Engineered Knottin Peptide Enables Noninvasive Optical Imaging of Intracranial Medulloblastoma

Central nervous system tumors carry grave clinical prognoses due to limited effectiveness of surgical resection, radiation, and chemotherapy. Thus, improved strategies for brain tumor visualization and targeted treatment are critically needed. We demonstrate that mouse cerebellar medulloblastoma (MB) can be targeted and illuminated with a fluorescent, engineered cystine knot (knottin) peptide that binds with high affinity to α β , α β , and α β integrin receptors. This integrin-binding knottin peptide, denoted EETI 2.5F, was evaluated as a molecular imaging probe in both orthotopic and genetic models of MB. Following tail vein injection, fluorescence arising from dye-conjugated EETI 2.5F was localized to the tumor compared with the normal surrounding brain tissue, as measured by optical imaging. The imaging signal intensity correlated with tumor volume. Due to its unique ability to bind to α β integrin, EETI 2.5F showed superior in vivo and ex vivo brain tumor imaging contrast compared with other engineered integrin-binding knottin peptides and with c(RGDfK), a well-studied integrin-binding peptidomimetic. Next, EETI 2.5F was fused to an antibody fragment crystallizable (Fc) domain (EETI 2.5F-Fc) to determine if a larger integrin-binding protein could also target intracranial brain tumors. EETI 2.5F-Fc, conjugated to a fluorescent dye, illuminated MB following i.v. injection and was able to distribute throughout the tumor parenchyma. In contrast, brain tumor imaging signals were not detected in mice injected with EETI 2.5F proteins containing a scrambled integrin-binding sequence, demonstrating the importance of target specificity. These results highlight the potential of using EETI 2.5F and EETI 2.5-Fc as targeted molecular probes for brain tumor imaging

Maria Auxiliadora Hospital in Lima, Peru as a model for neurosurgical outreach to international charity hospitals

A myriad of geopolitical and financial obstacles have kept modern neurosurgery from effectively reaching the citizens of the developing world. Targeted neurosurgical outreach by academic neurosurgeons to equip neurosurgical operating theaters and train local neurosurgeons is one method to efficiently and cost effectively improve sustainable care provided by international charity hospitals. The International Neurosurgical Children’s Association (INCA) effectively improved the available neurosurgical care in the Maria Auxiliadora Hospital of Lima, Peru through the advancement of local specialist education and training. Neurosurgical equipment and training were provided for the local neurosurgeons by a mission team from the University of California at San Diego. At the end of 3 years, with one intensive week trip per year, the host neurosurgeons were proficiently and independently applying microsurgical techniques to previously performed operations, and performing newly learned operations such as neuroendoscopy and minimally invasive neurosurgery. Our experiences may serve as a successful template for the execution of other small scale, sustainable neurosurgery missions worldwide

Crucial Role for BAFF-BAFF-R Signaling in the Survival and Maintenance of Mature B Cells

Defects in the expression of either BAFF (B cell activating factor) or BAFF-R impairs B cell development beyond the immature, transitional type-1 stage and thus, prevents the formation of follicular and marginal zone B cells, whereas B-1 B cells remain unaffected. The expression of BAFF-R on all mature B cells might suggest a role for BAFF-R signaling also for their in vivo maintenance. Here, we show that, 14 days following a single injection of an anti-BAFF-R mAb that prevents BAFF binding, both follicular and marginal zone B cell numbers are drastically reduced, whereas B-1 cells are not affected. Injection of control, isotype-matched but non-blocking anti-BAFF-R mAbs does not result in B cell depletion. We also show that this depletion is neither due to antibody-dependent cellular cytotoxicity nor to complement-mediated lysis. Moreover, prevention of BAFF binding leads to a decrease in the size of the B cell follicles, an impairment of a T cell dependent humoral immune response and a reduction in the formation of memory B cells. Collectively, these results establish a central role for BAFF-BAFF-R signaling in the in vivo survival and maintenance of both follicular and marginal zone B cell pools

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

Maria Auxiliadora Hospital in Lima, Peru as a model for neurosurgical outreach to international charity hospitals

A myriad of geopolitical and financial obstacles have kept modern neurosurgery from effectively reaching the citizens of the developing world. Targeted neurosurgical outreach by academic neurosurgeons to equip neurosurgical operating theaters and train local neurosurgeons is one method to efficiently and cost effectively improve sustainable care provided by international charity hospitals. The International Neurosurgical Children’s Association (INCA) effectively improved the available neurosurgical care in the Maria Auxiliadora Hospital of Lima, Peru through the advancement of local specialist education and training. Neurosurgical equipment and training were provided for the local neurosurgeons by a mission team from the University of California at San Diego. At the end of 3 years, with one intensive week trip per year, the host neurosurgeons were proficiently and independently applying microsurgical techniques to previously performed operations, and performing newly learned operations such as neuroendoscopy and minimally invasive neurosurgery. Our experiences may serve as a successful template for the execution of other small scale, sustainable neurosurgery missions worldwide

Plants versus animals: do they deal with stress in different ways?

