Antiseizure Medication Withdrawal, Risk of Epilepsy, and Longterm EEG Trends in Acute Symptomatic Seizures or Epileptic EEG Patterns.

Background and Objectives: Patients with acute symptomatic seizures (ASyS) and acute epileptiform findings on EEG are common. They are often prescribed long-term antiseizure medications (ASMs); it is unknown whether or when this is necessary. Primary outcome was late unprovoked seizure occurrence and association with ASM taper. The secondary outcome was EEG pattern evolution over time. Methods: This is a retrospective cohort study of patients from 2015 to 2021 with ASyS (clinical or electrographic) and/or epileptiform findings on index hospitalization EEGs who were discharged on ASMs and had subsequent follow-up including an outpatient EEG at Yale New Haven Hospital. All patients were seen in our postacute symptomatic seizure (PASS) clinic after hospital discharge. We also developed a simple predictive score, Epilepsy-PASS (EPI-PASS), using variables independently associated with seizure recurrence based on stepwise regression; each of the 3 identified variables was assigned a score of 0 (absent) or 1 (present), for a total score of 0-3. Results: Of 190 patients screened, 58 were excluded, leaving a final cohort of 112 patients. Twenty-four percent (27/112) patients developed a late unprovoked seizure (i.e., epilepsy). Independent predictors of epilepsy were persistence of epileptiform abnormalities on follow-up EEGs [56% developed epilepsy vs 19% without, 0.002, OR 7.18 (1.36-37.88)], clinical ASyS [32% vs 13%, p = 0.002, OR 7.45 (2.31-54.36)], and cortical involvement on imaging [40% vs 11%, p = 0.003, OR 7.63 (1.96-29.58)]. None of the 23 patients with none of these predictors (0 points on EPI-PASS) developed epilepsy, vs 13% with 1 predictor (EPI-PASS = 1) and 46% with 2 or 3 predictors (EPI-PASS = 2-3) at 1-year follow-up. ASM taper was not associated with seizure recurrence. Abnormal EEG findings in the index hospitalization usually resolved [54/69 (78%) patients] on subsequent EEGs. Discussion: Most patients with clinical ASyS or acute epileptiform EEG findings do not require long-term ASMs. Index hospitalization EEG findings usually resolve, but if they do not, there is a >50% chance of developing epilepsy. Other predictors of epilepsy are cortical involvement on imaging and clinical ASyS. A simple 4-point scale using these 3 predictors (EPI-PASS) may help predict the risk of developing epilepsy but requires independent validation.

Rare coronary artery variants are associated with increased mortality and reinterventions following the arterial switch operation.

OBJECTIVE: To determine the influence of coronary anatomy on long-term outcomes of the arterial switch operation (ASO). METHODS: We retrospectively reviewed patients with transposition of the great arteries or Taussig-Bing anomaly who underwent ASO at our institution between 1992 and 2022. The primary endpoint was freedom from a composite of death, transplantation, and coronary reintervention. RESULTS: A total of 632 patients (median age, 5.0 days; interquartile range [IQR], 4.0-7.0 days) underwent ASO. Coronary anatomy included the following categories: usual (n = 411; 65%), circumflex (Cx) from sinus 2 (n = 89; 14%), inverted (n = 55; 9%), single sinus (n = 46; 7%), and intramural (n = 31; 5%). Overall operative mortality was 3% (n = 16) and highest in patients with intramural cardiac anatomy (n = 3; 10%), although it dropped to 0% in this group in the most recent decade. The median duration of follow-up was 14.5 years (IQR, 6.0-20.3 years). Twenty-year freedom from the primary endpoint was 95 ± 1% for usual anatomy, 99 ± 1% for Cx from sinus 2, 90 ± 4% for inverted, 91 ± 4% for single sinus, and 80 ± 9% for intramural (P < .001). Intramurals had the highest 20-year incidence of coronary reintervention (11 ± 8%). Cox modeling identified intraoperative coronary revision (hazard ratio [HR], 20.1; 95% confidence interval [CI], 9.4-53.9; P < .001), Taussig-Bing anomaly (HR, 4.9; 95% CI, 2.2-10.9; P < .001), and an intramural coronary artery (HR, 2.9; 95% CI, 1.0-8.2; P = .04) to be risk factors for the composite endpoint. CONCLUSIONS: Rare coronary artery variants-particularly intramural-are associated with increased mortality and coronary reinterventions after ASO. A low threshold for unroofing intramurals is likely associated with declining mortality and improved outcomes. Additional investigations are needed to determine the long-term fate of the coronary arteries after ASO.

