Glia-derived secretory fatty acid binding protein Obp44a regulates lipid storage and efflux in the developing Drosophila brain.

Glia derived secretory factors play diverse roles in supporting the development, physiology, and stress responses of the central nervous system (CNS). Through transcriptomics and imaging analyses, we have identified Obp44a as one of the most abundantly produced secretory proteins from Drosophila CNS glia. Protein structure homology modeling and Nuclear Magnetic Resonance (NMR) experiments reveal Obp44a as a fatty acid binding protein (FABP) with a high affinity towards long-chain fatty acids in both native and oxidized forms. Further analyses demonstrate that Obp44a effectively infiltrates the neuropil, traffics between neuron and glia, and is secreted into hemolymph, acting as a lipid chaperone and scavenger to regulate lipid and redox homeostasis in the developing brain. In agreement with this essential role, deficiency of Obp44a leads to anatomical and behavioral deficits in adult animals and elevated oxidized lipid levels. Collectively, our findings unveil the crucial involvement of a noncanonical lipid chaperone to shuttle fatty acids within and outside the brain, as needed to maintain a healthy brain lipid environment. These findings could inspire the design of novel approaches to restore lipid homeostasis that is dysregulated in CNS diseases.

Automated Machine Learning for Predicting Diabetic Retinopathy Progression From Ultra-Widefield Retinal Images.

Importance: Machine learning (ML) algorithms have the potential to identify eyes with early diabetic retinopathy (DR) at increased risk for disease progression. Objective: To create and validate automated ML models (autoML) for DR progression from ultra-widefield (UWF) retinal images. Design, Setting and Participants: Deidentified UWF images with mild or moderate nonproliferative DR (NPDR) with 3 years of longitudinal follow-up retinal imaging or evidence of progression within 3 years were used to develop automated ML models for predicting DR progression in UWF images. All images were collected from a tertiary diabetes-specific medical center retinal image dataset. Data were collected from July to September 2022. Exposure: Automated ML models were generated from baseline on-axis 200° UWF retinal images. Baseline retinal images were labeled for progression based on centralized reading center evaluation of baseline and follow-up images according to the clinical Early Treatment Diabetic Retinopathy Study severity scale. Images for model development were split 8-1-1 for training, optimization, and testing to detect 1 or more steps of DR progression. Validation was performed using a 328-image set from the same patient population not used in model development. Main Outcomes and Measures: Area under the precision-recall curve (AUPRC), sensitivity, specificity, and accuracy. Results: A total of 1179 deidentified UWF images with mild (380 [32.2%]) or moderate (799 [67.8%]) NPDR were included. DR progression was present in half of the training set (590 of 1179 [50.0%]). The model's AUPRC was 0.717 for baseline mild NPDR and 0.863 for moderate NPDR. On the validation set for eyes with mild NPDR, sensitivity was 0.72 (95% CI, 0.57-0.83), specificity was 0.63 (95% CI, 0.57-0.69), prevalence was 0.15 (95% CI, 0.12-0.20), and accuracy was 64.3%; for eyes with moderate NPDR, sensitivity was 0.80 (95% CI, 0.70-0.87), specificity was 0.72 (95% CI, 0.66-0.76), prevalence was 0.22 (95% CI, 0.19-0.27), and accuracy was 73.8%. In the validation set, 6 of 9 eyes (75%) with mild NPDR and 35 of 41 eyes (85%) with moderate NPDR progressed 2 steps or more were identified. All 4 eyes with mild NPDR that progressed within 6 months and 1 year were identified, and 8 of 9 (89%) and 17 of 20 (85%) with moderate NPDR that progressed within 6 months and 1 year, respectively, were identified. Conclusions and Relevance: This study demonstrates the accuracy and feasibility of automated ML models for identifying DR progression developed using UWF images, especially for prediction of 2-step or greater DR progression within 1 year. Potentially, the use of ML algorithms may refine the risk of disease progression and identify those at highest short-term risk, thus reducing costs and improving vision-related outcomes.

Pre-Emptive Opioid-Sparing Medication Protocol Decreases Pain and Length of Hospital Stay in Children Undergoing Posterior Spinal Instrumented Fusion for Scoliosis.

