Predicting post-surgical functional status in high-grade glioma with resting state fMRI and machine learning.

PURPOSE: High-grade glioma (HGG) is the most common and deadly malignant glioma of the central nervous system. The current standard of care includes surgical resection of the tumor, which can lead to functional and cognitive deficits. The aim of this study is to develop models capable of predicting functional outcomes in HGG patients before surgery, facilitating improved disease management and informed patient care. METHODS: Adult HGG patients (N = 102) from the neurosurgery brain tumor service at Washington University Medical Center were retrospectively recruited. All patients completed structural neuroimaging and resting state functional MRI prior to surgery. Demographics, measures of resting state network connectivity (FC), tumor location, and tumor volume were used to train a random forest classifier to predict functional outcomes based on Karnofsky Performance Status (KPS < 70, KPS ≥ 70). RESULTS: The models achieved a nested cross-validation accuracy of 94.1% and an AUC of 0.97 in classifying KPS. The strongest predictors identified by the model included FC between somatomotor, visual, auditory, and reward networks. Based on location, the relation of the tumor to dorsal attention, cingulo-opercular, and basal ganglia networks were strong predictors of KPS. Age was also a strong predictor. However, tumor volume was only a moderate predictor. CONCLUSION: The current work demonstrates the ability of machine learning to classify postoperative functional outcomes in HGG patients prior to surgery accurately. Our results suggest that both FC and the tumor's location in relation to specific networks can serve as reliable predictors of functional outcomes, leading to personalized therapeutic approaches tailored to individual patients.

Predicting survival in glioblastoma with multimodal neuroimaging and machine learning.

PURPOSE: Glioblastoma (GBM) is the most common and aggressive malignant glioma, with an overall median survival of less than two years. The ability to predict survival before treatment in GBM patients would lead to improved disease management, clinical trial enrollment, and patient care. METHODS: GBM patients (N = 133, mean age 60.8 years, median survival 14.1 months, 57.9% male) were retrospectively recruited from the neurosurgery brain tumor service at Washington University Medical Center. All patients completed structural neuroimaging and resting state functional MRI (RS-fMRI) before surgery. Demographics, measures of cortical thickness (CT), and resting state functional network connectivity (FC) were used to train a deep neural network to classify patients based on survival (< 1y, 1-2y, >2y). Permutation feature importance identified the strongest predictors of survival based on the trained models. RESULTS: The models achieved a combined cross-validation and hold out accuracy of 90.6% in classifying survival (< 1y, 1-2y, >2y). The strongest demographic predictors were age at diagnosis and sex. The strongest CT predictors of survival included the superior temporal sulcus, parahippocampal gyrus, pericalcarine, pars triangularis, and middle temporal regions. The strongest FC features primarily involved dorsal and inferior somatomotor, visual, and cingulo-opercular networks. CONCLUSION: We demonstrate that machine learning can accurately classify survival in GBM patients based on multimodal neuroimaging before any surgical or medical intervention. These results were achieved without information regarding presentation symptoms, treatments, postsurgical outcomes, or tumor genomic information. Our results suggest GBMs have a global effect on the brain's structural and functional organization, which is predictive of survival.

Deploying digitalisation and artificial intelligence in sustainable development research.

Many industrialised countries have benefited from the advent of twenty-first century technologies, especially automation, that have fundamentally changed manufacturing and industrial production processes. The next step in the evolution of automation is the development of artificial intelligence (AI), i.e. intelligence which is demonstrated by machines and systems, which cannot only perform tasks but also work synergistically with humans and nature. Intelligent systems that can see, analyse situations and respond sensitively to real-time cues, from human gestures and facial expressions to pedestrians crossing a busy street, will reshape transportation, precision agriculture, biodiversity conservation, environmental modelling, public health, construction and manufacturing, as well as initiatives designed to promote prosperity on Earth. This paper explores the connections between AI systems and sustainable development (SD) research. By means of a literature review, world survey, and case studies, ways in which AI can support research on SD and, inter alia, contribute to a more sustainable and equitable world, are identified.

