Characterization and quantification of adeno-associated virus capsid-loading states by multi-wavelength analytical ultracentrifugation with UltraScan.

Aim: We present multi-wavelength (MW) analytical ultracentrifugation (AUC) methods offering superior accuracy for adeno-associated virus characterization and quantification. Methods: Experimental design guidelines are presented for MW sedimentation velocity and analytical buoyant density equilibrium AUC. Results: Our results were compared with dual-wavelength AUC, transmission electron microscopy and mass photometry. In contrast to dual-wavelength AUC, MW-AUC correctly quantifies adeno-associated virus capsid ratios and identifies contaminants. In contrast to transmission electron microscopy, partially filled capsids can also be detected and quantified. In contrast to mass photometry, first-principle results are obtained. Conclusion: Our study demonstrates the improved information provided by MW-AUC, highlighting the utility of several recently integrated UltraScan programs, and reinforces AUC as the gold-standard analysis for viral vectors.

Serologic Evaluations in the Distinction Between Sinusitis-Related Orbital Cellulitis and Periorbital Necrotizing Fasciitis.

PURPOSE: While sinusitis-related orbital cellulitis (SROC) and periorbital necrotizing fasciitis (PNF) share similar clinical presentations, they are managed differently, making rapid recognition of the appropriate clinical entity critical to optimal outcomes. This study was performed to assess whether serologic testing might help clinicians to distinguish between SROC and PNF. METHODS: A retrospective review analysis was used to compare initial complete blood counts and comprehensive metabolic panels among adult patients with SROC and PNF. Statistical evaluations were used to determine the significance of differences between the groups. RESULTS: Thirteen patients with PNF and 14 patients with SROC were identified. The 2 groups were similar in age, gender, and likelihood of immunosuppression ( p > 0.05 for each metric). Mean leukocyte counts were 18.52 (standard deviation = 7.02) and 10.31 (standard deviation = 5.77) for PNF and SROC, respectively ( p = 0.0057). White blood cell levels were above normal limits for 12 patients with PNF (92.3%) and 7 patients with SROC (50%) ( p = 0.017). No other laboratory test was significantly different between the 2 groups. CONCLUSIONS: While the majority of serologic testing was quite similar in patients with either SROC or PNF, leukocyte levels may represent an important clue to distinguish between the two diseases. Clinical evaluation remains the gold standard to make the proper diagnosis, but markedly elevated white blood cell counts should prompt clinicians to at least consider a diagnosis of PNF.

Racial Differences in Retinopathy of Prematurity.

PURPOSE: To delineate racial differences in the incidence and time course of ROP in a large cohort of premature infants. METHODS: The secondary analysis of data from the two Postnatal Growth and ROP Studies (G-ROP-1 and G-ROP-2) that were collected in 41 hospitals in North America from 2006 to 2017. According to self-reported maternal race, premature infants were classified into 3 groups: White (N = 5580), Black (N = 3252), and Asian (N = 353). Incidence, severity, and time course of ROP; plus disease; and postnatal weight gain rate were compared among racial groups. RESULTS: Black infants had significantly smaller BW (mean 1035 vs. 1131 vs.1144 grams, P < .001) and lower GA (28.2 vs. 28.6, vs. 29.1 weeks, P < .001) than White and Asian infants. However, Black infants had lower incidences of severe ROP (11.1% vs. 12.4% vs. 11.9%), ROP (42.1% vs. 43.2% vs. 30.6%), and plus disease (3.6% vs. 6.3%, vs. 5.9%) than White and Asian infants (BW and GA adjusted risk ratio for Black vs. White 0.69 for severe ROP, 0.83 for ROP, 0.44 for plus disease, all P < .0001). Mean daily-weight-gain on days of life 11-20 and 21-30 were similar across groups (P > .05), but lower in Black and Asian infants on days 31-40 (P < .001). There were no differences in the timing of severe ROP and ROP across racial groups. CONCLUSIONS: Despite relatively lower GA, BW, and daily-weight-gain, Black preterm infants had lower incidences of ROP and plus disease than White preterm infants. The mechanisms for these differences require further investigation.

Association of Cardiovascular Disease with Retinopathy of Prematurity.

