Sall4 regulates posterior trunk mesoderm development by promoting mesodermal gene expression and repressing neural genes in the mesoderm.

The trunk axial skeleton develops from paraxial mesoderm cells. Our recent study demonstrated that conditional knockout of the stem cell factor Sall4 in mice by TCre caused tail truncation and a disorganized axial skeleton posterior to the lumbar level. Based on this phenotype, we hypothesized that, in addition to the previously reported role of Sall4 in neuromesodermal progenitors, Sall4 is involved in the development of the paraxial mesoderm tissue. Analysis of gene expression and SALL4 binding suggests that Sall4 directly or indirectly regulates genes involved in presomitic mesoderm differentiation, somite formation and somite differentiation. Furthermore, ATAC-seq in TCre; Sall4 mutant posterior trunk mesoderm shows that Sall4 knockout reduces chromatin accessibility. We found that Sall4-dependent open chromatin status drives activation and repression of WNT signaling activators and repressors, respectively, to promote WNT signaling. Moreover, footprinting analysis of ATAC-seq data suggests that Sall4-dependent chromatin accessibility facilitates CTCF binding, which contributes to the repression of neural genes within the mesoderm. This study unveils multiple mechanisms by which Sall4 regulates paraxial mesoderm development by directing activation of mesodermal genes and repression of neural genes.

Sall4 restricts glycolytic metabolism in limb buds through transcriptional regulation of glycolytic enzyme genes.

Recent studies illustrate the importance of regulation of cellular metabolism, especially glycolysis and pathways branching from glycolysis, during vertebrate embryo development. For example, glycolysis generates cellular energy ATP. Glucose carbons are also directed to the pentose phosphate pathway, which is needed to sustain anabolic processes in the rapidly growing embryos. However, our understanding of the exact status of glycolytic metabolism as well as genes that regulate glycolytic metabolism are still incomplete. Sall4 is a zinc finger transcription factor that is highly expressed in undifferentiated cells in developing mouse embryos, such as blastocysts and the post-implantation epiblast. TCre; Sall4 conditional knockout mouse embryos exhibit various defects in the posterior part of the body, including hindlimbs. Using transcriptomics approaches, we found that many genes encoding glycolytic enzymes are upregulated in the posterior trunk, including the hindlimb-forming region, of Sall4 conditional knockout mouse embryos. In situ hybridization and qRT-PCR also confirmed upregulation of expression of several glycolytic genes in hindlimb buds. A fraction of those genes are bound by SALL4 at the promoters, gene bodies or distantly-located regions, suggesting that Sall4 directly regulates expression of several glycolytic enzyme genes in hindlimb buds. To further gain insight into the metabolic status associated with the observed changes at the transcriptional level, we performed a comprehensive analysis of metabolite levels in limb buds in wild type and Sall4 conditional knockout embryos by high-resolution mass spectrometry. We found that the levels of metabolic intermediates of glycolysis are lower, but glycolytic end-products pyruvate and lactate did not exhibit differences in Sall4 conditional knockout hindlimb buds. The increased expression of glycolytic genes would have caused accelerated glycolytic flow, resulting in low levels of intermediates. This condition may have prevented intermediates from being re-directed to other pathways, such as the pentose phosphate pathway. Indeed, the change in glycolytic metabolite levels is associated with reduced levels of ATP and metabolites of the pentose phosphate pathway. To further test whether glycolysis regulates limb patterning downstream of Sall4, we conditionally inactivated Hk2, which encodes a rate-limiting enzyme gene in glycolysis and is regulated by Sall4. The TCre; Hk2 conditional knockout hindlimb exhibited a short femur, and a lack of tibia and anterior digits in hindlimbs, which are defects similarly found in the TCre; Sall4 conditional knockout. The similarity of skeletal defects in Sall4 mutants and Hk2 mutants suggests that regulation of glycolysis plays a role in hindlimb patterning. These data suggest that Sall4 restricts glycolysis in limb buds and contributes to patterning and regulation of glucose carbon flow during development of limb buds.

