed in 2000, is presented and discussed.

Background: The mental health effects of healthcare work during the COVID-19 pandemic have been substantial, but it is not known how long they will persist. This study aimed to determine if hospital workers' burnout and psychological distress increased monotonically over 1 year, during which waves of case numbers and hospitalizations waxed and waned, or followed some other pattern., Methods: A prospective longitudinal survey was conducted at four time-points over 1 year in a cohort of 538 hospital workers and learners, which included validated measures of burnout (emotional exhaustion scale of Maslach Burnout Inventory) and psychological distress (K6). Repeated measures ANOVA tested changes over time and differences between subjects by occupational role, age and ethnic group. The direction and magnitude of changes over time were investigated by plotting rates of high scores (using cut-offs) at each time-point compared to case rates of COVID-19 in the city in which the study took place., Results: There were significant effects of occupational role (F = 11.2, p < .001) and age (F = 12.8, p < .001) on emotional exhaustion. The rate of high burnout was highest in nurses, followed by other healthcare professionals, other clinical staff, and lowest in non-clinical staff. Peak rates of high burnout occurred at the second or third measurement point for each occupational group, with lower rates at the fourth measurement point. Similarly to the results for emotional exhaustion, rates of high psychological distress peaked at the spring 2021 measurement point for most occupational groups and were higher in nurses than in other healthcare professionals., Conclusions: Neither emotional exhaustion nor psychological distress was rising monotonically. Burnout and psychological distress were consistently related to occupational role and were highest in nurses. Although emotional exhaustion improved as the case rate of COVID-19 decreased, rates of high emotional exhaustion in nurses and other healthcare professionals remained higher than was typically measured in hospital-based healthcare workers prior to the pandemic. Ongoing monitoring of healthcare workers' mental health is warranted. Organizational and individual interventions to support healthcare workers continue to be important., (© 2022. The Author(s).)

The intrinsic fluorescence properties of lipofuscin - naturally occurring granules that accumulate in the retinal pigment epithelium - are a potential biomarker for the health of the eye. A new modality is described here which combines adaptive optics technology with fluorescence lifetime detection, allowing for the investigation of functional and compositional differences within the eye and between subjects. This new adaptive optics fluorescence lifetime imaging ophthalmoscope was demonstrated in 6 subjects. Repeated measurements between visits had a minimum intraclass correlation coefficient of 0.59 Although the light levels were well below maximum permissible exposures, the safety of the imaging paradigm was tested using clinical measures; no concerns were raised. This new technology allows for in vivo adaptive optics fluorescence lifetime imaging of the human RPE mosaic., Competing Interests: KP: University of Rochester (P), QY: University of Rochester (P), JJH: University of Rochester (P)., (© 2022 Optica Publishing Group under the terms of the Optica Open Access Publishing Agreement.)

Fluorescence lifetime imaging has demonstrated promise as a quantitative measure of cell health. Adaptive optics two-photon excited fluorescence (TPEF) ophthalmoscopy enables excitation of intrinsic retinal fluorophores involved in cellular metabolism and the visual cycle, providing in vivo visualization of retinal structure and function at the cellular scale. Combining these technologies revealed that macaque cones had a significantly longer mean TPEF lifetime than rods at 730 nm excitation. At 900 nm excitation, macaque photoreceptors had a significantly longer mean TPEF lifetime than the retinal pigment epithelium layer. AOFLIO can measure the fluorescence lifetime of intrinsic retinal fluorophores on a cellular scale, revealing differences in lifetime between retinal cell classes., Competing Interests: SW, JF: IDEX Health & Science (E). JJH: University of Rochester (P)., (© 2021 Optica Publishing Group under the terms of the Optica Open Access Publishing Agreement.)

