Neurotoxicity assessment of the herbicide pethoxamid in zebrafish (Danio rerio) embryos/larvae.

Pethoxamid, a member of the chloroacetamide herbicide family, is a recently approved chemical for pre- or post-emergence weed control; however, toxicity data for sublethal effects in aquatic organisms exposed to pethoxamid are non-existent in literature. To address this, we treated zebrafish embryos/larvae to pethoxamid over a 7-day period post-fertilization and evaluated several toxicological endpoints associated with oxidative stress and neurotoxicity. Continuous pethoxamid exposure did not affect survival nor hatch success in embryos/larvae for 7 days up to 1000 µg L-1. Exposure to pethoxamid did not affect embryonic ATP-linked respiration, but it did reduce non-mitochondrial respiration at the highest concentration tested. We also noted a significant increase in both apoptosis and levels of reactive oxygen species (ROS) in larvae zebrafish following exposure to pethoxamid. Increases in apoptosis and ROS, however, were not correlated with any altered gene expression pattern for apoptotic and oxidative damage response transcripts. To assess neurotoxicity potential, we measured behavior and several transcripts implicated in neural processes in the central nervous system. While locomotor activity of larval zebrafish was affected by pethoxamid exposure (hyperactivity was observed at concentrations below 1 µg L-1, and hypoactivity was noted at higher exposures to 10 and 100 µg L-1 pethoxamid), there were no effects on steady state mRNA abundance for neurotoxicity-related transcripts tested. This data contributes to knowledge regarding exposure risks for chloroacetamide-based herbicides and is the first study investigating sublethal toxicity for this newly registered herbicide.

Cognitive function in adolescence and the risk of early-onset stroke.

BACKGROUND: Stroke is increasingly prevalent at younger ages but the risk factors are uncertain. We examined the association between adolescent cognitive function and early-onset stroke. METHODS: This was a nationwide population-based cohort study of 1 741 345 Israeli adolescents (42% women) who underwent comprehensive cognitive function tests at age 16-20 years, before mandatory military service, during 1987-2012. Cognitive function (range: 1-9) was categorised as low (1-3, corresponding to IQ score below 89), medium (4-7, IQ score range: 89-118), or high (8-9, IQ score above 118). Participant data were linked to the Israeli National Stroke Registry. Cox proportional hazard models were used to estimate risks for the first occurrence of ischaemic stroke during 2014-2018. RESULTS: During 8 689 329 person-years of follow-up, up to a maximum age of 50 years, 908 first stroke events occurred (767 ischaemic and 141 haemorrhagic). Compared with a reference group of people with high cognitive function, body mass index-adjusted and sociodemographic-adjusted HRs (95% CIs) for early-onset stroke were 1.78 (1.33-2.38) in medium and 2.68 (1.96-3.67) in low cognitive function groups. There was evidence of a dose-response relationship (P for trend <0.0001) such that one-unit of lower cognitive function z-score was associated with a 33% increased risk of stroke (1.33; 1.23-1.42). These associations were similar for ischaemic stroke but lower for haemorrhagic stroke; persisted in sensitivity analyses that accounted for diabetes status and hypertension; and were evident before age 40 years. CONCLUSIONS: Alongside adolescent obesity and hypertension, lower cognitive function may be a risk factor for early-onset stroke.

A Population-Based Approach to the Argument on Brain-First and Body-First Pathogenesis of Lewy Body Disease.

OBJECTIVE: To explore the clinical progression of the brain-/body-first categories within Lewy body disease (LBD): Parkinson's disease (PD), dementia with Lewy bodies (DLB), and PD dementia. METHODS: We used of the Rochester Epidemiology Project to establish a population-based cohort of clinically diagnosed LBD. We used two definitions for differentiating between brain- and body-first LBD: a previously hypothesized body-first presentation in patients with rapid eye movement sleep behavior onset before motor symptoms onset; and an expanded definition of body-first LBD when a patient had at least 2 premotor symptoms between constipation, erectile dysfunction, rapid eye movement sleep behavior, anosmia, or neurogenic bladder. RESULTS: Brain-first patients were more likely to be diagnosed with PD (RR = 1.43, p = 0.003), whereas body-first patients were more likely to be diagnosed with DLB (RR = 3.15, p < 0.001). Under the expanded definition, there was no difference in LBD diagnosis between brain-first and body-first patients (PD: RR = 1.03, p = 0.10; DLB: RR = 0.88, p = 0.58) There were no patterns between brain- or body-first presentation, PD dementia under either definition (original: p = 0.09, expanded: p = 0.97), and no significant difference in motor symptoms between brain-first and body-first. INTERPRETATION: Our findings do not support the dichotomous classification of body-first and brain-first LBD with the currently proposed definition. Biological exposures resulting in PD and DLB are unlikely to converge on a binary classification of top-down or bottom-up synuclein pathology. ANN NEUROL 2024.

