Acidic chitinase primes the protective immune response to gastrointestinal nematodes.

Acidic mammalian chitinase (AMCase) is known to be induced by allergens and helminths, yet its role in immunity is unclear. Using AMCase-deficient mice, we show that AMCase deficiency reduced the number of group 2 innate lymphoid cells during allergen challenge but was not required for establishment of type 2 inflammation in the lung in response to allergens or helminths. In contrast, AMCase-deficient mice showed a profound defect in type 2 immunity following infection with the chitin-containing gastrointestinal nematodes Nippostrongylus brasiliensis and Heligmosomoides polygyrus bakeri. The impaired immunity was associated with reduced mucus production and decreased intestinal expression of the signature type 2 response genes Il13, Chil3, Retnlb, and Clca1. CD103(+) dendritic cells, which regulate T cell homing, were also reduced in mesenteric lymph nodes of infected AMCase-deficient mice. Thus, AMCase functions as a critical initiator of protective type 2 responses to intestinal nematodes but is largely dispensable for allergic responses in the lung.

Mapping the NPHP-JBTS-MKS protein network reveals ciliopathy disease genes and pathways.

Nephronophthisis (NPHP), Joubert (JBTS), and Meckel-Gruber (MKS) syndromes are autosomal-recessive ciliopathies presenting with cystic kidneys, retinal degeneration, and cerebellar/neural tube malformation. Whether defects in kidney, retinal, or neural disease primarily involve ciliary, Hedgehog, or cell polarity pathways remains unclear. Using high-confidence proteomics, we identified 850 interactors copurifying with nine NPHP/JBTS/MKS proteins and discovered three connected modules: "NPHP1-4-8" functioning at the apical surface, "NPHP5-6" at centrosomes, and "MKS" linked to Hedgehog signaling. Assays for ciliogenesis and epithelial morphogenesis in 3D renal cultures link renal cystic disease to apical organization defects, whereas ciliary and Hedgehog pathway defects lead to retinal or neural deficits. Using 38 interactors as candidates, linkage and sequencing analysis of 250 patients identified ATXN10 and TCTN2 as new NPHP-JBTS genes, and our Tctn2 mouse knockout shows neural tube and Hedgehog signaling defects. Our study further illustrates the power of linking proteomic networks and human genetics to uncover critical disease pathways.

Collagen 18A1/Endostatin Expression in the Progression of Right Ventricular Remodeling and Dysfunction in Pulmonary Arterial Hypertension.

Numerous studies have demonstrated that endostatin (ES), a potent angiostatic peptide derived from collagen type XVIII alpha 1 chain and encoded by COL18A1, is elevated in pulmonary arterial hypertension (PAH). Importantly, elevated ES has consistently been associated with altered hemodynamics, poor functional status, and adverse outcomes in adult and pediatric PAH. This study used serum samples from patients with Group I PAH and plasma and tissue samples derived from the Sugen/Chronic hypoxic (SuHx) rat pulmonary hypertension (PH) model to define associations between COL18A1/ES and disease development, including hemodynamics, right ventricular (RV) remodeling, and RV dysfunction. Using cardiac magnetic resonance (CMR) imaging and advanced hemodynamic assessments with pressure-volume (PV) loops in patients with PAH to assess RV-pulmonary arterial (PA) coupling, we observed a strong relationship between circulating ES levels and metrics of RV structure and function. Specifically, RV mass and the ventricular mass index (VMI) were positively associated with ES while RV ejection fraction and RV-PA coupling were inversely associated with ES levels. Our animal data demonstrates that the development of PH is associated with increased COL18A1/ES in the heart as well as the lungs. Disease-associated increases in COL18A1 mRNA and protein were most pronounced in the RV compared to the left ventricle (LV) and lung. COL18A1 expression in the RV was strongly associated with disease-associated changes in RV mass, fibrosis, and myocardial capillary density. These findings indicate that COL18A1/ES increase early in disease development in the RV and implicate COL18A1/ES in pathologic RV dysfunction in PAH.

Quantification of Diffusion Magnetic Resonance Imaging for Prognostic Prediction of Neonatal Hypoxic-Ischemic Encephalopathy.