Childhood abuse, neglect, and loss are common in psychiatric patients, and the relationship between childhood adversity and adult mental illness is well known. However, beyond diagnoses that are specifically trauma-related, such as posttraumatic stress disorder, there has been little research on how childhood adversity contributes to complex presentations that require more intensive treatment. We examined the relationship between childhood adversity and other contributors to clinical complexity in adult outpatients seeking mental health assessment. In a cross-sectional study, patients completed standard measures of psychological distress and functional impairment. Psychiatrists completed an inventory of clinical complexity, which included childhood abuse, neglect, and loss. Of 4,903 patients seen over 15 months, 1,315 (27%) both consented to research and had the measure of complexity completed. Childhood abuse or neglect was identified in 474 (36.0%) and significant childhood loss in 236 (17.9%). Correcting for multiple comparisons and controlling for psychiatric diagnosis, age, and sex, patients with childhood abuse or neglect were significantly more likely to also have 11 of 31 other indices of clinical complexity, with odds ratios ranging from 1.7 to 5.0. Both childhood abuse or neglect and childhood loss were associated with greater overall complexity (i.e., more indices of complexity, χ 2 = 136 and 38 respectively, each p < .001). Childhood abuse and neglect (but not childhood loss) were significantly associated with psychological distress (Kessler Psychological Distress Scale [K10] score, F = 6.2, p = .01) and disability (World Health Organization Disability Assessment Scale 2.0 [WHODAS 2.0] score, F = 5.0, p = .03). Childhood abuse and neglect were associated with many characteristics that contribute to clinical complexity, and thus to suboptimal outcomes to standard, guideline-based care. Screening may alert psychiatrists to the need for intensive, patient-centered, and trauma-informed treatments. Identifying childhood adversity as a common antecedent of complexity may facilitate developing transdiagnostic programs that specifically target sources of complexity.

Objective: The COVID-19 pandemic is expected to have a sustained psychological impact on healthcare workers. We assessed individual characteristics related to changes in emotional exhaustion and psychological distress over time., Methods: A survey of diverse hospital staff measured emotional exhaustion (Maslach Burnout Inventory) and psychological distress (K6) in Fall 2020 (T 1 ) and Winter 2021 (T 2 ). Relationships between occupational, personal, and psychological variables were assessed using repeated measures ANOVA., Results: Of 539 T 1 participants, 484 (89.9%) completed T 2 . Emotional exhaustion differed by occupational role (F = 7.3, p < .001; greatest in nurses), with increases over time in those with children (F = 8.5, p = .004) or elders (F = 4.0, p = .047). Psychological distress was inversely related to pandemic self-efficacy (F = 110.0, p < .001), with increases over time in those with children (F = 7.0, p = .008). Severe emotional exhaustion occurred in 41.1% (95%CI 36.6-45.4) at T 1 and 49.8% (95%CI 45.4-54.2) at T 2 (McNemar test p < .001). Psychological distress occurred in 9.7% (95%CI 7.1-12.2) at T 1 and 11.6% (95%CI 8.8-14.4) at T 2 (McNemar test p = .33)., Conclusions: Healthcare workers' psychological burden is high and rising as the pandemic persists. Ongoing support is warranted, especially for nurses and those with children and elders at home. Modifiable protective factors, restorative sleep and self-efficacy, merit special attention., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)

Stem cell-based transplantation therapies offer hope for currently untreatable retinal degenerations; however, preclinical progress has been largely confined to rodent models. Here, we describe an experimental platform for accelerating photoreceptor replacement therapy in the nonhuman primate, which has a visual system much more similar to the human. We deployed fluorescence adaptive optics scanning light ophthalmoscopy (FAOSLO) to noninvasively track transplanted photoreceptor precursors over time at cellular resolution in the living macaque. Fluorescently labeled photoreceptors generated from a CRX +/tdTomato human embryonic stem cell (hESC) reporter line were delivered subretinally to macaques with normal retinas and following selective ablation of host photoreceptors using an ultrafast laser. The fluorescent reporter together with FAOSLO allowed transplanted photoreceptor precursor survival, migration, and neurite formation to be monitored over time in vivo. Histological examination suggested migration of photoreceptor precursors to the outer plexiform layer and potential synapse formation in ablated areas in the macaque eye., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Purpose: The development of new approaches to human vision restoration could be greatly accelerated with the use of nonhuman primate models; however, there is a paucity of primate models of outer retina degeneration with good spatial localization. To limit ablation to the photoreceptors, we developed a new approach that uses a near-infrared ultrafast laser, focused using adaptive optics, to concentrate light in a small focal volume within the retina., Methods: In the eyes of eight anesthetized macaques, 187 locations were exposed to laser powers from 50 to 210 mW. Laser exposure locations were monitored for up to 18 months using fluorescein angiography (FA), optical coherence tomography (OCT), scanning laser ophthalmoscopy (SLO), adaptive optics scanning laser ophthalmoscope (AOSLO) reflectance imaging, two-photon excited fluorescence (TPEF) ophthalmoscopy, histology, and calcium responses of retinal ganglion cells., Results: This method produced localized photoreceptor loss with minimal axial spread of damage to other retinal layers, verified by in-vivo structural imaging and histologic examination, although in some cases evidence of altered autofluorescence was found in the adjacent retinal pigment epithelium (RPE). Functional assessment using blood flow imaging of the retinal plexus and calcium imaging of the response of ganglion cells above the photoreceptor loss shows that inner retinal circuitry was preserved., Conclusions: Although different from a genetic model of retinal degeneration, this model of localized photoreceptor loss may provide a useful testbed for vision restoration studies in nonhuman primates., Translational Relevance: With this model, a variety of vision restoration methods can be tested in the non-human primate., Competing Interests: Disclosure: K.R. Dhakal, None; S. Walters, None; J.E. McGregor, None; C. Schwarz, None; J.M. Strazzeri, None; E. Aboualizadeh, None; B. Bateman, None; K.R. Huxlin, None; J.J. Hunter, None; D.R. Williams, Canon Inc. (R), P; W.H. Merigan, None, (Copyright 2020 The Authors.)