Neonatal hydrocephalus: an atypical presentation of malignant infantile osteopetrosis.

PURPOSE: Autosomal recessive osteopetrosis has a variable presentation, most commonly including failure to thrive, hypocalcemia, seizures, hepatosplenomegaly, hydrocephalus, vision or hearing loss, and cytopenias. Multiple symptoms are usually seen at presentation. The variability of presentation often delays diagnosis and subsequent treatment. Here, we present a case of an infant with this condition who initially presented with triventricular hydrocephalus with Chiari I malformation. This alone is not a common presentation of this disease, and we present this case to highlight autosomal recessive osteopetrosis as a potential diagnosis in infants presenting with hydrocephalus and discuss the other associated symptoms, management, and prognosis of this condition. CASE REPORT: The patient was a full-term infant with a routine newborn period. At 6 months, the infant had macrocephaly and frontal bossing with a bulging fontanelle. She was found to have hydrocephalus with moderate ventriculomegaly involving the third and lateral ventricles with an associated Chiari 1 malformation. The infant was asymptomatic at the time. The infant was promptly referred to neurosurgery and underwent an uncomplicated ventriculoperitoneal shunt placement. Post-operative X-rays showed increased density of the skull with other bone changes suggestive of autosomal recessive osteopetrosis. Subsequent lab work and imaging studies were consistent with this condition. The diagnosis was confirmed by genetic testing, and the patient has undergone treatment with hematopoietic stem cell transplant. CONCLUSION: Hydrocephalus is a common feature of this condition, typically seen in conjunction with other systemic symptoms and laboratory findings. Our patient had a limited initial presentation of triventricular hydrocephalus with Chiari I malformation and was otherwise clinically asymptomatic. There is limited literature of such a presentation, and we highlight this case to increase awareness, as timely diagnosis of these patients is critical for treatment and future outcomes.

The effect of thermal therapy on the blood-brain barrier and blood-tumor barrier.

The blood-brain and blood-tumor barriers represent highly specialized structures responsible for tight regulation of molecular transit into the central nervous system. Under normal circumstances, the relative impermeability of the blood-brain barrier (BBB) protects the brain from circulating toxins and contributes to a brain microenvironment necessary for optimal neuronal function. However, in the context of tumors and other diseases of central nervous system, the BBB and the more recently appreciated blood-tumor barrier (BTB) represent barriers that prevent effective drug delivery. Overcoming both barriers to optimize treatment of central nervous system diseases remains the subject of intense scientific investigation. Although many newer technologies have been developed to overcome these barriers, thermal therapy, which dates back to the 1890 s, has been known to disrupt the BBB since at least the early 1980s. Recently, as a result of several technological advances, laser interstitial thermal therapy (LITT), a method of delivering targeted thermal therapy, has gained widespread use as a surgical technique to ablate brain tumors. In addition, accumulating evidence indicates that laser ablation may also increase local BBB/BTB permeability after treatment. We herein review the structure and function of the BBB and BTB and the impact of thermal injury, including LITT, on barrier function.

State and Regional Variation in Prescription- and Payment-Related Promoters of Adherence to Blood Pressure Medication.

INTRODUCTION: Medication adherence can improve hypertension management. How blood pressure medications are prescribed and purchased can promote or impede adherence. METHODS: We used comprehensive dispensing data on prescription blood pressure medication from Symphony Health's 2017 Integrated Dataverse to assess how prescription- and payment-related factors that promote medication adherence (ie, fixed-dose combinations, generic formulations, mail order, low-cost or no-copay medications) vary across US states and census regions and across the market segments (grouped by patient age, prescriber type, and payer type) responsible for the greatest number of blood pressure medication fills. RESULTS: In 2017, 706.5 million prescriptions for blood pressure medication were filled, accounting for $29.0 billion in total spending (17.0% incurred by patients). As a proportion of all fills, factors that promoted adherence varied by state: fixed-dose combinations (from 5.8% in Maine to 17.9% in Mississippi); generic formulations (from 95.2% in New Jersey to 98.4% in Minnesota); mail order (from 4.7% in Rhode Island to 14.5% in Delaware); and lower or no copayment (from 56.6% in Utah to 72.8% in California). Furthermore, mean days' supply per fill (from 43.1 in Arkansas to 63.8 in Maine) and patient spending per therapy year (from $38 in Hawaii to $76 in Georgia) varied. Concentration of adherence factors differed by market segment. Patients aged 18 to 64 with a primary care physician prescriber and Medicaid coverage had the lowest concentration of fixed-dose combination fills, mean days' supply per fill, and patient spending per therapy year. Patients aged 65 years or older with a primary care physician prescriber and commercial insurance had the highest concentration of fixed-dose combinations fills and mail order fills. CONCLUSION: Addressing regional and market segment variation in factors promoting blood pressure medication adherence may increase adherence and improve hypertension management.

