Aqueous VEGF-A Levels as a Liquid Biopsy Biomarker of Retinoblastoma Vitreous Seed Response to Therapy.

Purpose: Regression of retinoblastoma vitreous seeds (VS) during intravitreal chemotherapy can be delayed, resulting in supernumerary injections. Similarly, VS relapse may not be clinically evident at first. A predictive biomarker of tumor regression and relapse could help guide real-time clinical decision making. Retinoblastoma is an oxygen-sensitive tumor; paradoxically, VS survive in the hypoxic vitreous. We hypothesized that VS elaborate pro-angiogenic cytokines. The purpose was to determine if pro-angiogenic cytokine signatures from aqueous humor could serve as a biomarker of VS response to treatment. Methods: Multiplex ELISA was performed on aqueous from rabbit eyes with human retinoblastoma VS xenografts to identify expressed proangiogenic cytokines and changes in aqueous cytokine levels during intravitreal treatment were determined. Confirmatory RNAscope in situ hybridization for VEGF-A was performed on human retinoblastoma tumor sections and VS xenografts from rabbits. For human eyes undergoing intravitreal chemotherapy, serial aqueous VEGF-A levels measured via VEGF-A-specific ELISA were compared to clinical response. Results: VEGF-A was highly expressed in human retinoblastoma VS in the xenograft model, and was the only proangiogenic cytokine that correlated with VS disease burden. In rabbits, aqueous VEGF-A levels decreased in response to therapy, consistent with quantitative VS reduction. In patients, aqueous VEGF-A levels associated with clinical changes in disease burden (regression, stability, or relapse), with changes in VEGF-A levels correlating with clinical response. Conclusions: Aqueous VEGF-A levels correlate with extent of retinoblastoma VS, suggesting that aqueous VEGF-A may serve as a predictive molecular biomarker of treatment response.

Perception of Physicians' Notes Among Parents of Different Health Literacy Levels.

OBJECTIVES: To explore the benefits and challenges of accessing physicians' notes during pediatric hospitalization across parents of different health literacy levels. METHODS: For this secondary analysis, we used semi-structured interviews conducted with 28 parents on their impressions of having access to their child's care team notes on a bedside table. Three researchers used thematic analysis to develop a codebook, coded interview data, and identified themes. Parent interviews and respective themes were then dichotomized into proficient or limited health literacy groups and compared. RESULTS: Nine themes were identified in this secondary analysis: 6 benefits and 3 challenges. All parents identified more benefits than challenges, including that the notes served as a recap of information and memory aid and increased autonomy, empowerment, and advocacy for their child. Both groups disliked receiving bad news in notes before face-to-face communication. Parents with proficient literacy reported that notes allowed them to check information accuracy, but that notes may not be as beneficial for parents with lower health literacy. Parents with limited literacy uniquely identified limited comprehension of medical terms but indicated that notes facilitated their understanding of their child's condition, increased their appreciation for their health care team, and decreased their anxiety, stress, and worry. CONCLUSIONS: Parents with limited health literacy uniquely reported that notes improved their understanding of their child's care and decreased (rather than increased) worry. Reducing medical terminology may be one equitable way to increase note accessibility for parents across the health literacy spectrum.

Laser Epilation as an Adjunct to Standard Care in Reducing Pilonidal Disease Recurrence in Adolescents and Young Adults: A Randomized Clinical Trial.

Importance: Recurrence continues to be a significant challenge in the treatment and management of pilonidal disease. Objective: To compare the effectiveness of laser epilation (LE) as an adjunct to standard care vs standard care alone in preventing recurrence of pilonidal disease in adolescents and young adults. Design, Setting, and Participants: This was a single-institution, randomized clinical trial with 1-year follow-up conducted from September 2017 to September 2022. Patients aged 11 to 21 years with pilonidal disease were recruited from a single tertiary children's hospital. Intervention: LE and standard care (improved hygiene and mechanical or chemical depilation) or standard care alone. Main Outcomes and Measures: The primary outcome was the rate of recurrence of pilonidal disease at 1 year. Secondary outcomes assessed during the 1-year follow-up included disability days, health-related quality of life (HRQOL), health care satisfaction, disease-related attitudes and perceived stigma, and rates of procedures, surgical excisions, and postoperative complications. Results: A total of 302 participants (median [IQR] age, 17 [15-18] years; 157 male [56.1%]) with pilonidal disease were enrolled; 151 participants were randomly assigned to each intervention group. One-year follow-up was available for 96 patients (63.6%) in the LE group and 134 (88.7%) in the standard care group. The proportion of patients who experienced a recurrence within 1 year was significantly lower in the LE treatment arm than in the standard care arm (-23.2%; 95% CI, -33.2 to -13.1; P < .001). Over 1 year, there were no differences between groups in either patient or caregiver disability days, or patient- or caregiver-reported HRQOL, health care satisfaction, or perceived stigma at any time point. The LE group had significantly higher Child Attitude Toward Illness Scores (CATIS) at 6 months (median [IQR], 3.8 [3.4-4.2] vs 3.6 [3.2-4.1]; P = .01). There were no differences between groups in disease-related health care utilization, disease-related procedures, or postoperative complications. Conclusions and Relevance: LE as an adjunct to standard care significantly reduced 1-year recurrence rates of pilonidal disease compared with standard care alone. These results provide further evidence that LE is safe and well tolerated in patients with pilonidal disease. LE should be considered a standard treatment modality for patients with pilonidal disease and should be available as an initial treatment option or adjunct treatment modality for all eligible patients. Trial Registration: ClinicalTrials.gov Identifier: NCT03276065.