The phenotypic and genotypic spectrum of individuals with mono- or biallelic ANK3 variants.

ANK3 encodes ankyrin-G, a protein involved in neuronal development and signaling. Alternative splicing gives rise to three ankyrin-G isoforms comprising different domains with distinct expression patterns. Mono- or biallelic ANK3 variants are associated with non-specific syndromic intellectual disability in 14 individuals (seven with monoallelic and seven with biallelic variants). In this study, we describe the clinical features of 13 additional individuals and review the data on a total of 27 individuals (16 individuals with monoallelic and 11 with biallelic ANK3 variants) and demonstrate that the phenotype for biallelic variants is more severe. The phenotypic features include language delay (92%), autism spectrum disorder (76%), intellectual disability (78%), hypotonia (65%), motor delay (68%), attention deficit disorder (ADD) or attention deficit hyperactivity disorder (ADHD) (57%), sleep disturbances (50%), aggressivity/self-injury (37.5%), and epilepsy (35%). A notable phenotypic difference was presence of ataxia in three individuals with biallelic variants, but in none of the individuals with monoallelic variants. While the majority of the monoallelic variants are predicted to result in a truncated protein, biallelic variants are almost exclusively missense. Moreover, mono- and biallelic variants appear to be localized differently across the three different ankyrin-G isoforms, suggesting isoform-specific pathological mechanisms.

Neurodevelopment of children exposed to prolonged anesthesia in infancy: GABA study interim analysis of resting-state brain networks at 2, 4, and 10-months old.

BACKGROUND: Previous studies have raised concerns regarding neurodevelopmental impacts of early exposures to general anesthesia and surgery. Electroencephalography (EEG) can be used to study ontogeny of brain networks during infancy. As a substudy of an ongoing study, we examined measures of functional connectivity in awake infants with prior early and prolonged anesthetic exposures and in control infants. METHODS: EEG functional connectivity was assessed using debiased weighted phase lag index at source and sensor levels and graph theoretical measures for resting state activity in awake infants in the early anesthesia (n = 26 at 10 month visit, median duration of anesthesia = 4 [2, 7 h]) and control (n = 38 at 10 month visit) groups at ages approximately 2, 4 and 10 months. Theta and low alpha frequency bands were of primary interest. Linear mixed models incorporated impact of age and cumulative hours of general anesthesia exposure. RESULTS: Models showed no significant impact of cumulative hours of general anesthesia exposure on debiased weighted phase lag index, characteristic path length, clustering coefficient or small-worldness (conditional R2 0.05-0.34). An effect of age was apparent in many of these measures. CONCLUSIONS: We could not demonstrate significant impact of general anesthesia in the first months of life on early development of resting state brain networks over the first postnatal year. Future studies will explore these networks as these infants grow older.

De novo variants in FRYL are associated with developmental delay, intellectual disability, and dysmorphic features.

FRY-like transcription coactivator (FRYL) belongs to a Furry protein family that is evolutionarily conserved from yeast to humans. The functions of FRYL in mammals are largely unknown, and variants in FRYL have not previously been associated with a Mendelian disease. Here, we report fourteen individuals with heterozygous variants in FRYL who present with developmental delay, intellectual disability, dysmorphic features, and other congenital anomalies in multiple systems. The variants are confirmed de novo in all individuals except one. Human genetic data suggest that FRYL is intolerant to loss of function (LoF). We find that the fly FRYL ortholog, furry (fry), is expressed in multiple tissues, including the central nervous system where it is present in neurons but not in glia. Homozygous fry LoF mutation is lethal at various developmental stages, and loss of fry in mutant clones causes defects in wings and compound eyes. We next modeled four out of the five missense variants found in affected individuals using fry knockin alleles. One variant behaves as a severe LoF variant, whereas two others behave as partial LoF variants. One variant does not cause any observable defect in flies, and the corresponding human variant is not confirmed to be de novo, suggesting that this is a variant of uncertain significance. In summary, our findings support that fry is required for proper development in flies and that the LoF variants in FRYL cause a dominant disorder with developmental and neurological symptoms due to haploinsufficiency.