Background: Adverse Childhood Experiences (ACEs) are common and associated with many illnesses. Most physicians do not routinely screen for ACEs. We aimed to determine if screening is related to knowledge or medical specialty, and to assess perceived barriers., Methods: Physicians in Ontario, Canada completed an online survey in 2018-2019. Data were analyzed in 2019., Results: Participants were 89 family physicians, 46 psychiatrists and 48 other specialists. Participants screened for ACEs "never or not usually" (N = 58, 31.7%), "when indicated" (N = 67, 36.6%), "routinely" (N = 50, 27.3%) or "other" (N = 5, 2.7%). Screening was strongly associated with specialty (Chi 2  = 181.0, p < .001). The modal responses were: family physicians - "when indicated" (66.3%), psychiatrists - "routinely" (91.3%), and other specialists - "never or not usually" (77.1%). Screening was not related to knowledge of prevalence of ACEs, or of the link between ACEs and mental health, but was significantly associated with knowing that ACEs are associated with physical health. Knowing that ACEs are linked to stroke, ischemic heart disease, COPD, and diabetes predicted greater screening (Chi 2 15.0-17.7, each p ≤ .001). The most prevalent perceived barriers to screening were lack of mental health resources (59.0%), lack of time (59.0%), concern about causing distress (49.7%) and lack of confidence (43.7%)., Conclusions: Enhancing knowledge about ACEs' negative influence on physical illness may increase screening. Efforts to promote screening should address concerns that screening is time-consuming and will increase referrals to mental health resources. Education should focus on increasing confidence with screening and with managing patient distress.

