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Background: Atrial fibrillation (AF) is a common complication of rheumatic heart disease (RHD) and is challenging to treat in lower-resourced settings in which RHD remains endemic. Objective: We characterized demographics, treatment outcomes, and factors leading to care retention for participants with RHD and AF in Uganda. Methods: We conducted a retrospective analysis of the Uganda national RHD registry between June 2009 and May 2018. Participants with AF or atrial flutter were included. Demographics, survival, and care metrics were compared with participants without AF. Multivariable logistic regression was used to identify factors associated with retention in care among participants with AF. Results: A total of 1530 participants with RHD were analyzed and 293 (19%) had AF. The median age was 24 (interquartile range 14-38) years. Mortality was similar in both groups (adjusted hazard ratio 1.183, P = .77) over a median follow-up of 203 (interquartile range 98-275) days. A total of 79% of AF participants were prescribed anticoagulation, and 43% were aware of their target international normalized ratio. Retention in care was higher in participants with AF (18% vs 12%, P < .01). Factors associated with decreased retention in care include New York Heart Association functional class III/IV (adjusted odds ratio [OR] 0.48, 95% confidence interval [CI] 0.30-0.76) and distance to nearest health center (adjusted OR 0.94, 95% CI 0.90-0.99). Anticoagulation prescription was associated with enhanced care retention (adjusted OR 1.86, 95% CI 1.24-2.79). Conclusion: Participants with RHD and AF in Uganda do not experience higher mortality than those without AF. Anticoagulation prescription rates are high. Although retention in care is poor among RHD participants, those with concurrent AF are more likely to be retained.

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Developmental Coordination Disorder (DCD) is a common neurodevelopmental disorder featuring deficits in motor coordination and motor timing among children. Deficits in rhythmic tracking, including perceptually tracking and synchronizing action with auditory rhythms, have been studied in a wide range of motor disorders, providing a foundation for developing rehabilitation programs incorporating auditory rhythms. We tested whether DCD also features these auditory-motor deficits among 7-10 year-old children. In a speech recognition task with no overt motor component, modulating the speech rhythm interfered more with the performance of children at risk for DCD than typically developing (TD) children. A set of auditory-motor tapping tasks further showed that, although children at risk for DCD performed worse than TD children in general, the presence of an auditory rhythmic cue (isochronous metronome or music) facilitated the temporal consistency of tapping. Finally, accuracy in the recognition of rhythmically modulated speech and tapping consistency correlated with performance on the standardized motor assessment. Together, the results show auditory rhythmic regularity benefits auditory perception and auditory-motor coordination in children at risk for DCD. This provides a foundation for future clinical studies to develop evidence-based interventions involving auditory-motor rhythmic coordination for children with DCD.

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Music and speech are complex and distinct auditory signals that are both foundational to the human experience. The mechanisms underpinning each domain are widely investigated. However, what perceptual mechanism transforms a sound into music or speech and how basic acoustic information is required to distinguish between them remain open questions. Here, we hypothesized that a sound's amplitude modulation (AM), an essential temporal acoustic feature driving the auditory system across processing levels, is critical for distinguishing music and speech. Specifically, in contrast to paradigms using naturalistic acoustic signals (that can be challenging to interpret), we used a noise-probing approach to untangle the auditory mechanism: If AM rate and regularity are critical for perceptually distinguishing music and speech, judging artificially noise-synthesized ambiguous audio signals should align with their AM parameters. Across 4 experiments (N = 335), signals with a higher peak AM frequency tend to be judged as speech, lower as music. Interestingly, this principle is consistently used by all listeners for speech judgments, but only by musically sophisticated listeners for music. In addition, signals with more regular AM are judged as music over speech, and this feature is more critical for music judgment, regardless of musical sophistication. The data suggest that the auditory system can rely on a low-level acoustic property as basic as AM to distinguish music from speech, a simple principle that provokes both neurophysiological and evolutionary experiments and speculations.

