Biologic Correlates and Consequences of the Social Determinants of Health and Disease.

The consequences of experiences and exposures suffered by those living in poverty can last a lifetime and can even be passed on to the next generation. The challenges associated with poverty have been labeled the "social determinants of health" (SDoH), but this is something of a misnomer. A more appropriate label would be the "social determinants of disease." This essay is a broad overview of the processes, including allostatic load and epigenetic aging, that might contribute to prolonging the adverse effects of the social determinants of disease.

Caritas only when.

IMPACT: Finding and respecting the human facets of the patient-parent-physician relationship will enable us to return to where we come from and to offer what is worthy of the appellation "care". The poem adds a piece to the mosaic of humanist pediatrics. Hopefully, the message will add a silver lining to the clouds of professional responsibility and burnout hovering over large parts of the pediatric workforce.

Retinopathy of prematurity.

Retinopathy of prematurity (ROP) is a devastating neurovascular disease of the retina in newborn infants that can lead to vision deficits or even blindness. In this concise review we discuss our current knowledge about diagnosis, etiology, pathogenesis, intervention, and outcomes of the disease. Major advancements have been made both in categorizing the disease in the new International Classification of Retinopathy of Prematurity, Third Edition classification and in treating severe ROP with anti-vascular endothelial growth factor (VEGF) agents. New development always creates new questions and opens up new areas of research. We will discuss in this review both the benefits and downsides of the new anti-VEGF treatment approaches in ROP, especially in light of our improved understanding of the underlying ROP pathophysiology. We also offer pointers to areas where more research is needed. WHAT THIS PAPER ADDS: Concise update on all aspects of retinopathy of prematurity (ROP), including advances in understanding and treatment. Benefits and risks of the new treatment method of anti-vascular endothelial growth factor injections in ROP are discussed. New research areas that deserve attention in the coming years are identified.

PRENATAL MATERNAL CHARACTERISTICS ASSOCIATED WITH RETINOPATHY OF PREMATURITY.

PURPOSE: Determine whether prenatal maternal characteristics such as sociodemographic characteristics, comorbidities, or pregnancy complications affect retinopathy of prematurity (ROP) development. METHODS: Medical records of 236 mother-infant dyads from our institution were reviewed, only including dyads in which infants were born at 30 weeks gestational age or earlier. The primary outcome measure was the risk of ROP (defined Stage 1 or greater in either eye) and its association with prenatal maternal variables. RESULTS: Maternal Medicaid insurance, smoking during pregnancy, and chorioamnionitis were associated with an increased risk of ROP. For Medicaid insurance and chorioamnionitis, these risks were not appreciably altered by adjustment for potential confounders. CONCLUSION: These results suggest that several prenatal maternal factors may independently affect the risk of ROP in preterm infants. Validation of our findings could aid in the identification of infants at high risk for ROP based on prenatal clinical features.

Retinal structure and visual pathway function at school age in children born extremely preterm: a population-based study.

BACKGROUND: Children born extremely preterm (gestational age < 28 weeks) show reduced visual function even without any cerebral or ophthalmological neonatal diagnosis. In this study, we aimed to assess the retinal structure with optical coherence tomography (OCT) and visual function with pattern-reversal visual evoked potentials (PR-VEPs) in a geographically defined population-based cohort of school-aged children born extremely preterm. Moreover, we aimed to explore the association between measures of retinal structure and visual pathway function in this cohort. METHODS: All children born extremely preterm from 2006-2011 (n = 65) in Central Norway were invited to participate. Thirty-six children (55%) with a median age of 13 years (range = 10-16) were examined with OCT, OCT-angiography (OCT-A), and PR-VEPs. The foveal avascular zone (FAZ) and circularity, central macular vascular density, and flow were measured on OCT-A images. Central retinal thickness, circumpapillary retinal nerve fibre layer (RNFL) and inner plexiform ganglion cell layer (IPGCL) thickness were measured on OCT images. The N70-P100 peak-to-peak amplitude and N70 and P100 latencies were assessed from PR-VEPs. RESULTS: Participants displayed abnormal retinal structure and P100 latencies (≥ 2 SD) compared to reference populations. Moreover, there was a negative correlation between P100 latency in large checks and RNFL (r = -.54, p = .003) and IPGCL (r = -.41, p = .003) thickness. The FAZ was smaller (p = .003), macular vascular density (p = .006) and flow were higher (p = .004), and RNFL (p = .006) and IPGCL (p = .014) were thinner in participants with ROP (n = 7). CONCLUSION: Children born extremely preterm without preterm brain injury sequelae have signs of persistent immaturity of retinal vasculature and neuroretinal layers. Thinner neuroretinal layers are associated with delayed P100 latency, prompting further exploration of the visual pathway development in preterms.