Current practices and perspectives on clerkship grading in obstetrics and gynecology.

BACKGROUND: Clerkship grades in obstetrics and gynecology play an increasingly important role in the competitive application process to residency programs. An analysis of clerkship grading practices has not been queried in the past 2 decades in our specialty. OBJECTIVE: This study aimed to investigate obstetrics and gynecology clerkship directors' practices and perspectives in grading. STUDY DESIGN: A 12-item electronic survey was developed and distributed to clerkship directors with active memberships in the Association of Professors of Gynecology and Obstetrics. RESULTS: A total of 174 of 236 clerkship directors responded to the survey (a response rate of 73.7%). Respondents reported various grading systems with the fewest (20/173 [11.6%]) using a 2-tiered or pass or fail system and the most (72/173 [41.6%]) using a 4-tiered system. Nearly one-third of clerkship directors (57/163 [35.0%]) used a National Board of Medical Examiners subject examination score threshold to achieve the highest grade. Approximately 45 of 151 clerkship directors (30.0%) had grading committees. Exactly half of the clerkship directors (87/174 [50.0%]) reported requiring unconscious bias training for faculty who assess students. In addition, some responded that students from groups underrepresented in medicine (50/173 [28.9%]) and introverted students (105/173 [60.7%]) received lower evaluations. Finally, 65 of 173 clerkship directors (37.6%) agreed that grades should be pass or fail. CONCLUSION: Considerable heterogeneity exists in obstetrics and gynecology clerkship directors' practices and perspectives in grading. Strategies to mitigate inequities and improve the reliability of grading include the elimination of a subject examination score threshold to achieve the highest grade and the implementation of both unconscious bias training and grading committees.

Changes and challenges in the residency application process in obstetrics and gynecology.

Faculty career advisors who guide applicants applying to obstetrics and gynecology residency programs need updated information and resources, given the constant changes and challenges to the residency application process. Initial changes included standardization of the application timeline and interview processes. More recent changes included the utilization of a standardized letter of evaluation, initiation of program signaling, second look visit guidelines, and updated sections in the Electronic Residency Application Service. Challenges in advising include the unmatched applicant and the applicant who is couples matching in the era of program signaling. Additional considerations include applying with the current status of reproductive health law restrictions and preparing for a new residency application platform. The Undergraduate Medical Education Committee of the Association of Professors of Gynecology and Obstetrics provides this updated guide of the prior 2021 resource for advisors to increase confidence in advising students, boost professional fulfillment with advising activities, and aid in satisfaction with advising resources. This guide covers the continuing challenges and future opportunities in the resident application process.

The Relationship Between Homeownership and Health by Race/Ethnicity Since the Foreclosure Crisis: California Health Interview Survey 2011-2018.

BACKGROUND: US housing policy places a high priority on homeownership, providing large homeowner subsidies that are justified in part by homeownership's purported health benefits. However, studies conducted before, during, and immediately after the 2007-2010 foreclosure crisis found that while homeownership is associated with better health-related outcomes for White households, that association is weaker or non-existent for African-American and Latinx households. It is not known whether those associations persist in the period since the foreclosure crisis changed the US homeownership landscape. OBJECTIVE: To examine the relationship between homeownership and health and whether that relationship differs by race/ethnicity in the period since the foreclosure crisis. DESIGN: We conducted a cross-sectional analysis of 8 waves (2011-2018) of the California Health Interview Survey (n = 143,854, response rate 42.3 to 47.5%). PARTICIPANTS: We included all US citizen respondents ages 18 and older. MAIN MEASURES: The primary predictor variable was housing tenure (homeownership or renting). The primary outcomes were self-rated health, psychological distress, number of health conditions, and delays in receiving necessary medical care and/or medications. KEY RESULTS: Compared to renting, homeownership is associated with lower rates of reporting fair or poor health (OR = 0.86, P < 0.001), fewer health conditions (incidence rate ratio = 0.95, P = 0.03), and fewer delays in receiving medical care (OR = 0.81, P < 0.001) and medication (OR = 0.78, P < 0.001) for the overall study population. Overall, race/ethnicity was not a significant moderator of these associations in the post-crisis period. CONCLUSIONS: Homeownership has the potential to provide significant health-related benefits to minoritized communities, but this potential may be threatened by practices of racial exclusion and predatory inclusion. Further study is needed to elucidate health-promoting mechanisms within homeownership as well as potential harms of specific homeownership-promoting policies to develop healthier, more equitable housing policy.