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In a previous study, heart xenografts from 10-gene-edited pigs transplanted into two human decedents did not show evidence of acute-onset cellular- or antibody-mediated rejection. Here, to better understand the detailed molecular landscape following xenotransplantation, we carried out bulk and single-cell transcriptomics, lipidomics, proteomics and metabolomics on blood samples obtained from the transplanted decedents every 6 h, as well as histological and transcriptomic tissue profiling. We observed substantial early immune responses in peripheral blood mononuclear cells and xenograft tissue obtained from decedent 1 (male), associated with downstream T cell and natural killer cell activity. Longitudinal analyses indicated the presence of ischemia reperfusion injury, exacerbated by inadequate immunosuppression of T cells, consistent with previous findings of perioperative cardiac xenograft dysfunction in pig-to-nonhuman primate studies. Moreover, at 42 h after transplantation, substantial alterations in cellular metabolism and liver-damage pathways occurred, correlating with profound organ-wide physiological dysfunction. By contrast, relatively minor changes in RNA, protein, lipid and metabolism profiles were observed in decedent 2 (female) as compared to decedent 1. Overall, these multi-omics analyses delineate distinct responses to cardiac xenotransplantation in the two human decedents and reveal new insights into early molecular and immune responses after xenotransplantation. These findings may aid in the development of targeted therapeutic approaches to limit ischemia reperfusion injury-related phenotypes and improve outcomes.

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Colonoscopy is accurate but inefficient for colorectal cancer (CRC) prevention due to the low (~ 7 to 8%) prevalence of target lesions, advanced adenomas. We leveraged rectal mucosa to identify patients who harbor CRC field carcinogenesis by evaluating chromatin 3D architecture. Supranucleosomal disordered chromatin chains (~ 5 to 20 nm, ~1 kbp) fold into chromatin packing domains (~ 100 to 200 nm, ~ 100 to 1000 kbp). In turn, the fractal-like conformation of DNA within chromatin domains and the folding of the genome into packing domains has been shown to influence multiple facets of gene transcription, including the transcriptional plasticity of cancer cells. We deployed an optical spectroscopic nanosensing technique, chromatin-sensitive partial wave spectroscopic microscopy (csPWS), to evaluate the packing density scaling D of the chromatin chain conformation within packing domains from rectal mucosa in 256 patients with varying degrees of progression to colorectal cancer. We found average packing scaling D of chromatin domains was elevated in tumor cells, histologically normal-appearing cells 4 cm proximal to the tumor, and histologically normal-appearing rectal mucosa compared to cells from control patients (p < 0.001). Nuclear D had a robust correlation with the model of 5-year risk of CRC with r2 = 0.94. Furthermore, rectal D was evaluated as a screening biomarker for patients with advanced adenomas presenting an AUC of 0.85 and 85% sensitivity and specificity. artificial intelligence-enhanced csPWS improved diagnostic performance with AUC = 0.90. Considering the low sensitivity of existing CRC tests, including liquid biopsies, to early-stage cancers our work highlights the potential of chromatin biomarkers of field carcinogenesis in detecting early, significant precancerous colon lesions.

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OBJECTIVE: To assess the long-term efficacy and safety of oral saffron, a natural antioxidant, in treating mild/moderate age-related macular degeneration (AMD). METHODS AND ANALYSIS: Open-label, extension trial of 93 adults (>50 years) with mild/moderate AMD and vision >20/70 Snellen equivalent in at least 1 eye. Exclusion criteria included confounding visual lesions or significant gastrointestinal disease impairing absorption.Participants were given oral saffron supplementation (20 mg/day) for 12 months. Those already consuming Age-Related Eye Diseases Study (AREDS) supplements or equivalent maintained these.Primary outcomes included changes in multifocal electroretinogram (mfERG) response density and latency, and changes in best-corrected visual acuity (BCVA). Secondary outcomes included safety outcomes, changes in mfERG and BCVA among participants on AREDS supplements and changes in microperimetry. RESULTS: At 12 months, mean mfERG response density was significantly higher in rings 1, 2 and overall (p<0.001 for all) but not in rings 3-6, and there was no difference in response between those taking AREDS supplements and those not (p>0.05). Mean mfERG latency was not significantly different in any of rings 1-6 or overall (p>0.05 for all), again with no difference between those taking AREDS supplements or not (p>0.05). Mean BCVA was 1.6 letters worse (p<0.05) with no difference between those on AREDS supplements or not, and this may have been related to cataract progression. No saffron-related serious adverse events were detected. CONCLUSION: Saffron supplementation modestly improved mfERG responses in participants with AMD, including those using AREDS supplements. Given the chronic nature of AMD, longer-term supplementation may produce greater benefits.

