Do germline genetic variants influence surgical outcomes in drug-resistant epilepsy?

OBJECTIVE: We retrospectively explored patients with drug-resistant epilepsy (DRE) who previously underwent presurgical evaluation to identify correlations between surgical outcomes and pathogenic variants in epilepsy genes. METHODS: Through an international collaboration, we evaluated adult DRE patients who were screened for surgical candidacy. Patients with pathogenic (P) or likely pathogenic (LP) germline variants in genes relevant to their epilepsy were included, regardless of whether the genetic diagnosis was made before or after the presurgical evaluation. Patients were divided into two groups: resective surgery (RS) and non-resective surgery candidates (NRSC), with the latter group further divided into: palliative surgery (vagus nerve stimulation, deep brain stimulation, responsive neurostimulation or corpus callosotomy) and no surgery. We compared surgical candidacy evaluations and postsurgical outcomes in patients with different genetic abnormalities. RESULTS: We identified 142 patients with P/LP variants. After presurgical evaluation, 36 patients underwent RS, while 106 patients were NRSC. Patients with variants in ion channel and synaptic transmission genes were more common in the NRSC group (48 %), compared with the RS group (14 %) (p<0.001). Most patients in the RS group had tuberous sclerosis complex. Almost half (17/36, 47 %) in the RS group had Engel class I or II outcomes. Patients with channelopathies were less likely to undergo a surgical procedure than patients with mTORopathies, but when deemed suitable for resection had better surgical outcomes (71 % versus 41 % with Engel I/II). Within the NRSC group, 40 underwent palliative surgery, with 26/40 (65 %) having ≥50 % seizure reduction after mean follow-up of 11 years. Favourable palliative surgery outcomes were observed across a diverse range of genetic epilepsies. SIGNIFICANCE: Genomic findings, including a channelopathy diagnosis, should not preclude presurgical evaluation or epilepsy surgery, and appropriately selected cases may have good surgical outcomes. Prospective registries of patients with monogenic epilepsies who undergo epilepsy surgery can provide additional insights on outcomes.

Distinct plasma metabolomic signatures differentiate autoimmune encephalitis from drug-resistant epilepsy.

OBJECTIVE: Differentiating forms of autoimmune encephalitis (AE) from other causes of seizures helps expedite immunotherapies in AE patients and informs studies regarding their contrasting pathophysiology. We aimed to investigate whether and how Nuclear Magnetic Resonance (NMR)-based metabolomics could differentiate AE from drug-resistant epilepsy (DRE), and stratify AE subtypes. METHODS: This study recruited 238 patients: 162 with DRE and 76 AE, including 27 with contactin-associated protein-like 2 (CASPR2), 29 with leucine-rich glioma inactivated 1 (LGI1) and 20 with N-methyl-d-aspartate receptor (NMDAR) antibodies. Plasma samples across the groups were analyzed using NMR spectroscopy and compared with multivariate statistical techniques, such as orthogonal partial least squares discriminant analysis (OPLS-DA). RESULTS: The OPLS-DA model successfully distinguished AE from DRE patients with a high predictive accuracy of 87.0 ± 3.1% (87.9 ± 3.4% sensitivity and 86.3 ± 3.6% specificity). Further, pairwise OPLS-DA models were able to stratify the three AE subtypes. Plasma metabolomic signatures of AE included decreased high-density lipoprotein (HDL, -(CH2)n-, -CH3), phosphatidylcholine and albumin (lysyl moiety). AE subtype-specific metabolomic signatures were also observed, with increased lactate in CASPR2, increased lactate, glucose, and decreased unsaturated fatty acids (UFA, -CH2CH=) in LGI1, and increased glycoprotein A (GlycA) in NMDAR-antibody patients. INTERPRETATION: This study presents the first non-antibody-based biomarker for differentiating DRE, AE and AE subtypes. These metabolomics signatures underscore the potential relevance of lipid metabolism and glucose regulation in these neurological disorders, offering a promising adjunct to facilitate the diagnosis and therapeutics.