Both plants and animals respond to stress by using adaptations that help them evade, tolerate, or recover from stress. In a synthetic paper A. D. Bradshaw (1972) noted that basic biological differences between plants and animals will have diverse evolutionary consequences, including those influencing how they deal with stress. For instance, Bradshaw argued that animals, because they have relatively well-developed sensory and locomotor capacities, can often use behavior and movement to evade or ameliorate environmental stresses. In contrast, he predicted that plants will have to emphasize increased physiological tolerance or phenotypic plasticity, and also that plants should suffer stronger selection and show more marked differentiation along environmental gradients. Here we briefly review the importance of behavior in mitigating stress, the behavioral capacities of animals and plants, and examples of plant responses that are functionally similar to behaviors of animals. Next, we try to test some of Bradshaw’s predictions. Unfortunately, critical data often proved non-comparable: plant and animal biologists often study different stressors (e.g., water versus heat) and measure different traits (photosynthesis versus locomotion). Nevertheless, we were able to test some of Bradshaw’s predictions and some related ones of our own. As Bradshaw predicted, the phenology of plants is more responsive to climate shifts than is that of animals and the microdistributions of non-mobile, intertidal invertebrates (‘‘plant’’ equivalents) are more sensitive to temperature than are those of mobile invertebrates. However, mortality selection is actually weaker for plants than for animals. We hope that our review not only redraws attention to some fascinating issues Bradshaw raised, but also encourages additional tests of his predictions. Such tests should be informative

Trends in the Diagnosis and Treatment of Pediatric Primary Spinal Cord Tumors

OBJECT: Pediatric primary spinal cord tumors (PSCTs) are rare, with limited comprehensive data regarding incidence and patterns of diagnosis and treatment. The authors evaluated trends in the diagnosis and treatment of PSCTs using a nationwide database. METHODS: The Surveillance, Epidemiology, and End Results (SEER) registry was queried for the years 1975-2007, evaluating clinical patterns in 330 patients 19 years of age or younger in whom a pediatric PSCT had been diagnosed. Histological diagnoses were grouped into pilocytic astrocytoma, other low-grade astrocytoma, ependymoma, and high-grade glioma. Patient demographics, tumor pathology, use of external beam radiation (EBR), and overall survival were analyzed. RESULTS: The incidence of pediatric PSCT was 0.09 case per 100,000 person-years and did not change over time. Males were more commonly affected than females (58% vs 42%, respectively; p \u3c 0.006). Over the last 3 decades, the specific diagnoses of pilocytic astrocytoma and ependymoma increased, whereas the use of EBR decreased (60.6% from 1975 to 1989 vs 31.3% from 1990 to 2007; p \u3c 0.0001). The 5- and 10-year survival rates did not differ between these time periods. CONCLUSIONS: While the incidence of pediatric PSCT has not changed over time, the pattern of pathological diagnoses has shifted, and pilocytic astrocytoma and ependymoma have been increasingly diagnosed. The use of EBR over time has declined. Relative survival of patients with low-grade PSCT has remained high regardless of the pathological diagnosis

Trends in the Diagnosis and Treatment of Pediatric Primary Spinal Cord Tumors

OBJECT: Pediatric primary spinal cord tumors (PSCTs) are rare, with limited comprehensive data regarding incidence and patterns of diagnosis and treatment. The authors evaluated trends in the diagnosis and treatment of PSCTs using a nationwide database. METHODS: The Surveillance, Epidemiology, and End Results (SEER) registry was queried for the years 1975-2007, evaluating clinical patterns in 330 patients 19 years of age or younger in whom a pediatric PSCT had been diagnosed. Histological diagnoses were grouped into pilocytic astrocytoma, other low-grade astrocytoma, ependymoma, and high-grade glioma. Patient demographics, tumor pathology, use of external beam radiation (EBR), and overall survival were analyzed. RESULTS: The incidence of pediatric PSCT was 0.09 case per 100,000 person-years and did not change over time. Males were more commonly affected than females (58% vs 42%, respectively; p \u3c 0.006). Over the last 3 decades, the specific diagnoses of pilocytic astrocytoma and ependymoma increased, whereas the use of EBR decreased (60.6% from 1975 to 1989 vs 31.3% from 1990 to 2007; p \u3c 0.0001). The 5- and 10-year survival rates did not differ between these time periods. CONCLUSIONS: While the incidence of pediatric PSCT has not changed over time, the pattern of pathological diagnoses has shifted, and pilocytic astrocytoma and ependymoma have been increasingly diagnosed. The use of EBR over time has declined. Relative survival of patients with low-grade PSCT has remained high regardless of the pathological diagnosis

Sex Differences in Age of Diagnosis and First Concern among Children with Autism Spectrum Disorder

© 2020 Society of Clinical Child & Adolescent Psychology. Objective: Early identification of autism spectrum disorder (ASD) is an essential healthcare priority. Girls may be at risk for late diagnosis, although research is equivocal regarding how sex and other factors relate to ASD identification. The goals of the current investigation were to (1) identify how child sex, cognitive abilities, and demographic factors relate to age of first concern (AOC) and age of diagnosis (AOD), (2) evaluate trends in AOC/AOD over time, and (3) consider whether main effects of sex on AOC/AOD are moderated by cognitive abilities or time. Method: Children (N = 365; 20% female; 85.6% identified as White) with ASD participated through the Province of Ontario Neurodevelopmental Disorders (POND) Network. Study records included AOD, date/timing of diagnosis (between 1996 and 2017), age of first parent concern, demographics, and standardized cognitive testing results (24.7% of children had IQ scores below standard scores of 70). Results: Average AOC occurred before 2 years of age whereas average AOD occurred after 5 years of age. Girls did not differ on AOC but had a later AOD than boys. Higher verbal IQ was associated with later AOD more strongly in girls than boys. Regarding time-related changes, average AOC and AOD increased across the study period, more strongly for girls. Conclusions: Results support that sex is a key factor underlying delays in ASD identification and highlight the urgent need to improve diagnostic practices among girls. Limitations and implications for improving the diagnostic process are discussed. Abbreviations: ASD=autism spectrum disorder; IQ=intelligence quotient; AOC=parental report of age of first concern; AOD=age of diagnosis