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Health agencies rely upon survey-based physical measures to estimate the prevalence of key global health indicators such as hypertension. Such measures are usually collected by nonhealthcare worker personnel and are potentially subject to measurement error due to variations in interviewer technique and setting, termed "interviewer effects." In the context of physical measurements, particularly in low- and middle-income countries, interviewer-induced biases have not yet been examined. Using blood pressure as a case study, we aimed to determine the relative contribution of interviewer effects on the total variance of blood pressure measurements in three large nationally representative health surveys from the Global South. We utilized 169,681 observations between 2008 and 2019 from three health surveys (Indonesia Family Life Survey, National Income Dynamics Study of South Africa, and Longitudinal Aging Study in India). In a linear mixed model, we modeled systolic blood pressure as a continuous dependent variable and interviewer effects as random effects alongside individual factors as covariates. To quantify the interviewer effect-induced uncertainty in hypertension prevalence, we utilized a bootstrap approach comparing subsamples of observed blood pressure measurements to their adjusted counterparts. Our analysis revealed that the proportion of variation contributed by interviewers to blood pressure measurements was statistically significant but small: ∼0.24--2.2% depending on the cohort. Thus, hypertension prevalence estimates were not substantially impacted at national scales. However, individual extreme interviewers could account for measurement divergences as high as 12%. Thus, highly biased interviewers could have important impacts on hypertension estimates at the subdistrict level.

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BACKGROUND: Gender and geographic access to care play a large role in health disparities in esophageal cancer care. The aim of our study was to evaluate disparities in peri-operative outcomes for patients undergoing esophagectomy based on gender and geographic location. METHODS: A retrospective cohort of prospectively collected data from patients who underwent esophagectomy from 2003 to 2022 was identified and analyzed based on gender and county, which were aggregated into existing state-level "metropolitan" versus "rural" designations. The demographics, pre-operative treatment, surgical complications, post-operative outcomes, and length of stay (LOS) of each group were analyzed using chi-squared, paired t-tests and single-factor ANOVA. RESULTS: Of the 1545 patients, men (83.6%) and women (16.4%) experienced similar rates of post-operative complications, but women experienced significantly longer hospital (p = 0.002) and ICU (p = 0.03) LOSs as compared with their male counterparts, with no differences in 30-day mortality. When separated by geographic criteria, rural women were further outliers, with significantly longer hospital LOSs (p < 0.001) and higher rates of ICU admission (p < 0.001). CONCLUSIONS: Rural female patients undergoing esophagectomy were more likely to have a longer inpatient recovery process compared with their female metropolitan or male counterparts, suggesting a need for more targeted interventions in this population.

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Objective: The purpose of this study was to characterize the impact of adolescent pregnancy on families and describe the needs of adolescent mothers and their infants in order to assess the need for intervention and identify potential intervention targets. Background: Adolescent mothers and their offspring face an increased risk of mental health problems. Adolescent mothers and their families also face significant resource constraints; 95% live in low- and middle-income countries (LMICs). Cost-effective interventions are needed to improve outcomes for this vulnerable group. Method: This qualitative study conducted in Lima, Peru, consisted of four clinician focus groups and 18 in-depth interviews with adolescent mothers and their family members. Data were coded thematically, and direct content analysis was employed. Results: The study identified the following issues facing adolescent parents: the transition to parenthood, the need for family support, difficulty accessing support, the difficulty for family members of providing support, and ideas about responsibility and adolescent autonomy. Conclusion: Overall, these findings demonstrate the need for interventions that engage families and address barriers to accessing support, including relationship conflict and differing beliefs about responsibility and autonomy. Implications: Interventions are needed for adolescent mothers in LMICs that mobilize family support. Clinicians who care for these patients need to be aware of the family context and the resources available where they practice.