Salivary Nitric Oxide Levels before and after Treating Caries in Children: A Comparative Study.

Objective: To assess salivary nitric oxide (NO) levels in children with caries at baseline before treatment and compare salivary NO levels before treatment and after 15 and 30 days of the treatment. Study design: The saliva sample was collected from a total of 31 children with caries aged between 6 and 12 years. NO levels were estimated in children with caries before and after treatment using Griess reaction. Decayed teeth in permanent dentition (DT) and and decayed teeth in primary dentition (dt) scores, pretreatment NO levels were recorded at the baseline. After completing the treatment, posttreatment NO levels were compared at 15 and 30 days using paired t-tests. Mann-Whitney U test was used for comparing NO levels with both genders. Further, the correlation of NO with age and dental caries was estimated using the Spearman correlation test. Results: A significant increase in salivary NO levels was found in children after treatment (p < 0.001). No significant correlation was found between NO, age, gender, and DT and dt scores. Conclusion: Higher levels of NO were associated with low caries experience. Clinical significance: The salivary NO in children is of higher diagnostic values as it can be used in caries risk assessment. How to cite this article: Jindal M, Sogi S, Shahi P, et al. Salivary Nitric Oxide Levels before and after Treating Caries in Children: A Comparative Study. Int J Clin Pediatr Dent 2023;16(S-2):S133-S137.

Gestational stress decreases postpartum mitochondrial respiration in the prefrontal cortex of female rats.

Postpartum depression (PPD) is a major psychiatric complication of childbirth, affecting up to 20% of mothers, yet remains understudied. Mitochondria, dynamic organelles crucial for cell homeostasis and energy production, share links with many of the proposed mechanisms underlying PPD pathology. Brain mitochondrial function is affected by stress, a major risk factor for development of PPD, and is linked to anxiety-like and social behaviors. Considering the importance of mitochondria in regulating brain function and behavior, we hypothesized that mitochondrial dysfunction is associated with behavioral alterations in a chronic stress-induced rat model of PPD. Using a validated and translationally relevant chronic mild unpredictable stress paradigm during late gestation, we induced PPD-relevant behaviors in adult postpartum Wistar rats. In the mid-postpartum, we measured mitochondrial function in the prefrontal cortex (PFC) and nucleus accumbens (NAc) using high-resolution respirometry. We then measured protein expression of mitochondrial complex proteins and 4-hydroxynonenal (a marker of oxidative stress), and Th1/Th2 cytokine levels in PFC and plasma. We report novel findings that gestational stress decreased mitochondrial function in the PFC, but not the NAc of postpartum dams. However, in groups controlling for the effects of either stress or parity alone, no differences in mitochondrial respiration measured in either brain regions were observed compared to nulliparous controls. This decrease in PFC mitochondrial function in stressed dams was accompanied by negative behavioral consequences in the postpartum, complex-I specific deficits in protein expression, and increased Tumor Necrosis Factor alpha cytokine levels in plasma and PFC. Overall, we report an association between PFC mitochondrial respiration, PPD-relevant behaviors, and inflammation following gestational stress, highlighting a potential role for mitochondrial function in postpartum health.

Clinical Evaluation of Retention of Hydrophilic and Hydrophobic Pit and Fissure Sealants in Permanent First Molars: An 18 Months Follow-up: Randomized Controlled Trial.