Characteristics of ocular injuries associated with mortality in patients admitted with major trauma.

BACKGROUND: Few ocular trauma studies have addressed mortality outcomes. We sought to determine characteristics of mortality-related ocular trauma admissions and compared them with non-fatal injuries. METHODS: A retrospective study was conducted using de-identified data of patients admitted with major trauma from the National Trauma Data Bank (2008-2014). Patients with ocular injury were identified using ICD- 9CM codes. Demographics, intention and mechanism, types of ocular and head injuries, and injury severity were documented. Mortality was determined using post-admission disposition. Statistical analysis using student t-test, chi-square, and odds ratios (OR) calculations were performed with STATA-17 software. Significance was set at P < 0.05. RESULTS: Of 316,485 patients admitted with ocular trauma, 12,233 (3.86%) were mortality related. Expired patients were older than survivors: mean (SD) of 50.1(25.5) vs. 41.5(22.8) years. White (OR = 1.32; P < 0.001), ≥ 65years old (OR = 2.25; P < 0.001), and male (OR = 1.05; P = 0.029) patients were most likely to expire than their counterparts. Common mechanisms of injury in survivors were falls (25.3%), motor vehicle traffic-occupant, MVTO (21.8%) and struck by/against (18.1%) and for fatal injuries, falls (29.7%), MVTO (21.9%) and firearms (11.5%). Traumatic brain injury (TBI) was documented in 88.2% of mortality-related admissions. Very severe injury severity scores (ISS > 24) (OR = 19.19; P < 0.001) and severe Glasgow Coma Score (GCS < 8) (OR = 19.22; P < 0.001) were most associated with mortality than survival. Firearms were most associated with very severe ISS (OR = 3.73; P < 0.001), severe GCS (OR = 4.68; P < 0.001) and mortality (OR = 5.21; P < 0.001) than other mechanisms. Patients with cut/pierce injuries had the greatest odds of survival (OR = 13.48; P < 0.001). Optic nerve/visual pathways injuries (3.1%) had the highest association with very severe ISS (OR = 2.51; P < 0.001), severe GCS (OR = 3.64; P < 0.001) and mortality (OR = 2.58; P < 0.001) than other ocular injuries. Black patients with very severe ISS (OR = 32.14; P < 0.001) and severe GCS (OR = 31.89; P < 0.001) were more likely to expire than other race/ethnicities with similar injury severity. CONCLUSIONS: Mortality-related admissions were older, male, and mostly of White race than ocular trauma admissions of survivors. Firearms were the deadliest mechanism. TBI was commonly associated and patients with optic nerve/pathway injuries, very severe ISS and severe GCS had higher mortality rates. Characteristics and demographic variations identified in this study may be useful in developing focused measures aimed at preventing trauma-related deaths.

Association of Lack of Speech Arrest During Cortical Stimulation With Interhemispheric Reorganization of the Functional Language Network in Patients With Brain Tumors.