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Nab-paclitaxel-related cystoid macular edema is a rare ophthalmic adverse drug reaction. We present a 54-year-old woman with metastatic hormone receptor positive, HER-2 negative breast carcinoma who developed profound bilateral vision loss after the seventh cycle of nab-paclitaxel treatment. Optical coherence tomography and macula microperimetry demonstrated macular edema and decreased threshold sensitivity, respectively. Cessation of nab-paclitaxel improved structural and functional vision after 4 weeks. The introduction of topical dorzolamide 1% in one eye demonstrated further rapid resolution of edema. We demonstrate the objective and subjective visual changes and recovery of nab-paclitaxel-related cystoid macular edema. [Ophthalmic Surg Lasers Imaging Retina 2024;55:xx-xx.].

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Prader-Willi syndrome (PWS) is a complex, genetic disorder characterized by multisystem involvement, including hyperphagia, maladaptive behaviors and endocrinological derangements. Recent developments in advanced neuroimaging have led to a growing understanding of PWS as a neural circuit disorder, as well as subsequent interests in the application of neuromodulatory therapies. Various non-invasive and invasive device-based neuromodulation methods, including vagus nerve stimulation (VNS), transcranial direct current stimulation (tDCS), repetitive transcranial magnetic stimulation (rTMS), and deep brain stimulation (DBS) have all been reported to be potentially promising treatments for addressing the major symptoms of PWS. In this systematic literature review, we summarize the recent literature that investigated these therapies, discuss the underlying circuits which may underpin symptom manifestations, and cover future directions of the field. Through our comprehensive search, there were a total of 47 patients who had undergone device-based neuromodulation therapy for PWS. Two articles described VNS, 4 tDCS, 1 rTMS and 2 DBS, targeting different symptoms of PWS, including aberrant behavior, hyperphagia and weight. Multi-center and multi-country efforts will be required to advance the field given the low prevalence of PWS. Finally, given the potentially vulnerable population, neuroethical considerations and dialogue should guide the field.

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A specific splicing isoform of RNASET2 is associated with worse oncologic outcomes in clear cell renal cell carcinoma (ccRCC). However, the interplay between wild-type RNASET2 and its splice variant and how this might contribute to the pathogenesis of ccRCC remains poorly understood. We sought to better understand the relationship of RNASET2 in the pathogenesis of ccRCC and the interplay with a pathogenic splicing isoform (RNASET2-SV) and the tumor immune microenvironment. Using data from The Cancer Genome Atlas and Clinical Proteomic Tumor Analysis Consortium, we correlated clinical variables to RNASET2 expression and the presence of a specific RNASET2-SV. Immunohistochemical staining with matched RNA sequencing of ccRCC patients was then utilized to understand the spatial relationships of RNASET2 with immune cells. Finally, in vitro studies were performed to demonstrate the oncogenic role of RNASET2 and highlight its potential mechanisms. RNASET2 gene expression is associated with higher grade tumors and worse overall survival in The Cancer Genome Atlas cohort. The presence of the RNASET2-SV was associated with increased expression of the wild-type RNASET2 protein and epigenetic modifications of the gene. Immunohistochemical staining revealed increased intracellular accumulation of RNASET2 in patients with increased RNA expression of RNASET2-SV. In vitro experiments reveal that this accumulation results in increased cell proliferation, potentially from altered metabolic pathways. RNASET2 exhibits a tumor-promoting role in the pathogenesis of ccRCC that is increased in the presence of a specific RNASET2-SV and associated with changes in the cellular localization of the protein.