Primary health care utilization and hospital readmission in children with asthma: a multi-site linked data cohort study.

OBJECTIVES: To (1) describe primary health care utilization and (2) estimate the effect of primary care early follow-up, continuity, regularity, frequency, and long consultations on asthma hospital readmission, including secondary outcomes of emergency (ED) presentations, asthma preventer adherence, and use of rescue oral corticosteroids within 12 months. METHODS: An Australian multi-site cohort study of 767 children aged 3-18 years admitted with asthma between 2017 and 2018, followed up for at least 12 months with outcome and primary care exposure data obtained through linked administrative datasets. We estimated the effect of primary care utilization through a modified Poisson regression adjusting for child age, asthma severity, socioeconomic status and self-reported GP characteristics. RESULTS: The median number of general practitioner (GP) consultations, unique GPs and clinics visited was 9, 5, and 4, respectively. GP care was irregular and lacked continuity, only 152 (19.8%) children visited their usual GP on more than 60% of occasions. After adjusting for confounders, there was overall weak indication of effects due to any of the exposures. Increased frequency of GP visits was associated with reduced readmissions (4-14 visits associated with risk ratio of 0.71, 95% CI 0.50-1.00, p = 0.05) and ED presentations (>14 visits associated risk ratio 0.62, 95% CI 0.42-0.91, p = 0.02). CONCLUSIONS: Our study demonstrates that primary care use by children with asthma is often irregular and lacking in continuity. This highlights the importance of improving accessibility, consistency in care, and streamlining discharge communication from acute health services.

Modifiable factors associated with pediatric asthma readmissions: a multi-center linked cohort study.

OBJECTIVES: To (a) identify rates of hospital readmission and emergency department (ED) re-presentation for asthma within a 12-month period, (b) estimate the effects of modifiable hospital, general practitioner (GP) and home environmental factors on hospital readmission, ED re-presentations and rescue oral corticosteroid use. METHODS: We recruited 767 children aged 3-18 years who were admitted to 3 hospitals in Victoria, Australia between 2017 and 2018 with a validated diagnosis of asthma on chart review. Primary outcome was hospital readmission with asthma within 12 months of index admission. Secondary outcomes were ED re-presentation for asthma and rescue oral corticosteroid use. All outcomes were identified through linked administrative datasets. Their caregivers and 277 nominated GPs completed study surveys regarding the home environment and their usual asthma management practices respectively. RESULTS: Within 12 months of an index admission for asthma 263 (34.3%) participants were readmitted to a hospital for asthma, with participants between the ages of 3-5 years accounting for 69.2% of those readmitted. The estimated effect of GP reported guideline discordant care on the odds of readmission was OR 1.57, 95% CI 1.00-2.47, p = 0.05. None of the hospital or home environmental factors appeared to be associated with hospital readmissions. CONCLUSIONS: Hospital readmissions among Australian children with asthma are increasing, and linked datasets are important for objectively identifying the health services burden of asthma. They also confirm the important role of the GP in the management of pediatric asthma.

Oral minocycline for the treatment of retinitis pigmentosa-associated cystoid macular edema: results of a phase I/II clinical trial.