Neonatal hypoxic-ischemic encephalopathy (HIE) is the leading cause of acquired neonatal brain injury with the risk of developing serious neurological sequelae and death. An accurate and robust prediction of short- and long-term outcomes may provide clinicians and families with fundamental evidence for their decision-making, the design of treatment strategies, and the discussion of developmental intervention plans after discharge. Diffusion tensor imaging (DTI) is one of the most powerful neuroimaging tools with which to predict the prognosis of neonatal HIE by providing microscopic features that cannot be assessed by conventional magnetic resonance imaging (MRI). DTI provides various scalar measures that represent the properties of the tissue, such as fractional anisotropy (FA) and mean diffusivity (MD). Since the characteristics of the diffusion of water molecules represented by these measures are affected by the microscopic cellular and extracellular environment, such as the orientation of structural components and cell density, they are often used to study the normal developmental trajectory of the brain and as indicators of various tissue damage, including HIE-related pathologies, such as cytotoxic edema, vascular edema, inflammation, cell death, and Wallerian degeneration. Previous studies have demonstrated widespread alteration in DTI measurements in severe cases of HIE and more localized changes in neonates with mild-to-moderate HIE. In an attempt to establish cutoff values to predict the occurrence of neurological sequelae, MD and FA measurements in the corpus callosum, thalamus, basal ganglia, corticospinal tract, and frontal white matter have proven to have an excellent ability to predict severe neurological outcomes. In addition, a recent study has suggested that a data-driven, unbiased approach using machine learning techniques on features obtained from whole-brain image quantification may accurately predict the prognosis of HIE, including for mild-to-moderate cases. Further efforts are needed to overcome current challenges, such as MRI infrastructure, diffusion modeling methods, and data harmonization for clinical application. In addition, external validation of predictive models is essential for clinical application of DTI to prognostication.

Evaluating Injury Severity in Neonatal Encephalopathy Using Automated Quantitative Electroencephalography Analysis: A Pilot Study.

Quantitative analysis of electroencephalography (qEEG) is a potential source of biomarkers for neonatal encephalopathy (NE). However, prior studies using qEEG in NE were limited in their generalizability due to individualized techniques for calculating qEEG features or labor-intensive pre-selection of EEG data. We piloted a fully automated method using commercially available software to calculate the suppression ratio (SR), absolute delta power, and relative delta, theta, alpha, and beta power from EEG of neonates undergoing 72 h of therapeutic hypothermia (TH) for NE between April 20, 2018, and November 4, 2019. We investigated the association of qEEG with degree of encephalopathy (modified Sarnat score), severity of neuroimaging abnormalities following TH (National Institutes of Child Health and Development Neonatal Research Network [NICHD-NRN] score), and presence of seizures. Thirty out of 38 patients met inclusion criteria. A more severe modified Sarnat score was associated with higher SR during all phases of TH, lower absolute delta power during all phases except rewarming, and lower relative delta power during the last 24 h of TH. In 21 patients with neuroimaging data, a worse NICHD-NRN score was associated with higher SR, lower absolute delta power, and higher relative beta power during all phases. QEEG features were not significantly associated with the presence of seizures after correction for multiple comparisons. Our results are consistent with those of prior studies using qEEG in NE and support automated qEEG analysis as an accessible, generalizable method for generating biomarkers of NE and response to TH. Additionally, we found evidence of an immature relative frequency composition in neonates with more severe brain injury, suggesting that automated qEEG analysis may have a use in the assessment of brain maturity.

Resistin predicts disease severity and survival in patients with pulmonary arterial hypertension.

BACKGROUND: Abnormal remodeling of distal pulmonary arteries in patients with pulmonary arterial hypertension (PAH) leads to progressively increased pulmonary vascular resistance, followed by right ventricular hypertrophy and failure. Despite considerable advancements in PAH treatment prognosis remains poor. We aim to evaluate the potential for using the cytokine resistin as a genetic and biological marker for disease severity and survival in a large cohort of patients with PAH. METHODS: Biospecimens, clinical, and genetic data for 1121 adults with PAH, including 808 with idiopathic PAH (IPAH) and 313 with scleroderma-associated PAH (SSc-PAH), were obtained from a national repository. Serum resistin levels were measured by ELISA, and associations between resistin levels, clinical variables, and single nucleotide polymorphism genotypes were examined with multivariable regression models. Machine-learning (ML) algorithms were applied to develop and compare risk models for mortality prediction. RESULTS: Resistin levels were significantly higher in all PAH samples and PAH subtype (IPAH and SSc-PAH) samples than in controls (P < .0001) and had significant discriminative abilities (AUCs of 0.84, 0.82, and 0.91, respectively; P < .001). High resistin levels (above 4.54 ng/mL) in PAH patients were associated with older age (P = .001), shorter 6-min walk distance (P = .001), and reduced cardiac performance (cardiac index, P = .016). Interestingly, mutant carriers of either rs3219175 or rs3745367 had higher resistin levels (adjusted P = .0001). High resistin levels in PAH patients were also associated with increased risk of death (hazard ratio: 2.6; 95% CI: 1.27-5.33; P < .0087). Comparisons of ML-derived survival models confirmed satisfactory prognostic value of the random forest model (AUC = 0.70, 95% CI: 0.62-0.79) for PAH. CONCLUSIONS: This work establishes the importance of resistin in the pathobiology of human PAH. In line with its function in rodent models, serum resistin represents a novel biomarker for PAH prognostication and may indicate a new therapeutic avenue. ML-derived survival models highlighted the importance of including resistin levels to improve performance. Future studies are needed to develop multi-marker assays that improve noninvasive risk stratification.