Adolescent Access to Clinicians' Notes: Adolescent, Parent, and Clinician Perspectives.

PURPOSE: In 2021, federal guidelines mandated that health-care organizations share clinicians' notes with patients to increase information transparency. While findings indicate advantages for adult patients, less is known about note-sharing from the viewpoint of adolescents. This study aims to identify adolescent, parent, and clinician perspectives on the anticipated benefits and concerns of giving adolescents access to clinicians' notes and strategies to support note-sharing in this population. METHODS: We conducted six focus groups with adolescents, parents, and clinicians at a children's hospital from May to October 2021. A semistructured facilitator guide captured participant perspectives of note-sharing benefits, concerns, and strategies. Two researchers independently coded and analyzed transcript data using thematic analysis; a third researcher reconciled discrepancies. RESULTS: 38 stakeholders (17 adolescents, 10 parents, and 11 clinicians) described four benefits, three concerns, and four implementation strategies regarding adolescent note-sharing. Potential benefits included adolescents using notes to remember and reinforce the visit, gaining knowledge about their health, strengthening the adolescent-clinician relationship, and increasing agency in health care decisions. Concerns included notes leading to a breach in confidentiality, causing negative emotions, and becoming less useful for clinicians. Strategies included making note-sharing more secure, optimizing note layout and content, setting clear expectations, and having a portion of the note for clinician use only. DISCUSSION: Stakeholders suggest multiple strategies to optimize the implementation of note-sharing to support adolescent patients, parents, and clinicians as hospitals work to comply with federal regulations. These strategies may reinforce the potential benefits and mitigate the challenges of sharing notes with adolescent patients.

A Rare Case of Penoscrotal Webbing and Extensive Hernias: An Anatomical Report With Genetic Insights.

During a routine anatomical dissection of an 81-year-old male cadaver received through the Gift Body Program of Saint Louis University School of Medicine (SLU SOM), a massive bulging in the abdominal area was observed that was consistent with numerous hernia repairs noted in the donor's self-reported medical history. Gross anatomical dissection of the cadaveric body revealed extensive herniation of portions of the small intestine and peritoneal sac along the costal margin and extending to the left aspect of the abdomen. Additionally, an uncircumcised phallus was buried within the suprapubic fat pad and demonstrated simple, grade III penoscrotal webbing (PSW), creating an impression of micropenis presence. To gain additional insights into the current case, analysis of the coding regions (exomes) of DNA procured from the body for putative genetic variants was performed using next-generation sequencing (NGS) technology. This analysis revealed 110 rare (minor allele frequency (MAF) ≤ 0.01), pathologic/deleterious genetic mutations. The most relevant variants to this case were the ones associated with male sexual development, BMP1 and BMP4; connective tissue development, COL3A1 and COL5A3; cilia morphogenesis and function, DNAH5 and MAPK15; as well as hormonal homeostasis, ESR1. Direct involvement of BMP1 both in male sexual development and hernia genesis makes it a strong candidate for linking the two pathologies, PSW and multiple hernias, observed in the present case. Yet the presence of a group of mutated genes linked to myopathies (ITGA7, NRAP, POLM, SCN5A, XIRP2) and muscular dystrophy (ITGA7) raises a question about the involvement of these muscular pathologies in hernia genesis and unsuccessful hernia repairs associated with the current case.

Effect of the essential amino acid-nitrogen to total nitrogen ratio on lysine requirement for nitrogen retention in growing pigs.