Background: Poorly controlled post-operative pain following Posterior Spinal Instrumented Fusion (PSIF) for scoliosis may be associated with delayed ambulation and longer hospital stays. Multimodal analgesia use has been shown to provide superior analgesia with improved recovery and reduction of post-operative morbidity in other orthopedic subspecialties, but has not been described with pediatric patients undergoing spinal surgery. Objective: We describe a novel, pre-emptive, opioid-sparing pediatric pain medication protocol that is started two days prior to surgery, in accordance with first-order pharmacokinetics, and continued post-operatively until discharge with the goal of decreasing post-operative pain, improving early mobilization, and ultimately decreasing the patient's length of hospital stay. Methods: We retrospectively reviewed 116 PSIF cases from March 2014 to November 2017. Fifty-two patients received standard analgesia before August 2016, and 64 patients after August 2016 received the pre-emptive protocol consisting of a standardized combination of acetaminophen, celecoxib, and gabapentin two days prior to surgery and continued during their inpatient stay. Scheduled oxycodone and intravenous hydromorphone via patient controlled analgesia (PCA) were given to both groups equally during the post-operative hospital stay. We analyzed length of stay, total opioid consumption, and maximum pain scores per day from surgical to discharge date. Results: 116 patients were included: 64 patients in the pre-emptive group and 52 patients in the standard group. Length of hospital stay significantly differed, with means of 3.9 days in the pre-emptive group and 4.5 days in the standard analgesia group (p<0.05). Patients in the pre-emptive group recorded significantly lower maximal pain levels than those in the standard analgesia group on post-operative days #1 (4.9 vs. 5.8, p=0.0196), #3 (4.4 vs. 6.1, p=0.0006), and #4 (4.2 vs. 5.4, p=0.0393). Total post-operative morphine equivalents taken did not significantly differ between the two groups. Conclusion: This is a preliminary report demonstrating a significant decrease in maximal pain score and length of stay following PSIF on a cohort of patients receiving a novel pre-emptive opioid-sparing pain medication protocol based on first order pharmacokinetics. Future studies should investigate degree of mobilization and opioid consumption and maximal pain level after discharge from the hospital. Level of Evidence: III.

Continuous Epidural Analgesia (CEA) via Single Catheter Providing Profound Analgesia for Pediatric Patients Following Posterior Spinal Fusion (PSF) in Adolescent Idiopathic Scoliosis (AIS).

INTRODUCTION: Posterior spinal fusion (PSF) is a commonly performed orthopedic procedure to correct scoliosis in children. Continuous epidural analgesia (CEA) is a proposed means of providing analgesia following PSF. Whether a single epidural catheter with the tip in the upper thorax can provide adequate analgesia for PSF, which often spans the upper thoracic to lower lumbar regions, is unresolved in the literature. METHOD: In this single-center, retrospective study, we reviewed 69 consecutive patients undergoing PSF for adolescent idiopathic scoliosis (AIS) with CEA at our institution from October 1, 2020 to May 26, 2022. Data for the entire cohort was divided into two time intervals before and after epidural removal, group epidural (Epi) and group no epidural (No Epi). Daily intravenous and oral opioid morphine equivalents per kilogram (OME/kg) plus mean and maximal visual analogue pain scores (VAS 0-10) were recorded from post-anesthesia care unit (PACU) discharge to the end of postoperative day (POD) three.  Results: 57 patients were included in the study. Opioid usage was 4.5 times greater in the 19 hours following removal of the epidural catheter when compared to the entire period (mean 65 hours) the epidural was in place (Group Epi 0.154 OME/kg vs Group No Epi 0.690 OME/kg, p<0.001). 51% (29/57) of patients did not require opioids (intravenous or oral) while the epidural was in place, all patients required opioids after epidural removal. Mean opioid usage while the epidural was in place was 9.3 OME, equivalent to approximately 6 mg of oxycodone. Mean and maximum pain scores increased significantly after removal of the epidural on POD 3 (mean pain score: Epi 3.4 (1.8) vs No Epi 4.1 (1.7); p<0.001) (max pain score: Epi 4.9 (2.5) vs No Epi 6.3 (2.1); p<0.001).  Conclusions: This is the first study we are aware of to report pain scores and cumulative opioid requirements for PSF patients receiving CEA with a single epidural catheter before and after epidural removal. Opioid usage increased over four times in the 19 hours after epidural removal compared to the total opioid requirements while the epidural was infusing. Mean and maximum pain scores increased significantly after removal of the epidural on POD 3. This study firmly establishes that CEA with a single epidural catheter can provide profound analgesia for patients having PSF for AIS.