Emergence of the natural history of Myhre syndrome: 47 patients evaluated in the Massachusetts General Hospital Myhre Syndrome Clinic (2016-2023).

Myhre syndrome is an increasingly diagnosed ultrarare condition caused by recurrent germline autosomal dominant de novo variants in SMAD4. Detailed multispecialty evaluations performed at the Massachusetts General Hospital (MGH) Myhre Syndrome Clinic (2016-2023) and by collaborating specialists have facilitated deep phenotyping, genotyping and natural history analysis. Of 47 patients (four previously reported), most (81%) patients returned to MGH at least once. For patients followed for at least 5 years, symptom progression was observed in all. 55% were female and 9% were older than 18 years at diagnosis. Pathogenic variants in SMAD4 involved protein residues p.Ile500Val (49%), p.Ile500Thr (11%), p.Ile500Leu (2%), and p.Arg496Cys (38%). Individuals with the SMAD4 variant p.Arg496Cys were less likely to have hearing loss, growth restriction, and aortic hypoplasia than the other variant groups. Those with the p.Ile500Thr variant had moderate/severe aortic hypoplasia in three patients (60%), however, the small number (n = 5) prevented statistical comparison with the other variants. Two deaths reported in this cohort involved complex cardiovascular disease and airway stenosis, respectively. We provide a foundation for ongoing natural history studies and emphasize the need for evidence-based guidelines in anticipation of disease-specific therapies.

Waterborne exposure to the antineoplastic 5-fluorouracil alters lipid composition in larval zebrafish (Danio rerio).

Antineoplastic medications are present in aquatic environments and are measured at relatively high concentrations in hospital sewage effluent. Thus, it is important to characterize risk associated with waterborne exposures to anticancer drugs. The drug 5-fluorouracil (5-FU) is used to treat several types of cancers, acting to inhibit cell division and cellular metabolism. The objectives of this study were to determine the effects of 5-FU on developmental endpoints and lipid composition in zebrafish. 5-FU did not negatively affect development nor survival in developing zebrafish at concentrations up to 1000 µg/L. However, 5-FU increased neutral lipid content in zebrafish larvae, indicating potential for lipid dysregulation. To further discern effects on lipids, lipidomics was conducted and a total of 164 lipids belonging to 14 lipid classes were identified. Significant changes (false discovery rate < 0.05) in abundance were detected for 19 lipids including some ceramides, ether-linked phosphatidylethanolamines, and sphingomyelins among others. We also measured the expression levels of 14 lipid-related enzymes and transporters (e.g., acox3, dgat1, fads2, fasn, elovl2) using real-time PCR; however, mRNA abundance levels were not affected, suggesting transcriptional changes may not be a primary mechanism underlying lipid dysregulation. Locomotor activity was measured in zebrafish as lipids are needed for swimming activity in larvae. Exposure to 5-FU did not affect locomotor activity up to 1000 µg/L. We conclude that lipids accumulate in larval zebrafish with exposure to 5-FU, which can subsequently affect lipid composition. These data reveal potential lipid signatures of 5-FU exposure and contribute to risk assessments for antineoplastic exposure in aquatic environments.

Navigating the Impact of the Dobbs Decision: Perspectives from Pediatric Surgeons on Reproductive Health Care.