Low protein diets supplemented with essential amino acids (EAA) fed to pigs reduce the excess supply of EAA and nitrogen (N). However, low protein diets may become limiting in non-essential amino acids (NEAA) and N, thus affecting the utilization of EAA for N retention. It has been suggested that the EAA-N:total N (E:T) ratio can give an indication of dietary N sufficiency. An N-balance study was conducted to determine the effect of E:T ratio on the Lys requirement for maximum N retention. A total of 80 growing barrows (19.3 ±â€…0.21 kg initial body weight) were randomly assigned to 1 of 10 diets (n = 8) in 8 blocks in a 2 × 5 factorial arrangement. Diets consisted of a low ratio (LR; E:T of 0.33) or a high ratio (HR; E:T of 0.36) with graded Lys content (0.82%, 0.92%, 1.02%, 1.12%, and 1.22% standardized ileal digestible [SID]). After a 7-d adaptation, a 4-d N-balance collection was conducted. Blood samples were obtained on d 2 of the collection period 2 h after the morning meal for plasma urea N (PUN) analysis. Data were analyzed using the MIXED model procedure with fixed effects of ratio (n = 2), Lys (n = 5), and their interactions. The experimental block (room) was included as a random effect (n = 8). The SID Lys requirement was estimated using PROC NLIN linear broken-line breakpoint model. There was a significant interaction between E:T ratio and Lys (P < 0.01), where LR diets had a higher N retention than HR diets, while increasing Lys linearly increased N retention (P = 0.01) in both HR and LR diets. The marginal efficiency of utilizing SID Lys (P < 0.01) reduced with increasing Lys content, while the efficiency of utilizing N (P < 0.05) increased as Lys increased. The SID Lys required to maximize N retention of pigs fed HR diets was estimated at 1.08% (R2 = 0.61) and LR diets at 1.21% (R2 = 0.80). The current results indicate that N may be limiting in diets with a high E:T ratio, limiting N retention. Supplying additional dietary N, as intact protein, can increase N retention, resulting in a greater Lys requirement.

Low protein diets supplemented with essential amino acids (EAA) can improve growth performance, but dietary non-essential amino acids (NEAA) and nitrogen (N) content may be limiting factors. This limitation may ultimately affect the efficient utilization of EAA for optimal N retention and growth performance. As a benchmark, appropriate quantities of EAA and total N (TN) must be provided, using the EAA-N to TN ratio (E:T) to indicate that both are supplied in sufficient amounts. The present study generally observed a linear increase in N retention with increasing dietary Lys, and N retention was greater in the low E:T as compared with high E:T diets. A greater Lys requirement was observed in the low E:T compared with the high E:T-fed pigs. A low E:T ratio with Lys above current recommendations is warranted to maximize N retention.

Disseminated blastomycosis presenting with genitourinary abscesses.

A 25 year old male presented with several weeks of fevers and testicular pain. Workup demonstrated scrotal and prostatic abscesses. Fluid from these following surgical drainage revealed Blastomyces dermatitidis. He was treated with 12 months of oral anti-fungal therapy and repeat Blastomyces urine antigen was negative at follow up. While disseminated blastomycosis most commonly presents with pulmonary and cutaneous manifestations, genitourinary symptoms are rarely seen, but important to consider.

A Unique Presentation of an Upper Subscapular Nerve Variation Accompanied by an Accessory Subscapular Artery.

The presence of an upper subscapular nerve branching from the posterior division of the superior trunk, and it being accompanied by an accessory subscapular artery, is of both clinical and surgical significance. During routine dissection of the root of the neck in a 75-year-old male cadaver, an unusual branch from the third part of the right subclavian artery was observed lateral to the dorsal scapular artery. Continued dissection revealed that this artery traveled between the anterior divisions of the superior and middle trunks of the brachial plexus before traveling alongside a nerve from the posterior division of the superior trunk of the brachial plexus. This artery and nerve descended on the anterior aspect of the subscapularis muscle before piercing into its muscle belly. We believe this to be a previously unreported unique variation of the upper subscapular nerve that is accompanied by an accessory subscapular artery on its course to the subscapularis muscle. Knowledge of anatomical variations like this may lead to decreased complications in nerve blocks and surgical procedures related to the shoulder.

Sexual and reproductive health education for patients with myelomeningocele.