BACKGROUND. Brain tumors induce language reorganization, which may influence the extent of resection in surgical planning. Direct cortical stimulation (DCS) allows definitive language mapping during awake surgery by locating areas of speech arrest (SA) surrounding the tumor. Although functional MRI (fMRI) combined with graph theory analysis can illustrate whole-brain network reorganization, few studies have corroborated these findings with DCS intraoperative mapping and clinical language performance. OBJECTIVE. We evaluated whether patients with low-grade gliomas (LGGs) without SA during DCS show increased right-hemispheric connections and better speech performance compared with patients with SA. METHODS. We retrospectively recruited 44 consecutive patients with left perisylvian LGG, preoperative language task-based fMRI, speech performance evaluation, and awake surgery with DCS. We generated language networks from ROIs corresponding to known language areas (i.e., language core) on fMRI using optimal percolation. Language core connectivity in the left and right hemispheres was quantified as fMRI laterality index (LI) and connectivity LI on the basis of fMRI activation maps and connectivity matrices. We compared fMRI LI and connectivity LI between patients with SA and without SA and used multivariable logistic regression (p < .05) to assess associations between DCS and connectivity LI, fMRI LI, tumor location, Broca area and Wernicke area involvement, prior treatments, age, handedness, sex, tumor size, and speech deficit before surgery, within 1 week after surgery, and 3-6 months after surgery. RESULTS. Patients with SA showed left-dominant connectivity; patients without SA lateralized more to the right hemisphere (p < .001). Between patients with SA and those without, fMRI LI was not significantly different. Patients without SA showed right-greater-than-left connectivity of Broca area and premotor area compared with patients with SA. Regression analysis showed significant association between no SA and right-lateralized connectivity LI (p < .001) and fewer speech deficits before (p < .001) and 1 week after (p = .02) surgery. CONCLUSION. Patients without SA had increased right-hemispheric connections and right translocation of the language core, suggesting language reorganization. Lack of interoperative SA was associated with fewer speech deficits both before and immediately after surgery. CLINICAL IMPACT. These findings support tumor-induced language plasticity as a compensatory mechanism, which may lead to fewer postsurgical deficits and allow extended resection.

LHX2 haploinsufficiency causes a variable neurodevelopmental disorder.

PURPOSE: LHX2 encodes the LIM homeobox 2 transcription factor (LHX2), which is highly expressed in brain and well conserved across species, but it has not been clearly linked to neurodevelopmental disorders (NDDs) to date. METHODS: Through international collaboration, we identified 19 individuals from 18 families with variable neurodevelopmental phenotypes, carrying a small chromosomal deletion, likely gene-disrupting or missense variants in LHX2. Functional consequences of missense variants were investigated in cellular systems. RESULTS: Affected individuals presented with developmental and/or behavioral abnormalities, autism spectrum disorder, variable intellectual disability, and microcephaly. We observed nucleolar accumulation for 2 missense variants located within the DNA-binding HOX domain, impaired interaction with co-factor LDB1 for another variant located in the protein-protein interaction-mediating LIM domain, and impaired transcriptional activation by luciferase assay for 4 missense variants. CONCLUSION: We implicate LHX2 haploinsufficiency by deletion and likely gene-disrupting variants as causative for a variable NDD. Our findings suggest a loss-of-function mechanism also for likely pathogenic LHX2 missense variants. Together, our observations underscore the importance of LHX2 in the nervous system and for variable neurodevelopmental phenotypes.

Longitudinal Evaluation of Brain Plasticity in Low-Grade Gliomas: fMRI and Graph-Theory Provide Insights on Language Reorganization.

Language reorganization may represent an adaptive phenomenon to compensate tumor invasion of the dominant hemisphere. However, the functional changes over time underlying language plasticity remain unknown. We evaluated language function in patients with low-grade glioma (LGG), using task-based functional MRI (tb-fMRI), graph-theory and standardized language assessment. We hypothesized that functional networks obtained from tb-fMRI would show connectivity changes over time, with increased right-hemispheric participation. We recruited five right-handed patients (4M, mean age 47.6Y) with left-hemispheric LGG. Tb-fMRI and language assessment were conducted pre-operatively (pre-op), and post-operatively: post-op1 (4-8 months), post-op2 (10-14 months) and post-op3 (16-23 months). We computed the individual functional networks applying optimal percolation thresholding. Language dominance and hemispheric connectivity were quantified by laterality indices (LI) on fMRI maps and connectivity matrices. A fixed linear mixed model was used to assess the intra-patient correlation trend of LI values over time and their correlation with language performance. Individual networks showed increased inter-hemispheric and right-sided connectivity involving language areas homologues. Two patterns of language reorganization emerged: Three/five patients demonstrated a left-to-codominant shift from pre-op to post-op3 (type 1). Two/five patients started as atypical dominant at pre-op, and remained unchanged at post-op3 (type 2). LI obtained from tb-fMRI showed a significant left-to-right trend in all patients across timepoints. There were no significant changes in language performance over time. Type 1 language reorganization may be related to the treatment, while type 2 may be tumor-induced, since it was already present at pre-op. Increased inter-hemispheric and right-side connectivity may represent the initial step to develop functional plasticity.