PURPOSE: To determine the associations of presence and types of cardiovascular diseases (CVDs) with development of retinopathy of prematurity (ROP) in premature infants undergoing ROP examinations. STUDY DESIGN: We performed secondary analyses of data from the multi-center Postnatal Growth and ROP Validation Study (GROP-2). CVD was categorized based on pulmonary blood flow (PBF), systemic blood flow (SBF), pulmonary hypertension (PPHN), or dysrhythmia. Adjusted odds ratios (aOR) and 95% confidence intervals (95% CI) were calculated from multivariable logistic regression models that included any ROP or severe ROP as outcome variable and any CVD or type of CVD as independent variable, with adjustment of covariates including birth weight (BW), gestational age (GA), and days on supplemental oxygen in the first month of postnatal life. RESULT: Among 3980 infants, 528 (13.3%) had CVD (304 had increased PBF, 101 had decreased PBF, and 49 had PPHN), 1643 (40.4%) developed ROP, and 503 (12.6%) developed severe ROP. In multivariable analyses, presence of CVD was not significantly associated with increased risk of any ROP (aOR = 1.15, 95% CI: 0.90-1.46, p = .26) or severe ROP (aOR = 0.98, 95% CI: 0.72-1.34, p = .92). However, there were trends associating CVD resulting in increased PBF with a higher risk of ROP (aOR = 1.32, 95% CI: 0.97-1.80, p = .08) and PPHN with a higher risk of severe ROP (aOR = 2.04, 95% CI: 0.96-4.35, p = .07). When adjusting only for BW and GA, these associations were significant (aOR = 1.47, 95% CI: 1.09-1.99, and aOR = 2.35, 95% CI: 1.19-4.65, respectively). CONCLUSION: CVD with increased PBF likely increases the risk of ROP. PPHN likely increases the risk of severe ROP.

Association of Surgical Necrotizing Enterocolitis and Its Timing with Retinopathy of Prematurity.

OBJECTIVE: The study aimed to determine the association of surgical necrotizing enterocolitis (NEC) and its timing, with the development and timing of retinopathy of prematurity (ROP). STUDY DESIGN: This was a secondary data analysis of 7,483 preterm infants from the Postnatal Growth and Retinopathy of Prematurity Study. Associations between infants with surgical NEC, early-onset surgical NEC (8-28 days), and late-onset surgical NEC (over 28 days) with ROP were evaluated by using multivariable logistic regression models, controlling for birth weight, gestational age, small for gestational age status, chronic lung disease, intraventricular hemorrhage, hydrocephalus, patent ductus arteriosus, and periventricular leukomalacia. RESULTS: Three hundred fifty-six (4.8%) infants had surgical NEC, with 56% having early surgical NEC. Infants with surgical NEC had a higher risk of any ROP and severe ROP (adjusted odds ratio [OR]: 2.7; 95% CI: 1.9-3.7) and 2.5 (95% CI: 1.9-3.3), respectively; p < 0.001) compared with infants without surgical NEC. Infants with early surgical NEC were at the highest risk of developing ROP and severe ROP (adjusted OR: 3.1 [95% CI: 2.1-4.8], and 3.3 [95% CI: 2.3-4.7] respectively, p < 0.001). Infants with late surgical NEC were also at increased risk of developing ROP and severe ROP (adjusted OR: 2.1 [95% CI: 1.3-3.4], and 1.9 [95% CI: 1.3-2.8] respectively, p < 0.001) compared with infants without surgical NEC. CONCLUSION: Infants with surgical NEC, especially early surgical NEC, are at higher risk of ROP and severe ROP. KEY POINTS: · Infants with surgical NEC are at higher risk of ROP and severe ROP than those without surgical NEC.. · Increased ROP risk is seen in infants with both early- or later onset surgical NEC.. · Early-onset surgical NEC is associated with a higher ROP risk compared with later onset surgical NEC..

Daily Oxygen Supplementation and Risk of Retinopathy of Prematurity.

