Lung nodule malignancy classification with associated pulmonary fibrosis using 3D attention-gated convolutional network with CT scans.

BACKGROUND: Chest Computed tomography (CT) scans detect lung nodules and assess pulmonary fibrosis. While pulmonary fibrosis indicates increased lung cancer risk, current clinical practice characterizes nodule risk of malignancy based on nodule size and smoking history; little consideration is given to the fibrotic microenvironment. PURPOSE: To evaluate the effect of incorporating fibrotic microenvironment into classifying malignancy of lung nodules in chest CT images using deep learning techniques. MATERIALS AND METHODS: We developed a visualizable 3D classification model trained with in-house CT dataset for the nodule malignancy classification task. Three slightly-modified datasets were created: (1) nodule alone (microenvironment removed); (2) nodule with surrounding lung microenvironment; and (3) nodule in microenvironment with semantic fibrosis metadata. For each of the models, tenfold cross-validation was performed. Results were evaluated using quantitative measures, such as accuracy, sensitivity, specificity, and area-under-curve (AUC), as well as qualitative assessments, such as attention maps and class activation maps (CAM). RESULTS: The classification model trained with nodule alone achieved 75.61% accuracy, 50.00% sensitivity, 88.46% specificity, and 0.78 AUC; the model trained with nodule and microenvironment achieved 79.03% accuracy, 65.46% sensitivity, 85.86% specificity, and 0.84 AUC. The model trained with additional semantic fibrosis metadata achieved 80.84% accuracy, 74.67% sensitivity, 84.95% specificity, and 0.89 AUC. Our visual evaluation of attention maps and CAM suggested that both the nodules and the microenvironment contributed to the task. CONCLUSION: The nodule malignancy classification performance was found to be improving with microenvironment data. Further improvement was found when incorporating semantic fibrosis information.

Pseudomonas aeruginosa-induced nociceptor activation increases susceptibility to infection.

We report a rapid reduction in blink reflexes during in vivo ocular Pseudomonas aeruginosa infection, which is commonly attributed and indicative of functional neuronal damage. Sensory neurons derived in vitro from trigeminal ganglia (TG) were able to directly respond to P. aeruginosa but reacted significantly less to strains of P. aeruginosa that lacked virulence factors such as pili, flagella, or a type III secretion system. These observations led us to explore the impact of neurons on the host's susceptibility to P. aeruginosa keratitis. Mice were treated with Resiniferatoxin (RTX), a potent activator of Transient Receptor Potential Vanilloid 1 (TRPV1) channels, which significantly ablated corneal sensory neurons, exhibited delayed disease progression that was exemplified with decreased bacterial corneal burdens and altered neutrophil trafficking. Sensitization to disease was due to the increased frequencies of CGRP-induced ICAM-1+ neutrophils in the infected corneas and reduced neutrophil bactericidal activities. These data showed that sensory neurons regulate corneal neutrophil responses in a tissue-specific matter affecting disease progression during P. aeruginosa keratitis. Hence, therapeutic modalities that control nociception could beneficially impact anti-infective therapy.

Trait profiles in difficult-to-treat asthma: Clinical impact and response to systematic assessment.