Erythrocyte transfusions are associated with retinopathy of prematurity in extremely low gestational age newborns.

AIM: Retinopathy of prematurity (ROP) is a major morbidity in preterm infants causing visual impairment including blindness. Prevention and timely treatment are critical. We investigated the potential role of red blood cell (RBC) transfusions as risk factor for ROP development. METHODS: Retrospective cohort study of data from 68 tertiary level neonatal intensive care units in Germany. Preterm infants born at 22 + 0 to 28 + 6 weeks of gestation between January 2009 and December 2021 were enrolled. RESULTS: We included n = 12 565 infants. Prevalence of any ROP was 49.2% with most infants being diagnosed with stage 1 (21.5%) and 2 disease (17.2%). ROP stage 3 was present in 10.2%, stage 4 in 0.3%, and ROP requiring treatment in 6.6%. Infants with ROP had significantly more frequently a history of RBC transfusions. Adjusting for confounders, RBC transfusions were associated with increased odds of ROP (OR 1.4, p < 0.001), ROP progression (OR 2.1, p < 0.01) and ROP requiring treatment (OR 3.6, p < 0.001). Restrictive transfusion approaches correlated with decreased (OR 0.7, p < 0.001), liberal regimes with increased odds (OR 1.2, p = 0.001). CONCLUSION: The present study confirmed an association of RBC transfusions and ROP. Our findings emphasise the need for anaemia prevention and critical re-evaluation of transfusion practices in preterm infants.

Visual function correlates with neurodevelopment in a population cohort of school-aged children born extremely preterm.

AIM: To investigate visual function and neurodevelopment in a geographically defined population cohort of school-aged children born extremely preterm. METHODS: All children born extremely preterm in Central Norway between 2006 and 2011 (n=65) were identified, and 36 (median age, min/max: 13, 10/16) were included. Best-corrected visual acuity (BCVA), contrast sensitivity (four spatial frequencies), parent-reported challenges and neuropsychological testing in learning, executive functions, motor skills, perception, reaction time, working and visual memory, processing speed, and pattern separation were measured. Brain MRI (3T) was acquired and read by a neuroradiologist. RESULTS: Median (min/max) BCVA letter score was 85 (35/91) in the better and 82 (13/89) in the worse eye. ROP participants (n=7) had lower contrast sensitivity in the two highest spatial frequencies (p = 0.024 and p = 0.004). Parent-reported challenges correlated negatively with BCVA (learning: p = 0.014; executive functions: p = 0.002; motor skills: p = 0.000; and perception: p = 0.001), while motor skills correlated negatively with one (p = 0.010) and perception with two (p = 0.003 and p = 0.009) of four spatial frequencies. Neuropsychological tests were reduced relative to norms. None had MRI-verified preterm brain injury. CONCLUSION: Visual function was subnormal and correlated with parent-reported challenges in a small cohort of extremely preterm school-aged children, indicating that visual function may be a marker of neurodevelopmental outcomes.

Causation and causal inference in obstetrics-gynecology.

Causation and causal inference are of utmost importance in obstetrics and gynecology. In many clinical situations, causal reasoning is involved in etiological explanations, diagnostic considerations, and conversations about prognosis. In this paper, we offer an overview of the philosophical accounts of causation that may not be familiar to, but still be appreciated by, the busy clinician. In our discussion, we do not try to simplify what is a rather complex range of ideas. We begin with an introduction to some important basic ideas, followed by 2 sections on the metaphysical and epistemological aspects of causality, which offer a more detailed discussion of some of its specific philosophical facets, using examples from obstetrical and gynecologic research and practice along the way. We hope our discussion will help deepen the thinking and discourse about causation and causal inference in gynecology and obstetrics.