HemOnc: A new standard vocabulary for chemotherapy regimen representation in the OMOP common data model.

Systematic application of observational data to the understanding of impacts of cancer treatments requires detailed information models allowing meaningful comparisons between treatment regimens. Unfortunately, details of systemic therapies are scarce in registries and data warehouses, primarily due to the complex nature of the protocols and a lack of standardization. Since 2011, we have been creating a curated and semi-structured website of chemotherapy regimens, HemOnc.org. In coordination with the Observational Health Data Sciences and Informatics (OHDSI) Oncology Subgroup, we have transformed a substantial subset of this content into the OMOP common data model, with bindings to multiple external vocabularies, e.g., RxNorm and the National Cancer Institute Thesaurus. Currently, there are >73,000 concepts and >177,000 relationships in the full vocabulary. Content related to the definition and composition of chemotherapy regimens has been released within the ATHENA tool (athena.ohdsi.org) for widespread utilization by the OHDSI membership. Here, we describe the rationale, data model, and initial contents of the HemOnc vocabulary along with several use cases for which it may be valuable.

Opioid use disorder in primary care: PEER umbrella systematic review of systematic reviews.

OBJECTIVE: To summarize the best available evidence regarding various topics related to primary care management of opioid use disorder (OUD). DATA SOURCES: MEDLINE, Cochrane Library, Google, and the references of included studies and relevant guidelines. STUDY SELECTION: Published systematic reviews and newer randomized controlled trials from the past 5 to 10 years that investigated patient-oriented outcomes related to managing OUD in primary care, diagnosis, pharmacotherapies (including buprenorphine, methadone, and naltrexone), tapering strategies, psychosocial interventions, prescribing practices, and management of comorbidities. SYNTHESIS: From 8626 articles, 39 systematic reviews and an additional 26 randomized controlled trials were included. New meta-analyses were performed where possible. One cohort study suggests 1 case-finding tool might be reasonable to assist with diagnosis (positive likelihood ratio of 10.3). Meta-analysis demonstrated that retention in treatment improves when buprenorphine or methadone are used (64% to 73% vs 22% to 39% for control), when OUD is treated in primary care (86% vs 67% in specialty care, risk ratio [RR] of 1.25, 95% CI 1.07 to 1.47), and when counseling is added to pharmacotherapy (74% vs 62% for controls, RR = 1.20, 95% CI 1.06 to 1.36). Retention was also improved with naltrexone (33% vs 25% for controls, RR = 1.35, 95% CI 1.11 to 1.64) and reduced with medication-related contingency management (eg, loss of take-home doses as a punitive measure; 68% vs 77% for no contingency, RR = 0.86, 95% CI 0.76 to 0.99). CONCLUSION: There is reasonable evidence that patients with OUD should be managed in the primary care setting. Diagnostic criteria for OUD remain elusive, with 1 reasonable case-finding tool. Methadone and buprenorphine improve treatment retention, while medication-related contingency methods could worsen retention. Counseling is beneficial when added to pharmacotherapy.

Predicting Glioblastoma Recurrence by Early Changes in the Apparent Diffusion Coefficient Value and Signal Intensity on FLAIR Images.