PURPOSE: The etiology of retinitis pigmentosa (RP)-associated cystoid macular edema (CME) has been related to retinal neuroinflammation and microglial activation. Minocycline, a drug FDA-approved for anti-microbial indications, also inhibits microglial activation and expression of inflammatory mediators. This study investigates the safety and efficacy of oral minocycline as primary treatment for RP-associated CME. METHODS: A single-center, prospective, open-label phase I/II clinical trial enrolled five participants with RP-associated CME. Participants had lead-in assessments prior to the initiation of oral minocycline 100 mg twice daily for 12 months. Main outcome variables included changes in best-corrected visual acuity (BCVA) and retinal central subfield thickness (CST) measured using spectral domain optical coherence tomography relative to mean of pre-treatment measurements. RESULTS: The study drug was well tolerated and not associated with any severe adverse events. No significant changes in mean BCVA from study baseline were noted in either the study eye (+ 0.7 ± 4.1 letters at 6 months, - 1.1 ± 1.7 letters at 12 months) or the qualifying fellow eye (- 0.3 ± 3.4 letters at 6 months, - 0.3 ± 4.6 letters at 12 months) (p > 0.05 for all comparisons). Mean percentage changes in CST from baseline however decreased progressively with treatment (decreases at 6 and 12 months: study eyes 3.9 and 9.8%; qualifying fellow eyes 1.4 and 7.7%). Considering all eyes (n = 10), mean percentage CST decrease at 6 and 12 months was 2.7 ± 9.5% (p = 0.39) and 8.7 ± 9.5% (p = 0.02) respectively. CONCLUSION: Oral minocycline administration over 12 months was associated with no significant changes in mean BCVA and a small but progressive decrease in mean CST. TRIAL REGISTRATION: NCT02140164 (05/2014).

Sall4 regulates neuromesodermal progenitors and their descendants during body elongation in mouse embryos.

Bi-potential neuromesodermal progenitors (NMPs) produce both neural and paraxial mesodermal progenitors in the trunk and tail during vertebrate body elongation. We show that Sall4, a pluripotency-related transcription factor gene, has multiple roles in regulating NMPs and their descendants in post-gastrulation mouse embryos. Sall4 deletion using TCre caused body/tail truncation, reminiscent of early depletion of NMPs, suggesting a role of Sall4 in NMP maintenance. This phenotype became significant at the time of the trunk-to-tail transition, suggesting that Sall4 maintenance of NMPs enables tail formation. Sall4 mutants exhibit expanded neural and reduced mesodermal tissues, indicating a role of Sall4 in NMP differentiation balance. Mechanistically, we show that Sall4 promotion of WNT/ß-catenin signaling contributes to NMP maintenance and differentiation balance. RNA-Seq and SALL4 ChIP-Seq analyses support the notion that Sall4 regulates both mesodermal and neural development. Furthermore, in the mesodermal compartment, genes regulating presomitic mesoderm differentiation are downregulated in Sall4 mutants. In the neural compartment, we show that differentiation of NMPs towards post-mitotic neuron is accelerated in Sall4 mutants. Our results collectively provide evidence supporting the role of Sall4 in regulating NMPs and their descendants.

Understanding caregiver perspectives on challenges and solutions to pediatric asthma care for children with a previous hospital admission: a multi-site qualitative study.

OBJECTIVE: Pediatric hospital admissions for asthma provide an opportunity to trigger a review of the current management with an aim of preventing readmissions. However, caregiver voices on how best to improve care are missing. METHODS: As part of a larger, mixed methods cohort study, we identified caregivers of children aged 3-18 years who had an index hospital admission to a tertiary pediatric, mixed adult and pediatric, or regional hospital in Victoria, Australia, between 1st September 2017 and 31st August 2018 with a discharge diagnosis of "Asthma" or "Wheeze" based on International Classification of Disease-10 coding. We conducted qualitative semi-structured interviews with a purposive sample of 39 caregivers. We used content analysis to identify themes from the data. RESULTS: Caregivers identified both challenges associated with asthma care for children with a previous hospital admission as well as solutions to improve care and potentially reduce readmissions. Key challenges included: unclear pathways for follow up care, inconsistent advice, lack of personalized management, delays in getting a diagnosis, delays in the prescription of a preventer medication, and difficulty accessing primary care during exacerbations. Follow up with an "asthma specialist", early access to a trial of preventer medication, personalized Written Asthma Action Plans and increased access to and quality of community-based asthma support services were identified as key solutions. CONCLUSIONS: Caregivers have identified several potential solutions that could be implemented to improve care and possibly reduce pediatric asthma hospital readmissions. The challenge now is to co-design, embed and evaluate these in healthcare systems.Supplemental data for this article can be accessed at publisher's website.