Purpose: Chemotherapy side effects diminish quality of life and can lead to treatment delay. Nausea and vomiting can occur prior to chemotherapy because of classical conditioning. We studied the effects of 20-minute behavioral interventions, administered by oncology nurses, of higher intensity (mindfulness relaxation-MR) or lower intensity (relaxing music-RM), on anticipatory nausea and vomiting (ANV)., Patients and Methods: Patients undergoing chemotherapy for solid tumors were randomized to MR (N = 160), RM (N = 159), or standard care SC (N = 155). Subjects were mostly female (91.8%) and white (86.1%) with breast cancer (85%). Most patients had early stage disease (Stage I: 26%; II: 52.9%; III: 19%; IV: 0.1%). Anticipatory nausea and vomiting were assessed at the midpoint and end of the chemotherapy course using the Morrow Assessment of Nausea and Emesis (MANE)., Results: Compared to SC, there was reduced anticipatory nausea at the midpoint of chemotherapy in those receiving MR (OR 0.44, 95% CI 0.20-0.93) and RM (OR 0.40, 95% CI 0.20-0.93), controlling for age, sex, cancer stage, and emetogenic level of chemotherapy. There was no difference between treatment groups in anticipatory nausea at the end of chemotherapy or in anticipatory vomiting and postchemotherapy nausea and vomiting at either time point., Conclusion: A brief nurse-delivered behavioral intervention can reduce midpoint ANV associated with chemotherapy., (© 2020 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Background: Adverse childhood experiences (ACEs) are associated with risk of poor adult health, including cardiometabolic diseases. Little is known about the correlates of ACEs for adults who have already developed cardiometabolic diseases, or who are at elevated risk., Methods: Adult primary care patients with cardiometabolic disease (hypertension, diabetes, stroke, angina, myocardial infarction, coronary artery bypass graft, angioplasty) or with a risk factor (obesity, smoking, high cholesterol, family history) were surveyed regarding ACEs, psychological distress, attachment insecurity, quality of life, behavior change goals, stages of change, and attitudes toward potential prevention strategies., Results: Of 387 eligible patients, 74% completed the ACEs survey. Exposure to ACEs was reported by 174 participants (61%). Controlling for age, gender, relationship status and income, number of ACEs was associated with psychological distress (F = 3.7, p = .01), quality of life (F = 8.9, p = .001), attachment anxiety (F = 3.4, p = .02), drinking alcohol most days (F = 4.0, p = .008) and smoking (F = 2.7, p = .04). Greater ACE exposure was associated with less likelihood of selecting diet or physical activity as a behavior change goal (linear-by-linear association p = .009). Stage of change was not associated with ACEs. ACEs exposure was not related to preferred resources for behavior change., Conclusions: ACEs are common among patients at cardiometabolic risk and are related to quality of life, psychological factors that influence cardiometabolic outcomes and behavior change goals. ACEs should be taken into account when managing cardiometabolic risk in family medicine.

Retinal function has long been studied with psychophysical methods in humans, whereas detailed functional studies of vision have been conducted mostly in animals owing to the invasive nature of physiological approaches. There are exceptions to this generalization, for example, the electroretinogram. This review examines exciting recent advances using in vivo retinal imaging to understand the function of retinal neurons. In some cases, the methods have existed for years and are still being optimized. In others, new methods such as optophysiology are revealing novel patterns of retinal function in animal models that have the potential to change our understanding of the functional capacity of the retina. Together, the advances in retinal imaging mark an important milestone that shifts attention away from anatomy alone and begins to probe the function of healthy and diseased eyes.

Progress is needed in developing animal models of photoreceptor degeneration and evaluating such models with longitudinal, noninvasive techniques. We employ confocal scanning laser ophthalmoscopy, optical coherence tomography (OCT) and high-resolution retinal imaging to noninvasively observe the retina of non-human primates with induced photoreceptor degeneration. Photoreceptors were imaged at the single-cell scale in three modalities of adaptive optics scanning light ophthalmoscopy: traditional confocal reflectance, indicative of waveguiding; a non-confocal offset aperture technique visualizing scattered light; and two-photon excited fluorescence, the time-varying signal of which, at 730 nm excitation, is representative of visual cycle function. Assessment of photoreceptor structure and function using these imaging modalities revealed a reduction in retinoid production in cone photoreceptor outer segments while inner segments appeared to remain present. Histology of one retina confirmed loss of outer segments and the presence of intact inner segments. This unique combination of imaging modalities can provide essential, clinically-relevant information on both the structural integrity and function of photoreceptors to not only validate models of photoreceptor degeneration but potentially evaluate the efficacy of future cell and gene-based therapies for vision restoration., Competing Interests: DRW: University of Rochester (P).

Purpose: Infrared ultrashort pulse lasers are becoming increasingly popular for applications in the living eye. However, safety standards are not yet well established. Here we investigate retinal damage close to threshold for this pulse regime in the living macaque eye., Methods: Retinal radiant exposures between 214 and 856 J/cm2 were delivered to the photoreceptor layer with an ultrashort pulse laser (730 nm, 55 fs, 80 MHz) through a two-photon adaptive optics scanning light ophthalmoscope. Retinal exposures were followed up immediately after and over several weeks with high-resolution reflectance and two-photon excited fluorescence ophthalmoscopy, providing structural and functional information., Results: Retinal radiant exposures of 856 J/cm2 resulted in permanent S cone damage. Immediately after the exposure, the affected cones emitted about 2.6 times less two-photon excited fluorescence (TPEF) and showed an altered TPEF time course. Several weeks after the initial exposure, S cone outer and inner segments had disappeared. The space was filled by rods in the peripheral retina and cones near the fovea., Conclusion: Interestingly, S cones are the receptor class with the lowest sensitivity in the near-infrared but are known to be particularly susceptible to ultraviolet and blue light. This effect of selective S cone damage after intense infrared ultrashort pulse laser exposure may be due to nonlinear absorption and distinct from pure thermal and mechanical mechanisms often associated with ultrashort pulse lasers.