Introduction: Deep pits and fissures are more prone to caries development due to their complex morphological anatomy. Preventive measures, such as pit and fissure sealants, can help in the reduction of dental caries. Conventional sealants being hydrophobic in nature, require isolation. Sealants which are hydrophilic have been introduced as an alternative where isolation is difficult to achieve. Aim: To compare and evaluate the retention and marginal integrity of hydrophilic pit and fissure sealant (Embrace WetBond) with hydrophobic pit and fissure sealant (Clinpro) in permanent first molars. Materials and methods: Sealants were applied randomly using the split-mouth design technique on 80 permanent first molars in children aged between 6 and 9 years and evaluation was done at 3, 6, 9, and 18 months. Results: The difference in retention rates between the groups was not significant using the Chi-squared test, though the WetBond group exhibited better results with 40% complete retention at the end of 18 months while in the Clinpro group, it was 37.50%. The marginal integrity in both the sealant groups was also found to be statistically insignificant. Caries incidence was found to be slightly higher in the Clinpro group. Conclusion: The clinical performance of Embrace WetBond was better when compared to Clinpro because of its moisture-tolerance capacity. Embrace Wetbond pit and fissure sealant can be the choice of material in cases where moisture control is a challenging issue. How to cite this article: Gyati O, Jain M, Sogi S, et al. Clinical Evaluation of Retention of Hydrophilic and Hydrophobic Pit and Fissure Sealants in Permanent First Molars: An 18 Months follow-up: Randomized Controlled Trial. Int J Clin Pediatr Dent 2023;16(2):350-356.

Molecular predictors of response to pembrolizumab in thymic carcinoma.

Thymic carcinoma is rare and has a poorer prognosis than thymomas. The treatment options are limited after failure of platinum-based chemotherapy. We previously performed a single-center phase II study of pembrolizumab in patients with advanced thymic carcinoma, showing a 22.5% response rate. Here, we characterize the genomic and transcriptomic profile of thymic carcinoma samples from 10 patients (5 non-responders versus 5 responders) in this cohort, with the main aim of identifying potential predictors of response to immunotherapy. We find that expression of PDL1 and alterations in genes or pathways that correlated with PD-L1 expression (CYLD and BAP1) could be potential predictors for response or resistance to immunotherapy in patients with advanced thymic carcinoma. Our study provides insights into potential predictive markers/pathways to select patients with thymic carcinoma for anti-PD-1 immunotherapy.

Local anesthetic systemic toxicity in children: a review of recent case reports and current literature.

BACKGROUND: Local anesthetic systemic toxicity (LAST) in children occurs at an estimated rate of 8 per 100 000 blocks (95% CI 0.3 to 1.6). Due to the potential lethality of this iatrogenic complication, a better clarity of risk factors, clinical presentation, and prognosis may be clinically useful for contemporary treatment and prevention. METHODS: An extensive literature search and detailed analysis of reported cases of LAST in patients less than 18 years of age published between April 2014 and August 2019 was performed. Clinical patterns were summarized. RESULTS: Thirty-two cases of LAST were described in 17 published articles and 2 additional cases reported to lipidrescue.org, for a total of 34 cases. Three patients did not meet the inclusion criteria. Thirty-one cases were included in the analysis. DISCUSSION: Infants represented a disproportionately large number of reports of LAST. The majority of local anesthetic doses were within currently published guidelines. Among the reported cases, penile and caudal blocks were the most commonly associated with LAST. Needle aspiration and test dosing with epinephrine failed to predict LAST with certainty. When LAST presented with severe cardiac compromise, intravenous lipid emulsion was given within 10 min in 43% of cases (13 of 30 reported cases). The vast majority of children were under general anesthesia when local anesthetic medications were administered. In children under general anesthesia, LAST presented with cardiac manifestations in 90% of cases (19 of 21 cases). There were no deaths or long-term morbidity reported.

Cardiomyocyte-specific circulating cell-free methylated DNA in esophageal cancer patients treated with chemoradiation.