PURPOSE: Excessive oxygen supplementation increases risk of retinopathy of prematurity (ROP). While numerous oxygen parameters could be considered when predicting ROP (saturation targets, actual saturation, fraction of inspired oxygen, etc.), complicated measures are impractical as screening criteria. We sought to develop a simple, clinically useful measure of daily oxygen supplementation during ages 0-28 days to improve prediction of ROP. METHODS: Secondary analysis of two Postnatal Growth and ROP (G-ROP) Study cohorts (G-ROP-1 and G-ROP-2) at 45 hospitals. Infants with a known ROP outcome and complete oxygen data were included. Associations between severe ROP and days on supplemental oxygen (FiO2 > 21%), during ages 0-28 days (DSO28) were assessed, controlling for birth weight (BW) and gestational age (GA). New screening criteria incorporating DSO were developed and compared to current guidelines. RESULTS: Among 8,949 studied infants, 459 (5.1%) developed type 1 ROP. DSO28 was associated with severe ROP (adjusted-OR 1.05 per day supplemental oxygen, 95%CI 1.03-1.07, p < .0001). The following criteria had 100% sensitivity for type 1 ROP and higher specificity than current guidelines: new BW/GA criteria with DSO (BW<901 g, GA<26 weeks, or DSO >3), 23.4% fewer infants examined; modified G-ROP criteria including DSO, 29.0% fewer infants; original G-ROP criteria, 31.8% fewer infants. CONCLUSION: In high-level neonatal-care settings, incorporating DSO (a simple measure of oxygen supplementation) into screening criteria improves sensitivity and specificity for type 1 ROP over current BW-GA criteria, but does not perform as well as the validated G-ROP criteria.

Pediatric glaucoma suspects: characteristics and outcomes.

PURPOSE: To determine the characteristics of children diagnosed with glaucoma suspect (GS) status, their clinical outcomes, and risk factors for progression to a diagnosis of glaucoma. METHODS: This was a retrospective sequential cohort study of children <18 years diagnosed as GS between 2013 and 2019, based on clinical (C-GS) and CGRN (CGRN-GS) criteria. Children with penetrating ocular trauma, steroid-response, treated ocular hypertension, and glaucoma at presentation were excluded. Outcomes included glaucoma, treated ocular hypertension, nonglaucomatous cupping (pseudoglaucomatous or physiologic), or persistent GS. Secondary outcomes were characteristics of children who progressed to glaucoma. RESULTS: A total of 887 children (mean age, 9.3 ± 4.7 years) were diagnosed as C-GS, because of optic nerve appearance (83%), family history (25%), ocular hypertension (15%), periocular lesion (4% [eg, Sturge-Weber]), blunt-trauma history (3%), ocular anomaly (2%), and systemic/genetic syndrome (1.5%). Outcomes among 487 children with one or more follow-up visits (mean, 1.7 ± 1.6 years) included 14 (3%) with glaucoma, 98 (20%) with physiologic cupping, 50 (10%) with prematurity-associated cupping, and 1 (0.2%) with treated ocular hypertension; 324 (67%) remained GS. Of children lost to follow-up, 116 (29%) were suspected physiologic or pseudoglaucomatous. Glaucoma diagnosis occurred at a mean age of 8.4 ± 5.5 years, based on elevated intraocular pressure (IOP; 79%), optical coherence tomography changes (43%), disk changes (21%), or field defects (14%). Risk factors for glaucoma were baseline IOP of ≥24 (P = 0.01) and periocular lesion (P = 0.008). Results from 773 children who met CGRN-GS criteria were similar. CONCLUSIONS: Risk of conversion to glaucoma diagnosis among children with glaucoma suspect status appears low. Baseline cup:disk ratio and family history of glaucoma were not predictive of glaucoma diagnosis. Baseline IOP >24 and presence of a periocular lesion carry higher risk.

Exploring the Conformational Landscape and Stability of Aurora A Using Ion-Mobility Mass Spectrometry and Molecular Modeling.

Protein kinase inhibitors are highly effective in treating diseases driven by aberrant kinase signaling and as chemical tools to help dissect the cellular roles of kinase signaling complexes. Evaluating the effects of binding of small molecule inhibitors on kinase conformational dynamics can assist in understanding both inhibition and resistance mechanisms. Using gas-phase ion-mobility mass spectrometry (IM-MS), we characterize changes in the conformational landscape and stability of the protein kinase Aurora A (Aur A) driven by binding of the physiological activator TPX2 or small molecule inhibition. Aided by molecular modeling, we establish three major conformations, the relative abundances of which were dependent on the Aur A activation status: one highly populated compact conformer similar to that observed in most crystal structures, a second highly populated conformer possessing a more open structure infrequently found in crystal structures, and an additional low-abundance conformer not currently represented in the protein databank. Notably, inhibitor binding induces more compact configurations of Aur A, as adopted by the unbound enzyme, with both IM-MS and modeling revealing inhibitor-mediated stabilization of active Aur A.