The impact of COVID-19 vaccine reactions on secondary vaccine hesitancy.

BACKGROUND: Primary and booster vaccinations are critical for mitigating COVID-19 transmission, morbidity, and mortality. Future booster vaccine campaigns rely on an increased understanding of vaccine hesitancy. OBJECTIVE: To evaluate self-reported allergic and skin vaccine reactions as factors potentially associated with vaccine hesitancy in a nationwide vaccine allergy registry. METHODS: Responses to survey questions concerning COVID-19 vaccine perceptions, coded from free text by 2 independent reviewers. Multivariable logistic regression models were used to determine the association between changed negative perception and respondent demographics, vaccination history, and reaction characteristics. RESULTS: A total of 993 individuals (median of 46 years [IQR, 36-59], 88% female, 82% White) self-reported reactions to COVID-19 vaccination. Reactions included the following: delayed large local skin reaction (40%), hives/urticaria (32%), immediate large local skin reaction (3%), swelling (3%), anaphylaxis (2%), and other or unspecified (20%). Most respondents were initially unconcerned about the safety of COVID-19 vaccines (56%). After reactions, 401 of 993 (40%) report negative change in perception of vaccination, with more than half of these respondents (n = 211, 53%) citing their reasoning as a negative experience with adverse effects. Of 102 individuals asked about future vaccination, 79 (77%) indicated that they were unlikely or very unlikely to receive future COVID-19 vaccinations. Increased negative perception after reaction was associated with younger age, later COVID-19 vaccination dose number, and reaction type. CONCLUSION: Our findings reveal that an individual's experience with allergic or cutaneous adverse effects after COVID-19 vaccination affects attitudes and decision-making regarding future vaccination, even in initially non-hesitant individuals. Further investigation of secondary vaccine hesitancy is necessary for adapting public health messaging to this important population.

Roles of pH and phosphate in rare earth element biosorption with living acidophilic microalgae.

The increasing demand for rare earth elements (REEs) has spurred interest in the development of recovery methods from aqueous waste streams. Acidophilic microalgae have gained attention for REE biosorption as they can withstand high concentrations of transition metals and do not require added organic carbon to grow, potentially allowing simultaneous sorption and self-replication of the sorbent. Here, we assessed the potential of Galdieria sulphuraria for REE biosorption under acidic, nutrient-replete conditions from solutions containing ≤ 15 ppm REEs. Sorption at pH 1.5-2.5 (the growth optimum of G. sulphuraria) was poor but improved up to 24-fold at pH 5.0 in phosphate-free conditions. Metabolic activity had a negative impact on REE sorption, additionally challenging the feasibility of REE biosorption under ideal growth conditions for acidophiles. We further examined the possibility of REE biosorption in the presence of phosphate for biomass growth at elevated pH (pH ≥ 2.5) by assessing aqueous La concentrations in various culture media. Three days after adding La into the media, dissolved La concentrations were up to three orders of magnitude higher than solubility predictions due to supersaturation, though LaPO4 precipitation occurred under all conditions when seed was added. We concluded that biosorption should occur separately from biomass growth to avoid REE phosphate precipitation. Furthermore, we demonstrated the importance of proper control experiments in biosorption studies to assess potential interactions between REEs and matrix ions such as phosphates. KEY POINTS: • REE biosorption with G. sulphuraria increases significantly when raising pH to 5 • Phosphate for biosorbent growth has to be supplied separately from biosorption • Biosorption studies have to assess potential matrix effects on REE behavior.

Bailout Distal Internal Carotid Artery Stenting after Carotid Endarterectomy: Indications, Technique, and Outcomes.