Visuopathy of prematurity: is retinopathy just the tip of the iceberg?

Research on retinopathy of prematurity (ROP) focuses mainly on the abnormal vascularization patterns that are directly visible for ophthalmologists. However, recent findings indicate that children born prematurely also exhibit changes in the retinal cellular architecture and along the dorsal visual stream, such as structural changes between and within cortical areas. Moreover, perinatal sustained systemic inflammation (SSI) is associated with an increased risk for ROP and the visual deficits that follow. In this paper, we propose that ROP might just be the tip of an iceberg we call visuopathy of prematurity (VOP). The VOP paradigm comprises abnormal vascularization of the retina, alterations in retinal cellular architecture, choroidal degeneration, and abnormalities in the visual pathway, including cortical areas. Furthermore, VOP itself might influence the developmental trajectories of cerebral structures and functions deemed responsible for visual processing, thereby explaining visual deficits among children born preterm.

Health Humanities in Medicina: The Auxiliary Stance.

At the core of medicine is the idea to help fellow human beings by improving or even restoring their health [...].

Evidence Mapping to Justify Health Interventions.

In order to support health interventions, biomedical and population health researchers need to collect solid evidence. This article asks what type of evidence this should be and expands on previous work that focused on etiological explanations, or causal-mechanical explanations of why and how illness occurs. The article proposes adding predictive evidence to the explanatory evidence, in order to form a joint evidence set, or JES = [A,B,C,D], which consists of four different types of evidence: association [A], biology [B], confirmation [C], and difference-making [D]. The article discusses explanatory coherence as a backbone for this proposal, suggests criteria for each type of evidence, and offers a rubric for multi-evidence mapping.

The prenatal phase of retinopathy of prematurity.

AIM: To explore the current literature on prenatal inflammation-associated risk factors for retinopathy of prematurity (ROP). METHODS: Subjective summary of selected experimental and epidemiological publications that support the authors' central hypothesis that the aetiology of ROP begins before birth. RESULTS: Based on current evidence we suggest that, contrary to current aetiological models, the process of ROP development begins with a prephase in utero. This beginning is likely initiated by inflammatory responses that are associated with intrauterine infection. CONCLUSION: We propose a novel aetio-pathogenetic model of ROP and suggest that the effects of postnatal exposure to inflammatory stressors (resulting from infection or hyperoxia or both) as well as those of other pre- and postnatal contributors to the complex pathogenesis of ROP might be modified by the prenatal phase of the disease.

Early Postnatal IGF-1 and IGFBP-1 Blood Levels in Extremely Preterm Infants: Relationships with Indicators of Placental Insufficiency and with Systemic Inflammation.

OBJECTIVE: To evaluate to what extent indicators of placenta insufficiency are associated with low concentrations of insulin-like growth factor 1 (IGF-1) and IGF-1-binding protein-1 (IGFBP-1) in neonatal blood, and to what extent the concentrations of these growth factors are associated with concentrations of proteins with inflammatory, neurotrophic, or angiogenic properties. STUDY DESIGN: Using multiplex immunoassays, we measured the concentrations of IGF-1 and IGFBP-1, as well as 25 other proteins in blood spots collected weekly from ≥ 880 infants born before the 28th week of gestation, and sought correlates of concentrations in the top and bottom quartiles for gestational age and day the specimen was collected. RESULTS: Medically indicated delivery and severe fetal growth restriction (sFGR) were associated with low concentrations of IGF-1 on the first postnatal day and with high concentrations of IGFBP-1 on almost all days. Elevated concentrations of IGF-1 and IGFBP-1 were accompanied by elevated concentrations of many other proteins with inflammatory, neurotrophic, or angiogenic properties. CONCLUSION: Disorders associated with impaired placenta implantation and sFGR appear to account for a relative paucity of IGF-1 on the first postnatal day. Elevated concentrations of IGF-1 and especially IGFBP-1 were associated with same-day elevated concentrations of inflammatory, neurotrophic, and angiogenic proteins.

Hill's Heuristics and Explanatory Coherentism in Epidemiology.