Background: Standardized measurement of physical and mental health is useful for identification of health problems. Personalized feedback of the results can influence health behavior, and treatment outcomes can be improved by monitoring feedback over time. However, few resources are available that are free for users, provide feedback from validated measurement instruments, and measure a wide range of health domains., Objective: This study aimed to develop an internet self-assessment resource that fills the identified gap and collects data to generate and test hypotheses about health, to test its feasibility, and to describe the characteristics of its users., Methods: The Self-Assessment Kiosk was built using validated health measurement instruments and implemented on a commercial internet survey platform. Data regarding usage and the characteristics of users were collected over 54 weeks. The rate of accrual of new users, popularity of measurement domains, frequency with which multiple domains were selected for measurement, and characteristics of users who chose particular questionnaires were assessed., Results: Of the 1435 visits, 441 (30.73%) were visiting for the first time, completed at least 1 measure, indicated that their responses were truthful, and consented to research. Growth in the number of users over time was approximately linear. Users were skewed toward old age and higher income and education. Most (53.9%, 234/434) reported at least 1 medical condition. The median number of questionnaires completed was 5. Internal reliability of most measures was good (Cronbach alpha>.70), with lower reliability for some subscales of coping (self-distraction alpha=.35, venting alpha=.50, acceptance alpha=.51) and personality (agreeableness alpha=.46, openness alpha=.45). The popular questionnaires measured depression (61.0%, 269/441), anxiety (60.5%, 267/441), attachment insecurity (54.2%, 239/441), and coping (46.0%, 203/441). Demographic characteristics somewhat influenced choice of instruments, accounting for <9% of the variance in this choice. Mean depression and anxiety scores were intermediate between previously studied populations with and without mental illness. Modeling to estimate the sample size required to study relationships between variables suggested that the accrual of users required to study the relationship between 3 variables was 2 to 3 times greater than that required to study a single variable., Conclusions: The value of the Self-Assessment Kiosk to users and the feasibility of providing this resource are supported by the steady accumulation of new users over time. The Self-Assessment Kiosk database can be interrogated to understand the relationships between health variables. Users who select particular instruments tend to have scores that are higher than those found in the general population, indicating that instruments are more likely to be selected when they are salient. Self-selection bias limits generalizability and needs to be taken into account when using the Self-Assessment Kiosk database for research. Ethical issues that were considered in developing and implementing the Self-Assessment Kiosk are discussed., (©Robert G Maunder, Jonathan J Hunter. Originally published in JMIR Mental Health (http://mental.jmir.org), 16.05.2018.)

Background: The study aimed to unravel vineyard row orientation (NS, EW, NE-SW, NW-SE) and grape ripeness level (23, 25, 27 °Balling) implications for grape and wine composition and sensory properties/style (non-wooded/wooded wines) of Vitis vinifera L. cv. Shiraz (rootstock 101-14 Mgt)., Results: Soluble solid/titratable acidity ratios were lowest for EW, whereas warmer canopy sides (NW, N, NE) advanced grape ripening. Skin anthocyanins and phenolics generally decreased with ripening. NW-SE rows and S, SE, E and NE canopy sides showed highest skin total anthocyanins and phenolics. Wine total anthocyanins and phenolics increased with grape ripening; EW had lower values. Wine phenolic contents differed between canopy sides; N, NE, E and SE tended higher. Wine sensory profiles increased with grape ripening. For non-wooded wines, NW-SE and NE-SW row orientations generally resulted in highest scores, followed by NS. For EW rows, the N side presented better wines. Wood addition enhanced specific sensory descriptor perceptions., Conclusion: A large collection of wine styles surfaced in the same vineyard and terroir, increasing options to contribute positively to sustainable products. The study generated globally applicable, novel information vital for unlocking and valorising terroir/site potential for grape and wine chemical composition and wine sensory/style properties. © 2017 Society of Chemical Industry., (© 2017 Society of Chemical Industry.)