Performance of Automated Machine Learning for Diabetic Retinopathy Image Classification from Multi-field Handheld Retinal Images.

PURPOSE: To create and validate code-free automated deep learning models (AutoML) for diabetic retinopathy (DR) classification from handheld retinal images. DESIGN: Prospective development and validation of AutoML models for DR image classification. PARTICIPANTS: A total of 17 829 deidentified retinal images from 3566 eyes with diabetes, acquired using handheld retinal cameras in a community-based DR screening program. METHODS: AutoML models were generated based on previously acquired 5-field (macula-centered, disc-centered, superior, inferior, and temporal macula) handheld retinal images. Each individual image was labeled using the International DR and diabetic macular edema (DME) Classification Scale by 4 certified graders at a centralized reading center under oversight by a senior retina specialist. Images for model development were split 8-1-1 for training, optimization, and testing to detect referable DR ([refDR], defined as moderate nonproliferative DR or worse or any level of DME). Internal validation was performed using a published image set from the same patient population (N = 450 images from 225 eyes). External validation was performed using a publicly available retinal imaging data set from the Asia Pacific Tele-Ophthalmology Society (N = 3662 images). MAIN OUTCOME MEASURES: Area under the precision-recall curve (AUPRC), sensitivity (SN), specificity (SP), positive predictive value (PPV), negative predictive value (NPV), accuracy, and F1 scores. RESULTS: Referable DR was present in 17.3%, 39.1%, and 48.0% of the training set, internal validation, and external validation sets, respectively. The model's AUPRC was 0.995 with a precision and recall of 97% using a score threshold of 0.5. Internal validation showed that SN, SP, PPV, NPV, accuracy, and F1 scores were 0.96 (95% confidence interval [CI], 0.884-0.99), 0.98 (95% CI, 0.937-0.995), 0.96 (95% CI, 0.884-0.99), 0.98 (95% CI, 0.937-0.995), 0.97, and 0.96, respectively. External validation showed that SN, SP, PPV, NPV, accuracy, and F1 scores were 0.94 (95% CI, 0.929-0.951), 0.97 (95% CI, 0.957-0.974), 0.96 (95% CI, 0.952-0.971), 0.95 (95% CI, 0.935-0.956), 0.97, and 0.96, respectively. CONCLUSIONS: This study demonstrates the accuracy and feasibility of code-free AutoML models for identifying refDR developed using handheld retinal imaging in a community-based screening program. Potentially, the use of AutoML may increase access to machine learning models that may be adapted for specific programs that are guided by the clinical need to rapidly address disparities in health care delivery. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found after the references.

Effect of gabapentin on length of stay, opioid use, and pain scores in posterior spinal fusion for adolescent idiopathic scoliosis: a retrospective review across a multi-hospital system.

BACKGROUND: Gabapentin has been adopted in Enhanced Recovery After Surgery protocols as a means to reduce opioid consumption while maintaining adequate post-operative analgesia. The purpose of our study was to review and compare changes in length of stay, opioid use, and patient reported pain scores after the addition of gabapentin into five, distinct pain protocols for posterior spinal fusion in adolescent idiopathic scoliosis. METHODS: A retrospective review was completed using a database of electronic medical data from a single pediatric orthopedic healthcare system that was queried for patients with adolescent idiopathic scoliosis who underwent first-time posterior spinal fusion. Perioperative data including demographics, hospital length of stay, surgical details, opioid use, patient reported pain scores, and non-opioid analgesic use were collected. RESULTS: From December 2012 to February 2019, 682 hospitalizations for posterior spinal fusion in adolescent idiopathic scoliosis were identified with complete inpatient data; 49% were administered gabapentin. For the gabapentin cohort, the system saw no statistically significant effect on length of stay or pain averaged over POD#0-3. Opioid use was statistically lower averaged over POD#0-3. Individual sites saw variation on length of stay and opioid use compared to the system. CONCLUSION: In conclusion, system-wide data showed gabapentin containing protocols reduced opioid use while maintaining clinically equivalent analgesia. However, variations of individual site results make it difficult to conclude the degree to which gabapentin were responsible for this effect.

Survey Response Rates to a Self-Initiated Longitudinal Survey Accessed by a Quick Response Code in Six Different Regions of the United States.