SUMMARY: Nationwide abortion restrictions resulting from the Dobbs v. Jackson Women's Health Organization (2022) decision have generated confusion and uncertainty among healthcare professionals, with concerns for liability impacting clinical decision-making and outcomes. The impact on pediatric surgery can be seen in prenatal counseling for fetal anomaly cases, counseling for fetal intervention, and recommendations for pregnant children and adolescents who seek termination. It is essential that all physicians and healthcare team members understand the legal implications on their clinical practices, engage with resources and organizations which can help navigate these circumstances, and consider advocating for patients and themselves. Pediatric surgeons must consider the impact of these changing laws on their ability to provide comprehensive and ethical care and counseling to all patients.

Improving Breath Detection From Pulsed-Flow Oxygen Sources Using a New Nasal Interface.

BACKGROUND: Patients with COPD and other lung diseases are treated with long-term oxygen therapy (LTOT). Portable oxygen sources are required to administer LTOT while maintaining patient autonomy. Existing portable oxygen equipment has limitations that can hinder patient mobility. A novel nasal interface is presented in this study, aiming to enhance breath detection and triggering efficiency of portable pulsed-flow oxygen devices, thereby improving patient mobility and independence. METHOD: To examine the effectiveness of the new interface, 8 respiratory therapists participated in trials using different oxygen sources (tank with oxygen-conserving device, SimplyGo Mini portable oxygen concentrator [POC], and OxyGo NEXT POC) and breathing types (nasal and oral) while using either the new nasal interface or a standard cannula. Each trial was video recorded so participant breaths could be retroactively matched with a pulse/no-pulse response, and triggering success rates were calculated by dividing the number of oxygen pulses by the number of breaths in each trial. After each trial, volunteers were asked to rate their perceived breathing resistance. RESULTS: Nasal breathing consistently resulted in higher triggering success rates compared to oral breathing for pulsed-flow oxygen devices. POCs exhibited higher triggering success rates than did the oxygen tanks with conserving device. However, there were no significant differences in triggering success rates between the two POC models. The new nasal interface demonstrated improved triggering success rates compared to the standard cannula. Whereas the new nasal interface was associated with a slight increase in perceived breathing resistance during nasal breathing trials, participants reported manageable resistance levels when using the interface. CONCLUSIONS: This study demonstrates that the new nasal interface can improve triggering success rates of pulsed-flow oxygen devices during both nasal and oral breathing scenarios. Further research involving patient trials is recommended to understand the clinical implications of improved pulse triggering.

Thoracoabdominal aneurysm repair using the Unitary Manifold Device.

OBJECTIVE: To present a single-center prospective study of 126 consecutively treated patients who underwent endovascular repair of a thoracoabdominal aortic aneurysm with the physician-modified, nonanatomic-based Unitary Manifold (UM) device. METHODS: Data were collected from 126 consecutive all-comer patients treated with the physician-modified, nonanatomic-based UM from 2015 to 2023. Treatment was performed at a single center by a single physician under a Physician Sponsored Investigation Exemption G140207. RESULTS: The UM was indicated for repair of all Crawford extents including juxtarenal, pararenal, and short-neck infrarenal aneurysms (<10 mm) in 126 consecutive patients. Patients were not excluded from the study based on presentation, extent of aneurysm or dissection, or history of a spinal cord event. Patients with a thoracoabdominal aortic aneurysm were categorized by Crawford classification: types I and V (3.3%, n = 4), type II (3.3%, n = 4), type III (1%, n = 1), and type IV (93.3%, n = 117). The type IV classification patients were further categorized with 33 (28.2%) true type IV, 68 (58.1%) pararenal or infrarenal, and 16 (13.7%) with dissection. Technical success was 99.2% (n = 125). The most common major adverse event within both 30 days and 365 days of all patients was respiratory failure (11.9%, n = 15, and 13.5%, n = 17, respectively). One patient (0.8%) experienced persistent paraplegia at 365 days. Reintervention for patients at 365 days was 5.6% (n = 7). Of the 444 branches stented, the primary patency rate was remarkably high as only three patients (2.4%) required reintervention due to loss of limb patency within 365 days. Aneurysm enlargement (≥5 mm) occurred in 1.6% (n = 2) patients, and no patients experienced aneurysm rupture. No patients underwent conversion to open repair. The aneurysm-related mortality at 365 days for all patients was 4.0% (n = 5), whereas all-cause mortality was 16.7% (n = 21). Physician-modified endograft device integrity failure was not observed in any patient. CONCLUSIONS: The UM device demonstrated remarkable technical surgical success, treatment success, and device patency rates with very reasonable major adverse events and reintervention rates. This study is the most representative example of the general population in comparison with other studies of off-the-shelf devices, with 126 consecutive all-comer patients with diverse pathologies.