Objective: An attachment model was used to understand how maternal sensitivity and adverse childhood experiences are related to somatization., Methods: We examined maternal sensitivity at 6 and 18 months and somatization at 5 years in 292 children in a longitudinal cohort study. We next examined attachment insecurity and somatization (health anxiety, physical symptoms) in four adult cohorts: healthy primary care patients (AC1, n = 67), ulcerative colitis in remission (AC2, n = 100), hospital workers (AC3, n = 157), and paramedics (AC4, n = 188). Recall of childhood adversity was measured in AC3 and AC4. Attachment insecurity was tested as a possible mediator between childhood adversity and somatization in AC3 and AC4., Results: In children, there was a significant negative relationship between maternal sensitivity at 18 months and somatization at age 5 years (B = -3.52, standard error = 1.16, t = -3.02, p = .003), whereas maternal sensitivity at 6 months had no significant relationship. In adults, there were consistent, significant relationships between attachment insecurity and somatization, with the strongest findings for attachment anxiety and health anxiety (AC1, β = 0.51; AC2, β = 0.43). There was a significant indirect effect of childhood adversity on physical symptoms mediated by attachment anxiety in AC3 and AC4., Conclusions: Deficits in maternal sensitivity at 18 months of age are related to the emergence of somatization by age 5 years. Adult attachment insecurity is related to somatization. Insecure attachment may partially mediate the relationship between early adversity and somatization.

In vivo cellular scale fluorescence lifetime imaging of the mouse retina has the potential to be a sensitive marker of retinal cell health. In this study, we demonstrate fluorescence lifetime imaging of extrinsic fluorophores using adaptive optics fluorescence lifetime imaging ophthalmoscopy (AOFLIO). We recorded AOFLIO images of inner retinal cells labeled with enhanced green fluorescent protein (EGFP) and capillaries labeled with fluorescein. We demonstrate that AOFLIO can be used to differentiate spectrally overlapping fluorophores in the retina. With further refinements, AOFLIO could be used to assess retinal health in early stages of degeneration by utilizing lifetime-based sensors or even fluorophores native to the retina.

Although imaging of the living retina with adaptive optics scanning light ophthalmoscopy (AOSLO) provides microscopic access to individual cells, such as photoreceptors, retinal pigment epithelial cells, and blood cells in the retinal vasculature, other important cell classes, such as retinal ganglion cells, have proven much more challenging to image. The near transparency of inner retinal cells is advantageous for vision, as light must pass through them to reach the photoreceptors, but it has prevented them from being directly imaged in vivo. Here we show that the individual somas of neurons within the retinal ganglion cell (RGC) layer can be imaged with a modification of confocal AOSLO, in both monkeys and humans. Human images of RGC layer neurons did not match the quality of monkey images for several reasons, including safety concerns that limited the light levels permissible for human imaging. We also show that the same technique applied to the photoreceptor layer can resolve ambiguity about cone survival in age-related macular degeneration. The capability to noninvasively image RGC layer neurons in the living eye may one day allow for a better understanding of diseases, such as glaucoma, and accelerate the development of therapeutic strategies that aim to protect these cells. This method may also prove useful for imaging other structures, such as neurons in the brain., Competing Interests: E.A.R. has filed patent applications on aspects of the technology described in this manuscript. D.R.W. and Q.Y. have patents on aspects of the technology described in this manuscript. Some of D.R.W.’s patents have been licensed by Canon, Inc.

Purpose: Two-photon excited fluorescence (TPEF) imaging has potential as a functional tool for tracking visual pigment regeneration in the living eye. Previous studies have shown that all-trans-retinol is likely the chief source of time-varying TPEF from photoreceptors. Endogenous TPEF from retinol could provide the specificity desired for tracking the visual cycle. However, in vivo characterization of native retinol kinetics is complicated by visual stimulation from the imaging beam. We have developed an imaging scheme for overcoming these challenges and monitored the formation and clearance of retinol., Methods: Three macaques were imaged by using an in vivo two-photon ophthalmoscope. Endogenous TPEF was excited at 730 nm and recorded through the eye's pupil for more than 90 seconds. Two-photon excited fluorescence increased with onset of light and plateaued within 40 seconds, at which point, brief incremental stimuli were delivered at 561 nm. The responses of rods to stimulation were analyzed by using first-order kinetics., Results: Two-photon excited fluorescence resulting from retinol production corresponded to the fraction of rhodopsin bleached. The photosensitivity of rhodopsin was estimated to be 6.88 ± 5.50 log scotopic troland. The rate of retinol clearance depended on intensity of incremental stimulation. Clearance was faster for stronger stimuli and time constants ranged from 50 to 300 seconds., Conclusions: This study demonstrates a method for rapidly measuring the rate of clearance of retinol in vivo. Moreover, TPEF generated due to retinol can be used as a measure of rhodopsin depletion, similar to densitometry. This enhances the utility of two-photon ophthalmoscopy as a technique for evaluating the visual cycle in the living eye.