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Objectives: Data are scarce on whether the composition of the lung microbiome (extending from the nasopharynx to the peripheral lung tissue) varies according to histology or grade of non-small cell lung cancer. We hypothesized that the composition of the lung microbiome would vary according to the histology and the grade of non-small cell lung cancer. Methods: We collected naso-oral and central lobar (cancer affected, ipsilateral unaffected, and contralateral unaffected) bronchoalveolar lavage fluid and brushing samples from patients with clinical early-stage lung cancer between July 2018 and February 2020 at a single academic center. We performed bacterial 16S rRNA sequencing and then compared clinical and pathologic findings with microbiome signatures. Results: Samples were collected from 28 patients. Microbial composition in affected lobes displayed unique enrichment of oropharyngeal bacterial species that was significantly different compared with that from the unaffected contralateral lobes; patients with chronic obstructive pulmonary disease had similar diversity to those without chronic obstructive pulmonary disease (P = .1312). The lung microbiome diversity in patients with adenocarcinoma was similar to those with squamous cell cancer (P = .27). There were no differences in diversity or composition in the unaffected lobes of patients with adenocarcinoma versus squamous cell cancer. There was a trend toward lower lung microbial diversity in poorly differentiated adenocarcinomas compared with well-differentiated adenocarcinomas (P = .08). Conclusions: The lung microbiota differs between cancer affected and unaffected lobes in the same patient. Furthermore, poorly differentiated lung cancers were associated with lower microbial diversity. Larger studies will be required to confirm these findings.

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In mammalian research, it has been debated what can initiate an evolutionary tradeoff between different senses, and the phenomenon of sensory tradeoff in rodents, the most abundant mammalian clade, is not evident. The Nile rat (Arvicanthis niloticus), a murid rodent, recently adapted to a diurnal niche through an evolutionary acquisition of daylight vision with enhanced visual acuity. As such, this model provides an opportunity for a cross-species investigation where comparative morphological and multi-omic analyses of the Nile rat are made with its closely related nocturnal species, e.g. the mouse (Mus musculus) and the rat (Rattus norvegicus). Thus, morphological examinations were performed, and evolutionary reductions in relative sizes of turbinal bone surfaces, the cribriform plate, and the olfactory bulb were discovered in Nile rats. Subsequently, we compared multiple murid genomes, and profiled olfactory epithelium transcriptomes of mice and Nile rats at various ages with RNA sequencing. The results further demonstrate that, in comparison with mouse olfactory receptor (OR) genes, Nile rat OR genes have experienced less frequent gain, more frequent loss, and more frequent expression reduction during their evolution. Furthermore, functional degeneration of coding sequences in the Nile rat lineage was found in OR genes, yet not in other genes. Taken together, these results suggest that acquisition of improved vision in the Nile rat has been accompanied by degeneration of both olfaction-related anatomical structures and OR gene repertoires, consistent with the hypothesis of an olfaction-vision tradeoff initiated by the switch from a nocturnal to a diurnal lifestyle in mammals.