AIM: To evaluate the sexual and reproductive health education received by patients with myelomeningocele, the most severe form of spina bifida. METHOD: A survey designed to assess the sexual and reproductive health education given by a healthcare provider to patients with myelomeningocele was offered to all English-speaking patients aged 12 years or older with a myelomeningocele clinic visit. RESULTS: In total, 67 surveys were completed. Menstruation and menstrual management were discussed at a rate of 85% in females. Few patients had discussions with a provider about fertility (42%), sexuality (37%), risk of sexually transmitted infections (45%), or had a relationship with a reproductive healthcare provider (54%). Differences by sex were observed for contraceptive education. The rate of discussions increased with age. A total of 67% of female patients and 33% of male patients requested a referral to a reproductive healthcare provider. INTERPRETATION: Sexual and reproductive health education is part of comprehensive care for all patients and those with disabilities should not be excluded. The lack of consistent education received by patients supports the need for increased attention to this topic. We encourage multidisciplinary myelomeningocele clinics to establish a process for delivering complete and patient-specific sexual and reproductive health education.

Parent Perspectives on Sharing Pediatric Hospitalization Clinical Notes.

BACKGROUND AND OBJECTIVES: Federal guidelines mandate that hospitals provide patients and caregivers with free, online access to their physician's clinical notes. This study sought to identify parent perceptions of the benefits and challenges of real-time note access during their child's hospitalization and strategies to optimize note-sharing at the bedside. METHODS: This qualitative study was conducted with parents of children aged <12 years admitted to a pediatric hospitalist service in April 2019. Parents were given access to their child's admission and daily progress notes on a bedside tablet (iPad), and interviewed upon discharge. In-depth, 60-minute interviews were audio-recorded and transcribed. Two researchers developed and refined a codebook and coded data inductively and deductively with validation by a third researcher. Thematic analysis was used to identify emergent themes. RESULTS: The 28 interviewed parents described 6 benefits of having note access, which: provided a recap and improved their knowledge about their child's care plan, enhanced communication, facilitated empowerment, increased autonomy, and incited positive emotions. Potential challenges included that notes: caused confusion, hindered communication with the health care team, highlighted problems with note content, and could incite negative emotions. Parents recommended 4 strategies to support sharing: provide preemptive communication about expectations, optimize the note release process, consider parent-friendly note template modifications, and offer informational resources for parents. CONCLUSIONS: Findings provide a framework for operationalizing note-sharing with parents during hospitalization. These results have important implications for hospitals working to comply with federal regulations and researchers assessing the effects of increased information transparency in the inpatient setting.

Use and Accuracy of Intraoperative Frozen Section Analysis for Ovarian Masses in Children and Adolescents.

STUDY OBJECTIVE: Describe the current practice patterns and diagnostic accuracy of frozen section (FS) pathology for children and adolescents with ovarian masses DESIGN: Prospective cohort study from 2018 to 2021 SETTING: Eleven children's hospitals PARTICIPANTS: Females age 6-21 years undergoing surgical management of an ovarian mass INTERVENTIONS: Obtaining intraoperative FS pathology MAIN OUTCOME MEASURE: Diagnostic accuracy of FS pathology RESULTS: Of 691 patients who underwent surgical management of an ovarian mass, FS was performed in 27 (3.9%), of which 9 (33.3%) had a final malignant pathology. Among FS patients, 12 of 27 (44.4%) underwent ovary-sparing surgery, and 15 of 27 (55.5%) underwent oophorectomy with or without other procedures. FS results were disparate from final pathology in 7 of 27 (25.9%) cases. FS had a sensitivity of 44.4% and specificity of 94.4% for identifying malignancy, with a c-statistic of 0.69. Malignant diagnoses missed on FS included serous borderline tumor (n = 1), mucinous borderline tumor (n = 2), mucinous carcinoma (n = 1), and immature teratoma (n = 1). FS did not guide intervention in 10 of 27 (37.0%) patients: 9 with benign FS underwent oophorectomy, and 1 with malignant FS did not undergo oophorectomy. Of the 9 patients who underwent oophorectomy with benign FS, 5 (55.6%) had benign and 4 (44.4%) had malignant final pathology. CONCLUSIONS: FSs are infrequently utilized for pediatric and adolescent ovarian masses and could be inaccurate for predicting malignancy and guiding operative decision-making. We recommend continued assessment and refinement of guidance before any standardization of use of FS to assist with intraoperative decision-making for surgical resection and staging in children and adolescents with ovarian masses.

The effects of administering different metaphylactic antimicrobials on growth performance and health outcomes of high-risk, newly received feedlot steers.