Two-photon ophthalmoscopy has potential for in vivo assessment of function of normal and diseased retina. However, light safety of the sub-100 fs laser typically used is a major concern and safety standards are not well established. To test the feasibility of safe in vivo two-photon excitation fluorescence (TPEF) imaging of photoreceptors in humans, we examined the effects of ultrashort pulsed light and the required light levels with a variety of clinical and high resolution imaging methods in macaques. The only measure that revealed a significant effect due to exposure to pulsed light within existing safety standards was infrared autofluorescence (IRAF) intensity. No other structural or functional alterations were detected by other imaging techniques for any of the exposures. Photoreceptors and retinal pigment epithelium appeared normal in adaptive optics images. No effect of repeated exposures on TPEF time course was detected, suggesting that visual cycle function was maintained. If IRAF reduction is hazardous, it is the only hurdle to applying two-photon retinal imaging in humans. To date, no harmful effects of IRAF reduction have been detected.

Objectives: To develop and assess the validity of measures of patients' attachment-related perceptions of experiences with healthcare providers (HCPs)., Setting: Online survey., Participants: 181 people provided consent and 119 completed the survey (66%). Most participants were women (80%)., Primary and Secondary Outcome Measures: Questions were developed to assess possible attachment functions served by an HCP and patients' attachment-related attitudes towards an HCP. Scales were constructed based on exploratory factor analysis. Measures of adult attachment, therapeutic alliance, perceived HCP characteristics and health utilisation were used to validate scales., Results: Possible safe haven and secure base functions served by HCPs were strongly endorsed. A model with good fit (root mean square error of approximation=0.056) yielded 3 factors: 'HCP experienced as supportive and safe' (SUPPORT, α=0.94), 'HCP experienced as aversive' (AVERSE, α=0.86) and 'more and closer contact wanted with HCP' (WANT, α=0.85). SUPPORT was correlated with positive HCP characteristics and not with attachment insecurity. AVERSE was inversely correlated with positive HCP attributes and correlated with attachment insecurity. WANT was unrelated to positive HCP attributes, but correlated with attachment insecurity. Frequency of HCP contact was related to WANT (Kruskal-Wallis=21.9, p<0.001) and SUPPORT (Kruskal-Wallis=13.2, p=0.02), but not to AVERSE (Kruskal-Wallis=1.7, p=0.89)., Conclusions: Patients attribute attachment functions of secure base and safe haven to HCPs. SUPPORT is related to positive appraisal of HCP characteristics; AVERSE is associated with discomfort in the HCP relationship that is related with perceived HCP characteristics and patients' insecure attachment; WANT is associated with unmet needs for connection with an HCP related to insecure attachment, but not to perceived HCP characteristics. These scales may be useful in studying the application of attachment theory to the HCP-patient relationship., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/)

Purpose: Although extrinsic fluorophores can be introduced to label specific cell types in the retina, endogenous fluorophores, such as NAD(P)H, FAD, collagen, and others, are present in all retinal layers. These molecules are a potential source of optical contrast and can enable noninvasive visualization of all cellular layers. We used a two-photon fluorescence adaptive optics scanning light ophthalmoscope (TPF-AOSLO) to explore the native autofluorescence of various cell classes spanning several layers in the unlabeled retina of a living primate eye., Methods: Three macaques were imaged on separate occasions using a custom TPF-AOSLO. Two-photon fluorescence was evoked by pulsed light at 730 and 920 nm excitation wavelengths, while fluorescence emission was collected in the visible range from several retinal layers and different locations. Backscattered light was recorded simultaneously in confocal modality and images were postprocessed to remove eye motion., Results: All retinal layers yielded two-photon signals and the heterogeneous distribution of fluorophores provided optical contrast. Several structural features were observed, such as autofluorescence from vessel walls, Müller cell processes in the nerve fibers, mosaics of cells in the ganglion cell and other nuclear layers of the inner retina, as well as photoreceptor and RPE layers in the outer retina., Conclusions: This in vivo survey of two-photon autofluorescence throughout the primate retina demonstrates a wider variety of structural detail in the living eye than is available through conventional imaging methods, and broadens the use of two-photon imaging of normal and diseased eyes.