Assessing Concordance Across Nonprofit Hospitals' Public Reporting on Housing as a Community Health Need in the Era of the Affordable Care Act.

Although the Affordable Care Act requires nonprofit hospital organizations to report how they identify and invest in community health needs, the utility of mandated reporting documents for tracking investments in the social determinants of health has been questioned. Using public reporting documents and focusing on housing as a social determinant of health, we describe how nonprofit hospital organizations in 5 communities with the highest rates of homelessness document needs and investments related to housing on their Community Health Needs Assessments, Implementation Strategies, and Schedule H (990H) tax forms. Of 47 organizations, 55% identified housing as a health need, 36% described housing-related implementation strategies, and 26% reported relevant 990H spending. Overall concordance among identified needs, strategies, and spending was low, with only 15% of organizations addressing housing across all 3 documents. Regulatory reform could help promote accountability and transparency in organizations' efforts to address housing and other health-related social needs.

Magnetically Modulated Fluorescence of Nitrogen-Vacancy Centers in Nanodiamonds for Ultrasensitive Biomedical Analysis.

The negatively charged nitrogen-vacancy center in fluorescent nanodiamonds (FNDs) is a point defect with unique magneto-optical properties. It emits far-red fluorescence at ∼700 nm, and its intensity can be magnetically modulated with a depth of more than 10% at a field strength of 30 mT. We have closely examined this property and illustrated its practical use in biomedicine by applying a periodic, time-varying magnetic field to FNDs deposited on a surface or dispersed in a solution with a lock-in detection method. We achieved selective and sensitive detection of 100 nm FNDs on a nitrocellulose membrane at a particle density of 0.04 ng/mm2 (or ∼2 × 104 particles/mm2) and in an aqueous solution with a particle concentration of 1 ng/mL (or ∼1 fM) in 10 s as the detection limits. The utility and versatility of the technique were demonstrated with an application to background-free detection of FNDs as reporters for FND-based lateral flow immunoassays as well as selective quantification of FNDs in tissue digests for in vivo studies.

Unmet Medical Needs Among Adults Who Move due to Unaffordable Housing: California Health Interview Survey, 2011-2017.

BACKGROUND: Stable, affordable housing is an established determinant of health. As affordable housing shortages across the USA threaten to displace people from their homes, it is important to understand the implications of cost-related residential moves for healthcare access. OBJECTIVE: To examine the relationship between cost-related moves and unmet medical needs. DESIGN: We performed a cross-sectional analysis of 7 waves (2011-2017) of the California Health Interview Survey. PARTICIPANTS: We included all respondents ages 18 and older. MAIN MEASURES: The primary predictor variable was residential move history in the past 5 years (cost-related move, non-cost-related move, or no move). The primary outcome was unmet medical needs in the past year (necessary medications and/or medical care that were delayed or not received). KEY RESULTS: Our sample included 146,417 adults (42-47% response rate), representing a weighted population of 28,518,590. Overall, 20.3% of the sample reported unmet medical needs in the past year, and 4.9% reported a cost-related move in the past 5 years. In multivariable logistic regression models, adjusted risk of unmet medical needs increased for adults with both cost-related moves (aOR 1.38; 95% CI 1.19-1.59) and non-cost-related moves (aOR 1.17; 95% CI 1.09-1.26) compared to those with no moves. Among people who had moved, those with cost-related moves were more likely to report unmet medical needs compared to people with non-cost-related moves (p = 0.03). CONCLUSIONS: People who have moved due to unaffordable housing represent a population at increased risk for unmet medical needs. Policy makers seeking to improve population health should consider strategies to limit cost-related moves and to mitigate their adverse effects on healthcare access.

The Patient Care Ownership Scale: External Validation of an Instrument that Measures Patient Care Ownership Among Internal Medicine Trainees-a Multi-Institutional Study.