Evidence-Based Assessment of Congenital Heart Disease Genes to Enable Returning Results in a Genomic Study.

BACKGROUND: Congenital heart disease (CHD) is the most common major congenital anomaly and causes significant morbidity and mortality. Epidemiologic evidence supports a role of genetics in the development of CHD. Genetic diagnoses can inform prognosis and clinical management. However, genetic testing is not standardized among individuals with CHD. We sought to develop a list of validated CHD genes using established methods and to evaluate the process of returning genetic results to research participants in a large genomic study. METHODS: Two-hundred ninety-five candidate CHD genes were evaluated using a ClinGen framework. Sequence and copy number variants involving genes in the CHD gene list were analyzed in Pediatric Cardiac Genomics Consortium participants. Pathogenic/likely pathogenic results were confirmed on a new sample in a clinical laboratory improvement amendments-certified laboratory and disclosed to eligible participants. Adult probands and parents of probands who received results were asked to complete a post-disclosure survey. RESULTS: A total of 99 genes had a strong or definitive clinical validity classification. Diagnostic yields for copy number variants and exome sequencing were 1.8% and 3.8%, respectively. Thirty-one probands completed clinical laboratory improvement amendments-confirmation and received results. Participants who completed postdisclosure surveys reported high personal utility and no decision regret after receiving genetic results. CONCLUSIONS: The application of ClinGen criteria to CHD candidate genes yielded a list that can be used to interpret clinical genetic testing for CHD. Applying this gene list to one of the largest research cohorts of CHD participants provides a lower bound for the yield of genetic testing in CHD.

Genomic Biomarkers Associated with Response to Induction Chemotherapy in Patients with Localized Pancreatic Ductal Adenocarcinoma.

PURPOSE: There is increasing use of neoadjuvant chemotherapy in the management of localized pancreatic ductal adenocarcinoma (PDAC), yet there are few validated biomarkers to guide therapy selection. We aimed to determine whether somatic genomic biomarkers predict response to induction FOLFIRINOX or gemcitabine/nab-paclitaxel. EXPERIMENTAL DESIGN: This single-institution cohort study included consecutive patients (N = 322) with localized PDAC (2011-2020) who received at least one cycle of FOLFIRINOX (N = 271) or gemcitabine/nab-paclitaxel (N = 51) as initial treatment. We assessed somatic alterations in four driver genes (KRAS, TP53, CDKN2A, and SMAD4) by targeted next-generation sequencing, and determined associations between these alterations and (1) rate of metastatic progression during induction chemotherapy, (2) surgical resection, and (3) complete/major pathologic response. RESULTS: The alteration rates in driver genes KRAS, TP53, CDKN2A, and SMAD4 were 87.0%, 65.5%, 26.7%, and 19.9%, respectively. For patients receiving first-line FOLFIRINOX, SMAD4 alterations were uniquely associated with metastatic progression (30.0% vs. 14.5%; P = 0.009) and decreased rate of surgical resection (37.1% vs. 66.7%; P < 0.001). For patients receiving induction gemcitabine/nab-paclitaxel, alterations in SMAD4 were not associated with metastatic progression (14.3% vs. 16.2%; P = 0.866) nor decreased rate of surgical resection (33.3% vs. 41.9%; P = 0.605). Major pathologic response was rare (6.3%) and not associated with type of chemotherapy regimen. CONCLUSIONS: SMAD4 alterations were associated with more frequent development of metastasis and lower probability of reaching surgical resection during neoadjuvant FOLFIRINOX but not gemcitabine/nab-paclitaxel. Confirmation in a larger, diverse patient cohort will be important before prospective evaluation of SMAD4 as a genomic biomarker to guide treatment selection.

Impact of preheart transplant spirometry and DCLO measurement on post-transplant pulmonary outcomes.