Exposure to the antineoplastic ifosfamide alters molecular pathways related to cardiovascular function, increases heart rate, and induces hyperactivity in zebrafish (Danio rerio).

Ifosfamide is an alkylating antineoplastic drug used in chemotherapy, but it is also detected in wastewater. Here, the objectives were to (1) determine teratogenic, cardiotoxic, and mitochondrial toxicity potential of ifosfamide exposure; (2) elucidate mechanisms of toxicity; (3) characterize exposure effects on larval behavior. Survival rate, hatch rate, and morphological deformity incidence were not different amongst treatments following exposure levels up to 1000 µg/L ifosfamide over 7 days. RNA-seq reveled 231 and 93 differentially expressed transcripts in larvae exposed to 1 µg/L and 100 µg/L ifosfamide, respectively. Several gene networks related to vascular resistance, cardiovascular response, and heart rate were affected, consistent with tachycardia observed in exposed embryonic fish. Hyperactivity in larval zebrafish was observed with ifosfamide exposure, potentially associated with dopamine-related gene networks. This study improves ecological risk assessment of antineoplastics by elucidating molecular mechanisms related to ifosfamide toxicity, and to alkylating agents in general.

BIPOC experiences of (anti-)racist patient engagement in adolescent and young adult oncology research: an electronic Delphi study.

Aims: To characterize Black, Indigenous and People of Color (BIPOC) adolescent and young adult (AYA) cancer patients' experiences of patient engagement in AYA oncology and derive best practices that are co-developed by BIPOC AYAs and oncology professionals. Materials & methods: Following a previous call to action from AYA oncology professionals, a panel of experts composed exclusively of BIPOC AYA cancer patients (n = 32) participated in an electronic Delphi study. Results: Emergent themes described BIPOC AYA cancer patients' direct experiences and consensus opinion on recommendations to advance antiracist patient engagement from BIPOC AYA cancer patients and oncology professionals. Conclusion: The findings reveal high-priority practices across all phases of research and are instructional for advancing health equity.

hnRNP A1 dysfunction alters RNA splicing and drives neurodegeneration in multiple sclerosis (MS).

Neurodegeneration is the primary driver of disease progression in multiple sclerosis (MS) resulting in permanent disability, creating an urgent need to discover its underlying mechanisms. Herein, we establish that dysfunction of the RNA binding protein heterogeneous nuclear ribonucleoprotein A1 (hnRNP A1) results in differential of binding to RNA targets causing alternative RNA splicing, which contributes to neurodegeneration in MS and its models. Using RNAseq of MS brains, we discovered differential expression and aberrant splicing of hnRNP A1 target RNAs involved in neuronal function and RNA homeostasis. We confirmed this in vivo in experimental autoimmune encephalomyelitis employing CLIPseq specific for hnRNP A1, where hnRNP A1 differentially binds and regulates RNA, including aberrantly spliced targets identified in human samples. Additionally, dysfunctional hnRNP A1 expression in neurons caused neurite loss and identical changes in splicing, corroborating hnRNP A1 dysfunction as a cause of neurodegeneration. Collectively, these data indicate hnRNP A1 dysfunction causes altered neuronal RNA splicing, resulting in neurodegeneration in MS.

Cyfip2 controls the acoustic startle threshold through FMRP, actin polymerization, and GABAB receptor function.