Thoracic high dose radiation therapy (RT) for cancer has been associated with early and late cardiac toxicity. To assess altered rates of cardiomyocyte cell death due to RT we monitored changes in cardiomyocyte-specific, cell-free methylated DNA (cfDNA) shed into the circulation. Eleven patients with distal esophageal cancer treated with neoadjuvant chemoradiation to 50.4 Gy (RT) and concurrent carboplatin and paclitaxel were enrolled. Subjects underwent fasting blood draws prior to the initiation and after completion of RT as well as 4-6 months following RT. An island of six unmethylated CpGs in the FAM101A locus was used to identify cardiomyocyte-specific cfDNA in serum. After bisulfite treatment this specific cfDNA was quantified by amplicon sequencing at a depth of >35,000 reads/molecule. Cardiomyocyte-specific cfDNA was detectable before RT in the majority of patient samples and showed some distinct changes during the course of treatment and recovery. We propose that patient-specific cardiac damages in response to the treatment are indicated by these changes although co-morbidities may obscure treatment-specific events.

Clinical features which predict neuronal surface autoantibodies in new-onset focal epilepsy: implications for immunotherapies.

OBJECTIVE: To generate a score which clinically identifies surface-directed autoantibodies in adults with new-onset focal epilepsy, and evaluate the value of immunotherapy in this clinical setting. METHODS: Prospective clinical and autoantibody evaluations in a cohort of 219 consecutive patients with new-onset focal epilepsy. RESULTS: 10.5% (23/219) of people with new-onset focal epilepsy had detectable serum autoantibodies to known or novel cell surface antigenic targets. 9/23 with autoantibodies were diagnosed with encephalitis, by contrast to 0/196 without autoantibodies (p<0.0001). Multivariate analysis identified six features which predicted autoantibody positivity (area under the curve=0.83): age ≥54 years, ictal piloerection, lowered self-reported mood, reduced attention, MRI limbic system changes and the absence of conventional epilepsy risk factors. 11/14 (79%) patients with detectable autoantibodies, but without encephalitis, showed excellent long-term outcomes (modified Rankin Score=0) despite no immunotherapy. These outcomes were superior to those of immunotherapy-treated patients with confirmed autoantibody-mediated encephalitis (p<0.05). CONCLUSIONS: Seizure semiology, cognitive and mood phenotypes, alongside inflammatory investigation findings, aid the identification of surface autoantibodies among unselected people with new-onset focal epilepsy. The excellent immunotherapy-independent outcomes of autoantibody-positive patients without encephalitis suggests immunotherapy administration should be guided by clinical features of encephalitis, rather than autoantibody positivity. Our findings suggest that, in this cohort, immunotherapy-responsive seizure syndromes with autoantibodies largely fall under the umbrella of autoimmune encephalitis.

Risk Factors for Early Childhood Caries in Toddlers: An Institution-based Study.

Background Tooth decay experience among toddlers and preschoolers is of epidemic proportions worldwide and dental caries still remains an important childhood disease affecting a considerable part of this population. Though the prevalence of Early Childhood Caries (ECC) is associated with several risk factors such as feeding and oral hygiene practices, Streptococcus mutans levels, socioeconomic status (SES), etc., it is suggested that these factors should be studied adequately to aid in the early prevention and management of ECC. Objective The objectives of the study were to: a) evaluate the distribution of ECC, b) study the role of SES in the occurrence of ECC, c) record the variations in feeding and dietary practices along with oral hygiene practices and d) Correlate the sweet score with ECC. Materials and Methods This cross-sectional observational study was conducted over a period of 6 months among 100 toddlers (12-36 months) attending the Pediatric outpatient department of a single medical institution in Chennai, India. The study consisted of an intra-oral examination followed by a face to face interview of the mothers of the children using a validated structured oral health questionnaire. Results SES and ECC were negatively correlated with statistically significant association. Majority of the subjects did not follow any oral hygiene practices before teeth erupted; few subjects used tooth brush and tooth paste after teeth erupted and followed oral hygiene practices once a day. Statistically significant positive correlation with ICDAS scores was noted in relation to the sweet score and the frequency of intake of sweet foods, candy, etc. Cavitated lesions were more common than non-cavitated lesions and majority of the posterior teeth had ICDAS score 4. Conclusion Healthcare providers for children must be well informed on the etiology and risk factors of ECC and guide children for their first dental visit within one year of age.