BACKGROUND: Multidisciplinary systematic assessment improves outcomes in difficult-to-treat asthma, but without clear response predictors. Using a treatable-traits framework, we stratified patients by trait profile, examining clinical impact and treatment responsiveness to systematic assessment. METHODS: We performed latent class analysis using 12 traits on difficult-to-treat asthma patients undergoing systematic assessment at our institution. We examined Asthma Control Questionnaire (ACQ-6) and Asthma Quality of Life Questionnaire (AQLQ) scores, FEV1 , exacerbation frequency, and maintenance oral corticosteroid (mOCS) dose, at baseline and following systematic assessment. RESULTS: Among 241 patients, two airway-centric profiles were characterized by early-onset with allergic rhinitis (n = 46) and adult onset with eosinophilia/chronic rhinosinusitis (n = 60), respectively, with minimal comorbid or psychosocial traits; three non-airway-centric profiles exhibited either comorbid (obesity, vocal cord dysfunction, dysfunctional breathing) dominance (n = 51), psychosocial (anxiety, depression, smoking, unemployment) dominance (n = 72), or multi-domain impairment (n = 12). Compared to airway-centric profiles, non-airway-centric profiles had worse baseline ACQ-6 (2.7 vs. 2.2, p < .001) and AQLQ (3.8 vs. 4.5, p < .001) scores. Following systematic assessment, the cohort showed overall improvements across all outcomes. However, airway-centric profiles had more FEV1 improvement (5.6% vs. 2.2% predicted, p < .05) while non-airway-centric profiles trended to greater exacerbation reduction (1.7 vs. 1.0, p = .07); mOCS dose reduction was similar (3.1 mg vs. 3.5 mg, p = .782). CONCLUSION: Distinct trait profiles in difficult-to-treat asthma are associated with different clinical outcomes and treatment responsiveness to systematic assessment. These findings yield clinical and mechanistic insights into difficult-to-treat asthma, offer a conceptual framework to address disease heterogeneity, and highlight areas responsive to targeted intervention.

Expression of 4E-BP1 in juvenile mice alleviates mTOR-induced neuronal dysfunction and epilepsy.

Hyperactivation of the mTOR pathway during foetal neurodevelopment alters neuron structure and function, leading to focal malformation of cortical development and intractable epilepsy. Recent evidence suggests a role for dysregulated cap-dependent translation downstream of mTOR signalling in the formation of focal malformation of cortical development and seizures. However, it is unknown whether modifying translation once the developmental pathologies are established can reverse neuronal abnormalities and seizures. Addressing these issues is crucial with regards to therapeutics because these neurodevelopmental disorders are predominantly diagnosed during childhood, when patients present with symptoms. Here, we report increased phosphorylation of the mTOR effector and translational repressor, 4E-BP1, in patient focal malformation of cortical development tissue and in a mouse model of focal malformation of cortical development. Using temporally regulated conditional gene expression systems, we found that expression of a constitutively active form of 4E-BP1 that resists phosphorylation by focal malformation of cortical development in juvenile mice reduced neuronal cytomegaly and corrected several neuronal electrophysiological alterations, including depolarized resting membrane potential, irregular firing pattern and aberrant expression of HCN4 ion channels. Further, 4E-BP1 expression in juvenile focal malformation of cortical development mice after epilepsy onset resulted in improved cortical spectral activity and decreased spontaneous seizure frequency in adults. Overall, our study uncovered a remarkable plasticity of the juvenile brain that facilitates novel therapeutic opportunities to treat focal malformation of cortical development-related epilepsy during childhood with potentially long-lasting effects in adults.

Survey of stigma across healthcare workers in an urban, academic medical center regarding perinatal patients using opioids.

BACKGROUND AND OBJECTIVES: To examine healthcare workers' attitudes towards pregnant woman using opioids across provider type, specialty, and years of service. METHODS: Cross-sectional, anonymous survey of healthcare workers at an urban, academic medical center regarding attitudes towards pregnant women using opioids. RESULTS: One hundred and nineteen surveys were completed. Nurses were less likely to feel sympathetic towards pregnant women that use opioids (p = .016). DISCUSSION AND CONCLUSIONS: Differences in attitudes towards pregnant women using opioids were found between clinicians and nurses. SCIENTIFIC SIGNIFICANCE: Training and experience may contribute to attitude differences towards pregnant women using opioids.

Small Extracellular Vesicles Control Dendritic Spine Development through Regulation of HDAC2 Signaling.