Animals process a constant stream of sensory input, and to survive they must detect and respond to dangerous stimuli while ignoring innocuous or irrelevant ones. Behavioral responses are elicited when certain properties of a stimulus such as its intensity or size reach a critical value, and such behavioral thresholds can be a simple and effective mechanism to filter sensory information. For example, the acoustic startle response is a conserved and stereotyped defensive behavior induced by sudden loud sounds, but dysregulation of the threshold to initiate this behavior can result in startle hypersensitivity that is associated with sensory processing disorders including schizophrenia and autism. Through a previous forward genetic screen for regulators of the startle threshold a nonsense mutation in Cytoplasmic Fragile X Messenger Ribonucleoprotein (FMRP)-interacting protein 2 (cyfip2) was found that causes startle hypersensitivity in zebrafish larvae, but the molecular mechanisms by which Cyfip2 establishes the acoustic startle threshold are unknown. Here we used conditional transgenic rescue and CRISPR/Cas9 to determine that Cyfip2 acts though both Rac1 and FMRP pathways, but not the closely related FXR1 or FXR2, to establish the acoustic startle threshold during early neurodevelopment. To identify proteins and pathways that may be downstream effectors of Rac1 and FMRP, we performed a candidate-based drug screen that indicated that Cyfip2 can also act acutely to maintain the startle threshold branched actin polymerization and N-methyl D-aspartate receptors (NMDARs). To complement this approach, we used unbiased discovery proteomics to determine that loss of Cyfip2 alters cytoskeletal and extracellular matrix components while also disrupting oxidative phosphorylation and GABA receptor signaling. Finally, we functionally validated our proteomics findings by showing that activating GABAB receptors, which like NMDARs are also FMRP targets, restores normal startle sensitivity in cyfip2 mutants. Together, these data reveal multiple mechanisms by which Cyfip2 regulates excitatory/inhibitory balance in the startle circuit to control the processing of acoustic information.

Relationships Between Schistosoma mansoni Infection Intensity and Nutritional Status and Anemia Among Preschool-aged Children in Uganda.

In a cross-sectional analysis of 354 Ugandan children (age 12-48 months) infected with Schistosoma mansoni, we assessed relationships between infection intensity and nutritional morbidities. Higher intensity was associated with an increased risk for anemia (RR = 1.05, 95% confidence interval [CI] 1.01-1.10) yet not associated with risk for underweight, stunting, or wasting.

Risk of hospitalization in synucleinopathies and impact of psychosis.

Background: Few studies have investigated the risk of hospitalization among patients with synucleinopathies (Parkinson disease, Dementia with Lewy Bodies, Parkinson disease dementia, Multiple System Atrophy) with associated psychosis and the impact of antipsychotic treatments on hospital admissions and duration of the stay. Objective: To determine the risk of hospitalization among patients with synucleinopathies and in patients with associated psychosis. To evaluate the impact of antipsychotic treatments on hospital admission of patients with synucleinopathies and psychosis in an incident cohort study in Olmsted County, Minnesota (MN). Methods: We used the Rochester Epidemiology Project (REP) to define an incident cohort of patients with clinically diagnosed synucleinopathies (1991-2010) in Olmsted County, MN. A movement disorder specialist reviewed all medical records to confirm the clinical diagnosis of synucleinopathies using the NINDS/NIMH unified diagnostic criteria. Results: We included 416 incident cases of clinically diagnosed synucleinopathies from 2,669 hospitalizations. 409 patients (98.3%) were admitted to the hospital at least once for any cause after the onset of parkinsonism. The median number of hospitalizations for a single patient was 5. In total, 195 (46.9%) patients met the criteria for psychosis: patients with psychosis had a 49% (HR = 1.49, p < 0.01) increased risk of hospitalization compared to patients without psychosis. Among patients with psychosis, 76 (39%) received antipsychotic medication. Treatment with antipsychotic medications did not affect the risk of hospitalization (HR = 0.93, p = 0.65). The median length of hospitalization among the entire cohort was 1 (IQR 0-4) day. There was no difference between hospitalization length for patients with no psychosis and patients with active psychosis (RR = 1.08, p = 0.43) or patients with resolved psychosis (RR = 0.79, p = 0.24). Conclusion: Psychosis increases the risk of hospitalization in patients with clinically defined synucleinopathies; however, it does not affect the length of hospital stays in our cohort. Antipsychotic treatment does not affect the risk of hospitalization in our study.

Chronic Nerve Root Injury in Pediatric Patients With Chronic Lumbar Stress Fractures: A Retrospective Review.

