Imaging Modalities for Assessing the Vascular Component of Diabetic Retinal Disease: Review and Consensus for an Updated Staging System.

Purpose: To review the evidence for imaging modalities in assessing the vascular component of diabetic retinal disease (DRD), to inform updates to the DRD staging system. Design: Standardized narrative review of the literature by an international expert workgroup, as part of the DRD Staging System Update Effort, a project of the Mary Tyler Moore Vision Initiative. Overall, there were 6 workgroups: Vascular Retina, Neural Retina, Systemic Health, Basic and Cellular Mechanisms, Visual Function, and Quality of Life. Participants: The Vascular Retina workgroup, including 16 participants from 4 countries. Methods: Literature review was conducted using standardized evidence grids for 5 modalities: standard color fundus photography (CFP), widefield color photography (WFCP), standard fluorescein angiography (FA), widefield FA (WFFA), and OCT angiography (OCTA). Summary levels of evidence were determined on a validated scale from I (highest) to V (lowest). Five virtual workshops were held for discussion and consensus. Main Outcome Measures: Level of evidence for each modality. Results: Levels of evidence for standard CFP, WFCP, standard FA, WFFA, and OCTA were I, II, I, I, and II respectively. Traditional vascular lesions on standard CFP should continue to be included in an updated staging system, but more studies are required before they can be used in posttreatment eyes. Widefield color photographs can be used for severity grading within the area covered by standard CFPs, although these gradings may not be directly interchangeable with each other. Evaluation of the peripheral retina on WFCP can be considered, but the method of grading needs to be clarified and validated. Standard FA and WFFA provide independent prognostic value, but the need for dye administration should be considered. OCT angiography has significant potential for inclusion in the DRD staging system, but various barriers need to be addressed first. Conclusions: This study provides evidence-based recommendations on the utility of various imaging modalities for assessment of the vascular component of DRD, which can inform future updates to the DRD staging system. Although new imaging modalities offer a wealth of information, there are still major gaps and unmet research needs that need to be addressed before this potential can be realized. Financial Disclosures: Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Report From the 2022 Mary Tyler Moore Vision Initiative Diabetic Retinal Disease Clinical Endpoints Workshop.

The Mary Tyler Moore Vision Initiative Diabetic Retinal Disease (DRD) Clinical Endpoints Workshop was held on October 22, 2022 to accelerate progress toward establishment of useful clinical and research endpoints and development of new therapeutics that have important relevance across the full spectrum of DRD pathology. More than 90 patient representatives, clinicians, scientists, funding and regulatory agencies, diagnostic, therapeutic and biotech industry representatives discussed the needs for new diagnostic and therapeutic approaches to prevent and restore retinal neurovascular unit integrity. Phase I of the MTM Vision Initiative plans, notably updating the DRD staging system and severity scale, establishing a human ocular biorepository and resource, and clinical endpoints and biomarker development and validation, was emphasized.

Frontiers in diabetic retinal disease.

Diabetic retinal disease (DRD) remains a leading cause of vision loss and blindness globally. Although treatments can be effective when given at vision-threatening stages of DRD, there is a lack of knowledge about the earliest mechanisms leading to the development of clinically evident DRD. Recent advances in retinal imaging methods for patients with diabetes allow a more precise and granular characterization of the different stages of DRD than is provided by the classic Diabetic Retinopathy Severity Scale based on fundus photographs. In addition, recent clinical studies have yielded more information on how to adjust blood glucose levels, lipid levels and blood pressure to minimize the risk of DRD. Given the incomplete success of current therapies, there is a critical need for better understanding of the mechanisms underlying DRD and novel treatment targets that address the entire neurovascular retina. Moreover, the causes for interindividual variability in the development of DRD in patients with similar glycemic history and other metabolic factors are not yet clarified either. Finally, greater focus on patients' experience with visual disabilities and treatment effects should be addressed in research in this field.

It is time for a moonshot to find "Cures" for diabetic retinal disease.

Diabetic retinal disease (DRD), the most common complication of diabetes and a leading cause of blindness in working age individuals, is now understood to be a form of sensory neuropathy or neurovascular degeneration. Current treatments are focused on advanced vision-threatening disease and a single molecular target, vascular endothelial growth factor, has an approved therapy. We trace the evolution of understanding of DRD pathogenesis, identify new approaches to clinical assessment, trials infrastructure and design, and target identification to accelerate selection and evaluation of new therapeutics that will speed development of potentially curative interventions. Critically, the "Restoring Vision Moonshot" framework will address gaps in knowledge to be filled to achieve the goal of restoring sight and preventing vision loss in persons with diabetes.