Somatic mutation signatures in primary liver tumors of workers exposed to ionizing radiation.

Liver cancer is associated with genetic mutations caused by environmental exposures, including occupational exposure to alpha radiation emitted by plutonium. We used whole exome sequencing (WES) to characterize somatic mutations in 3 histologically distinct primary liver tumors (angiosarcoma of the liver (ASL), cholangiocarcinoma (CCA) and hepatocellular carcinoma (HCC)) from Mayak worker subjects occupationally exposed to ionizing radiation (IR) to investigate the contribution of IR to the mutational landscape of liver cancer. DNA sequence analysis revealed these tumors harbor an excess of deletions, with a deletions:substitutions ratio similar to that previously reported in radiation-associated tumors. These tumors were also enriched for clustered mutations, a signature of radiation exposure. Multiple tumors displayed similarities in abrogated gene pathways including actin cytoskeletal signaling and DNA double-strand break (DSB) repair. WES identified novel candidate driver genes in ASL involved in angiogenesis and PIK3CA/AKT/mTOR signaling. We confirmed known driver genes of CCA, and identified candidate driver genes involved in chromatin remodeling. In HCC tumors we validated known driver genes, and identified novel putative driver genes involved in Wnt/ß-catenin signaling, chromatin remodeling, PIK3CA/AKT/mTOR signaling, and angiogenesis. This pilot study identifies several novel candidate driver mutations that are likely to be caused by IR exposure, and provides the first data on the mutational landscape of liver cancer after IR exposure.

Risk factors for post-induction hypotension in children presenting for surgery.

BACKGROUND: Preoperative factors have been correlated with pre-incision hypotension (PIH) in children undergoing surgery, suggesting that PIH can be predicted through preoperative screening. We studied blood pressure (BP) changes in the 12 min following the induction of anesthesia to study the incidence of post-induction hypotension and to assess the feasibility of predicting PIH in low-risk children without preoperative hypotension or comorbid features. METHODS: We retrospectively evaluated 200 patients ranging in age from 2 to 8 years with American Society of Anesthesiologists' (ASA) physical status I or II, undergoing non-cardiac surgery. Patients were excluded if they had preoperative (baseline) hypotension (systolic blood pressure (SBP) < 5th percentile for age). BP and heart rate (HR) were recorded at 3 min intervals for 12 min after the induction of anesthesia. Pre-incision hypotension (PIH) was initially defined as SBP < 5th percentile for age: (1) at any timepoint within 12 min of induction; (2) for the median SBP obtained during the 12 min study period; or (3) at 2 or more timepoints including the final point at 12 min after the induction of anesthesia (sustained hypotension). In addition, we examined PIH defined as > 20% decrease in SBP from baseline: (4) at any timepoint within 12 min of the induction of anesthesia; (5) for the median SBP obtained during the 12 min study period; or (6) at two or more timepoints including the final point at 12 min after the induction of anesthesia. Agreement among the six definitions was analyzed, in addition to the effects of age, gender, type of anesthetic induction, use of premedication, preoperative BP, preoperative HR, and body mass index on the incidence of PIH according to each definition. RESULTS: Five patients were excluded due to baseline hypotension and six were excluded for missing data. In the remaining cohort, estimated PIH prevalence ranged from 4% [definition (Stewart et al., in Paediatr Anaesth 26:844-851, 2016), sustained PIH according to SBP percentile-for-age] to 57% [definition (Task Force on Blood Pressure Control in Children, in Pediatrics 79:1-25, 1987), at least one timepoint where SBP was > 20% lower than baseline]. Pairwise agreement among the six definitions ranged from 49 to 91% agreement. No sequelae of PIH were noted during subsequent anesthetic or postoperative care. On multivariable analysis, no covariates were consistently associated with PIH risk across all six definitions of PIH. CONCLUSION: The present study describes the incidence and prediction of PIH in a cohort of relatively healthy children. In this setting, accurate prediction of PIH appears to be hampered by lack of agreement between definitions of PIH. Overall, there was a low PIH incidence when the threshold of SBP < 5th percentile for age was used. LEVEL OF EVIDENCE: II.