INTRODUCTION: Many orthopedic providers currently treat chronic spondylolysis as self-limited fractures. While the condition has previously been associated with back pain in pediatrics, there has been little attention on the risk of neurologic harm. Electromyography (EMG) is a common study used to evaluate nerve injury, but it has not been previously reported for testing pediatric patients with stress fractures. In this study, pediatric patients with chronic pars fractures and muscle extremity weakness who underwent EMG testing were reviewed to analyze their risk of chronic nerve injury. METHODS: 120 pediatric patients who underwent EMG testing between 2015 and 2021 were analyzed, and 41(21F,20M) patients with a mean age of 16(13-20) met criteria of chronic lumbar pediatric spondylolysis with weakness on ankle dorsiflexion or plantarflexion. No exclusions were made. Initial EMG testing was indicated for the extremity weakness; pain was not the major concern. All exams were completed by JWM. Thin-cut lumbar CT studies were done at the same institution, and EMGs were completed by one of three physiatrists. EMGs were determined as normal, abnormal but not meeting chronic nerve injury threshold, or abnormal and meeting threshold for chronic nerve injury. RESULTS: Of the 41 patients, 33 had bilateral and 8 had unilateral fractures with 95% (39/41) of them located at L4 or L5. 55% (18/33) of the bilateral fractures had abnormal EMGs and demonstrated chronic nerve injury; 1 had an abnormal EMG but did meet chronic injury threshold. 75% (6/8) of the unilateral fractures had abnormal EMGs and demonstrated chronic nerve injury; 1 had an abnormal EMG but did meet chronic injury threshold. Overall, 36% (15/41) had normal EMGs, 5% (2/41) had abnormal results but did not reach chronic injury threshold, and 59% (24/41) met threshold for chronic nerve injury. CONCLUSION: Chronic pars fractures have historically been treated as a benign and self-limited sports injury. However, our analysis showed that 59% of adolescent patients presenting with chronic pars fractures and dorsiflexion or plantarflexion weakness have developed a chronic nerve injury. This study is the first to demonstrate the risk of neurologic harm in unhealed pediatric lumbar stress fractures, and it indicates the importance of EMG testing in young patients presenting with chronic spondylolysis and extremity weakness.

Sleep Disorders in Early-Onset Parkinsonism: A Population-Based Study.

BACKGROUND: Sleep disturbances are common in parkinsonian disorders; however, whether sleep disorders affect individuals with early-onset parkinsonism and whether they differ from individuals with typical-onset parkinsonism is unknown. OBJECTIVE: To compare the prevalence and incidence of sleep disorders before and after parkinsonian motor symptom onset between individuals with early onset parkinsonism (age ≤50 at motor symptom onset) and typical-onset parkinsonism (age >50 at motor symptom onset). METHODS: We used a population-based, 1991 to 2015 incident-cohort study of parkinsonism including 38 patients with early-onset and 1,001 patients with typical-onset parkinsonism. Presence or absence and type of sleep disorder as well as the relationship between motor and sleep symptoms were abstracted from the medical records. Rates of sleep disorders before and after onset of parkinsonism were compared with logistic regression and Cox proportional hazards models. RESULTS: The prevalence of sleep disorders prior to the onset of parkinsonism in early vs. typical parkinsonism (24% vs. 16% p = 0.19) and incidence of sleep disorders after parkinsonism onset (5.85 cases per 100 person-years vs. 4.11 cases per 100 person-years; HR 1.15 95% CI: 0.74-1.77) were similar between the two groups. Early-onset parkinsonism had a higher risk for developing post-motor insomnia compared with typical-onset parkinsonism (HR 1.73, 95% CI: 1.02-2.93); the risk for developing all other sleep disorders considered was similar between groups. CONCLUSION: Sleep disorders are common in individuals with early-onset parkinsonism and occur with similar frequency to those with typical-onset parkinsonism, except for insomnia, which was more frequent in the early-onset group.

Molecular Cage Reports on Its Contents: Spectroscopic Signatures of Cryo-Cooled K+- and Ba2+-Benzocryptand Complexes.