For the love of reading: Recreational reading reduces psychological distress in college students and autonomous motivation is the key.

OBJECTIVE: Reading is often cited as beneficial for one's mental health, but the research on this topic is limited. The goal of the present research was to examine whether recreational reading is beneficial for mental health during college, and to determine what motivates recreational reading. PARTICIPANTS: Participants were 231 university students from a large Canadian University. Methods: A longitudinal design was employed and students completed online surveys on recreational reading, motivation, psychological distress and need frustration at the beginning and end of the academic year. Results: Recreational reading was associated with reduced psychological distress over the school year. Recreational reading seemed to buffer against the frustration of one's basic psychological needs which led to improved mental health over the school year. Students who were more autonomously motivated reported reading more books recreationally. Conclusion: Recreational reading is a simple and cost-effective tool to help college students cope with mental health problems.

Autonomous motivation and support flourishes for individuals higher in collaborative personality factors: Agreeableness, assisted autonomy striving, and secure attachment.

INTRODUCTION: Individuals who strive autonomously for their goals, and who perceive autonomy supportive environments are more successful during goal pursuit. What dispositional factors predict autonomy flourishing during goal pursuit? METHODS: Four longitudinal studies were conducted over an 8-month academic year, and university students (Ntotal  = 1,544) completed surveys on motivation, support, and personality. Structural equation models were created using Mplus software to test whether collaborative personality factors were related to growth in autonomous motivation and autonomy support. RESULTS: All three distinct collaborative personality factors, trait Agreeableness, assisted autonomy striving, and secure parental attachment, were related to increases in autonomous motivation over the academic year. Conscientiousness, assisted autonomy, and secure attachment were related to increases in perceived autonomy support. A higher order latent collaborative traits factor, composed of Agreeableness, assisted autonomy, and secure attachment was found to be related to increased autonomous motivation and support over the academic year and resulted in increased goal progress. CONCLUSION: These results suggest that individuals higher in collaborative personality factors experience growth in personal autonomy during goal pursuit. Future research is needed to determine how to promote collaboration in goal pursuit to further help individuals successfully strive for their goals.

Precision medicine in human heart modeling : Perspectives, challenges, and opportunities.

Precision medicine is a new frontier in healthcare that uses scientific methods to customize medical treatment to the individual genes, anatomy, physiology, and lifestyle of each person. In cardiovascular health, precision medicine has emerged as a promising paradigm to enable cost-effective solutions that improve quality of life and reduce mortality rates. However, the exact role in precision medicine for human heart modeling has not yet been fully explored. Here, we discuss the challenges and opportunities for personalized human heart simulations, from diagnosis to device design, treatment planning, and prognosis. With a view toward personalization, we map out the history of anatomic, physical, and constitutive human heart models throughout the past three decades. We illustrate recent human heart modeling in electrophysiology, cardiac mechanics, and fluid dynamics and highlight clinically relevant applications of these models for drug development, pacing lead failure, heart failure, ventricular assist devices, edge-to-edge repair, and annuloplasty. With a view toward translational medicine, we provide a clinical perspective on virtual imaging trials and a regulatory perspective on medical device innovation. We show that precision medicine in human heart modeling does not necessarily require a fully personalized, high-resolution whole heart model with an entire personalized medical history. Instead, we advocate for creating personalized models out of population-based libraries with geometric, biological, physical, and clinical information by morphing between clinical data and medical histories from cohorts of patients using machine learning. We anticipate that this perspective will shape the path toward introducing human heart simulations into precision medicine with the ultimate goals to facilitate clinical decision making, guide treatment planning, and accelerate device design.

Childhood infectious diseases and old age cognitive functioning: a nationally representative sample of community-dwelling older adults.