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PURPOSE: To evaluate 2-year efficacy, durability, and safety of the bispecific antibody faricimab, which inhibits both angiopoietin-2 and VEGF-A. DESIGN: TENAYA (ClinicalTrials.gov identifier, NCT03823287) and LUCERNE (ClinicalTrials.gov identifier, NCT03823300) were identically designed, randomized, double-masked, active comparator-controlled phase 3 noninferiority trials. PARTICIPANTS: Treatment-naive patients with neovascular age-related macular degeneration (nAMD) 50 years of age or older. METHODS: Patients were randomized (1:1) to intravitreal faricimab 6.0 mg up to every 16 weeks (Q16W) or aflibercept 2.0 mg every 8 weeks (Q8W). Faricimab fixed dosing based on protocol-defined disease activity at weeks 20 and 24 up to week 60, followed up to week 108 by a treat-and-extend personalized treatment interval regimen. MAIN OUTCOME MEASURES: Efficacy analyses included change in best-corrected visual acuity (BCVA) from baseline at 2 years (averaged over weeks 104, 108, and 112) and proportion of patients receiving Q16W, every 12 weeks (Q12W), and Q8W dosing at week 112 in the intention-to-treat population. Safety analyses included ocular adverse events (AEs) in the study eye through study end at week 112. RESULTS: Of 1326 patients treated across TENAYA/LUCERNE, 1113 (83.9%) completed treatment (n = 555 faricimab; n = 558 aflibercept). The BCVA change from baseline at 2 years was comparable between faricimab and aflibercept groups in TENAYA (adjusted mean change, +3.7 letters [95% confidence interval (CI), +2.1 to +5.4] and +3.3 letters [95% CI, +1.7 to +4.9], respectively; mean difference, +0.4 letters [95% CI, -1.9 to +2.8]) and LUCERNE (adjusted mean change, +5.0 letters [95% CI, +3.4 to +6.6] and +5.2 letters [95% CI, +3.6 to +6.8], respectively; mean difference, -0.2 letters [95% CI, -2.4 to +2.1]). At week 112 in TENAYA and LUCERNE, 59.0% and 66.9%, respectively, achieved Q16W faricimab dosing, increasing from year 1, and 74.1% and 81.2%, achieved Q12W or longer dosing. Ocular AEs in the study eye were comparable between faricimab and aflibercept groups in TENAYA (55.0% and 56.5% of patients, respectively) and LUCERNE (52.9% and 47.5% of patients, respectively) through week 112. CONCLUSIONS: Treat-and-extend faricimab treatment based on nAMD disease activity maintained vision gains through year 2, with most patients achieving extended dosing intervals. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

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Cellular metabolism plays an essential role in the regrowth and regeneration of a neuron following physical injury. Yet, our knowledge of the specific metabolic pathways that are beneficial to neuron regeneration remains sparse. Previously, we have shown that modulation of O-linked ß-N-acetylglucosamine (O-GlcNAc) signaling, a ubiquitous post-translational modification that acts as a cellular nutrient sensor, can significantly enhance in vivo neuron regeneration. Here, we define the specific metabolic pathway by which O-GlcNAc transferase (ogt-1) loss of function mediates increased regenerative outgrowth. Performing in vivo laser axotomy and measuring subsequent regeneration of individual neurons in C. elegans, we find that glycolysis, serine synthesis pathway (SSP), one-carbon metabolism (OCM), and the downstream transsulfuration metabolic pathway (TSP) are all essential in this process. The regenerative effects of ogt-1 mutation are abrogated by genetic and/or pharmacological disruption of OCM and the SSP linking OCM to glycolysis. Testing downstream branches of this pathway, we find that enhanced regeneration is dependent only on the vitamin B12 independent shunt pathway. These results are further supported by RNA sequencing that reveals dramatic transcriptional changes by the ogt-1 mutation, in the genes involved in glycolysis, OCM, TSP, and ATP metabolism. Strikingly, the beneficial effects of the ogt-1 mutation can be recapitulated by simple metabolic supplementation of the OCM metabolite methionine in wild-type animals. Taken together, these data unearth the metabolic pathways involved in the increased regenerative capacity of a damaged neuron in ogt-1 animals and highlight the therapeutic possibilities of OCM and its related pathways in the treatment of neuronal injury.