The release of small extracellular vesicles (sEVs) has recently been reported, but knowledge of their function in neuron development remains limited. Using LC-MS/MS, we found that sEVs released from developing cortical neurons in vitro obtained from mice of both sexes were enriched in cytoplasm, exosome, and protein-binding and DNA/RNA-binding pathways. The latter included HDAC2, which was of particular interest, because HDAC2 regulates spine development, and populations of neurons expressing different levels of HDAC2 co-exist in vivo during the period of spine growth. Here, we found that HDAC2 levels decrease in neurons as they acquire synapses and that sEVs from HDAC2-rich neurons regulate HDAC2 signaling in HDAC2-low neurons possibly through HDAC2 transfer. This regulation led to a transcriptional decrease in HDAC2 synaptic targets and the density of excitatory synapses. These data suggest that sEVs provide inductive cell-cell signaling that coordinates the development of dendritic spines via the activation of HDAC2-dependent transcriptional programs.SIGNIFICANCE STATEMENT A role of small extracellular vesicles (sEVs; also called exosomes) in neuronal development is of particular interest, because sEVs could provide a major signaling modality between developing neurons when synapses are not fully functional or immature. However, knowledge of sEVs on neuron, and more precisely spine development, is limited. We provide several lines of evidence that sEVs released from developing cortical neurons regulate the development of dendritic spines via the regulation of HDAC2 signaling. This paracrine communication is temporally restricted during development because of the age-dependent decrease in sEV release as neurons mature and acquire spines.

A Mechanistic Understanding of Monoclonal Antibody Interfacial Protection by Hydrolytically Degraded Polysorbate 20 and 80 under IV Bag Conditions.

PURPOSE: Polysorbates (PS) contain polyoxyethylene (POE) sorbitan/isosorbide fatty acid esters that can partially hydrolyze over time in liquid drug products to generate degradants and a remaining intact PS fraction with a modified ester distribution. The degradants are composed of free fatty acids (FFAs) --primarily lauric acid for PS20 and oleic acid for PS80-- and POE head groups. We previously demonstrated that under IV bag agitation conditions, mAb1 (a surface-active IgG4) aggregation increased with increasing amounts of degradants for PS20 but not for PS80. The purpose of this work is to understand the mechanism behind this observation. METHODS: The surface tension of the remaining intact PS fraction without degradants was modeled and compared with that of enzymatically degraded PS solutions. Next, mAb1 aggregation in saline was measured in the presence of laurate and oleate salts during static storage. Lastly, colloidal and conformational stability of mAb1 in the presence of these salts was investigated through differential scanning fluorimetry and dynamic light scattering under IV bag solution conditions. RESULTS: The surface tension was primarily influenced by FFAs rather than the modified ester distribution of the remaining intact PS. MAb1 bulk aggregation increased in the presence of laurate but not oleate salts. Both salt types increased the melting temperature of mAb1 indicating FFA-mAb1 interactions. However, only laurate salt increased mAb1 self-association potentially explaining the higher aggregation propensity in its presence. CONCLUSION: Our results help explain the observed differences between hydrolytically degraded PS20 and PS80 in affecting mAb1 aggregation under IV bag agitation conditions.

Toward safer opioid prescribing: effects of the TOWER intervention on HIV care providers.

ABSTRACTRates of opioid use disorder and associated deaths remain alarmingly high. Measures to address the epidemic have included reductions in opioid prescribing, in part guided by the Centers for Disease Control Opioid Prescribing Guideline (CDCG). While reductions in over-prescribing have occurred, these measures have also resulted in decreased access and adverse outcomes for some stable opioid-treated chronic pain patients. The TOWard SafER Opioid Prescribing (TOWER) intervention was designed to support HIV primary care providers in use of the CDCG and in decision-making and patient-provider communication regarding safe opioid prescribing. Eleven HIV primary care providers and 40 of their patients were randomized into intervention and control groups. Transcripts from 21 patient visits were analyzed, focusing on opioid and pain-related communications. Findings from this research indicate greater alignment with the CDCG among visits carried out with providers in the TOWER intervention group. However, control group visits were notably consistent with guideline recommendations in several key areas. Differences observed between the intervention and control group visits demonstrate intervention strengths, as well as areas where additional work needs to be done to ensure prescribing and communication consistent with the CDCG.