BACKGROUND: Cumulative evidence suggests that health-related risk factors during midlife and old-age are associated with cognitive impairment. However, studies are needed to clarify the association between early-life risk factors and impaired cognitive functioning to increment existing knowledge. OBJECTIVE: To examine the association between childhood infectious diseases and late-life cognitive functioning in a nationally representative sample of older adults. PARTICIPANTS: Eligible respondents were 2994 community-dwelling individuals aged 65-85. MEASUREMENTS: Cognitive functioning was assessed using the Mini-Mental State Examination (MMSE). Childhood infectious diseases (i.e. chicken pox, measles, and mumps) were self-reported. The study covariates were age, sex, highest educational level achieved, smoking status, body mass index, and depression. The primary statistical analysis examined the association between the number of childhood infectious diseases and total MMSE scores, accounting for all study covariates. Regression models of progressive complexity were examined for parsimony. The robustness of the primary results was tested in 17 sensitivity analyses. RESULTS: The most parsimonious model was a linear adjusted model (Bayesian Information Criterion = 12646.09). Late-life cognitive functioning significantly improved as the number of childhood infectious diseases increased (ß = 0.18; 95% CI = 0.11, 0.26; p < 0.001). This effect was not significantly attenuated in all sensitivity analyses. CONCLUSION: The current study results are consistent with prior ecological findings indicating that some childhood infectious diseases are associated with better cognitive functioning in old-age. This points to an early-life modifiable risk factor associated with older-life cognitive functioning. Our results may reflect selective mortality and/or beneficial effects via hormetic processes.

Systematic analysis of the number needed to treat.

The number needed to treat is often used to measure the efficacy of a binary outcome in randomized clinical trials. There are three different available measures of the number needed to treat. Two of these measures, Furukawa and Leucht's and Kraemer and Kupfer's, focus on converting Cohen's δ index into the number needed to treat, while Laupacis et al.'s measure deals primarily with the number needed to treat's estimation rather than with a reformulation. Mathematical and numerical analysis of numbers needed to treat and their estimators was conducted. Three novel number needed to treat estimators were introduced to supplement the numbers needed to treat introduced by Laupacis, Furukawa and Leucht, and Kraemer and Kupfer. The analysis showed that Laupacis et al.'s number needed to treat is intrinsically different from Kraemer and Kupfer's number needed to treat, and that Furukawa and Leucht's estimator is appropriate to use only for normally distributed outcomes with equal standard deviations. Based on the numerical analysis, the novel numbers needed to treat outperformed the existing ones under correct model specifications. Asymptotic analysis was used to test three different types of confidence intervals to supplement the numbers needed to treat. An R-package to calculate these numbers needed to treat and their confidence intervals has been developed and made available for users online.

Feasibility of INTACT (INcisionless TArgeted Core Tissue) biopsy procedure for perinatal autopsy.

OBJECTIVES: To determine the feasibility and tissue yield of a perinatal incisionless ultrasound-guided biopsy procedure, the INcisionless Targeted Core Tissue (INTACT) technique, in the context of minimally invasive autopsy. METHODS: Cases of perinatal death in which the parents consented for minimally invasive autopsy underwent postmortem magnetic resonance imaging and an INTACT biopsy procedure, defined as needle biopsy of organs via the umbilical cord, performed under ultrasound guidance. In each case, three cores of tissue were obtained from seven target organs (both lungs, both kidneys, heart, spleen and liver). Biopsy success was predefined as an adequate volume of the intended target organ for pathological analysis, as judged by a pathologist blinded to the case and biopsy procedure. RESULTS: Thirty fetuses underwent organ sampling. Mean gestational age was 30 weeks (range, 18-40 weeks) and mean delivery-to-biopsy interval was 12 days (range, 6-22 days). The overall biopsy success rate was 153/201 (76.1%) samples, with the success rates in individual organs being highest for the heart and lungs (93% and 91%, respectively) and lowest for the spleen (11%). Excluding splenic samples, the biopsy success rate was 150/173 (86.7%). Histological abnormalities were found in 4/201 (2%) samples, all of which occurred in the lungs and kidneys of a fetus with pulmonary hypoplasia and multicystic kidney disease. CONCLUSIONS: Incisionless ultrasound-guided organ biopsy using the INTACT procedure is feasible, with an overall biopsy success rate of over 75%. This novel technique offers the ideal combination of an imaging-led autopsy with organ sampling for parents who decline the conventional invasive approach. © 2019 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of the International Society of Ultrasound in Obstetrics and Gynecology.

Initial severity of major depression and efficacy of new generation antidepressants: individual participant data meta-analysis.