BACKGROUND: Distal internal carotid artery (ICA) stenting may be employed as a bailout maneuver when an inadequate end point or clamp injury is encountered at the time of carotid endarterectomy (CEA) in a surgically inaccessible region of the distal ICA. We sought to characterize the indications, technique, and outcomes for this infrequently encountered clinical scenario. METHODS: We performed a retrospective review of all patients who underwent distal ICA stenting at the time of CEA at our institution between September 2008 and July 2022. Procedural details and postoperative follow-up were reviewed for each patient. RESULTS: Six patients were identified during the study period. All were male with an age range of 63 to 82 years. Five underwent carotid revascularization for asymptomatic carotid artery stenosis, and one patient was treated for amaurosis fugax. Three patients were on dual antiplatelet therapy preoperatively, whereas 2 were on aspirin monotherapy, and one was on aspirin and low-dose rivaroxaban. Five patients underwent CEA with patch angioplasty, and one underwent eversion CEA. The indication for stenting was distal ICA dissection due to clamp or shunt injury in 2 patients and an inadequate distal ICA end point in 4 patients. In all cases, access for stenting was obtained under direct visualization within the common carotid artery, and a standard carotid stent was deployed with its proximal aspect landing within the endarterectomized site. Embolic protection was typically achieved via proximal common carotid artery and external carotid artery clamping for flow arrest with aspiration of debris before restoration of antegrade flow. There was 100% technical success. Postoperatively, 2 patients were found to have a cranial nerve injury, likely occurring due to the need for high ICA exposure. Median length of stay was 2 days (range 1-7 days) with no instances of perioperative stroke or myocardial infarction. All patients were discharged on dual antiplatelet therapy with no further occurrence of stroke, carotid restenosis, or reintervention through a median follow-up of 17 months. CONCLUSIONS: Distal ICA stenting is a useful adjunct in the setting of CEA complicated by inadequate end point or vessel dissection in a surgically inaccessible region of the ICA and can minimize the need for high-risk extensive distal dissection of the ICA in this situation.

Predicting academic productivity among American Shoulder and Elbow Surgeons fellowship faculty from publications acquired before and during surgical training.

BACKGROUND: Orthopedic residency and fellowship applicants with a strong research record are highly valued for their potential in continuing academic excellence. Despite this, the association between research productivity during training and future academic productivity as an attending orthopedic surgeon is not well-established. We assess the effects of research output during different periods of surgical training as well as residency location on long-term academic productivity as an attending shoulder and elbow surgeon. METHODS: A search of the 2022-2023 American Shoulder and Elbow Surgeons Fellowship Directory was conducted to identify a list of orthopedic shoulder and elbow fellowship faculty members. Each surgeon's residency, fellowship and current institution of practice were determined and stratified by geographic location. Total publication counts acquired before residency, during residency, during fellowship, and after fellowship were collected for each faculty member. Attending publication rates and H-indices were calculated. A multivariate linear regression model was created, and significance was set at a P value <.05. RESULTS: A total of 149 shoulder and elbow fellowship faculty members representing 34 fellowship programs were identified. The average number of total publications per surgeon was 88.8 ± 102. The average attending publication rate was 5.29 ± 6.89 publications per year. The average H-index for included surgeons was 27.8 ± 24.4. The number of publications acquired before residency (ß = 0.293; P < .001), during residency (ß = 0.110; P = .025) and during fellowship (ß = 0.593; P < .001) were significantly associated with an increased attending publication rate, but no association was observed with the H-index [before residency (ß = -0.221; P = .574), during residency (ß = 0.045; P = .866), during fellowship (ß = 0.198; P = .678)]. There were no significant differences in total publication count (P = .397), attending publication rate (P = .237), or H-index (P = .364) based on location of residency training. DISCUSSION: Research output before and during surgical training is predictive of continued academic productivity as a shoulder and elbow surgeon. In particular, greater productivity during surgical fellowship was most predictive of academic output as an attending. While long-term academic productivity does not seem to be influenced by the geographic location of residency training, attending surgeons practicing in the Midwest had significantly greater total publication counts and H-indices but similar annual publication rates.

Brain injury plasma biomarkers in patients on veno-arterial extracorporeal membrane oxygenation: A pilot prospective observational study.