Changes in institutional oxygen saturation targets are associated with an increased rate of severe retinopathy of prematurity.

PURPOSE: To evaluate the effect of changes in institutional peripheral oxygen saturation (SpO2) targets, made in response to recent randomized trials, on risk of developing severe retinopathy of prematurity (ROP). METHODS: This study was a secondary analysis of data from 21 North American hospitals during the periods 2006-2012 and 2015-2017. Hospitals were categorized based on whether or not SpO2 targets were increased between the two study periods. Severe ROP (type 1, type 2, or zone III stage 3+) rates were compared within and between groups. Generalized mixed effect models with random intercepts were used to account for within-center clustering and to calculate odds ratios (aOR) adjusted by birth weight (BW) and gestational age (GA), using patient-level data. RESULTS: A total of 8,142 infants underwent ROP examinations at 21 hospitals during the two study periods: 5,716 in 2006-2012 (mean BW, 1109 ± 369 g; GA, 28.0 ± 2.6; 11.6% severe ROP); 2,426 in 2015-2017 (mean BW, 1086 ± 347 g; GA, 28.0 ± 2.8; 12.8% severe ROP). Fourteen hospitals increased SpO2 targets, and 7 hospitals did not. Hospitals that increased targets had a 3% increase in severe ROP (from 12% to 15%; aOR = 1.25; 95% CI, 1.01-1.55; P = 0.044); hospitals without SpO2 changes had a 2% decrease (from 11% to 9%; aOR = 0.72; 95% CI, 0.52-1.00; P = 0.049). The difference in change of severe ROP between groups of hospitals was significant (P = 0.005). CONCLUSIONS: Increases in institutional SpO2 targets in response to recent randomized trials were associated with increased severe ROP. Hospitals considering increasing their SpO2 targets should anticipate increases in rates of severe ROP and manage screening and treatment resources accordingly.

Embryonic and early postnatal cranial bone volume and tissue mineral density values for C57BL/6J laboratory mice.

BACKGROUND: Laboratory mice are routinely used in craniofacial research based on the relatively close genetic relationship and conservation of developmental pathways between humans and mice. Since genetic perturbations and disease states may have localized effects, data from individual cranial bones are valuable for the interpretation of experimental assays. We employ high-resolution microcomputed tomography to characterize cranial bones of C57BL/6J mice at embryonic day (E) 15.5 and E17.5, day of birth (P0), and postnatal day 7 (P7) and provide estimates of individual bone volume and tissue mineral density (TMD). RESULTS: Average volume and TMD values are reported for individual bones. Significant differences in volume and TMD during embryonic ages likely reflect early mineralization of cranial neural crest-derived and intramembranously forming bones. Although bones of the face and vault had higher TMD values during embryonic ages, bones of the braincase floor had significantly higher TMD values by P7. CONCLUSIONS: These ontogenetic data on cranial bone volume and TMD serve as a reference standard for future studies using mice bred on a C57BL/6J genetic background. Our findings also highlight the importance of differentiating "control" data from mice that are presented as "unaffected" littermates, particularly when carrying a single copy of a cre-recombinase gene.

Recovery of Vision after Optic Nerve Sheath Fenestration in Children and Adolescents with Elevated Intracranial Pressure.