OBJECTIVE: The role of baseline severity as effect modifier in various psychiatric disorders is a topic of controversy and of clinical import. This study aims to examine whether baseline severity modifies the efficacy of various antidepressants for major depression through individual participant data (IPD) meta-analysis. METHOD: We identified all placebo-controlled, double-blind randomised trials of new generation antidepressants in the acute phase treatment of major depression conducted in Japan and requested their IPD through the public-private partnerships (PPPs) between the relevant academic societies and the pharmaceutical companies. The effect modification by baseline depression severity was examined through six increasingly complex competing mixed-effects models for repeated measures. RESULTS: We identified eleven eligible trials and obtained IPD from six, which compared duloxetine, escitalopram, mirtazapine, paroxetine or bupropion against placebo (total n = 2464). The best-fitting model revealed that the interaction between baseline severity and treatment was not statistically significant (coefficient = -0.04, 95% confidence interval: -0.16 to 0.08, P = 0.49). Several sensitivity analyses confirmed the robustness of the findings. CONCLUSION: We may expect as much benefit from antidepressant treatments for mild, moderate or severe major depression. Clinical practice guidelines will need to take these findings into consideration.

Autism risk following antidepressant medication during pregnancy.

BACKGROUND: Previous studies have examined if maternal antidepressant medication during pregnancy increase the risk of autism spectrum disorder (ASD) in the offspring, but the results have been conflicting. METHODS: In a population-based cohort of 179 007 children born in 2006 and 2007 and followed through 2014 when aged 7 and 8, we estimated relative risks (RRs) of ASD and 95% confidence intervals (CIs) from Cox regression in children exposed to any antidepressant medication during pregnancy, and nine specific antidepressant drugs. Analyses were adjusted for potential confounders and were conducted in the full population sample, and in a clinically relevant sub-sample of mothers with at least one diagnosis of depression or anxiety during life. RESULTS: The adjusted RR of ASD in children of mothers who used antidepressant medication during pregnancy was estimated at 1.23 (95% CI 0.96-1.57), and at 1.07 (95% CI 0.80-1.43) in women with a history of depression or anxiety. Analyses of specific antidepressants initially revealed increased RRs of offspring ASD confined to citalopram and escitalopram (RR: 1.47; 95% CI 0.92-2.35) and clomipramine (RR: 2.86; 95% CI 1.04-7.82). CONCLUSION: Medication with antidepressants during pregnancy does not appear to be causally associated with an increased risk of ASD in the offspring. Instead, the results suggest that the association is explained by factors related to the underlying susceptibility to psychiatric disorders. Based on these findings, the risk of ASD in the offspring should not be a consideration to withhold treatment with commonly used antidepressant drugs from pregnant women.

Stillbirth and intrauterine fetal death: role of routine histological organ sampling to determine cause of death.

OBJECTIVES: Guidelines for the investigation of intrauterine death and sudden unexpected death in infancy (SUDI) recommend, based on expert opinion, autopsy procedures and tissue sampling strategies for histological analysis. Although stillbirth is much more common than SUDI, there have been no large-scale studies published which evaluate the usefulness of histological evaluation of specific organs in stillbirth for determining cause of death. Our aim was to evaluate the use of macroscopic and microscopic assessment of internal organs to determine cause of intrauterine death. METHODS: As part of a larger study evaluating several aspects of autopsy findings in intrauterine death, a dedicated database was used to collate antenatal and postmortem examination details for cases of intrauterine death examined between 2005 and 2013 at two tertiary specialist centers in London, UK. Histological findings for all organs were examined in relation to the final cause of death, as determined by objective criteria. RESULTS: Among 1064 intrauterine deaths, the majority (> 80%) of cases had internal organs that were normal on both macroscopic and microscopic examination. There was no case in which histological cardiac examination provided the cause of death when the macroscopic appearance of the heart was normal. Microscopic examination of lung tissue revealed 13 (1%) cases with histological abnormalities that provided the cause of death when the macroscopic appearance was normal, but there was only one (0.1%) case in which the diagnosis would not have been apparent on placental examination: a case of congenital cytomegalovirus infection. There was no case in which microscopic examination of macroscopically normal liver, kidneys, adrenals, spleen, thymus, intestines, pancreas, brain or thyroid provided the cause of death. CONCLUSION: In this large series of autopsies in cases of intrauterine death, only around 1% of cases demonstrated histological abnormalities which provided the cause of death when the internal organs appeared normal macroscopically. There was no case in which routine histological examination of most tissues provided diagnostically useful information that was not apparent from other examinations, such as placental pathology. There is little benefit, purely in terms of determining cause of death, in obtaining tissue from most macroscopically normal organs for routine histological examination. Copyright © 2016 ISUOG. Published by John Wiley & Sons Ltd.