Background A quick response (QR) code allows rapid access to an online survey via a smartphone and may improve response rates for web-based surveys. We report the response rates for a QR code-based, self-initiated, longitudinal survey of opioid use and pain scores following hospital discharge in pediatric surgical patients. Methodology All parents of pediatric patients who underwent surgery at one of six pediatric medical facilities were asked to participate in the study from October 5, 2020, until July 15, 2021. Those who chose to participate accessed the initial enrollment survey using a QR code on a handout provided. The next day they received an emailed link to a daily survey until their child was not requiring opioids and had pain scores of less than 4 for the previous 48 hours. Results A total of 1,759 families were asked to participate in the study. The parents of 44 patients completed the initial enrollment survey by accessing the QR code (response rate of 2.5%). Of those who completed the initial survey, 67% were lost to follow-up during the survey series. Conclusions We found an extremely low response rate for a self-initiated survey accessed by QR code. Additionally, we found a drop in the response rate with each successive daily email-based survey. At the end of the survey series, the majority of the initial participants had dropped out. We recommend using alternative modalities (informed consent, telephone call, weekly surveys) for initiating and delivering surveys to improve response rates for similarly designed studies.

RODFormer: High-Precision Design for Rotating Object Detection with Transformers.

Aiming at the problem of Transformers lack of local spatial receptive field and discontinuous boundary loss in rotating object detection, in this paper, we propose a Transformer-based high-precision rotating object detection model (RODFormer). Firstly, RODFormer uses a structured transformer architecture to collect feature information of different resolutions to improve the collection range of feature information. Secondly, a new feed-forward network (spatial-FFN) is constructed. Spatial-FFN fuses the local spatial features of 3 × 3 depthwise separable convolutions with the global channel features of multilayer perceptron (MLP) to solve the deficiencies of FFN in local spatial modeling. Finally, based on the space-FFN architecture, a detection head is built using the CIOU-smooth L1 loss function and only returns to the horizontal frame when the rotating frame is close to the horizontal, so as to alleviate the loss discontinuity of the rotating frame. Ablation experiments of RODFormer on the DOTA dataset show that the Transformer-structured module, the spatial-FFN module and the CIOU-smooth L1 loss function module are all effective in improving the detection accuracy of RODFormer. Compared with 12 rotating object detection models on the DOTA dataset, RODFormer has the highest average detection accuracy (up to 75.60%), that is, RODFormer is more competitive in rotating object detection accuracy.

Prolonged Use of a Continuous Peripheral Nerve Block Catheter for Analgesia after Pediatric Foot and Ankle Surgery.

Continuous peripheral nerve blocks (CPNB) have a variety of indications and have been shown to be a safe and effective means of minimizing pain postoperatively. Early studies have indicated duration of catheter use greater than 48 hours as a main contributor to infection risk in CPNBs. Recent studies, though, have suggested that the risk of infection does not increase until 4 days after insertion. In the following case report, we recount our experience in using a continuous popliteal-sciatic peripheral nerve block for postoperative pain control in a pediatric patient following calcaneal and first metatarsal osteotomy. The catheter remained in place for 65 hours postoperatively without signs of local inflammation or infection. The prolonged CPNB use resulted in a significant decrease in postoperative opioid use and pain and increase in patient satisfaction when compared to the same procedure done one year prior on the opposite foot.

CFH Y402H polymorphism is associated with elevated vitreal GM-CSF and choroidal macrophages in the postmortem human eye.