BACKGROUND: Patient care ownership improves accountability, clinical skills, and quality of patient care among resident physicians, but appears to be gradually eroding. Research is limited by the lack of a reliable, objective measure of ownership. OBJECTIVE: To validate the Patient Care Ownership Scale, an instrument that measures decision ownership among internal medicine residents. DESIGN: Multi-institutional, cross-sectional study using a 66-item, online survey that queried residents on ownership's key constructs (advocacy, responsibility, accountability, follow-through, knowledge, communication, initiative, continuity of care, autonomy, self-efficacy, and perceived ownership) as well as mood and burnout. PARTICIPANTS: Internal medicine residents in five geographically diverse residency programs completing an inpatient rotation. MAIN MEASURES: We performed exploratory and confirmatory factor analysis in two randomly split groups to evaluate for subscales and inform item reduction. We conducted reliability testing with Cronbach's α. We performed bivariate analyses to examine construct validity and identify correlates of ownership. KEY RESULTS: Of the 785 eligible residents, 625 completed the survey (80% response rate); we included responses from 563 in the analysis. We identified three factors corresponding to assertiveness, conscientiousness, and confidence or perceived competence. After iterative item reduction, the 13-item ownership scale demonstrated good reliability (Cronbach's α = 0.82). Convergent validity was supported by a significant association with perceived ownership (eliminated from the final scale) (r = 0.67, p < 0.001). There was a positive association between ownership and training level (p < 0.01) and prior experience in the intensive care unit (p < 0.001). There were significant, inverse relationships between ownership and self-defined burnout (r = - 0.24, p < 0.001), depression (r = - 0.22, p < 0.001), detachment (r = - 0.26, p < 0.001), and frustration (r = - 0.15, p = 0.02), and significant positive associations between ownership and feeling energetic (r = 0.29, p < 0.001), happy (r = 0.33, p < 0.001), and fulfilled (r = 0.34, p < 0.001). CONCLUSIONS: The Patient Care Ownership Scale is valid in diverse residency program settings. Medical educators and investigators can use our scale to assess interventions aimed at fostering ownership.

Reducing asthma hospitalisations in at-risk children: A systematic review.

AIM: To identify interventions that reduce hospitalisations and improve related outcomes in children at risk of asthma hospital admissions. METHODS: Medline, Embase, Pubmed and Cochrane Library search from January 2002 to April 2020. INCLUSION CRITERIA: randomised controlled trials of any intervention for children with asthma who are at risk of hospitalisations. OUTCOMES: hospitalisation (primary outcome), rescue oral corticosteroid use, school absences, quality of life and cost-effectiveness. RESULTS: Twelve randomised controlled trials were conducted with 2719 participants. Due to heterogeneity of interventions and reporting of outcomes, a meta-analysis was not conducted. Multi-modal interventions comprising caregiver education, reduction of home environmental allergens and regular follow-up reduced hospitalisations, rescue corticosteroid use and improved quality of life. Cost-effectiveness was not reported. Three studies scored an overall low risk of bias, and nine had some concerns. CONCLUSION: Multi-modal interventions can be effective in reducing hospitalisations, rescue oral corticosteroid use and quality of life but cost-effectiveness is unknown.

Mobile Health Apps for Pregnant Women: Systematic Search, Evaluation, and Analysis of Features.