INTRODUCTION: Early diagnosis of acute brain injury (ABI) is critical for patients on veno-arterial extracorporeal membrane oxygenation (V-A ECMO) to guide anticoagulation strategy; however, neurological assessment in ECMO is often limited by patient sedation. METHODS: In this pilot study of adults from June 2018 to May 2019, plasma samples of glial fibrillary acidic protein (GFAP), neurofilament light chain (NFL), and tubulin associated unit (Tau) were collected daily after V-A ECMO cannulation and measured using a multiplex platform. Primary outcomes were occurrence of ABI, assessed clinically, and neurologic outcome, assessed by modified Rankin Scale (mRS). RESULTS: Of 20 consented patients (median age = 48.5°years; 55% female), 8 (40%) had ABI and 15 (75%) had unfavorable neurologic outcome at discharge. 10 (50%) patients were centrally cannulated. Median duration on ECMO was 4.5°days (IQR: 2.5-9.5). Peak GFAP, NFL, and Tau levels were higher in patients with ABI vs. without (AUC = 0.77; 0.85; 0.57, respectively) and in patients with unfavorable vs. favorable neurologic outcomes (AUC = 0.64; 0.59; 0.73, respectively). GFAP elevated first, NFL elevated to the highest degree, and Tau showed limited change regardless of ABI. CONCLUSION: Further studies are warranted to determine how plasma biomarkers may facilitate early detection of ABIs in V-A ECMO to assist timely clinical decision-making.

Plasma Biomarkers of Evolving Encephalopathy and Brain Injury in Neonates with Hypoxic-Ischemic Encephalopathy.

OBJECTIVE: The objective of the study was to evaluate the relationship between a panel of candidate plasma biomarkers and (1) death or severe brain injury on magnetic resonance imaging (MRI) and (2) dysfunctional cerebral pressure autoregulation as a measure of evolving encephalopathy. STUDY DESIGN: Neonates with moderate-to-severe hypoxic-ischemic encephalopathy (HIE) at 2 level IV neonatal intensive care units were enrolled into this observational study. Patients were treated with therapeutic hypothermia (TH) and monitored with continuous blood pressure monitoring and near-infrared spectroscopy. Cerebral pressure autoregulation was measured by the hemoglobin volume phase (HVP) index; a higher HVP index indicates poorer autoregulation. Serial blood samples were collected during TH and assayed for Tau, glial fibrillary acidic protein, and neurogranin. MRIs were assessed using National Institutes of Child Health and Human Development scores. The relationships between the candidate biomarkers and (1) death or severe brain injury on MRI (defined as a National Institutes of Child Health and Human Development score of ≥ 2B) and (2) autoregulation were evaluated using bivariate and adjusted logistic regression models. RESULTS: Sixty-two patients were included. Elevated Tau levels on days 2-3 of TH were associated with death or severe injury on MRI (aOR: 1.06, 95% CI: 1.03-1.09; aOR: 1.04, 95% CI: 1.01-1.06, respectively). Higher Tau was also associated with poorer autoregulation (higher HVP index) on the same day (P = .022). CONCLUSIONS: Elevated plasma levels of Tau are associated with death or severe brain injury by MRI and dysfunctional cerebral autoregulation in neonates with HIE. Larger-scale validation of Tau as a biomarker of brain injury in neonates with HIE is warranted.

An oral glucose tolerance test does not affect cerebral blood flow: role of NOS.

Animal data indicate that insulin triggers a robust nitric oxide synthase (NOS)-mediated dilation in cerebral arteries similar to the peripheral tissue vasodilation observed in healthy adults. Insulin's role in regulating cerebral blood flow (CBF) in humans remains unclear but may be important for understanding the links between insulin resistance, diminished CBF, and poor brain health outcomes. We tested the hypothesis that an oral glucose challenge (oral glucose tolerance test, OGTT), which increases systemic insulin and glucose, would acutely increase CBF in healthy adults due to NOS-mediated vasodilation, and that changes in CBF would be greater in anterior regions where NOS expression or activity may be greater. In a randomized, single-blind approach, 18 young healthy adults (24 ± 5 yr) underwent magnetic resonance imaging (MRI) with a placebo before and after an OGTT (75 g glucose), and 11 of these adults also completed an NG-monomethyl-l-arginine (l-NMMA) visit. Four-dimensional (4-D) flow MRI quantified macrovascular CBF and arterial spin labeling (ASL) quantified microvascular perfusion. Subjects completed baseline imaging with a placebo (or l-NMMA), then consumed an OGTT followed by MRI scans and blood sampling every 10-15 min for 90 min. Contrary to our hypothesis, total CBF (P = 0.17) and global perfusion (P > 0.05) did not change at any time point up to 60 min after the OGTT, and no regional changes were detected. l-NMMA did not mediate any effect of OGTT on CBF. These data suggest that insulin-glucose challenge does not acutely alter CBF in healthy adults.

Discrepancies in clavicle-to-carotid bifurcation length measurements for transcarotid artery revascularization using different imaging modalities.