OBJECTIVE: Recurrence of glioblastoma multiforme (GBM) arises from areas of microscopic tumor infiltration that have yet to disrupt the blood-brain barrier. We hypothesize that these microscopic foci of invasion cause subtle variations in the apparent diffusion coefficient (ADC) and FLAIR signal detectable with the use of computational big-data modeling. MATERIALS AND METHODS: Twenty-six patients with native GBM were studied immediately after undergoing gross total tumor resection. Within the peritumoral region, areas of future GBM recurrence were identified through coregistration of follow-up MRI examinations. The likelihood of tumor recurrence at each individual voxel was assessed as a function of signal intensity on ADC maps and FLAIR images. Both single and combined multivariable logistic regression models were created. RESULTS: A total of 419,473 voxels of data (105,477 voxels of data within tumor recurrence and 313,996 voxels of data on surrounding peritumoral edema) were analyzed. For future areas of recurrence, a 9.5% decrease in the ADC value (p < 0.001) and a 9.2% decrease in signal intensity on FLAIR images (p < 0.001) were shown, compared with findings for the surrounding peritumoral edema. Logistic regression revealed that the amount of signal loss on both ADC maps and FLAIR images correlated with the likelihood of tumor recurrence. A combined multiparametric logistic regression model was more specific in the prediction of tumor recurrence than was either single-variable model alone. CONCLUSION: Areas of future GBM recurrence exhibit small but highly statistically significant differences in signal intensity on ADC maps and FLAIR images months before the development of abnormal enhancement occurs. A multiparametric logistic model calibrated to these changes can be used to estimate the burden of microscopic nonenhancing tumor and predict the location of recurrent disease. Computational big-data modeling performed at the voxel level is a powerful technique capable of discovering important but subtle patterns in imaging data.

Conditionals by inversion provide a universal method for the generation of conditional alleles.

Conditional mutagenesis is becoming a method of choice for studying gene function, but constructing conditional alleles is often laborious, limited by target gene structure, and at times, prone to incomplete conditional ablation. To address these issues, we developed a technology termed conditionals by inversion (COIN). Before activation, COINs contain an inverted module (COIN module) that lies inertly within the antisense strand of a resident gene. When inverted into the sense strand by a site-specific recombinase, the COIN module causes termination of the target gene's transcription and simultaneously provides a reporter for tracking this event. COIN modules can be inserted into natural introns (intronic COINs) or directly into coding exons as part of an artificial intron (exonic COINs), greatly simplifying allele design and increasing flexibility over previous conditional KO approaches. Detailed analysis of over 20 COIN alleles establishes the reliability of the method and its broad applicability to any gene, regardless of exon-intron structure. Our extensive testing provides rules that help ensure success of this approach and also explains why other currently available conditional approaches often fail to function optimally. Finally, the ability to split exons using the COIN's artificial intron opens up engineering modalities for the generation of multifunctional alleles.

Molecular subtype and response to dasatinib, an Src/Abl small molecule kinase inhibitor, in hepatocellular carcinoma cell lines in vitro.

UNLABELLED: Hepatocellular carcinoma (HCC) is the fifth most common malignancy and is the third leading cause of cancer death worldwide. Recently, the multitargeted kinase inhibitor sorafenib was shown to be the first systemic agent to improve survival in advanced HCC. Unlike other malignancies such as breast cancer, in which molecular subtypes have been clearly defined (i.e., luminal, HER2 amplified, basal, etc.) and tied to effective molecular therapeutics (hormone blockade and trastuzumab, respectively), in HCC this translational link does not exist. Molecular profiling studies of human HCC have identified unique molecular subtypes of the disease. We hypothesized that a panel of human HCC cell lines would maintain molecular characteristics of the clinical disease and could then be used as a model for novel therapeutics. Twenty human HCC cell lines were collected and RNA was analyzed using the Agilent microarray platform. Profiles from the cell lines in vitro recapitulate previously described subgroups from clinical material. Next, we evaluated whether molecular subgroup would have predictive value for response to the Src/Abl inhibitor dasatinib. The results demonstrate that sensitivity to dasatinib was associated with a progenitor subtype. Dasatinib was effective at inducing cell cycle arrest and apoptosis in "progenitor-like" cell lines but not in resistant lines. CONCLUSION: These findings suggest that cell line models maintain the molecular background of HCC and that subtype may be important for selecting patients for response to novel therapies. In addition, it highlights a potential role for Src family signaling in this progenitor subtype of HCC.