BACKGROUND: Many pregnant women use the internet to obtain information about pregnancy and childbirth. Over 50% of pregnant women use pregnancy apps and must search through thousands of pregnancy or women's health-related apps available on app stores. The COVID-19 pandemic is changing how women receive prenatal care. Mobile health apps may help maintain women's satisfaction with their prenatal care. OBJECTIVE: Our objective is to identify pregnancy mobile apps and to evaluate the apps using a modified APPLICATIONS (app comprehensiveness, price, privacy, literature used, in-app purchases, connectivity, advertisements, text search field, images/videos, other special features, navigation ease, subjective presentation) scoring system. METHODS: A list of pregnancy apps was identified in the first 20 Google search results using the search term "pregnancy app." After excluding irrelevant, inaccurate, malfunctioning, or no longer available apps, all unique apps were downloaded and evaluated with the modified APPLICATIONS scoring system, which includes both objective and subjective criteria and evaluation of special features. RESULTS: A list of 57 unique pregnancy apps was generated. After 28 apps were excluded, the remaining 29 apps were evaluated, with a mean score of 9.4 points out of a maximum of 16. The highest scoring app scored 15 points. Over 60% (18/29) of apps did not have comprehensive information for every stage of pregnancy or did not contain all four desired components of pregnancy apps: health promotion/patient education, communication, health tracking, and notifications and reminders. Only 24% (7/29) of apps included a text search field, and only 28% (8/29) of apps cited literature. CONCLUSIONS: Our search yielded many high-scoring apps, but few contained all desired components and features. This list of identified and rated apps can lessen the burden on pregnant women and providers to find available apps on their own. Although health care providers should continue to vet apps before recommending them to patients, these findings also highlight that a Google search is a successful way for patients and providers to find useful and comprehensive pregnancy apps.

Longitudinal Study of Dark Adaptation as a Functional Outcome Measure for Age-Related Macular Degeneration.

PURPOSE: To investigate the natural history of dark adaptation (DA) function as measured by the change in rod intercept time (RIT) over 4 years and to correlate RIT change with age-related macular degeneration (AMD) severity. DESIGN: Longitudinal, single-center, observational study. PARTICIPANTS: A total of 77 participants aged ≥50 years with a range of AMD severities. METHODS: Participants each contributing a single study eye to the analysis were assigned into person-based AMD severity groups based on fundus characteristics (drusen, pigmentary changes, late AMD, and subretinal drusenoid deposits [SDDs]). The DA function was assessed in study eyes at baseline and 3, 6, 12, 18, 24, 36, and 48 months. Mean change in DA function over time was calculated using the slope of linear regression fits of longitudinal RIT data. Patient-reported responses on a Low Luminance Questionnaire (LLQ) were obtained at baseline and yearly. Nonparametric statistical testing was performed on all comparisons. MAIN OUTCOME MEASURE: The RIT, defined as the time taken after a photobleach for visual sensitivity to recover detection of a 5×10-3 cd/m2 stimulus (a decrease of 3 log units), was monitored in study eyes over 4 years, and the mean rate of change was computed. RESULTS: Longitudinal analysis of 65 study eyes followed on the standard testing protocol (mean age, 71±9.3 years; 49% were female) revealed that higher rates of RIT prolongation were correlated with AMD severity group assignment at baseline (P = 0.026) and with severity group assignments at year 4 (P = 0.0011). Study eyes that developed SDD during follow-up demonstrated higher rates of RIT prolongation relative to those that did not (P < 0.0001). Overall, higher rates of RIT prolongation were significantly correlated with greater 4-year decreases in LLQ scores (total mean score, P = 0.0032). CONCLUSIONS: Longitudinal decline in DA function, which correlated with patient-reported functional deficits, was accelerated in eyes with greater AMD severity and especially in eyes with SDD both at baseline and at 4 years. The RIT prolongation as a measure of changing DA function may be a functional outcome measure in AMD clinical studies.

LONGITUDINAL CHANGES IN EYES WITH HYDROXYCHLOROQUINE RETINAL TOXICITY.