OBJECTIVE: Transcarotid artery revascularization (TCAR) has emerged as an effective method for carotid artery stenting. However, anatomic eligibility for TCAR is most often limited by an inadequate clavicle-to-carotid bifurcation length of <5 cm. Preoperative clavicle-to-carotid bifurcation distances may be underestimated when using conventional straight-line measurements on computed tomographic angiography (CTA) imaging. We therefore compared clavicle-to-carotid bifurcation lengths as measured by straight-line CTA, center-line CTA, and intraoperative duplex ultrasound (US), to assess potential differences. METHODS: We conducted a single-center, retrospective review of consecutive TCAR procedures performed between 2016 and 2019 for atherosclerotic carotid disease. For each patient, we compared clavicle-to-carotid bifurcation lengths measured by straight-line CTA, center-line CTA using TeraRecon image reconstruction, and intraoperative duplex US with neck extension and rotation. We further assessed patient and imaging characteristics in individuals with a ≥0.5 cm difference among the measurement methods. In particular, common carotid artery (CCA) tortuosity, defined as the inability to visualize the entire CCA from clavicle to carotid bifurcation on both a single coronal and sagittal imaging cut, was examined as a contributing factor for these discrepancies. RESULTS: Of the 70 TCAR procedures identified, 46 had all three imaging modalities available for review. The median clavicle-to-carotid bifurcation length was found to be 6.4 cm (interquartile range [IQR], 5.4-6.7 cm) on straight-line CTA, 7.0 cm (IQR, 6.0-7.5 cm) on intraoperative duplex US, and 7.2 cm (IQR, 6.5-7.5 cm) on center-line CTA (P < .001). Patients with a ≥0.5 cm difference between their straight-line CTA and either their intraoperative duplex US or center-line CTA measurements were more likely to have tortuous CCAs (60.0% vs 19.1%; P = .01; 51.4% vs 0.0%; P = .01). There were no notable differences in age, gender, prior neck/cervical spine surgery, or neck immobility among these individuals. In patients with tortuous CCAs, duplex US and center-line CTA measurements added 1.0 cm (IQR, 0.6-1.5 cm) and 1.1 cm (IQR, 0.9-1.6 cm) more in length than straight-line CTA measurements, respectively. There was a strong linear correlation between the additional lengths provided by duplex US measurements and those provided by center-line CTA measurements for each individual within the tortuous CCA group (r = 0.83). CONCLUSIONS: The use of straight-line CTA during preoperative planning can underestimate the clavicle-to-carotid bifurcation lengths in patients undergoing carotid revascularization, particularly in those with tortuous CCAs. Both duplex US performed with extended-neck surgical positioning and center-line CTA provide similar and longer carotid length measurements, and should be utilized in patients with tortuous carotid vessels to better determine TCAR anatomic eligibility.

Recurrent laryngeal motor nerve conduction studies in a rat model: Establishing an objective measure for investigating laryngeal innervation.

INTRODUCTION/AIMS: Disease or injury can cause neuromuscular changes to the larynx that can affect voice, breathing, and swallowing. Motor nerve conduction studies have had limited use in the study of laryngeal neurophysiology, despite their importance in other anatomic sites. The aim of this study was to explore the feasibility of performing recurrent laryngeal motor nerve conduction studies (rlMNCS) in a rat model. METHODS: rlMNCS were performed in 15 rats under anesthesia. A bipolar stimulating electrode was placed on the recurrent laryngeal nerve (RLN) 5 mm below the cricoid cartilage. Via direct laryngoscopy, a recording electrode was placed transorally into the thyroarytenoid muscle. The RLN was maximally stimulated to determine the compound muscle action potential (CMAP). Three consecutive trials were averaged. RESULTS: The mean stimulating threshold to the RLN to achieve a CMAP from the thyroarytenoid was 1.7 ± 0.6 mA. RLN stimulation caused a visible adductor twitch of the vocal fold in all animals. The mean negative amplitude was 2.0 ± 0.8 mV, and the total area was 1.0 ± 0.4 mV ms. The CMAP latency and negative duration were 1.0 ± 0.1 ms and 0.9 ± 0.2 ms, respectively. DISCUSSION: rlMNCS are feasible and may be useful in understanding laryngeal neurophysiology with disease or injury. This work could provide a tractable animal model for studying and monitoring treatment of neuromuscular conditions affecting voice, breathing, and swallowing.

Serum brain injury biomarkers are gestationally and post-natally regulated in non-brain injured neonates.