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OBJECTIVES: Cryoablation is increasingly being utilized as an alternative to epidurals for patients undergoing thoracotomies. Current evidence suggests cryoablation may decrease postoperative analgesia utilization, but could increase operative times. We hypothesized that the adoption of intraoperative cryoablation to manage post-thoracotomy pain would result in reduced length of stay and reduced perioperative analgesia compared to routine epidural use. METHODS: A retrospective analysis was performed from a single, quaternary referral centre, prospective database on patients receiving thoracotomies between January 2020 and March 2022. Patients undergoing transthoracic hiatal hernia repair, lung resection or double-lung transplant were divided between epidural and cryoablation cohorts. Primary outcomes were length of stay, intraoperative procedure time, crossover pain management and oral narcotic usage the day before discharge. RESULTS: During the study period, 186 patients underwent a transthoracic hiatal hernia repair, lung resection or double-lung transplant with 94 receiving a preoperative epidural and 92 undergoing cryoablation. Subgroup analysis demonstrated no significant differences in demographics, operative length, length of stay or perioperative narcotic use. Notably, over a third of patients in each cryoablation subgroup received a postoperative epidural (45.5% transthoracic hiatal hernia repair, 38.5% lung resection and 45.0% double-lung transplant) for further pain management during their admission. CONCLUSIONS: Cryoablation use was not associated with an increase in procedure time, a decrease in narcotic use or length of stay. Surprisingly, many cryoablation patients received epidurals in the postoperative period for further pain control. Additional analysis is needed to fully understand the benefits and costs of epidural versus cryoablation strategies.

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Racial and ethnic inequities in paediatric care have received increased research attention over the past two decades, particularly in the past 5 years, alongside an increased societal focus on racism. In this Series paper, the first in a two-part Series focused on racism and child health in the USA, we summarise evidence on racial and ethnic inequities in the quality of paediatric care. We review studies published between Jan 1, 2017 and July 31, 2022, that are adjusted for or stratified by insurance status to account for group differences in access, and we exclude studies in which differences in access are probably driven by patient preferences or the appropriateness of intervention. Overall, the literature reveals widespread patterns of inequitable treatment across paediatric specialties, including neonatology, primary care, emergency medicine, inpatient and critical care, surgery, developmental disabilities, mental health care, endocrinology, and palliative care. The identified studies indicate that children from minoritised racial and ethnic groups received poorer health-care services relative to non-Hispanic White children, with most studies drawing on data from multiple sites, and accounting for indicators of family socioeconomic position and clinical characteristics (eg, comorbidities or condition severity). The studies discussed a range of potential causes for the observed disparities, including implicit biases and differences in site of care or clinician characteristics. We outline priorities for future research to better understand and address paediatric treatment inequities and implications for practice and policy. Policy changes within and beyond the health-care system, discussed further in the second paper of this Series, are essential to address the root causes of treatment inequities and to promote equitable and excellent health for all children.

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BACKGROUND: To compare the change in lesion area over 4 years of follow-up in eyes with neovascular age-related macular degeneration (nAMD) treated with anti-vascular endothelial growth factor (VEGF) agents using either a proactive or a reactive regimen in routine clinical practice. METHODS: This was a multicentre, retrospective comparative study. Totally, 202 treatment-naïve nAMD eyes (183 patients) received anti-VEGF therapy according to a proactive (n = 105) or reactive (n = 97) regimen. Eyes were included if they had received anti-VEGF injections for a period of at least 4 years and had baseline fluorescein angiography and annual optical coherence tomography (OCT) imaging. Two masked graders independently delineated the lesion's margins from serial OCT images and growth rates were calculated. RESULTS: At baseline, the mean [SD] lesion area was 7.24 [5.6] mm2 in the proactive group and 6.33 [4.8] mm2 in the reactive group respectively (p = 0.22). After four years of treatment, the mean [SD] lesion area in the proactive group was 5.16 [4.5] mm2 showing a significant reduction compared to the baseline (p < 0.001). By contrast, the mean [SD] lesion area kept expanding in the reactive group during the follow-up and was 9.24 [6.0] mm2 at four years (p < 0.001). The lesion area at 4 years was significantly influenced by treatment regimen, baseline lesion area, and proportion of visits with active lesions. CONCLUSIONS: Eyes treated using a reactive strategy had an increased lesion area and worse visual outcomes at 4 years. By contrast, the proactive regimen was associated with fewer recurrences of active disease, shrinkage of the lesion area, and better vision at four years.

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