Bovine respiratory disease (BRD) is the primary animal health concern facing feedlot producers. Many antimicrobial mitigation strategies are available, but few studies have compared feedlot performance during both the receiving and finishing periods following application of different antimicrobials used as metaphylaxis at arrival. The objective of this study was to compare antimicrobial metaphylaxis methods on clinical health and growth performance across both the receiving and finishing periods. A total of 238 multiple-sourced steers in two source blocks were used in a generalized complete block design. The four treatments included: 1) a negative control, 5 mL of sterile saline injected subcutaneously (CON); 2) subcutaneous administration of florfenicol at 40 mg/kg of BW (NUF); 3) subcutaneous administration of ceftiofur in the posterior aspect of the ear at 6.6 mg/kg of BW (EXC); and 4) subcutaneous administration of tulathromycin at 2.5 mg/kg of BW (DRA). The morbidity rate for the first treatment of BRD was decreased for the DRA and EXC treatments compared to CON and NUF (P < 0.01). Additionally, average daily gain (ADG), dry matter intake (DMI), and gain-to-feed (G:F) were greater (P ≤ 0.02) in the DRA treatment during the receiving period compared to all other treatments. The ADG was also greater (P < 0.05) for EXC than the CON treatment throughout the finishing period. Nonetheless, other growth performance variables did not differ among metaphylactic treatments during the finishing period (P ≥ 0.14). Likewise, no differences in carcass characteristics or liver abscess score were observed (P ≥ 0.18). All complete blood count (CBC) variables were affected by day (P ≤ 0.01) except mean corpuscular hemoglobin concentration (P = 0.29). Treatment × time interactions were observed for platelet count, white blood cell (WBC) count, monocyte count and percentage, and lymphocyte percentage (P ≤ 0.03). However, there were no observed hematological variables that differed among treatment (P ≥ 0.10). The results indicate that some commercially available antimicrobials labeled for metaphylactic use are more efficacious than others in decreasing morbidity rate.

Metaphylactic antimicrobial effects on occurrences of antimicrobial resistance in Salmonella enterica, Escherichia coli and Enterococcus spp. measured longitudinally from feedlot arrival to harvest in high-risk beef cattle.

AIMS: Our objective was to determine how injectable antimicrobials affected populations of Salmonella enterica, Escherichia coli and Enterococcus spp. in feedlot cattle. METHODS AND RESULTS: Two arrival date blocks of high-risk crossbred beef cattle (n = 249; mean BW = 244 kg) were randomly assigned one of four antimicrobial treatments administered on day 0: sterile saline control (CON), tulathromycin (TUL), ceftiofur (CEF) or florfenicol (FLR). Faecal samples were collected on days 0, 28, 56, 112, 182 and study end (day 252 for block 1 and day 242 for block 2). Hide swabs and subiliac lymph nodes were collected the day before and the day of harvest. Samples were cultured for antimicrobial-resistant Salmonella, Escherichia coli and Enterococcus spp. The effect of treatment varied by day across all targeted bacterial populations (p ≤ 0.01) except total E. coli. Total E. coli counts were greatest on days 112, 182 and study end (p ≤ 0.01). Tulathromycin resulted in greater counts and prevalence of Salmonella from faeces than CON at study end (p ≤ 0.01). Tulathromycin and CEF yielded greater Salmonella hide prevalence and greater counts of 128ERYR E. coli at study end than CON (p ≤ 0.01). No faecal Salmonella resistant to tetracyclines or third-generation cephalosporins were detected. Ceftiofur was associated with greater counts of 8ERYR Enterococcus spp. at study end (p ≤ 0.03). By the day before harvest, antimicrobial use did not increase prevalence or counts for all other bacterial populations compared with CON (p ≥ 0.13). CONCLUSIONS: Antimicrobial resistance (AMR) in feedlot cattle is not caused solely by using a metaphylactic antimicrobial on arrival, but more likely a multitude of environmental and management factors.

Effects of physical activity and feed and water restriction at reimplanting time on feed intake patterns, growth performance, and carcass characteristics of finishing beef steers.

In the feedlot, there can be a decrease in dry matter intake (DMI) associated with reimplanting cattle that negatively affects growth performance. This study was conducted to determine the mechanisms causing a decrease in DMI after reimplanting and identify a strategy to mitigate the decrease. Crossbred steers (n = 200; 10 pens/treatment; initial bodyweight [BW] = 386 ±â€…4.9 kg) were used in a randomized complete block design experiment. Cattle were implanted with Revalor-IS on day 0. Treatments included a Revalor-200 implant on day 90 before feeding with the following management practices imposed: 1) steers were returned to their home pen immediately after reimplant (PCON); 2) steers were placed in pens and restricted from feed and water for 4 h (RES); 3) steers were walked an additional 805 m after reimplant and then returned home (LOC); 4) steers were restricted from feed and water for 4 h and walked an additional 805 m (RES + LOC); 5) steers were given an oral bolus of Megasphaera elsdenii (Lactipro; MS Biotec, Wamego, KS) and were restricted from feed and water for 4 h, and then walked an additional 805 m (LACT). One hundred steers were given an ear tag to record minutes of activity (ESense Flex Tags, Allflex Livestock Intelligence, Madison, WI). As a percentage of BW, DMI was 5% greater (P = 0.01) from reimplant to end for PCON vs. RES, LOC, and RES + LOC treatments. Likewise, as a percentage of BW, DMI was 6.6% greater (P = 0.03) from reimplant to end and 4.0% greater (P = 0.05) overall for the PCON treatment vs. the LOC treatment. Overall, DMI as a percentage of BW was 3.3% greater (P = 0.02) for PCON vs. RES, LOC, and RES + LOC treatments. There was an increase in G:F from reimplant to end (P = 0.05) for RES + LOC vs. the LACT treatment. From these data, we conclude that restricting cattle from feed and water for 4 h after reimplanting did not alter subsequent DMI. Increasing locomotion had the greatest negative effect on DMI and growth performance. Management strategies to decrease locomotion associated with reimplanting would be beneficial to DMI and overall growth performance of finishing beef steers.