In this essay, I argue that Ted Poston's theory of explanatory coherentism is well-suited as a tool for causal explanation in the health sciences, particularly in epidemiology. Coherence has not only played a role in epidemiology for more than half a century as one of Hill's viewpoints, it can also provide background theory for the development of explanatory systems by integrating epidemiologic evidence with a diversity of other error-independent data. I propose that computational formalization of Hill's viewpoints in an explanatory coherentist framework would provide an excellent starting point for a formal epistemological (knowledge-theoretical) project designed to improve causal explanation in the health sciences. As an example, I briefly introduce Paul Thagard's ECHO system and offer my responses to possible objections to my proposal.

The risk of neurodevelopmental disorders at age 10 years associated with blood concentrations of interleukins 4 and 10 during the first postnatal month of children born extremely preterm.

BACKGROUND: Interleukin (IL)-4 and IL-10 are viewed mainly as anti-inflammatory cytokines. Yet, high concentrations have also been associated with inflammation-related diseases in newborns. METHODS: We measured the concentrations of IL-4 and IL-10, as well as IL-8 and ICAM-1 in blood specimens collected on postnatal day 21 (N = 555), day 28 (N = 521), and both days 21 and 28 (N = 449) from children born extremely preterm (EP) (<28 weeks gestation) who at age 10 years had a DAS-II IQ Z-score > -2 (which approximates a score of >70) and the following assessments, CCC-2, and CSI-4, DAS-II, NEPSY-II, OWLS-II, SCQ, and WIAT-III. Selected children also were assessed with the ADI-R and the ADOS-2. We modeled the risk of low scores or dysfunctions associated with top quartile concentrations of IL-4 and IL-10 on each day and on both days. RESULTS: The risks of low scores on the Animal Sorting and Arrows components of the NEPSY-II, both components of the OWLS-II, and the PseudoWord and Spelling components of the WIAT-III were heightened among children who had top quartile concentrations of IL-4 on postnatal days 21 and 28. Children who had high concentrations of IL-10 on days 21 and 28, individually and collectively, were at increased risk of low scores on the WIAT-III Spelling component. High concentrations of IL-4 on day 28 were associated with autism spectrum disorder (ASD). High concentrations of IL-10 on day 28 were also associated with a doubling of ASD risk, but this did not achieve statistical significance. Top quartile concentrations of IL-4 and IL10 on both days were not associated with increased risk of social, language, or behavioral dysfunctions. CONCLUSION: Among children born EP, those who had top quartile concentrations of IL-4 and/or IL-10 on postnatal days 21 and/or 28 were more likely than their peers to have low scores on components of the NEPSY-II, OWLS-II, and WIAT-III assessments, as well as identification as having an ASD. What is known: What is not known: What this study adds.

Hypoxia-ischemia is not an antecedent of most preterm brain damage: the illusion of validity.

Brain injury in preterm newborn infants is often attributed to hypoxia-ischemia even when neither hypoxia nor ischemia is documented, and many causative speculations are based on the same assumption. We review human and animal study contributions with their strengths and limitations, and conclude that - despite all the work done in human fetal neuropathology and developmental models in animals - the evidence remains unconvincing that hypoxemia, in the fetus or newborn infant, contributes appreciably to any encephalopathy of prematurity. Giving an inappropriate causal name to a disorder potentially limits the options for change, should our understanding of the etiologies advance. The only observationally-based title we think appropriate is 'encephalopathy of prematurity'. Future pathophysiological research should probably include appropriately designed epidemiology studies, highly active developmental processes, infection and other inflammatory stimuli, the immature immune system, long chain fatty acids and their transporters, and growth (neurotrophic) factors. WHAT THIS PAPER ADDS: Fetal hypoxemia is rarely documented in brain injury studies. Animal studies fail to consider human-animal fetal anatomical differences. Putative treatments from animal models have not found clinical use. Observational studies constitute the only approach to etiological understanding. No convincing evidence yet that hypoxemia injures preterm brain. Encephalopathy of prematurity is preferable to hypoxia-ischemia as a term for this disorder. Encephalopathy of prematurity is preferable to hypoxia-ischemia as a term for this disorder.