Stillbirth and intrauterine fetal death: factors affecting determination of cause of death at autopsy.

OBJECTIVES: There have been several attempts to classify cause of death (CoD) in stillbirth; however, all such systems are subjective, allowing for observer bias and making comparisons between systems challenging. This study aimed to examine factors relating to determination of CoD using a large dataset from two specialist centers in which observer bias had been reduced by classifying findings objectively and assigning CoD based on predetermined criteria. METHODS: Detailed autopsy reports from intrauterine deaths in the second and third trimesters during 2005-2013 were reviewed and findings entered into a specially designed database, in which CoD was assigned using predefined objective criteria. Data regarding CoD categories and factors affecting determination of CoD were examined. RESULTS: There were 1064 intrauterine deaths, including 246 early intrauterine fetal deaths (IUFD) (< 20 weeks), 179 late IUFDs (20-23 weeks) and 639 stillbirths (≥ 24 weeks' gestation). Overall, around 40% (n = 412) had a clear CoD identified, whilst around 60% (n = 652) were classified as 'unexplained', including around half with identified risk factors or lesions of uncertain significance, with the remaining half (n = 292 (45%)) being entirely unexplained. A stepwise increase in the proportion of unexplained deaths was observed with increasing maceration. Black and Asian women had significantly greater proportions of deaths due to ascending infection, whilst women aged over 40 years had significantly increased placenta-related CoDs. There was no significant difference in CoD distribution according to maternal body mass index or with increasing postmortem interval. Around half of those with an identifiable CoD could be identified from clinical review and external fetal examination or imaging, with most of the remainder being determined following placental examination. CONCLUSIONS: Based on objective criteria, many intrauterine deaths throughout gestation remain unexplained despite autopsy examination. The rate of unexplained death varies from around 30% to 60% depending on interpretation of the significance of features. CoD determination is dependent on both the classification system used and subjective interpretation, such that variation in the proportion of 'unexplained' cases is based largely on speculation regarding mechanisms of death. Novel methods to determine objectively the mechanism of death at postmortem examination are required. Copyright © 2016 ISUOG. Published by John Wiley & Sons Ltd.

Effects of intrauterine retention and postmortem interval on body weight following intrauterine death: implications for assessment of fetal growth restriction at autopsy.

OBJECTIVE: According to the classification system used, 15-60% of stillbirths remain unexplained, despite undergoing recommended autopsy examination, with variable attribution of fetal growth restriction (FGR) as a cause of death. Distinguishing small-for-gestational age (SGA) from pathological FGR is a challenge at postmortem examination. This study uses data from a large, well-characterized series of intrauterine death autopsies to investigate the effects of secondary changes such as fetal maceration, intrauterine retention and postmortem interval on body weight. METHODS: Autopsy findings from intrauterine death investigations (2005-2013 inclusive, from Great Ormond Street Hospital and St George's Hospital, London) were collated into a research database. Growth charts published by the World Health Organization were used to determine normal expected weight centiles for fetuses born ≥ 24 weeks' gestation, and the effects of intrauterine retention (maceration) and postmortem interval were calculated. RESULTS: There were 1064 intrauterine deaths, including 533 stillbirths ≥ 24 weeks' gestation with a recorded birth weight. Of these, 192 (36%) had an unadjusted birth weight below the 10th centile and were defined as SGA. The majority (86%) of stillborn SGA fetuses demonstrated some degree of maceration, indicating a significant period of intrauterine retention after death. A significantly greater proportion of macerated fetuses were present in the SGA population compared with the non-SGA population (P = 0.01). There was a significant relationship between increasing intrauterine retention interval and both more severe maceration and reduction in birth weight (P < 0.0001 for both), with an average artifactual reduction in birth weight of around -0.8 SD of expected weight. There was an average 12% reduction in fetal weight between delivery and autopsy and, as postmortem interval increased, fetal weight loss increased (P = 0.0001). CONCLUSION: Based on birth weight alone, 36% of stillbirths are classified as SGA. However, fetuses lose weight in utero with increasing intrauterine retention and continue to lose weight between delivery and autopsy, resulting in erroneous overestimation of FGR. Copyright © 2016 ISUOG. Published by John Wiley & Sons Ltd.