UV photofragment spectroscopy and IR-UV double resonance methods are used to determine the structure and spectroscopic responses of a three-dimensional [2.2.2]-benzocryptand cage to the incorporation of a single K+ or Ba2+ imbedded inside it (labeled as K+-BzCrypt, Ba2+-BzCrypt). We studied the isolated ion-cryptand complex under cryo-cooled conditions, brought into the gas phase by nano-electrospray ionization. Incorporation of a phenyl ring in place of the central ethyl group in one of the three N-CH2-CH2-O-CH2-CH2-O-CH2-CH2-N chains provides a UV chromophore whose S0-S1 transition we probe. K+-BzCrypt and Ba2+-BzCrypt have their S0-S1 origin transitions at 35,925 and 36,446 cm-1, respectively, blue-shifted by 174 and 695 cm-1 from that of 1,2-dimethoxybenzene. These origins are used to excite a single conformation of each complex selectively and record their IR spectra using IR-UV dip spectroscopy. The alkyl CH stretch region (2800-3000 cm-1) is surprisingly sensitive to the presence and nature of the encapsulated ion. We carried out an exhaustive conformational search of cage conformations for K+-BzCrypt and Ba2+-BzCrypt, identifying two conformations (A and B) that lie below all others in energy. We extend our local mode anharmonic model of the CH stretch region to these strongly bound ion-cage complexes to predict conformation-specific alkyl CH stretch spectra, obtaining quantitative agreement with experiment for conformer A, the gas-phase global minimum. The large electrostatic effect of the charge on the O- and N-lone pairs affects the local mode frequencies of the CH2 groups adjacent to these atoms. The localized CH2 scissors modes are pushed up in frequency by the adjacent O/N-atoms so that their overtones have little effect on the alkyl CH stretch region. However, the localized CH2 wags are nearly degenerate and strongly coupled to one another, producing an array of delocalized wag normal modes, whose highest frequency members reach up above 1400 cm-1. As such, their overtones mix significantly with the CH stretch modes, most notably involving the CH2 symmetric stretch fundamentals of the central ethyl groups in the all-alkyl chains and the CH stretches adjacent to the N-atoms and antiperiplanar to the nitrogen lone pair.

Adolescent body mass index and cognitive performance: a nationwide study of 2.48 million Israeli adolescents.

IMPORTANCE: The increased incidence of adolescent obesity over recent decades may be associated with lower cognitive performance than the expected potential. OBJECTIVE: We aimed to assess the association between adolescent body mass index (BMI) and cognitive function. DESIGN: A nationwide, cross-sectional, population-based study. SETTING: Pre-recruitment evaluation for military service during 1967-2018. PARTICIPANTS: All Israeli-born adolescents, 1 459 522 males and 1 027 953 females aged 16 to ≤20 years. EXPOSURES: Weight and height were measured to calculate BMI. MAIN OUTCOME: Cognitive performance was assessed by using a validated intelligence-quotient-equivalent test and was standardized to the year- and sex-Z-score. For 445 385 persons, parental cognitive scores could be identified. Multinomial logistic regression models were applied. RESULTS: Among male adolescents with severe obesity, 29.4% achieved a cognitive score below the 25th percentile, compared with 17.7% among their normal-weight (50th-84th percentile) counterparts. A J-shaped relation was observed between BMI and the odds ratio (OR) for a low cognitive score among male adolescents: underweight, 1.45 (1.43-1.48); overweight, 1.13 (1.12-1.15); mild obesity, 1.36 (1.33-1.39); and severe obesity, 1.58 (1.52-1.64). Similar findings were observed in females. For both sexes, point estimates were overall consistent in models adjusted for sociodemographic confounders, coexisting morbidities, and parental cognitive scores. Examinees with abnormal BMI had higher ORs for a lower-than-expected cognitive score, based on their parents' data as adolescents, in a manner that depends on obesity severity. CONCLUSION AND RELEVANCE: Obesity, is associated with increased odds for a lower cognitive performance, and the inability to fully achieve cognitive potential, regardless of sociodemographic background.

Ultrahigh Areal Capacity Li Electrodeposition at Metal-Solid Electrolyte Interfaces under Minimal Stack Pressures Enabled by Interfacial Na-K Liquids.