Pial synangiosis for moyamoya syndrome in children with sickle cell anemia: a comprehensive review of reported cases.

OBJECT: Pediatric patients with sickle cell anemia (SCA) carry a significant risk of developing moyamoya syndrome (MMS) and brain ischemia. The authors sought to review the safety and efficacy of pial synangiosis in the treatment of MMS in children with SCA by performing a comprehensive review of all previously reported cases in the literature. METHODS: The authors retrospectively reviewed the clinical and radiographic records in 17 pediatric patients with SCA treated at the Morgan Stanley Children's Hospital of New York (MSCHONY) who developed radiological evidence of MMS and underwent pial synangiosis between 1996 and 2012. The authors then added any additional reported cases of pial synangiosis for this population in the literature for a combined analysis of clinical and radiographic outcomes. RESULTS: The combined data consisted of 48 pial synangiosis procedures performed in 30 patients. Of these, 27 patients (90%) presented with seizure, stroke, or transient ischemic attack, whereas 3 (10%) were referred after transcranial Doppler screening. At the time of surgery, the median age was 12 years. Thirteen patients (43%) suffered an ischemic stroke while on chronic transfusion therapy. Long-term follow-up imaging (MR angiography or catheter angiography) at a mean of 25 months postoperatively was available in 39 (81%) treated hemispheres. In 34 (87%) of those hemispheres there were demonstrable collateral vessels on imaging. There were 4 neurological events in 1590 cumulative months of follow-up, or 1 event per 33 patient-years. In the patients in whom complete data were available (MSCHONY series, n = 17), the postoperative stroke rate was reduced more than 6-fold from the preoperative rate (p = 0.0003). CONCLUSIONS: Pial synangiosis in patients with SCA, MMS, and brain ischemia appears to be a safe and effective treatment option. Transcranial Doppler and/or MRI screening in asymptomatic patients with SCA is recommended for the diagnosis of MMS.

Endoscopic endonasal optic nerve decompression in children younger than 2 years old with congenital optic canal stenosis: illustrative cases.

BACKGROUND: Congenital optic canal stenosis causing compressive optic neuropathy is a rare disorder that presents unique diagnostic and treatment challenges. Endoscopic endonasal optic nerve decompression (EOND) has been described for optic nerve compression in adults and adolescents but has never been reported for young children without pneumatized sphenoid sinuses. The authors describe preoperative and intraoperative considerations for three patients younger than 2 years of age with congenital optic canal stenosis due to genetically confirmed osteopetrosis or chondrodysplasia. OBSERVATIONS: Serial ophthalmological examinations, with a particular focus on object tracking ability, fundoscopic examination, and visual evoked potential trends in preverbal children, are important for detecting progressive optic neuropathy. The lack of pneumatization of the sphenoid sinus presents unique challenges and requires the surgical creation of a sphenoid sinus with the use of neuronavigation to determine the limits of bony exposure given the lack of easily identifiable anatomical landmarks such as the opticocarotid recess. There were no perioperative complications. LESSONS: EOND for congenital optic canal stenosis is safe and technically feasible even given the lack of pneumatization of the sphenoid sinus in young patients. The key operative step is surgically creating the sphenoid sinus through careful bony removal with the aid of neuronavigation. https://thejns.org/doi/10.3171/CASE23559.

Association of germinal matrix hemorrhage volume with neurodevelopment and hydrocephalus.