BACKGROUND: Pulmonary function tests (PFT) are a frequent component of heart transplant evaluation. In cardiac surgery abnormal PFTs, especially reduced DLCO, have been associated with poor outcomes. We sought to evaluate the impact of pretransplant PFTs on post-transplant pulmonary outcomes and patient survival. METHODS: Among the 652 adult heart transplant recipients between January 1, 2010 and July 31, 2021, 462 had PFTs and constituted the patient cohort. Obstructive ventilatory defects (OVD), restrictive ventilatory defects (RVD), and reduced DLCO were defined according to established criteria. The primary outcome was the combined endpoint of a post-transplant pulmonary complication defined as reintubation, postoperative pneumonia, prolonged intubation, or tracheostomy. Secondary outcomes included 90-day all-cause mortality, length of stay, and the odds of individual pulmonary complications. Kaplan-Meier survival analysis, multivariable Cox proportional-hazards regression, and multivariable logistic regression were performed to compare outcomes between the groups. RESULTS: Patients with severe OVD (OR 1.48, 95% CI 1.18-5.23, p = 0.02) or severely reduced DLCO (OR 1.95, 95% CI 1.19-3.20, p = 0.008) had increased odds of post-transplant pulmonary complications. Following multivariable adjustment, severe OVD (aOR 2.67, 95% CI 1.15-6.19, p = 0.02) and severely reduced DLCO (aOR 1.79, 95% CI 1.05-3.04) remained strongly associated with post-transplant pulmonary complications. Patients with any degree of extrinsic RVD, moderate or less OVD, or moderately reduced DLCO or less did not have increased odds of post-transplant pulmonary complications. Ninety-day post-transplant survival was significantly reduced for both severe OVD (97.2% vs 86.5%, p = 0.04) and severely reduced DLCO (97.3% vs 90.4%, p = 0.004). Post-transplant ICU and hospital length of stay were nominally longer for both groups as well. CONCLUSIONS: Severe OVD or severely reduced DLCO on preheart transplant PFTs were associated with increased odds of post-transplant pulmonary complications and early mortality.

Segmental Versus Diffuse Main Duct Intraductal Papillary Mucinous Neoplasm: Examination of Main Pancreatic Duct Morphology and Implications for Malignancy Risk and Extent of Surgical Resection.

OBJECTIVE: To determine whether the morphologic features of the main pancreatic duct (MPD) of main-duct-involved-intraductal papillary mucinous neoplasm (IPMN) (ie, main duct or mixed main duct/side branch) have implications for the risk of malignancy and extent of resection. BACKGROUND: International consensus guidelines acknowledge the presence of various MPD morphologies (ie, diffuse vs segmental main-duct-involved-IPMN) without a precise definition of each entity and with limited data to guide treatment strategy. METHODS: All consecutive main-duct-involved-IPMN patients (2005-2019) with a MPD diameter ≥5 mm by cross-sectional imaging were reviewed from a prospective institutional database. Morphologic features of the MPD were correlated with the identification of high-grade dysplasia or pancreatic ductal adenocarcinoma (HGD/PDAC) by logistic regression modeling. In patients who underwent partial pancreatectomy, preoperative MPD morphologic features were correlated with the future development of HGD/PDAC in the pancreatic remnant by Cox hazards modeling. RESULTS: In a cohort of 214 main-duct-involved-IPMN patients, the overall rate of HGD/PDAC was 54.2%. MPD morphologic characteristics associated with HGD/PDAC included: maximal MPD diameter (5-10 mm: 29.8%; 10-14 mm: 59.0%; 15-19 mm: 78.6%; ≥20 mm: 95.8%; P <0.001), segmental extent of maximal dilation (<25%: 28.2%; 25%-49%: 54.9%; 50%-74%: 63.1%; ≥75%: 67.9%; P =0.002), and nonsegmental MPD diameter (<5 mm: 21.5% vs ≥5 mm: 78.5%, P <0.001). Diffuse MPD dilation involving ≥90% extent was rare (5.6%). After a median follow-up of 50 months, 7 (7.2%) patients who underwent partial pancreatectomy for IPMN without associated PDAC developed HGD/PDAC in the pancreatic remnant. Maximal MPD diameter, segmental extent of maximal dilation, or nonsegmental MPD diameter were not associated with the development of HGD/PDAC in the pancreatic remnant. However, a mural nodule on preoperative imaging was associated with the development of HGD/PDAC in the pancreatic remnant. CONCLUSIONS: "Diffuse" involvement with homogenous dilation of the MPD was rare. For the majority of patients with segmental main-duct-involved-IPMN, the MPD morphology conferred malignancy risk. Duct morphology was not predictive for the development of HGD or invasive disease in the pancreatic remnant, implying the safety of limited pancreatic resection for initial surgical management.