PURPOSE: To evaluate the effect of optic nerve sheath fenestration (ONSF) on the recovery of visual function in pediatric patients with optic disc swelling owing to increased intracranial pressure. DESIGN: Retrospective case series. METHODS: Medical chart review of all pediatric patients who underwent ONSF between 2009 and 2020 at the Children's Hospital of Philadelphia. Visual function was assessed at pre and postoperative visits. The main outcome measures were visual acuity, color vision, extraocular motility, visual field mean deviation, retinal nerve fiber layer thickness measured by optical coherence tomography. RESULTS: Fourteen pediatric patients (10 females; mean ± SD age of 14 ± 2.6 years; range, 8.5-17.5 years) were included. Five patients underwent bilateral surgeries. Ten patients were diagnosed with idiopathic intracranial hypertension. Of the 10 idiopathic intracranial hypertension patients, 3 had a previous history of weight gain and 2 of systemic steroid treatment; these can be referred to as pseudotumor cerebri. The mean ± SD follow-up length was 16.4 ± 12.3 months. VA improved from 20/138 to 20/68 in the operated eye (P = .0003) and from 20/78 to 20/32 in the nonoperated eye (P = .02). Color vision improved in the operated eye (P = .04), extraocular motility improved in the operated and nonoperated eye (P = .002 and P = .04 respectively). Visual field mean deviation improved in the operated (-23.4 dB to -11.5 dB, P < .0001) and nonoperated eye (-19.8 dB to -6.8 dB, P = .02). Retinal nerve fiber layer thickness improved in the operated eye (349.1 to 66.2 µm; P < .0001). The postoperative improvement was observed as early as the postoperative day 1. CONCLUSIONS: ONSF produces a rapid and persistent vision improvement in both the operated eye and the nonoperated eye. In children and young adults with papilledema and elevated intracranial pressure causing vision loss that is severe at presentation or refractory to standard medical management, ONSF should be considered.

Pulsed-Focused Ultrasound Slows B16 Melanoma and 4T1 Breast Tumor Growth through Differential Tumor Microenvironmental Changes.

Focused ultrasound (FUS) has shown promise as a non-invasive treatment modality for solid malignancies. FUS targeting to tumors has been shown to initiate pro-inflammatory immune responses within the tumor microenvironment. Pulsed FUS (pFUS) can alter the expression of cytokines, chemokines, trophic factors, cell adhesion molecules, and immune cell phenotypes within tissues. Here, we investigated the molecular and immune cell effects of pFUS on murine B16 melanoma and 4T1 breast cancer flank tumors. Temporal changes following sonication were evaluated by proteomics, RNA-seq, flow-cytometry, and histological analyses. Proteomic profiling revealed molecular changes occurring over 24 h post-pFUS that were consistent with a shift toward inflamed tumor microenvironment. Over 5 days post-pFUS, tumor growth rates were significantly decreased while flow cytometric analysis revealed differences in the temporal migration of immune cells. Transcriptomic analyses following sonication identified differences in gene expression patterns between the two tumor types. Histological analyses further demonstrated reduction of proliferation marker, Ki-67 in 4T1, but not in B16 tumors, and activated cleaved-caspase 3 for apoptosis remained elevated up to 3 days post-pFUS in both tumor types. This study revealed diverse biological mechanisms following pFUS treatment and supports its use as a possible adjuvant to ablative tumor treatment to elicit enhanced anti-tumor responses and slow tumor growth.

Retinal Detachment after Treatment of Retinopathy of Prematurity with Laser versus Intravitreal Anti-Vascular Endothelial Growth Factor.

PURPOSE: To compare rates of short-term retinal detachment (RD) of infants treated for type 1 retinopathy of prematurity (ROP) with intravitreal anti-vascular endothelial growth factor (VEGF) therapy with infants treated with laser therapy. The choice between these 2 treatments remains controversial. Comparative data are limited and describe re-treatment rates rather than retinal structural outcomes predictive of long-term vision. Anti-vascular endothelial growth factor acts faster than laser therapy, which may be beneficial for more aggressive ROP. DESIGN: Nonrandomized, comparative cohort study. PARTICIPANTS: The study included 1167 eyes of 640 infants treated for type 1 ROP. Among these, 164 eyes received anti-VEGF therapy and 1003 eyes received laser therapy. METHODS: Pretreatment and posttreatment examinations and treatments were completed by ophthalmologists with expertise in ROP. The study was a secondary analysis of data from the retrospective Postnatal Growth and Retinopathy of Prematurity Study (G-ROP) 1 study (2006-2012) and the prospective G-ROP 2 study (2015-2017). MAIN OUTCOME MEASURES: Rate of RD (ROP stages 4A, 4B, or 5) within 8 weeks of initial treatment, an end point predictive of poor long-term vision. The results were stratified by postmenstrual age (PMA) at treatment as occurring before versus at or after 36 weeks and 0 days, because earlier disease may be considered more aggressive. RESULTS: Among 458 eyes treated before PMA 36 weeks and 0 days, the short-term RD rate was higher after laser therapy (29/368 eyes [7.9%]) than after anti-VEGF therapy (0/90 eyes [0%]; P < 0.001). Of 709 eyes treated at or after PMA 36 weeks and 0 days, short-term RD risk did not differ between groups (laser [20/635 eyes], 3.1%; anti-VEGF [1/74 eyes], 1.4%; P = 0.27). CONCLUSIONS: Anti-vascular endothelial growth factor therapy results in better short-term structural outcomes than laser therapy when type 1 ROP is treated before 36 weeks' PMA. After this age, both treatments have very low rates of short-term RD. The faster action of anti-VEGF agents likely is responsible for these findings.