Age-based analysis of pediatric upper airway dimensions using computed tomography imaging.

BACKGROUND: Recent studies have challenged the historically accepted fact that the larynx is cone-shaped in infants and children. The present study used computed tomography (CT)-based measurements to evaluate airway dimensions. The purpose of this investigation was to determine the dimensional transition between the subglottic area and the cricoid ring in children. METHODS: This is a retrospective review of 220 CT scans of children aged 1 month to 10 years undergoing radiological evaluation unrelated to airways symptomatology. The CT scans were evaluated in children either sleeping naturally or sedated throughout the study period. Anteroposterior (AP) and Transverse (T) diameters were measured at the subglottic level and at the cricoid ring. RESULTS: The mean (±SD) age was 47.4 ± 33.1 months. The mean AP and transverse diameters were 9.2 ± 1.9 and 7.5 ± 1.6 mm at the subglottic area and 8.5 ± 1.7 and 8.3 ± 1.5 mm at the cricoid. AP dimension showed a decrease from the subglottis to the cricoid ring. A more rapid enlargement of the airway from the subglottis to cricoid ring is observed in the transverse dimension (P < 0.05). A linear progression in the size of airway dimensions between both levels was observed with age (r > 0.7). CONCLUSION: The narrower transverse dimension compared to the AP diameter suggests that the airway is elliptical immediately below the vocal cords. The present study demonstrates that the airway characteristics in children between the subglottic area and the cricoid change from an elliptical to a round (circular) shape. The cone-shaped airway characteristic, which has been historically proposed, was not observed. Given that subglottic transverse diameter is the smallest area dimension, one must assume this is the most likely area of resistance to the passage of an endotracheal tube rather than only the cricoid.

Vesicular expression and release of ATP from dopaminergic neurons of the mouse retina and midbrain.

Vesicular nucleotide transporter (VNUT) is required for active accumulation of adenosine tri-phosphate (ATP) into vesicles for purinergic neurotransmission, however, the cell types that express VNUT in the central nervous system remain unknown. This study characterized VNUT expression within the mammalian retina and brain and assessed a possible functional role in purinergic signaling. Two native isoforms of VNUT were detected in mouse retina and brain based on RNA transcript and protein analysis. Using immunohistochemistry, VNUT was found to co-localize with tyrosine hydroxylase (TH) positive, dopaminergic (DA) neurons of the substantia nigra and ventral tegmental area, however, VNUT expression in extranigral non-DA neurons was also observed. In the retina, VNUT labeling was found to co-localize solely with TH-positive DA-cells. In the outer retina, VNUT-positive interplexiform cell processes were in close contact with horizontal cells and cone photoreceptor terminals, which are known to express P2 purinergic-receptors. In order to assess function, dissociated retinal neurons were loaded with fluorescent ATP markers (Quinacrine or Mant-ATP) and the DA marker FFN102, co-labeled with a VNUT antibody and imaged in real time. Fluorescent ATP markers and FFN102 puncta were found to co-localize in VNUT positive neurons and upon stimulation with high potassium, ATP marker fluorescence at the cell membrane was reduced. This response was blocked in the presence of cadmium. These data suggest DA neurons co-release ATP via calcium dependent exocytosis and in the retina this may modulate the visual response by activating purine receptors on closely associated neurons.

An in vitro and in vivo validation of a novel color-coded syringe device for measuring the intracuff pressure in cuffed endotracheal tubes.