Evaluation of intravitreal topotecan dose levels, toxicity and efficacy for retinoblastoma vitreous seeds: a preclinical and clinical study.

BACKGROUND: Current melphalan-based intravitreal regimens for retinoblastoma (RB) vitreous seeds cause retinal toxicity. We assessed the efficacy and toxicity of topotecan monotherapy compared with melphalan in our rabbit model and patient cohort. METHODS: Rabbit experiments: empiric pharmacokinetics were determined following topotecan injection. For topotecan (15 µg or 30 µg), melphalan (12.5 µg) or saline, toxicity was evaluated by serial electroretinography (ERG) and histopathology, and efficacy against vitreous seed xenografts was measured by tumour cell reduction and apoptosis induction. PATIENTS: retrospective cohort study of 235 patients receiving 990 intravitreal injections of topotecan or melphalan. RESULTS: Intravitreal topotecan 30 µg (equals 60 µg in humans) achieved the IC90 across the rabbit vitreous. Three weekly topotecan injections (either 15 µg or 30 µg) caused no retinal toxicity in rabbits, whereas melphalan 12.5 µg (equals 25 µg in humans) reduced ERG amplitudes 42%-79%. Intravitreal topotecan 15 µg was equally effective to melphalan to treat WERI-Rb1 cell xenografts in rabbits (96% reduction for topotecan vs saline (p=0.004), 88% reduction for melphalan vs saline (p=0.004), topotecan vs melphalan, p=0.15). In our clinical study, patients received 881 monotherapy injections (48 topotecan, 833 melphalan). Patients receiving 20 µg or 30 µg topotecan demonstrated no significant ERG reductions; melphalan caused ERG reductions of 7.6 µV for every injection of 25 µg (p=0.03) or 30 µg (p<0.001). Most patients treated with intravitreal topotecan also received intravitreal melphalan at some point during their treatment course. Among those eyes treated exclusively with topotecan monotherapy, all eyes were salvaged. CONCLUSIONS: Taken together, these experiments suggest that intravitreal topotecan monotherapy for the treatment of RB vitreous seeds is non-toxic and effective.

Consumption of dietary fat causes loss of olfactory sensory neurons and associated circuitry that is not mitigated by voluntary exercise in mice.

Excess nutrition causes loss of olfactory sensory neurons (OSNs) and reduces odour discrimination and odour perception in mice. To separate diet-induced obesity from the consumption of dietary fat, we designed pair-feeding experiments whereby mice were maintained on isocaloric diets for 5 months, which prevented increased fat storage. To test our hypothesis that adiposity was not a prerequisite for loss of OSNs and bulbar projections, we used male and female mice with an odorant receptor-linked genetic reporter (M72tauLacZ; Olfr160) to visualize neural circuitry changes resulting from elevated fat in the diet. Simultaneously we monitored glucose clearance (diagnostic for prediabetes), body fat deposition, ingestive behaviours, select inflammatory markers and energy metabolism. Axonal projections to defined olfactory glomeruli were visualized in whole-mount brains, and the number of OSNs was manually counted across whole olfactory epithelia. After being pair fed a moderately high-fat (MHF) diet, mice of both sexes had body weight, adipose deposits, energy expenditure, respiratory exchange ratios and locomotor activity that were unchanged from control-fed mice. Despite this, they were still found to lose OSNs and associated bulbar projections. Even with unchanged adipocyte storage, pair-fed animals had an elevation in TNF cytokines and an intermediate ability for glucose clearance. Albeit improving health metrics, access to voluntary running while consuming an ad libitum fatty diet still precipitated a loss of OSNs and associated axonal projections for male mice. Our results support that long-term macronutrient imbalance can drive anatomical loss in the olfactory system regardless of total energy expenditure. KEY POINTS: Obesity can disrupt the structure and function of organ systems, including the olfactory system that is important for food selection and satiety. We designed dietary treatments in mice such that mice received fat, but the total calories provided were the same as in control diets so that they would not gain weight or increase adipose tissue. Mice that were not obese but consumed isocaloric fatty diets still lost olfactory neuronal circuits, had fewer numbers of olfactory neurons, had an elevation in inflammatory signals and had an intermediate ability to clear glucose (prediabetes). Mice were allowed access to running wheels while consuming fatty diets, yet still lost olfactory structures. We conclude that a long-term imbalance in nutrition that favours fat in the diet disrupts the olfactory system of mice in the absence of obesity.