Poor postnatal weight growth is a late finding after sepsis in very preterm infants.

OBJECTIVE: To characterise the association between sepsis and postnatal weight growth when accounting for the degree of growth restriction present at birth. DESIGN: Retrospective matched cohort study using data from the Postnatal Growth and Retinopathy of Prematurity study. Participants were born with birth weights of <1500 g or gestational ages of <32 weeks between 2006 and 2011 at 29 neonatal centres in the USA and Canada. Sepsis was defined as a culture-confirmed bacterial or fungal infection of the blood or cerebrospinal fluid before 36 weeks' postmenstrual age (PMA). Growth was assessed as the change in weight z-score between birth and 36 weeks' PMA. RESULTS: Of 4785 eligible infants, 813 (17%) developed sepsis and 693 (85%) were matched 1:1 to controls. Sepsis was associated with a greater decline in weight z-score (mean difference -0.09, 95% CI -0.14 to -0.03). Postnatal weight growth failure (decline in weight z- score>1) was present in 237 (34%) infants with sepsis and 179 (26%) controls (adjusted OR 1.49, 95% CI 1.12 to 1.97). Longitudinal growth trajectories showed similar initial changes in weight z-scores between infants with and without sepsis. By 3 weeks after sepsis onset, there was a greater decline in weight z-scores relative to birth values in those with sepsis than without sepsis (delta z-score -0.89 vs -0.77; mean difference -0.12, 95% CI -0.18 to -0.05). This significant difference persisted until 36 weeks or discharge. CONCLUSION: Infants with sepsis had similar early weight growth trajectories as infants without sepsis but developed significant deficits in weight that were not apparent until several weeks after the onset of sepsis.

Incidence, timing and risk factors of type 1 retinopathy of prematurity in a North American cohort.

BACKGROUND/AIMS: Early detection and timely treatment of type 1 retinopathy of prematurity (ROP) can reduce the risk of blindness. To evaluate the incidence, timing and risk factors of type 1 ROP in a large, broad-risk cohort of premature infants. METHODS: Secondary analysis of data from the two Postnatal Growth and Retinopathy of Prematurity studies. Main outcomes are the incidence and timing of type 1 ROP. RESULTS: Among 11 463 infants (mean birth weight (BW), 1095 g; mean gestational age (GA), 28 weeks), 677 (5.9%, 95% CI 5.5% to 6.3%) developed type 1 ROP. Rate of type 1 ROP decreased with larger GA (28.8% for GA ≤23 weeks, 0.2% for GA of 31-32 weeks) and no infants with GA >32 weeks developed type 1 ROP. Type 1 ROP was first diagnosed at a median postmenstrual age (PMA) of 36 weeks (range 30-46 weeks) or postnatal age (PNA) of 11 weeks (range 5-21 weeks). The mean PMA at diagnosis of type 1 ROP increased with GA (35 weeks for GA of 22-24 weeks, 41 weeks for GA of 29-30 weeks), but the mean PNA at diagnosis of type 1 ROP was similar (11-13 weeks) across GA of 22-29 weeks. GA and BW dominate the association (area under the receiver operating characteristic curve=0.87, 95% CI 0.86 to 0.88). CONCLUSIONS: Type 1 ROP developed in about 6% of premature infants over wide time windows in terms of both PMA and PNA. BW and GA are the dominant risk factors for type 1 ROP, while other prenatal factors add minimal predictive power for type 1 ROP.