BACKGROUND: The clinical practice of pediatric anesthesiology has changed with a transition to the use of cuffed endotracheal tubes (ETTs) in infants and children. The monitoring of intracuff pressure has been suggested as one means to limit the potential for damage to the tracheal mucosa. The current study evaluates the accuracy of a novel, color-coded syringe device which provides three zones (green, clear, and red) to estimate the intracuff pressure. METHOD: The study was conducted in two phases. Phase 1 was an in vitro study where cuffed ETTs of sizes 4.0 mm, 5.0 mm and 6.0 mm ID were placed into polyvinylchloride tubing of appropriate sizes. A manometer and the syringe device were simultaneously attached to measure the intracuff pressure at the middle of the 3 different zones on the device (red, clear, and green). Phase 2 was an in vivo study where the syringe device and the manometer were simultaneously attached to the pilot balloon to measure the intracuff pressure and the corresponding zone on the color-coded syringe following endotracheal intubation. Statistical analysis included a descriptive reporting of the mean ± SD, median, range, and 95% confidence intervals (CI) of the actual intracuff pressure readings at the three zones of the syringe device during both its in vitro and in vivo use. RESULTS: For phase 1 of the study, the 95% CI for the green, clear, and red zones were 21.5-21.8, 29.2-29.5, and 46.5-47.4 cmH2O respectively. This correlated well with the manufacturer reported values of 20-30, 30-40, and 40-60 cmH2O for the 3 zones (green, clear, and red respectively). Phase 2 of the study included 200 patients ranging in age from 0.1 to 21.8 years (6.7 ± 5.1 years) and in weight from 4.0 to 129.1 kilograms (29.4 ± 23.3 kgs). The size of the ETTs ranged from 3.0 to 7.0 mm ID. The intracuff pressure measured by the manometer ranged from 4 to 65 cmH2O (27.6 ± 9.7 cmH2O). The 95% CI for the green, clear, and red zones were 20.5-21.7, 27.7-29.1, and 41.2-46.5 cmH2O respectively. There was no significant differences noted when comparing different patient ages or sizes of ETT. CONCLUSION: The current study demonstrates a clinically acceptable correlation between the zones on this novel, color-coded syringe device and the actual measurement of the intracuff pressure obtained by a manometer for both in vitro and in vivo use. This device is a simple, reliable, portable and affordable method to monitor intracuff pressure.

Penicillin allergy and surgical prophylaxis: Cephalosporin cross-reactivity risk in a pediatric tertiary care center.

BACKGROUND: First generation cephalosporins are commonly used as antibiotic prophylaxis prior to surgery. Patients labeled as penicillin-allergic are often precluded from receiving cephalosporins because of an allergic cross-reactivity. The aims of this study were to evaluate the clinical practice for surgical prophylaxis at Nationwide Children's Hospital and to determine the incidence of adverse effects and allergic reactions when using cephalosporins in patients labeled as penicillin-allergic. METHODS: A retrospective chart review was performed to identify patients who were allergic to penicillin, penicillin antibiotic family, who required surgical treatment for an existing medical condition, and received an antibiotic to prevent surgical site infection. RESULTS: Five hundred thirteen penicillin-allergic patients were identified, encompassing 624 surgical cases. Cephalosporins were administered in 153 cases (24.5%) with cefazolin used 83% of the time. Only one documented case of nonanaphylactic reaction was reported. Clindamycin was the most common cephalosporin substitute (n=387), and the reported adverse reaction rate was 1.5%. No cases of anaphylaxis were documented. CONCLUSIONS: Our data suggest that the administration of cephalosporins for surgical prophylaxis following induction of anesthesia in a patient with a known or reported penicillin-allergy appears appropriate and results in a lower adverse event rate that when clindamycin is administered.

Changes in intracuff pressure of a cuffed endotracheal tube during prolonged surgical procedures.