BACKGROUND: To determine the association of gestational age (GA) and day of life (DOL) with the circulating serum concentration of six brain injury-associated biomarkers in non-brain injured neonates born between 23 and 41 weeks' GA. METHODS: In a multicenter prospective observational cohort study, serum CNS-insult, inflammatory and trophic proteins concentrations were measured daily in the first 7 DOL. RESULTS: Overall, 3232 serum samples were analyzed from 745 enrollees, median GA 32.3 weeks. BDNF increased 3.7% and IL-8 increased 8.9% each week of gestation. VEGF, IL-6, and IL-10 showed no relationship with GA. VEGF increased 10.8% and IL-8 18.9%, each DOL. IL-6 decreased by 15.8% each DOL. IL-10 decreased by 81.4% each DOL for DOL 0-3. BDNF did not change with DOL. Only 49.67% of samples had detectable GFAP and 33.15% had detectable NRGN. The odds of having detectable GFAP and NRGN increased by 53% and 11%, respectively, each week after 36 weeks' GA. The odds of having detectable GFAP and NRGN decreased by 15% and 8%, respectively, each DOL. CONCLUSIONS: BDNF and IL-8 serum concentrations vary with GA. VEGF and interleukin concentrations are dynamic in the first week of life, suggesting circulating levels should be adjusted for GA and DOL for clinically relevant assessment of brain injury. IMPACT: Normative data of six brain injury-related biomarkers is being proposed. When interpreting serum concentrations of brain injury biomarkers, it is key to adjust for gestational age at birth and day of life during the first week to correctly assess for clinical brain injury in neonates. Variation in levels of some biomarkers may be related to gestational and postnatal age and not necessarily pathology.

Interaction of hydrocortisone and illness severity on head growth in cohort of ELBW infants.

BACKGROUND: Extremely low birth weight (ELBW) infants comprise a fragile population at risk for neurodevelopmental disabilities (NDD). Systemic steroids were previously associated with NDD, but more recent studies suggest hydrocortisone (HCT) may improve survival without increasing NDD. However, the effects of HCT on head growth adjusted for illness severity during NICU hospitalization are unknown. Thus, we hypothesize that HCT will protect head growth, accounting for illness severity using a modified neonatal Sequential Organ Failure Assessment (M-nSOFA) score. METHODS: We conducted a retrospective study that included infants born at 23-29 weeks gestational age (GA) and < 1000 g. Our study included 73 infants, 41% of whom received HCT. RESULTS: We found negative correlations between growth parameters and age, similar between HCT and control patients. HCT-exposed infants had lower GA but similar normalized birth weights; HCT-exposed infants also had higher illness severity and longer lengths of hospital stay. We found an interaction between HCT exposure and illness severity on head growth, such that infants exposed to HCT had better head growth compared to those not exposed to HCT when adjusted for illness severity. CONCLUSION: These findings emphasize the importance of considering patient illness severity and suggest that HCT use may offer additional benefits not previously considered. IMPACT: This is the first study to assess the relationship between head growth and illness severity in extremely preterm infants with extremely low birth weights during their initial NICU hospitalization. Infants exposed to hydrocortisone (HCT) were overall more ill than those not exposed, yet HCT exposed infants had better preserved head growth relative to illness severity. Better understanding of the effects of HCT exposure on this vulnerable population will help guide more informed decisions on the relative risks and benefits for HCT use.

Targeted inhibition of thrombin attenuates murine neonatal necrotizing enterocolitis.

Necrotizing enterocolitis (NEC) is an inflammatory bowel necrosis of premature infants and an orphan disease with no specific treatment. Most patients with confirmed NEC develop moderate-severe thrombocytopenia requiring one or more platelet transfusions. Here we used our neonatal murine model of NEC-related thrombocytopenia to investigate mechanisms of platelet depletion associated with this disease [K. Namachivayam, K. MohanKumar, L. Garg, B. A. Torres, A. Maheshwari, Pediatr. Res. 81, 817-824 (2017)]. In this model, enteral administration of immunogen trinitrobenzene sulfonate (TNBS) in 10-d-old mouse pups produces an acute necrotizing ileocolitis resembling human NEC within 24 h, and these mice developed thrombocytopenia at 12 to 15 h. We hypothesized that platelet activation and depletion occur during intestinal injury following exposure to bacterial products translocated across the damaged mucosa. Surprisingly, platelet activation began in our model 3 h after TNBS administration, antedating mucosal injury or endotoxinemia. Platelet activation was triggered by thrombin, which, in turn, was activated by tissue factor released from intestinal macrophages. Compared to adults, neonatal platelets showed enhanced sensitivity to thrombin due to higher expression of several downstream signaling mediators and the deficiency of endogenous thrombin antagonists. The expression of tissue factor in intestinal macrophages was also unique to the neonate. Targeted inhibition of thrombin by a nanomedicine-based approach was protective without increasing interstitial hemorrhages in the inflamed bowel or other organs. In support of these data, we detected increased circulating tissue factor and thrombin-antithrombin complexes in patients with NEC. Our findings show that platelet activation is an important pathophysiological event and a potential therapeutic target in NEC.