OBJECTIVE: The objective of this study was to evaluate whether volumetric measurements on early cranial ultrasound (CUS) in high-grade germinal matrix hemorrhage-intraventricular hemorrhage (GMH-IVH) are associated with hydrocephalus and neurodevelopmental metrics. METHODS: A retrospective case series analysis of infants with high-grade GMH-IVH admitted to the St. Louis Children's Hospital neonatal intensive care unit between 2007 and 2015 who underwent neurodevelopmental testing using the Bayley Scales of Infant and Toddler Development, 3rd Edition (Bayley-III) at 2 years of corrected age was performed. GMH volume, periventricular hemorrhagic infarction volume, and frontotemporal horn ratio were obtained from direct review of neonatal CUS studies. Univariate and multivariable regression models were used to evaluate the association between hemorrhage volumes and hydrocephalus requiring permanent CSF diversion with ventricular shunt or endoscopic third ventriculostomy with or without choroid plexus cauterization and composite Bayley-III cognitive, language, and motor scores. RESULTS: Forty-three infants (29 males, mean gestational age 25 weeks) met the inclusion criteria. The mean age at time of the CUS with the largest hemorrhage volume or first diagnosis of highest grade was 6.2 days. Nineteen patients underwent treatment for hydrocephalus with permanent CSF diversion. In multivariable analyses, larger GMH volume was associated with worse estimated Bayley-III cognitive (left-sided GMH volume: p = 0.048, total GMH volume: p = 0.023) and motor (left-sided GMH volume: p = 0.010; total GMH volume: p = 0.014) scores. Larger periventricular hemorrhagic infarction volume was associated with worse estimated Bayley-III motor scores (each side p < 0.04). Larger left-sided (OR 2.55, 95% CI 1.10-5.88; p = 0.028) and total (OR 1.35, 95% CI 1.01-1.79; p = 0.041) GMH volumes correlated with hydrocephalus. There was no relationship between early ventricular volume and hydrocephalus or neurodevelopmental outcomes. CONCLUSIONS: Location-specific hemorrhage volume on early CUS may be prognostic for neurodevelopmental and hydrocephalus outcomes in high-grade GMH-IVH.

Type 1 Diabetes Genetic Risk in 109,954 Veterans With Adult-Onset Diabetes: The Million Veteran Program (MVP).

OBJECTIVE: To characterize high type 1 diabetes (T1D) genetic risk in a population where type 2 diabetes (T2D) predominates. RESEARCH DESIGN AND METHODS: Characteristics typically associated with T1D were assessed in 109,594 Million Veteran Program participants with adult-onset diabetes, 2011-2021, who had T1D genetic risk scores (GRS) defined as low (0 to <45%), medium (45 to <90%), high (90 to <95%), or highest (≥95%). RESULTS: T1D characteristics increased progressively with higher genetic risk (P < 0.001 for trend). A GRS ≥90% was more common with diabetes diagnoses before age 40 years, but 95% of those participants were diagnosed at age ≥40 years, and their characteristics resembled those of individuals with T2D in mean age (64.3 years) and BMI (32.3 kg/m2). Compared with the low-risk group, the highest-risk group was more likely to have diabetic ketoacidosis (low GRS 0.9% vs. highest GRS 3.7%), hypoglycemia prompting emergency visits (3.7% vs. 5.8%), outpatient plasma glucose <50 mg/dL (7.5% vs. 13.4%), a shorter median time to start insulin (3.5 vs. 1.4 years), use of a T1D diagnostic code (16.3% vs. 28.1%), low C-peptide levels if tested (1.8% vs. 32.4%), and glutamic acid decarboxylase antibodies (6.9% vs. 45.2%), all P < 0.001. CONCLUSIONS: Characteristics associated with T1D were increased with higher genetic risk, and especially with the top 10% of risk. However, the age and BMI of those participants resemble those of people with T2D, and a substantial proportion did not have diagnostic testing or use of T1D diagnostic codes. T1D genetic screening could be used to aid identification of adult-onset T1D in settings in which T2D predominates.

Electroconvulsive shock ameliorates disease processes and extends survival in huntingtin mutant mice.