Purpose: The retinoid cycle maintains vision by regenerating bleached visual pigment through metabolic events, the kinetics of which have been difficult to characterize in vivo. Two-photon fluorescence excitation has been used previously to track autofluorescence directly from retinoids and pyridines in the visual cycle in mouse and frog retinas, but the mechanisms of the retinoid cycle are not well understood in primates., Methods: We developed a two-photon fluorescence adaptive optics scanning light ophthalmoscope dedicated to in vivo imaging in anesthetized macaques. Using pulsed light at 730 nm, two-photon fluorescence was captured from rods and cones during light and dark adaptation through the eye's pupil., Results: The fluorescence from rods and cones increased with light exposure but at different rates. During dark adaptation, autofluorescence declined, with cone autofluorescence decreasing approximately 4 times faster than from rods. Rates of autofluorescence decrease in rods and cones were approximately 4 times faster than their respective rates of photopigment regeneration. Also, subsets of sparsely distributed cones were less fluorescent than their neighbors immediately following bleach at 565 nm and they were comparable with the S cone mosaic in density and distribution., Conclusions: Although other molecules could be contributing, we posit that these fluorescence changes are mediated by products of the retinoid cycle. In vivo two-photon ophthalmoscopy provides a way to monitor noninvasively stages of the retinoid cycle that were previously inaccessible in the living primate eye. This can be used to assess objectively photoreceptor function in normal and diseased retinas.

Importance: Stargardt disease (STGD1) is characterized by macular atrophy and flecks in the retinal pigment epithelium. The causative ABCA4 gene encodes a protein localizing to photoreceptor outer segments. The pathologic steps by which ABCA4 mutations lead to clinically detectable retinal pigment epithelium changes remain unclear. We investigated early STGD1 using adaptive optics scanning light ophthalmoscopy., Observations: Adaptive optics scanning light ophthalmoscopy imaging of 2 brothers with early STGD1 and their unaffected parents was compared with conventional imaging. Cone and rod spacing were increased in both patients (P < .001) with a dark cone appearance. No foveal cones were detected in the older brother. In the younger brother, foveal cones were enlarged with low density (peak cone density, 48.3 × 103 cones/mm2). The ratio of cone to rod spacing was increased in both patients, with greater divergence from normal approaching the foveal center, indicating that cone loss predominates centrally and rod loss increases peripherally. Both parents had normal photoreceptor mosaics. Genetic testing revealed 3 disease-causing mutations., Conclusions and Relevance: This study provides in vivo images of rods and cones in STGD1. Although the primary clinical features of STGD1 are retinal pigment epithelial lesions, adaptive optics scanning light ophthalmoscopy reveals increased cone and rod spacing in areas that appear normal in conventional images, suggesting that photoreceptor loss precedes clinically detectable retinal pigment epithelial disease in STGD1.

Anthocyanin and mechanical properties were evaluated on Shiraz grapes, picked from both sides of North-South and East-West vineyard row orientations at two harvest dates. Wines were made from each combination. The evaluation and evolution of crushed skin mechanical properties during maceration-fermentation, as also affected by grape ripeness, are shown for the first time. No significant differences in anthocyanin content were found in the grapes between the two vineyard row orientations. However, a significant decrease in anthocyanins and berry skin break force (also referred as skin hardness or strength) was found between the two harvest dates. During maceration, a reduction in the crushed berry skin break force of more than 15% occurred. The intact berries and macerated skins showed similarity in skin break energy values. The anthocyanin profile of the grapes and of the wines prominently displayed malvidin forms, changed mainly by the ripeness level of the grapes., (Copyright © 2014 Elsevier Ltd. All rights reserved.)