PURPOSE: To characterize functional and structural changes in hydroxychloroquine (HCQ) retinal toxicity after drug cessation. METHODS: Twenty-two patients (91% female; mean age 58.7 ± 11.4 years; mean duration of HCQ treatment 161.1 ± 90 months; mean dose 5.9 ± 1.9 mg/kg) with detected HCQ retinopathy were monitored for 6 months to 82 months after HCQ cessation with multimodal imaging including spectral domain optical coherence tomography and fundus autofluorescence imaging at 488 nm (standard) and 787 nm (near-infrared autofluorescence). Tests of visual function including visual acuity, Humphrey visual field testing, and multifocal electroretinography (mfERG) were performed. Study eyes were categorized into four separate severity stages by qualitative grading of spectral domain optical coherence tomography macular scans taken at the time of HCQ cessation. Changes in outcome measures between drug cessation and last follow-up visit were computed and compared between eyes of different severity stages. RESULTS: Study eyes (n = 44) were categorized based on optical coherence tomography criteria into: Stage 1 (subtle changes confined to parafoveal region; n = 14), Stage 2 (clear localized changes in parafovea; n = 17), Stage 3 (extensive parafoveal changes; n = 7), and Stage 4 (foveal involvement, n = 6). Visual acuity measurements across follow-up were stable in Stage 1 and Stage 2 eyes but decreased significantly in Stage 3 and 4 eyes. Humphrey visual field measures were also stable in stages 1 and 2 but deteriorated in Stage 3 eyes. mfERG testing demonstrated significant improvement in the R1/R2 ratio after HCQ cessation in Stage 1 eyes (mean change = -0.86 ± 0.79, P = 0.03) but did not change significantly in eyes of higher stages. Decreases in macular thickness in ≥1 of 9 Early Treatment Diabetic Retinopathy Study subfields on spectral domain optical coherence tomography were found in eyes of all stages, with Stage 2 eyes demonstrating thinning in most subfields (eight of nine subfields). In eyes with a measurable central foveal ellipsoid zone band island (9 of 17 Stage 2 eyes and 7 of 7 Stage 3 eyes), progressive decrease in the foveal ellipsoid zone band length was observed in 6 of 9 (67%) Stage 2 eyes and 6 of 7 (86%) Stage 3 eyes. Changes indicative of progressing retinopathy were detected in 17% of Stage 1 eyes, 46% of Stage 2 eyes, and 43% of Stage 3 eyes on standard fundus autofluorescence imaging, and in 17% of Stage 1 eyes, 38% of Stage 2 eyes, and 14% of Stage 3 eyes on near-infrared autofluorescence imaging. CONCLUSION: Eyes with detected HCQ retinopathy do not demonstrate general stability in retinal structure and function after HCQ cessation but instead demonstrate a range of changes during follow-up whose magnitudes correlate with retinopathy severity at the time of cessation. After cessation, eyes with only subtle and localized retinopathy were mostly stable and may show some functional improvement, whereas more severely affected eyes continued to progress. These findings provide evidence that early detection and prompt cessation in HCQ retinopathy may be needed to arrest retinopathy progression and to optimize long-term outcomes.

Renal Artery Stenosis and Congestive Heart Failure: What Do We Really Know?

PURPOSE OF REVIEW: Congestive heart failure (CHF) is a major cause of morbidity, mortality, and health care expenditure. Although the role of renal artery stenosis (RAS) in CHF has been known, there are a number of areas of uncertainty. RECENT FINDINGS: The prevalence of RAS in subjects with CHF varies from 15 to 54% depending on the cohort studied and the diagnostic modality used to identify RAS. In subjects with CHF, the presence of RAS is associated with worse renal function and a higher risk for mortality during long-term follow-up. There are many unanswered questions regarding the role of RAS in subjects with CHF. This review highlights those questions and helps to set the research agenda in this area.

Arterial Structure and Function Following Viral Myocarditis.

Acute viral myocarditis is an uncommon inflammatory disease of the myocardium. Little is known about the long-term cardiovascular risk for individuals who have recovered from the acute illness. We compared intermediate vascular phenotypes relating to arterial structure (aortic and carotid intima-media thickness) and function (pulse wave velocity, carotid arterial distensibility and compliance) in 15 participants, a median of 9.1 years after an episode of acute viral myocarditis, and 45 control participants. Following adjustment for age, sex and triglycerides, there were no differences in mean and maximum carotid and aortic intima-media thickness, pulse wave velocity, carotid artery distensibility and compliance between viral myocarditis participants and controls. In conclusion, we found no evidence of changes in intermediate vascular phenotypes indicative of increased cardiovascular risk in individuals who had fully recovered from viral myocarditis.