Tactile sensitivity and motor coordination in infancy: Effect of age, prior surgery, anaesthesia & critical illness.

BACKGROUND: Tactile sensitivity in the infant period is poorly characterized, particularly among children with prior surgery, anaesthesia or critical illness. The study aims were to investigate tactile sensitivity of the foot and the associated coordination of lower limb motor movement in typically developing infants with and without prior hospital experience, and to develop feasible bedside sensory testing protocols. MATERIALS AND METHODS: A prospective, longitudinal study in 69 infants at 2 and 4 months-old, with and without prior hospital admission. Mechanical stimuli were applied to the foot at graded innocuous and noxious intensities. Primary outcome measures were tactile and nociceptive threshold (lowest force required to evoke any leg movement, or brisk leg withdrawal, respectively), and specific motor flexion threshold (ankle-, knee-, hip-flexion). Secondary analysis investigated (i) single vs multiple trials reliability, and (ii) the effect of age and prior surgery, anaesthesia, or critical illness on mechanical threshold. RESULTS: Magnitude of evoked motor activity increased with stimulus intensity. Single trials had excellent reliability for knee and hip flexion at age 1-3m and 4-7m (ICC range: 0.8 to 0.98, p >0.05). Nociceptive threshold varied as a function of age. Tactile sensitivity was independent of age, number of surgeries, general anaesthesia and ICU stay. CONCLUSIONS: This brief sensory testing protocol may reliably measure tactile and nociceptive reactivity in human infants. Age predicts nociceptive threshold which likely reflects ongoing maturation of spinal and supraspinal circuits. Prior hospital experience has a negligible global effect on sensory processing demonstrating the resilience of the CNS in adverse environments.

Alterations in Somatic Driver Genes Are Associated with Response to Neoadjuvant FOLFIRINOX in Patients with Localized Pancreatic Ductal Adenocarcinoma.

BACKGROUND: There is increased use of neoadjuvant fluorouracil, leucovorin, irinotecan, and oxaliplatin (FOLFIRINOX) in the management of localized pancreatic ductal adenocarcinoma (PDAC), yet there are few validated biomarkers of treatment response. STUDY DESIGN: Consecutive patients (n = 196) with resectable, borderline resectable or locally advanced PDAC (2012-2019) receiving FOLFIRINOX as initial treatment and with targeted sequencing of a pretreatment biopsy were identified in a prospective institutional database. Genomic alterations were determined in the 4 driver mutations (KRAS, TP53, CDKN2A, SMAD4), and associations between genomic alterations and clinical outcomes were assessed. RESULTS: Alterations in KRAS (n = 172, 87.8%) and TP53 (n = 131, 66.8%) were common; alterations in CDKN2A (n = 49, 25.0%) and SMAD4 (n = 36, 18.4%) were less frequently observed. A total of 105 patients (53.6%) were able to undergo resection, of whom 8 (7.6%) had a complete/near-complete pathologic response. There were no somatic alterations associated with major pathologic response. Alterations in SMAD4 were associated with a lower rate of surgical resection (27.8% vs 59.4%, p < 0.001); this was additionally observed in a multivariable regression model accounting for resectability status (OR 0.35, 95% confidence interval [CI] 0.15-0.85). Thirty-three patients (16.8%) developed metastatic disease while on neoadjuvant therapy. SMAD4 alterations were associated with a significant risk of metastatic progression on therapy when controlling for resectability status (OR 3.31, 95% CI 1.44-7.60). CONCLUSIONS: SMAD4 alterations are associated with more frequent development of metastasis during neoadjuvant FOLFIRINOX and lower probability of reaching surgical resection. Evaluation of alternative chemotherapy regimens in patients with SMAD4 alterations will be important to distinguish whether this represents a prognostic or predictive biomarker.