Tenapanor: A new treatment option for hyperphosphatemia in end stage kidney disease.

PURPOSE: This narrative review explores the currently published studies that have evaluated tenapanor for the treatment of hyperphosphatemia in end-stage kidney disease (ESKD) patients on hemodialysis. This medication's new phosphate lowering mechanism of action reduces intestinal phosphate absorption predominantly through reduction of passive paracellular phosphate flux by inhibition of the sodium/hydrogen exporter isoform 3 (NHE3). Tenapanor additionally prevents active transcellular phosphate absorption compensation by decreasing the expression of sodium phosphorus 2b transport protein (NaPi2b). METHODS: A comprehensive search of the literature was conducted using PubMed and ClinicalTrials.gov search engines. The search term "tenapanor hyperphosphatemia" was used for study retrieval. Results were limited to studies published in the English language and excluded review articles. Human, animal, and in vitro studies were included. No date range was specified. RESULTS: A total of 11 primary studies were identified and included in this review, the largest human study of which enrolled 236 patients. Each study is presented in table format along with measured end points. CONCLUSIONS: Tenapanor is the first drug in its class that lowers hyperphosphatemia in ESKD patients through a novel mechanism of action involving paracellular inactive transport. Although more studies are needed, early results indicate that tenapanor may have a place in managing hyperphosphatemia in ESKD patients both as monotherapy and as an adjunct to existing phosphate binder therapy.

A Comprehensive Review: Chronic Pain Sequelae in the Presence of Ehlers-Danlos Syndrome.

PURPOSE OF REVIEW: Patients diagnosed with Ehlers-Danlos syndromes (EDS), and especially those with the hypermobility subtype, often experience a diverse range of acute and chronic pain conditions throughout their lifetime. These can present in a variety of different phenotypes and comorbidities, making it difficult to develop structured treatment protocols. This review seeks to summarize the current literature to address old and novel treatments for EDS. RECENT FINDINGS: Historically, medications and surgery have been used to treat patients with EDS but with low efficacy. Newer therapies that have shown promising effects for both decreasing pain and increasing quality of life include physical/occupational therapy, transcutaneous electrical nerve stimulation units, trigger point injections, low-dose naltrexone, and laser therapy. In addition, addressing the psychosocial aspects of pain with EDS through methods like cognitive behavioral therapy and patient education has shown to be vital in minimizing pain. Most research also emphasizes that pain management should not only focus on pain reduction, but on helping reduce symptoms of hypermobility, central sensitization, and fatigue to make an impactful difference. Research on pain in EDS is still limited with good clinical practice guidelines often limited by poor sample size and lack of clinical studies. Treatment options should be structured based on the specific type of pain pathology and presenting symptoms of each patient and their comorbidities. Future research should attempt to prioritize larger sample sizes, clear definitions of EDS subtypes, randomized trials for treatment efficacy, and more studies dedicated to non-musculoskeletal forms of pain.

Repeated adrenaline requirements for anaphylaxis.

We examined the pattern of adrenaline administration in patients presenting with anaphylaxis. Forty-four percent required repeated adrenaline administration, among whom there had been greater cardiorespiratory compromise. Repeated administration was more frequent in males and older patients, and those triggered by insect sting or unknown cause; no other patient factors were identified. This study supports the provision of two adrenaline auto-injectors to all anaphylaxis patients.

Sciatic, Femoral, and Lateral Femoral Cutaneous Nerve Ultrasound-Guided Percutaneous Peripheral Nerve Stimulation.