Huntington's disease (HD) is an inherited neurodegenerative disorder caused by expanded polyglutamine repeats in the huntingtin (Htt) protein. Mutant Htt may damage and kill striatal neurons by a mechanism involving reduced production of brain-derived neurotrophic factor (BDNF) and increased oxidative and metabolic stress. Because electroconvulsive shock (ECS) can stimulate the production of BDNF and protect neurons against stress, we determined whether ECS treatment would modify the disease process and provide a therapeutic benefit in a mouse model of HD. ECS (50 mA for 0.2 s) or sham treatment was administered once weekly to male N171-82Q Htt mutant mice beginning at 2 months of age. Endpoints measured included motor function, striatal and cortical pathology, and levels of protein chaperones and BDNF. ECS treatment delayed the onset of motor symptoms and body weight loss and extended the survival of HD mice. Striatal neurodegeneration was attenuated and levels of protein chaperones (Hsp70 and Hsp40) and BDNF were elevated in striatal neurons of ECS-treated compared with sham-treated HD mice. Our findings demonstrate that ECS can increase the resistance of neurons to mutant Htt resulting in improved functional outcome and extended survival. The potential of ECS as an intervention in subjects that inherit the mutant Htt gene merits further consideration.

Second-Order Nonlinear Optics as an Orientation-Independent Probe of Molecular Environments at Interfaces.

Measurement techniques that probe the second-order susceptibility, such as second-harmonic and sum-frequency generation, are recognized for their ability to study environments with broken centrosymmetry. As a result, they serve as reporters of molecules at surfaces because the second-order susceptibility is often zero in the adjacent bulk media. Although the signals measured in such experiments carry unique information about the interfacial environment, the challenge is to disentangle properties related to the electronic structure as they are wrapped up in the orientation distribution. Over the past 30 years, this challenge has been turned into an opportunity, as many studies have sought to learn about the arrangement of molecules at surfaces. Here we demonstrate that the flipped case is possible, where fundamental properties of the interfacial environment can be extracted in a manner that is completely independent of, and therefore oblivious to, the orientation distribution. Using p-cyanophenol adsorbed at the air-water interface as an example, we illustrate that the cyano group polarizability varies less along the direction of the C-N bond when at the surface than when the same molecules are in the bulk aqueous phase.

Deferoxamine Prevents Neonatal Posthemorrhagic Hydrocephalus Through Choroid Plexus-Mediated Iron Clearance.

Posthemorrhagic hydrocephalus occurs in up to 30% of infants with high-grade intraventricular hemorrhage and is associated with the worst neurocognitive outcomes in preterm infants. The mechanisms of posthemorrhagic hydrocephalus after intraventricular hemorrhage are unknown; however, CSF levels of iron metabolic pathway proteins including hemoglobin have been implicated in its pathogenesis. Here, we develop an animal model of intraventricular hemorrhage using intraventricular injection of hemoglobin at post-natal day 4 that results in acute and chronic hydrocephalus, pathologic choroid plexus iron accumulation, and subsequent choroid plexus injury at post-natal days 5, 7, and 15. This model also results in increased expression of aquaporin-1, Na+/K+/Cl- cotransporter 1, and Na+/K+/ATPase on the apical surface of the choroid plexus 24 h post-intraventricular hemorrhage. We use this model to evaluate a clinically relevant treatment strategy for the prevention of neurological sequelae after intraventricular hemorrhage using intraventricular administration of the iron chelator deferoxamine at the time of hemorrhage. Deferoxamine treatment prevented posthemorrhagic hydrocephalus for up to 11 days after intraventricular hemorrhage and prevented the development of sensorimotor gating deficits. In addition, deferoxamine treatment facilitated acute iron clearance through the choroid plexus and subsequently reduced choroid plexus iron levels at 24 h with reversal of hemoglobin-induced aquaporin-1 upregulation on the apical surface of the choroid plexus. Intraventricular administration of deferoxamine at the time of intraventricular hemorrhage may be a clinically relevant treatment strategy for preventing posthemorrhagic hydrocephalus and likely acts through promoting iron clearance through the choroid plexus to prevent hemoglobin-induced injury.