The need for higher energy density rechargeable batteries has generated interest in metallic electrodes paired with solid electrolytes. However, impedance growth at the Li metal-solid electrolyte interface due to void formation during cycling at practical current densities and areal capacities, e.g., greater than 0.5 mA cm-2 and 1.5 mAh cm-2 respectively, remains a significant barrier. Here, we show that introducing a wetting interfacial film of Na-K liquid between the Li metal and the Li6.75La3Zr1.75Ta0.25O12 (LLZTO) solid electrolyte permits reversible stripping and plating of up to 150 µm of Li (30 mAh cm-2), approximately 10 times the areal capacity of today's lithium-ion batteries, at current densities above 0.5 mA cm-2 and stack pressures below 75 kPa, all with minimal changes in cell impedance. We further show that this increase in the accessible areal capacity at high stripping current densities is due to the presence of Na-K liquid at the Li stripping interface; this performance improvement is not enabled in the absence of the Na-K liquid. This design approach holds promise for overcoming interfacial stability issues that have heretofore limited the performance of solid-state metal batteries.

Prevalence of Childhood Hearing Loss in Rural Alaska.

OBJECTIVES: Childhood hearing loss has well-known lifelong consequences. Certain rural populations are at higher risk for infection-related hearing loss. For Alaska Native children, historical data on hearing loss prevalence suggest a higher burden of infection-related hearing loss, but updated prevalence data are urgently needed in this high-risk population. DESIGN: Hearing data were collected as part of two school-based cluster-randomized trials in 15 communities in rural northwest Alaska over two academic years (2017-2019). All enrolled children from preschool to 12th grade were eligible. Pure-tone thresholds were obtained using standard audiometry and conditioned play when indicated. The analysis included the first available audiometric assessment for each child (n = 1634 participants, 3 to 21 years), except for the high-frequency analysis, which was limited to year 2 when higher frequencies were collected. Multiple imputation was used to quantify the prevalence of hearing loss in younger children, where missing data were more frequent due to the need for behavioral responses. Hearing loss in either ear was evaluated using both the former World Health Organization (WHO) definition (pure-tone average [PTA] > 25 dB) and the new WHO definition (PTA ≥ 20 dB), which was published after the study. Analyses with the new definition were limited to children 7 years and older due to incomplete data obtained on younger children at lower thresholds. RESULTS: The overall prevalence of hearing loss (PTA > 25 dB; 0.5, 1, 2, 4 kHz) was 10.5% (95% confidence interval [CI], 8.9 to 12.1). Hearing loss was predominately mild (PTA >25 to 40 dB; 8.9%, 95% CI, 7.4 to 10.5). The prevalence of unilateral hearing loss was 7.7% (95% CI, 6.3 to 9.0). Conductive hearing loss (air-bone gap of ≥ 10 dB) was the most common hearing loss type (9.1%, 95% CI, 7.6 to 10.7). Stratified by age, hearing loss (PTA >25 dB) was more common in children 3 to 6 years (14.9%, 95% CI, 11.4 to 18.5) compared to children 7 years and older (8.7%, 95% CI, 7.1 to 10.4). In children 7 years and older, the new WHO definition increased the prevalence of hearing loss to 23.4% (95% CI, 21.0 to 25.8) compared to the former definition (8.7%, 95% CI, 7.1 to 10.4). Middle ear disease prevalence was 17.6% (95% CI, 15.7 to 19.4) and was higher in younger children (23.6%, 95% CI, 19.7 to 27.6) compared to older children (15.2%, 95% CI, 13.2 to 17.3). High-frequency hearing loss (4, 6, 8kHz) was present in 20.5% (95% CI, 18.4 to 22.7 [PTA >25 dB]) of all children and 22.8% (95% CI, 20.3 to 25.3 [PTA >25 dB]) and 29.7% (95% CI, 27.0 to 32.4 [PTA ≥ 20 dB]) of children 7 years and older (limited to year 2). CONCLUSIONS: This analysis represents the first prevalence study on childhood hearing loss in Alaska in over 60 years and is the largest cohort with hearing data ever collected in rural Alaska. Our results highlight that hearing loss continues to be common in rural Alaska Native children, with middle ear disease more prevalent in younger children and high-frequency hearing loss more prevalent with increasing age. Prevention efforts may benefit from managing hearing loss type by age. Lastly, continued research is needed on the impact of the new WHO definition of hearing loss on field studies.