OBJECTIVE: With advances in peripheral nerve stimulation technology, there has been an emergence of new minimally invasive techniques to provide neurostimulation therapies for chronic pain. This technical note describes the utilization of ultrasonography for percutaneous placement of peripheral nerve stimulation leads at the sciatic, femoral, and lateral femoral cutaneous nerves. METHODS: Ultrasound can be utilized to localize a specific nerve, view neighboring soft tissue anatomy, and plan a needle trajectory. Various ultrasound techniques and transducer orientations allow for multiple options for lead placement relative to the targeted nerve. CONCLUSIONS: The option of ultrasound-guided percutaneous technique for neurostimulation lead placement allows this treatment modality to be made available to more patients with chronic pain in specific nerve distributions.

Extraforaminal Thoracic and Lumbar Spinal Nerve Ultrasound-Guided Percutaneous Peripheral Nerve Stimulation.

OBJECTIVE: Peripheral nerve stimulation provides targeted stimulation and pain relief within a specific nerve distribution. This technical case report provides a method to perform selective nerve root stimulation of thoracic and lumbar spinal nerves using ultrasonography. METHODS: Ultrasound-guided peripheral nerve stimulation of thoracic and lumbar spinal nerves allows better visualization of soft tissue anatomy and planning of needle trajectory. CONCLUSIONS: Ultrasound-guided peripheral nerve stimulation procedures may provide a safer method for neurostimulation lead placement when compared with fluoroscopic-guided techniques.

Mechanism of Peripheral Nerve Stimulation in Chronic Pain.

INTRODUCTION: With the advancement of technology, peripheral nerve stimulation (PNS) has been increasingly used to treat various chronic pain conditions. Its origin is based on the gate control theory postulated by Wall and Melzack in 1965. However, the exact mechanism behind PNS' analgesic effect is largely unknown. In this article, we performed a comprehensive literature review to overview the PNS mechanism of action. DESIGN: A comprehensive literature review on the mechanism of PNS in chronic pain. METHODS: Comprehensive review of the available literature on the mechanism of PNS in chronic pain. Data were derived from database searches of PubMed, Scopus, and the Cochrane Library and manual searches of bibliographies and known primary or review articles. RESULTS: Animal, human, and imaging studies have demonstrated the peripheral and central analgesic mechanisms of PNS by modulating the inflammatory pathways, the autonomic nervous system, the endogenous pain inhibition pathways, and involvement of the cortical and subcortical areas. CONCLUSIONS: Peripheral nerve stimulation exhibits its neuromodulatory effect both peripherally and centrally. Further understanding of the mechanism of PNS can help guide stimulation approaches and parameters to optimize the use of PNS.

Understanding the evolving phenotype of vascular complications in telomere biology disorders.

Vascular complications such as bleeding due to gastrointestinal telangiectatic anomalies, pulmonary arteriovenous malformations, hepatopulmonary syndrome, and retinal vessel abnormalities are being reported in patients with telomere biology disorders (TBDs) more frequently than previously described. The international clinical care consortium of telomere-associated ailments and family support group Dyskeratosis Congenita Outreach, Inc. held a workshop on vascular abnormalities in the TBDs at the National Cancer Institute in October 2017. Clinicians and basic scientists reviewed current data on vascular complications, hypotheses for the underlying biology and developed new collaborations to address the etiology and clinical management of vascular complications in TBDs.

Pharmacokinetics, Pharmacodynamics, and PKPD Modeling of Curcumin in Regulating Antioxidant and Epigenetic Gene Expression in Healthy Human Volunteers.