Variability in the management of adhesive small bowel obstruction in children.

BACKGROUND: This study assessed inter-hospital variability in operative-vs-nonoperative management of pediatric adhesive small bowel obstruction (ASBO). METHODS: A multi-institutional retrospective study was performed examining patients 1-21 years-of-age presenting with ASBO from 2010 to 2019 utilizing the Pediatric Health Information System. Multivariable mixed-effects logistic regression was performed assessing inter-hospital variability in operative-vs-nonoperative management of ASBO. RESULTS: Among 6410 pediatric ASBO admissions identified at 46 hospitals, 3,239 (50.5%) underwent surgery during that admission. The hospital-specific rate of surgery ranged from 35.3% (95%CI: 28.5-42.6%) to 74.7% (66.3-81.6%) in the unadjusted model (p < 0.001), and from 35.1% (26.3-45.1%) to 73.9% (66.7-79.9%) in the adjusted model (p < 0.001). Factors associated with operative management for ASBO included admission to a surgical service (OR 2.8 [95%CI: 2.4-3.2], p < 0.001), congenital intestinal and/or rotational anomaly (OR 2.5 [2.1-3.1], p < 0.001), diagnostic workup including advanced abdominal imaging (OR 1.7 [1.5-1.9], p < 0.001), non-emergent admission status (OR 1.5 [1.3-1.8], p < 0.001), and increasing number of complex chronic comorbidities (OR 1.3 [1.2-1.4], p < 0.001). Factors associated with nonoperative management for ASBO included increased hospital-specific annual ASBO volume (OR 0.98 [95%CI: 0.97-0.99], p = 0.002), older age (OR 0.97 [0.96-0.98], p < 0.001), public insurance (OR 0.87 [0.78-0.96], p = 0.008), and presence of coinciding non-intestinal congenital anomalies, neurologic/neuromuscular disease, and/or medical technology dependence (OR 0.57 [95%CI: 0.47-0.68], p < 0.001). CONCLUSIONS: Rates of surgical intervention for ASBO vary significantly across tertiary children's hospitals in the United States. The variability was independent of patient and hospital characteristics and is likely due to practice variation. LEVEL OF EVIDENCE: III.

CropPol: A dynamic, open and global database on crop pollination.

Seventy five percent of the world's food crops benefit from insect pollination. Hence, there has been increased interest in how global change drivers impact this critical ecosystem service. Because standardized data on crop pollination are rarely available, we are limited in our capacity to understand the variation in pollination benefits to crop yield, as well as to anticipate changes in this service, develop predictions, and inform management actions. Here, we present CropPol, a dynamic, open, and global database on crop pollination. It contains measurements recorded from 202 crop studies, covering 3,394 field observations, 2,552 yield measurements (i.e., berry mass, number of fruits, and fruit density [kg/ha], among others), and 47,752 insect records from 48 commercial crops distributed around the globe. CropPol comprises 32 of the 87 leading global crops and commodities that are pollinator dependent. Malus domestica is the most represented crop (32 studies), followed by Brassica napus (22 studies), Vaccinium corymbosum (13 studies), and Citrullus lanatus (12 studies). The most abundant pollinator guilds recorded are honey bees (34.22% counts), bumblebees (19.19%), flies other than Syrphidae and Bombyliidae (13.18%), other wild bees (13.13%), beetles (10.97%), Syrphidae (4.87%), and Bombyliidae (0.05%). Locations comprise 34 countries distributed among Europe (76 studies), North America (60), Latin America and the Caribbean (29), Asia (20), Oceania (10), and Africa (7). Sampling spans three decades and is concentrated on 2001-2005 (21 studies), 2006-2010 (40), 2011-2015 (88), and 2016-2020 (50). This is the most comprehensive open global data set on measurements of crop flower visitors, crop pollinators and pollination to date, and we encourage researchers to add more datasets to this database in the future. This data set is released for non-commercial use only. Credits should be given to this paper (i.e., proper citation), and the products generated with this database should be shared under the same license terms (CC BY-NC-SA).