The role of noninvasive imaging in the diagnostic workup for pulsatile tinnitus.

OBJECTIVE: We sought to assess the diagnostic yield of advanced noninvasive imaging in the evaluation of patients with pulsatile tinnitus. BACKGROUND: Pulsatile tinnitus can be caused by high-risk cerebrovascular pathologies such as arteriovenous fistulae. The role of advanced noninvasive imaging, including magnetic resonance angiography and magnetic resonance venography, in the diagnostic evaluation of pulsatile tinnitus is not well defined. DESIGN AND METHODS: We performed a retrospective cohort study of patients presenting for outpatient diagnostic evaluation of pulsatile tinnitus from January 2018 to March 2020 at Weill Cornell Medicine. Patients with non-pulsatile tinnitus and established etiologic diagnoses were excluded. Systematic chart abstraction was summarized using standard descriptive statistics. Univariate logistic regression was used to identify factors associated with nondiagnostic noninvasive imaging. RESULTS: A total of 187 patients (139 (74.3%) women) took part in this study, with a mean age of 48.6 years (standard deviation (SD) = 15.5 years) and a mean body mass index (BMI) of 26.9 kg/m2 (SD = 6.1 kg/m2). Of the 187 patients, 121 (64.7%) underwent exclusively noninvasive imaging, and 66 (35.3%) patients also had digital subtraction angiography (DSA). In patients who had exclusively noninvasive imaging, 62 (51.2%) patients received a diagnosis. In patients who underwent noninvasive and DSA imaging, 14 (21.2%) patients received a diagnosis based on DSA. Patients who were older at symptom onset (odds ratio (OR) = 1.05; 95% confidence interval (CI) 1.01-1.09) and those with a lower BMI (OR = 0.88, 95% CI 0.77-0.98) were more likely to have nondiagnostic noninvasive imaging. CONCLUSION: Noninvasive cerebrovascular imaging often uncovers the etiology of pulsatile tinnitus. DSA remains useful for additional evaluation for patients with specific associated features.

Assessing the long-term safety and efficacy of gamma knife and linear accelerator radiosurgery for vestibular schwannoma: A systematic review and meta-analysis.

BACKGROUND: Differences in long-term outcomes of single-fraction stereotactic radiosurgery (SRS) between gamma knife (GK) and linear accelerator (LINAC) systems for vestibular schwannoma (VS) management remain unclear. To investigate differences in safety and efficacy between modalities, we conducted a meta-analysis of studies over the past decade. METHODS: MEDLINE, EMBASE, and Cochrane databases were queried for studies with the following inclusion criteria: English language, published between January 2010 and April 2020, cohort size ≥30, and mean/median follow-up ≥5 years. Odds ratios (OR) compared rates of tumor control, hearing preservation, and cranial nerve toxicities before and after SRS. RESULTS: Thirty-nine studies were included (29 GK, 10 LINAC) with 6516 total patients. Tumor control rates were 93% (95% CI 91-94%) and 94% (95% CI 91-97%) for GK and LINAC, respectively. Both GK (OR 0.06, 95% CI 0.02-0.13) and LINAC (OR 0.47, 95% CI 0.29-0.76) reduced odds of serviceable hearing. Neither GK (OR 0.71, 95% CI 0.41-1.22) nor LINAC (OR 1.13, 95% CI 0.64-2.00) impacted facial nerve function. GK decreased odds of trigeminal nerve (TN) impairment (OR 0.55, 95% CI 0.32-0.94) while LINAC did not impact TN function (OR 1.45, 95% CI 0.81-2.61). Lastly, LINAC offered decreased odds of tinnitus (OR 0.15, 95% CI 0.03-0.87) not observed with GK (OR 0.70, 95% CI 0.48-1.01). CONCLUSIONS: VS tumor control and hearing preservation rates are comparable between GK and LINAC SRS. GK may better preserve TN function, while LINAC decreases tinnitus rates. Future studies are warranted to investigate the efficacy of GK and LINAC SRS more directly.