No Difference in Complication or Reoperation Rates Between Arthroscopic and Open Debridement for Lateral Epicondylitis: A National Database Study.

PURPOSE: To compare complication rates and 5-year reoperation rates between open debridement (OD) and arthroscopic debridement (AD) for lateral epicondylitis. METHODS: The PearlDiver MUExtr database (2010-2019) was reviewed for patients diagnosed with lateral epicondylitis (queried by International Classification of Diseases, Ninth Revision and International Classification of Diseases, Tenth Revision [ICD-10] codes) undergoing OD or AD of the common extensor tendon without repair (queried by Current Procedural Terminology codes). Patients were stratified into 2 cohorts: those who underwent AD and those who underwent OD. Nonoperative treatment modalities were reported for both groups within 1 year before index procedure. The rates of 90-day postoperative complications were compared, and multivariate logistic regression analysis was used to identify risk factors for complications. The 5-year reoperation rates, using laterality-specific ICD-10 codes, were also compared between the 2 groups. RESULTS: In total, 19,280 patients (OD = 17,139, AD = 2,141) were analyzed in this study. The most common nonoperative treatments for patients who underwent OD or AD were corticosteroid injections (49.5% vs 43.2%), physical therapy (24.8% vs 25.7%), bracing (2.8% vs 3.2%), and platelet-rich plasma injections (1.3% vs 1.0%). There were no significant differences in radial nerve injuries, hematomas, surgical site infections, wound dehiscence, and sepsis events between the 2 procedures (P = .50). The 5-year reoperation rate was not significantly different between the AD (5.0%) and OD (3.9%) cohorts (P = .10). CONCLUSIONS: For lateral epicondylitis, both AD and OD of the extensor carpi radialis brevis (without repair) were found to have low rates of 90-day adverse events, with no significant differences between the 2 approaches. Similarly, the 5-year reoperation rate was low and not statistically different for those treated with OD or AD. LEVEL OF EVIDENCE: Level III, cross-sectional study.

Perioperative risk stratification tools for shoulder arthroplasty: a systematic review.

BACKGROUND: Risk stratification tools are being increasingly utilized to guide patient selection for outpatient shoulder arthroplasty. The purpose of this study was to identify the existing calculators used to predict discharge disposition, postoperative complications, hospital readmissions, and patient candidacy for outpatient shoulder arthroplasty and to compare the specific components used to generate their prediction models. METHODS: This review was conducted in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analysis protocol. PubMed, Cochrane Library, Scopus, and OVID Medline were searched for studies that developed calculators used to determine patient candidacy for outpatient surgery or predict discharge disposition, the risk of postoperative complications, and hospital readmissions after anatomic or reverse total shoulder arthroplasty (TSA). Reviews, case reports, letters to the editor, and studies including hemiarthroplasty cases were excluded. Data extracted included authors, year of publication, study design, patient population, sample size, input variables, comorbidities, method of validation, and intended purpose. The pros and cons of each calculator as reported by the respective authors were evaluated. RESULTS: Eleven publications met inclusion criteria. Three tools assessed patient candidacy for outpatient TSA, 3 tools evaluated the risk of 30- or 90-day hospital readmission and postoperative complications, and 5 tools predicted discharge destination. Four calculators validated previously constructed comorbidity indices used as risk predictors after shoulder arthroplasty, including the Charlson Comorbidity Index, Elixhauser Comorbidity Index, modified Frailty Index, and the Outpatient Arthroplasty Risk Assessment, while 7 developed newcalculators. Nine studies utilized multiple logistic regression to develop their calculators, while 1 study developed their algorithm based on previous literature and 1 used univariate analysis. Five tools were built using data from a single institution, 2 using data pooled from 2 institutions, and 4 from large national databases. All studies used preoperative data points in their algorithms with one tool additionally using intraoperative data points. The number of inputs ranged from 5 to 57 items. Four calculators assessed psychological comorbidities, 3 included inputs for substance use, and 1 calculator accounted for race. CONCLUSION: The variation in perioperative risk calculators after TSA highlights the need for standardization and external validation of the existing tools. As the use of outpatient shoulder arthroplasty increases, these calculators may become outdated or require revision. Incorporation of socioeconomic and psychological measures into these calculators should be investigated.