Intravitreal HDAC Inhibitor Belinostat Effectively Eradicates Vitreous Seeds Without Retinal Toxicity In Vivo in a Rabbit Retinoblastoma Model.

Purpose: Current melphalan-based regimens for intravitreal chemotherapy for retinoblastoma vitreous seeds are effective but toxic to the retina. Thus, alternative agents are needed. Based on the known biology of histone deacetylases (HDACs) in the retinoblastoma pathway, we systematically studied whether the HDAC inhibitor belinostat is a viable, molecularly targeted alternative agent for intravitreal delivery that might provide comparable efficacy, without toxicity. Methods: In vivo pharmacokinetic experiments in rabbits and in vitro cytotoxicity experiments were performed to determine the 90% inhibitory concentration (IC90). Functional toxicity by electroretinography and structural toxicity by optical coherence tomography (OCT), OCT angiography, and histopathology were evaluated in rabbits following three injections of belinostat 350 µg (2× IC90) or 700 µg (4× IC90), compared with melphalan 12.5 µg (rabbit equivalent of the human dose). The relative efficacy of intravitreal belinostat versus melphalan to treat WERI-Rb1 human cell xenografts in rabbit eyes was directly quantified. RNA sequencing was used to assess belinostat-induced changes in RB cell gene expression. Results: The maximum nontoxic dose of belinostat was 350 µg, which caused no reductions in electroretinography parameters, retinal microvascular loss on OCT angiography, or retinal degeneration. Melphalan caused severe retinal structural and functional toxicity. Belinostat 350 µg (equivalent to 700 µg in the larger human eye) was equally effective at eradicating vitreous seeds in the rabbit xenograft model compared with melphalan (95.5% reduction for belinostat, P < 0.001; 89.4% reduction for melphalan, P < 0.001; belinostat vs. melphalan, P = 0.10). Even 700 µg belinostat (equivalent to 1400 µg in humans) caused only minimal toxicity. Widespread changes in gene expression resulted. Conclusions: Molecularly targeted inhibition of HDACs with intravitreal belinostat was equally effective as standard-of-care melphalan but without retinal toxicity. Belinostat may therefore be an attractive agent to pursue clinically for intravitreal treatment of retinoblastoma.

Efficacy, Toxicity, and Pharmacokinetics of Intra-Arterial Chemotherapy Versus Intravenous Chemotherapy for Retinoblastoma in Animal Models and Patients.

Purpose: Through controlled comparative rabbit experiments and parallel patient studies, our purpose was to understand mechanisms underlying differences in efficacy and toxicity between intra-arterial chemotherapy (IAC) and intravenous chemotherapy (IVC). Methods: In rabbits, ocular tissue drug levels were measured following IAC and IVC. Retinal toxicity was assessed using electroretinography, fluorescein angiography, optical coherence tomography (OCT) and OCT angiography. Efficacy to eradicate retinoblastoma orthotopic xenografts was compared. In IAC and IVC patients, we measured blood carboplatin pharmacokinetics and compared efficacy and toxicity. Results: In rabbits receiving IAC, maximum carboplatin levels were 134 times greater in retina (P = 0.01) and 411 times greater in vitreous (P < 0.001), and total carboplatin (area under the curve) was 123 times greater in retina (P = 0.005) and 131 times greater in vitreous (P = 0.02) compared with IVC. Melphalan levels were 12 times greater (P = 0.003) in retina and 26 times greater in vitreous (P < 0.001) for IAC. Blood levels were not different. IAC melphalan (but not IV melphalan or IV carboplatin, etoposide, and vincristine) caused widespread apoptosis in retinoblastoma xenografts but no functional retinal toxicity or cytopenias. In patients, blood levels following IVC were greater (P < 0.001) but, when adjusted for treatment dose, were not statistically different. Per treatment cycle in patients, IVC caused higher rates of anemia (0.32 ± 0.29 vs. 0.01 ± 0.04; P = 0.0086), thrombocytopenia (0.5 ± 0.42 vs. 0.0 ± 0.0; P = 0.0042), and neutropenia (0.58 ± 0.3 vs. 0.31 ± 0.25; P = 0.032) but lower treatment success rates (P = 0.0017). Conclusions: The greater efficacy and lower systemic toxicity with IAC appear to be attributable to the greater ocular-to-systemic drug concentration ratio compared with IVC. Translational Relevance: Provides an overarching hypothesis for a mechanism of efficacy/toxicity to guide future drug development.