Curcumin is a major component of the spice turmeric ( Curcuma longa), often used in food or as a dietary supplement. Many preclinical studies on curcumin suggest health benefits in many diseases due to its antioxidant/anti-inflammatory and epigenetic effects. The few human studies and curcumin's unfavorable pharmacokinetics (PK) have limited its potential, leading researchers to study and develop formulations to improve its PK. The purpose of this clinical study is to describe the acute pharmacokinetics and pharmacodynamics (PK/PD) of commercially marketed curcumin in normal, healthy human volunteers. Twelve volunteers received a 4 g dose of curcumin capsules with a standard breakfast. Plasma samples were collected at specified time points and analyzed for curcumin and its glucuronide levels. RNA was extracted from leukocytes and analyzed for expression of select antioxidant and epigenetic histone deacetylase (HDAC) genes. Plasma levels of parent curcumin were below the detection limit by HPLC-ITMS/MS/MS. However, curcumin-O-glucuronide (COG), a major metabolite of curcumin, was detected as soon as 30 min. These observations of little to no curcumin and some levels of metabolite are in line with previous studies. PD marker antioxidant genes NRF2, HO-1, and NQO1 and epigenetic genes HDAC1, HDAC2, HDAC3, and HDAC4 were quantified by qPCR. COG PK is well-described by a one-compartment model, and the PK/PD of COG and its effect on antioxidant and epigenetic gene expression are captured by an indirect response model (IDR). A structural population PK model was sequentially established using a nonlinear mixed-effect model program (Monolix Lixoft, Orsay, France). Physiologically based pharmacokinetic modeling (PBPK) and simulation using Simcyp correlated well with the observed data. Taken together, these results show that the bioavailability of the parent curcumin compound is low, and oral administration of curcumin can still deliver detectable levels of curcumin glucuronide metabolite. But most importantly, it elicits antioxidant and epigenetic effects which could contribute to the overall health beneficial effects of curcumin.

Evaluating a voriconazole dose modification guideline to optimize dosing in patients with hematologic malignancies.

BACKGROUND: Voriconazole is an azole antifungal utilized for prophylaxis and treatment of invasive fungal infections in hematologic patients. Previous studies have revealed decreased efficacy and increased toxicity with subtherapeutic <1 mcg/mL and supratherapeutic > 4 mcg/mL levels. A voriconazole dose modification guideline was introduced in July 2014 based on a retrospective analysis. OBJECTIVE: The primary objective was to evaluate the voriconazole dose modification guideline. Secondary objectives were to identify patient-specific characteristics that contribute to inadequate levels, adverse effects, and breakthrough invasive fungal infections. METHODS: This prospective study included 128 patients with 250 admissions who received voriconazole from July 2014 to February 2016. Eligible adult patients receiving voriconazole for prophylaxis or treatment with at least one trough level, drawn appropriately, were included. Demographics, adverse effects, and breakthrough invasive fungal infections were documented. RESULTS: Voriconazole use was categorized as: new start, new start with loading dose, or continuation of home therapy. The median initial levels were 1.5, 3.5, and 1.7 mcg/mL with 62% (73/119), 55% (6/11), and 60% (72/120) within the therapeutic range, respectively. Using the voriconazole dose modification guideline, 80% were within goal by the second dose adjustment. Age ≤ 30 and BMI ≤ 25 kg/m2 had higher rates of subtherapeutic levels in the new start cohorts (p = 0.024 and p = 0.009). Approximately 7.6% of patients experienced an adverse effect with neurologic/psychological being the most common. A total of 8.5% of patients had a possible, probable or proven breakthrough invasive fungal infections while on voriconazole. CONCLUSION: Using the voriconazole dose modification guideline, the number of patients that reached therapeutic range improved from 36% to 80% by the second dose adjustment (p = 0.007). This voriconazole dose modification guideline can be utilized to help dose and adjust voriconazole in order to achieve therapeutic levels.

High incidence of respiratory disease in Australian infants despite low rate of maternal cigarette smoking.