Symmetry of Disease in Retinopathy of Prematurity in the Postnatal Growth and Retinopathy of Prematurity (G-ROP) Study.

PURPOSE: To determine the symmetry of retinopathy of prematurity (ROP) between fellow eyes in a broad-risk cohort. METHODS: A retrospective cohort study, the Postnatal Growth and ROP (G-ROP) Study, of 7483 infants undergoing ROP examinations conducted at 29 hospitals in the United States and Canada from 2006 to 2012. The main outcomes were the symmetry for the highest stage and the most severe type (1, 2, not 1 or 2, no ROP) of ROP and disease course of the fellow eye when only one eye developed type 1. RESULTS: 93% of infants had eyes symmetric for the highest stage and 94% for type. Among 459 infants who developed type 1, 379 (82.6%) did so in both eyes simultaneously and were treated bilaterally; 44 (10%) were treated for type 1 in one eye and type 2 in the fellow eye; and 36 (8%) were treated unilaterally initially, of which 6 fellow eyes developed type 1 and were treated (4 within 2 weeks, all within 4 weeks); 5 developed type 2 and regressed; and 25 developed ROP less than type 1 or 2, which was treated in 13 cases and regressed spontaneously in 12 cases. CONCLUSIONS: ROP was highly symmetric between eyes with respect to the presence and severity of disease in a large, broad-risk cohort representative of infants undergoing ROP screening. When type 1 develops in one eye and type 2 in the fellow eye, the risk of progression to type 1 in the fellow eye appears very low if it has not occurred within 4 weeks.

Evaluation of the economic impact of modified screening criteria for retinopathy of prematurity from the Postnatal Growth and ROP (G-ROP) study.

IMPORTANCE: The Postnatal Growth and Retinopathy of Prematurity (G-ROP) Study showed that the addition of postnatal weight gain to birth weight and gestational age detects similar numbers of infants with ROP, but requires examination of fewer infants. OBJECTIVE: To determine the incremental cost-effectiveness of screening with G-ROP compared with conventional screening. DESIGN, SETTING AND PARTICIPANTS: We built a microsimulation model of a 1-year US birth cohort <32 weeks gestation, using data from the G-ROP study. We obtained resource utilization estimates from the G-ROP dataset and from secondary sources, and test characteristics from the G-ROP cohort. RESULTS: Among 78,281 infants nationally, screening with G-ROP detected ~25 additional infants with Type 1 ROP. This was accomplished with 36,233 fewer examinations, in 14,073 fewer infants, with annual cost savings of approximately US$2,931,980 through hospital discharge. CONCLUSIONS: Screening with G-ROP reduced costs while increasing the detection of ROP compared with current screening guidelines.

The Impact of Focused Ultrasound in Two Tumor Models: Temporal Alterations in the Natural History on Tumor Microenvironment and Immune Cell Response.

Image-guided focused ultrasound (FUS) has been successfully employed as an ablative treatment for solid malignancies by exposing immune cells to tumor debris/antigens, consequently inducing an immune response within the tumor microenvironment (TME). To date, immunomodulation effects of non-ablative pulsed-FUS (pFUS) on the TME are poorly understood. In this study, the temporal differences of cytokines, chemokines, and trophic factors (CCTFs) and immune cell populations induced by pFUS were interrogated in murine B16 melanoma or 4T1 breast cancer cells subcutaneously inoculated into C57BL/6 or BALB/c mice. Natural history growth characteristics during the course of 11 days showed a progressive increase in size for both tumors, and proteomic analysis revealed a shift toward an immunosuppressive TME. With respect to tumor natural growth, pFUS applied to tumors on days 1, 5, or 9 demonstrated a decrease in the growth rate 24 h post-sonication. Flow cytometry analysis of tumors, LNs, and Sp, as well as CCTF profiles, relative DNA damage, and adaptive T-cell localization within tumors, demonstrated dynamic innate and adaptive immune-modulation following pFUS in early time points of B16 tumors and in advanced 4T1 tumors. These results provide insight into the temporal dynamics in the treatment-associated TME, which could be used to evaluate an immunomodulatory approach in different tumor types.