PURPOSE: Age-related macular degeneration (AMD) is the leading cause of irreversible blindness in people 50 years of age or older in developed countries. The homozygous CC genotype in the complement factor H (CFH) Y402H single nucleotide polymorphism (SNP; rs1061170) is widely recognized as a risk factor for the development of AMD. In this study, we examined vitreal levels of granulocyte macrophage colony-stimulating factor (GM-CSF), a hematopoietic cytokine, and macrophages in the choroid of postmortem human eyes genotyped for the CFH Y402H SNP. METHODS: Twenty-two pairs of postmortem, non-diseased, human donor eyes were obtained. The vitreous and retinal tissues of the left eyes were collected for GM-CSF level measurement and CFH Y402H genotyping, respectively. The right eyes were paraffin-embedded and sectioned for immunohistochemistry using a macrophage and microglia marker, CD68. Cell cultures of RPE cells were stimulated with complement C3a, C5a, 4-hydroxynonenal (HNE), or tumor necrosis factor alpha (TNF-α), and GM-CSF expression was measured with a suspension assay or quantitative PCR. RESULTS: Eyes genotyped with the CC or the CT risk variant of the CFH Y402H SNP showed significantly increased levels of GM-CSF in the vitreous compared to eyes with the protective TT variant (mean ± standard error of mean, 607.54±85.83 pg/ml or 656.32±15.20 pg/ml versus 286.69±81.96 pg/ml, p<0.05). The choroid of eye tissues genotyped with the CC variant showed higher levels of CD68 immunoreactivity than the tissues genotyped with the TT variant (p<0.05). The GM-CSF levels detected in the supernatant of RPE cells in culture treated with HNE or TNF-α were significantly higher compared to the non-treated control (145.88±5.06 pg/ml and 149.32±3.76 pg/ml versus 123.27±4.05 pg/ml, p<0.05). Furthermore, the gene expression of GM-CSF detected in the lysate of RPE cells stimulated with complement C3a or C5a showed significantly increased fold changes compared to the non-treated control (C3a: 2.38±0.31 fold, p<0.05; C5a: 2.84±0.54 fold, p<0.01). CONCLUSIONS: Our data showed a relationship between the CFH Y402H polymorphism and GM-CSF levels in the vitreous and accumulation of choroidal macrophages in the postmortem eye. These data suggest that the at-risk variant of the CFH gene may contribute to the dysregulation of proinflammatory cytokines locally in the eye.

Core-shell α-Fe2O3@α-MoO3 nanorods as lithium-ion battery anodes with extremely high capacity and cyclability.

α-Fe2O3 nanoparticles are uniformly coated on the surface of α-MoO3 nanorods through a two-step hydrothermal synthesis method. As the anode of a lithium-ion battery, α-Fe2O3@α-MoO3 core-shell nanorods exhibit extremely high lithium-storage performance. At a rate of 0.1 C (10 h per half cycle), the reversible capacity of α-Fe2O3@α-MoO3 core-shell nanorods is 1481 mA h g(-1) and a value of 1281 mA h g(-1) is retained after 50 cycles, which is much higher than that retained by bare α-MoO3 and α-Fe2O3 and higher than traditional theoretical results. Such a good performance can be attributed to the synergistic effect between α-Fe2O3 and α-MoO3 , the small size effect, one-dimensional nanostructures, short paths for lithium diffusion, and interface spaces. Our results reveal that core-shell nanocomposites have potential applications as high-performance lithium-ion batteries.

Technical brief: isolation of total DNA from postmortem human eye tissues and quality comparison between iris and retina.

BACKGROUND: Recent genomic technologies have propelled our understanding of the mechanisms underlying complex eye diseases such as age-related macular degeneration (AMD). Genotyping postmortem eye tissues for known single nucleotide polymorphisms (SNPs) associated with AMD may prove valuable, especially when combined with information obtained through other methods such as immunohistochemistry, western blot, enzyme-linked immunosorbent assay (ELISA), and proteomics. Initially intending to genotype postmortem eye tissues for AMD-related SNPs, our group became interested in isolating and comparing the quality of DNA from the iris and retina of postmortem donor eyes. Since there is no previously published protocol in the literature on this topic, we present a protocol suitable for isolating high-quality DNA from postmortem eye tissues for genomic studies. METHODS: DNA from 33 retinal samples and 35 iris samples was extracted using the phenol-chloroform-isoamyl method from postmortem donor eye tissues. The quantity of DNA was measured with a spectrophotometer while the quality was checked using gel electrophoresis. The DNA samples were then amplified with PCR for the complement factor H (CFH) gene. The purified amplified products were then genotyped for the SNPs in the CFH gene. RESULTS: Regarding concentration, the retina yielded 936 ng/µl of DNA, while the iris yielded 78 ng/µl of DNA. Retinal DNA was also purer than iris DNA (260/280=1.78 vs. 1.46, respectively), and produced superior PCR results. Retinal tissue yielded significantly more DNA than the iris tissue per mg of sample (21.7 ng/µl/mg vs. 7.42 ng/µl/mg). Retinal DNA can be readily amplified with PCR, while iris DNA can also be amplified by adding bovine serum albumin. Overall, retinal tissues yielded DNA of superior quality, quantity, and suitability for genotyping and genomic studies. CONCLUSIONS: The protocol presented here provides a clear and reliable method for isolating total DNA from postmortem eye tissues. Retinal tissue provides DNA of excellent quantity and quality for genotyping and downstream genomic studies. However, DNA isolated from iris tissues, and treated with bovine serum albumin, may also be a valuable source of DNA for genotyping and genomic studies.