AIM: The burden of wheezing illnesses in Australian infants has not been documented since the success of initiatives to reduce maternal cigarette smoking. We aimed to determine the incidence of wheeze and related health-care utilisation during the first year of life among a contemporary Australian birth cohort. METHODS: A birth cohort of 1074 infants was assembled between 2010 and 2013. Parents completed questionnaires periodically. Several non-exclusive infant respiratory disease phenotypes were defined, including any wheeze, wheeze with shortness of breath and recurrent wheeze. Skin prick testing was performed to determine atopic wheeze. Health-care utilisation for respiratory disease was determined from questionnaires and hospital medical records. RESULTS: Retention to 1 year was 840/1074 (83%). The incidence of any wheeze was 51.8% (95% confidence interval (CI) 48.3-55.2%), wheeze with shortness of breath 20.6% (95% CI 17.9-23.5), recurrent wheeze 19.4% (95% CI 16.8-22.2) and atopic wheeze 6% (95% CI 4.6-7.8). Respiratory illness resulted in primary health-care utilisation in 82.2% (95% CI 79.3-84.8) of participants and hospital presentation in 8.8% (95% CI 7.2-10.6). Maternal smoking during pregnancy was uncommon (15.7%) and was not associated with wheeze or health resource utilisation. Male gender, familial atopy and asthma and smaller household size were associated with a higher incidence of wheeze. CONCLUSIONS: The incidence of wheezing illness among Australian infants remains high despite relatively low rates of maternal smoking during pregnancy. The majority of the health-care burden is borne by primary health-care services. Further research is required to inform novel prevention strategies.

Investigation of Pediatric Anemia in the Commonwealth of the Northern Mariana Islands.

Objective To report on the prevalence and etiology of pediatric anemia in the Commonwealth of the Northern Mariana Islands (CNMI). Method A retrospective chart review was conducted that included patients up to 19 years of age who presented for well child care and whose hemoglobin or hematocrit was checked in the CNMI from 2014 to 2015. Lab values, diagnoses and treatment plans, patient reported ethnicity, and follow-up results were collected from eligible patients. Results The records for 1483 pediatric patients who had 1584 well child visits were reviewed. The prevalence of anemia amongst all eligible patients was 8.0% (5.4-10.7). This included 292 9 to 18 months old patients, which is estimated to be 40% of the total pediatric population of CNMI in that age group. Among the 9 to 18 months old patients, the prevalence of anemia is 5.5% (2.6-8.4). Etiology of anemia was investigated and of the patients treated with iron, 55.2% had a documented response. The majority of those without documentation of improvement with iron were patients who were lost to follow-up. In addition, a total of 10 patients were found to have an alpha or beta thalassemia variant discovered initially by anemia screening or sibling tracing. Discussion In this United States Commonwealth, prevalence of anemia appears lower than prevalence reported for other independent Pacific Island nations and closer to that of the US. Thalassemia is documented within this population. Limitations to this data were use of a convenient sample that may be hampered by lack of presentation to well-child care. This study will guide future public health studies on anemia prevalence and can guide public health intervention decisions to improve pediatric care in the CNMI.

Normalizing translation through 4E-BP prevents mTOR-driven cortical mislamination and ameliorates aberrant neuron integration.

Hyperactive mammalian target of rapamycin complex 1 (mTORC1) is a shared molecular hallmark in several neurodevelopmental disorders characterized by abnormal brain cytoarchitecture. The mechanisms downstream of mTORC1 that are responsible for these defects remain unclear. We show that focally increasing mTORC1 activity during late corticogenesis leads to ectopic placement of upper-layer cortical neurons that does not require altered signaling in radial glia and is accompanied by changes in layer-specific molecular identity. Importantly, we found that decreasing cap-dependent translation by expressing a constitutively active mutant of the translational repressor eukaryotic initiation factor 4E-binding protein 1 (4E-BP1) prevents neuronal misplacement and soma enlargement, while partially rescuing dendritic hypertrophy induced by hyperactive mTORC1. Furthermore, overactivation of translation alone through knockdown of 4E-BP2 was sufficient to induce neuronal misplacement. These data show that many aspects of abnormal brain cytoarchitecture can be prevented by manipulating a single intracellular process downstream of mTORC1, cap-dependent translation.