BACKGROUND: With the introduction of redesigned cuffed endotracheal tubes (ETTs), there has been an increasing trend toward their use in pediatric patients. Despite improvements in design, an unintended and prolonged hyperinflation of the cuff can compromise tracheal mucosal perfusion. The current study prospectively monitors changes in intracuff pressure continuously in pediatric patients undergoing prolonged surgical procedures. METHODS: The study was conducted on pediatric patients who were scheduled to undergo prolonged surgical procedures (more than 4h) with a cuffed ETT. After placement of the cuffed ETT, the cuff was inflated using the air-leak test with a CPAP of 20cmH2O in the anesthesia circuit. After inflation, the inflating port of the pilot balloon was connected to the transducer of the invasive pressure monitoring device using our previously described technique to continuously measure the intracuff pressure. Measurements were recorded every 15min for the first 1h, and then every 30min throughout the surgical procedure. RESULTS: The study cohort included 30 patients who ranged in age from 1.2 to 17.6 years and in weight from 9.4 to 113.4kg. There were 16 boys and 14 girls. The size of the cuffed ETT ranged from 3.5mm to 8.0mm ID. The baseline intracuff pressure at the time of inflation was 17.6±8.8cmH2O. The absolute change in the intraoperative intracuff pressure when compared to the baseline intracuff pressure ranged from -25.8 to +16.3cmH2O. In 9 patients (30%), the decrease of the intracuff pressure was ≥10cmH2O. In 6 patients (20%), the increase of the intracuff pressure was ≥10cmH2O. In 5 of 30 patients (17%), the absolute intracuff pressure was greater than 30cmH2O at least once intraoperatively. In no patient, did the intracuff pressure remain the same as the baseline throughout the procedure. CONCLUSION: We noted significant variations in the intracuff pressure during prolonged surgical procedures. These unintended changes, both increases and decreases, may impact the perioperative course of patients. Our study suggests the need for continuously monitoring intracuff pressure if a cuffed ETT is used in children for prolonged surgical procedures.

Modulus-dependent characteristics of Wharton's jelly mesenchymal stem cells (WJMSC) encapsulated in hydrogel microspheres.

Recent studies revealing stem cell behavior dependence on mechanical properties of a substrate has initiated the need to probe matrix mechanics and its influence on stem cell fate in a physiologically relevant three-dimensional (3D) microenvironment. We investigated the proliferative and osteogenic potentials of Wharton's jelly mesenchymal stem cells (WJMSCs) immobilized in alginate microspheres with respect to the mechanical properties of alginate hydrogels (1, 1.5 and 2% (w/v)) post incubation in a simulated in vivo environment. Compressive moduli, degradation profile, and swelling kinetics of the hydrogels varied proportionally with alginate concentration and with exposure to simulated conditions. Degradation profile and morphological analysis showed that hydrogels exhibiting high modulus (2% w/v) remained the most intact at the end of day 21. High cell viability in all conditions was observed throughout the culture period. Low-modulus hydrogels (1% w/v) facilitated proliferation of WJMSCs whereas high-modulus hydrogels demonstrated better osteogenic differentiation inferred by an up regulation of osteo-specific genes, expressions of osteocalcin, and quantification of calcium deposition. These findings present a step forward in the development of application-specific hydrogel matrices for stem cell-based tissue engineering.

AKT pathway genes define 5 prognostic subgroups in glioblastoma.

Activity of GFR/PI3K/AKT pathway inhibitors in glioblastoma clinical trials has not been robust. We hypothesized variations in the pathway between tumors contribute to poor response. We clustered GBM based on AKT pathway genes and discovered new subtypes then characterized their clinical and molecular features. There are at least 5 GBM AKT subtypes having distinct DNA copy number alterations, enrichment in oncogenes and tumor suppressor genes and patterns of expression for PI3K/AKT/mTOR signaling components. Gene Ontology terms indicate a different cell of origin or dominant phenotype for each subgroup. Evidence suggests one subtype is very sensitive to BCNU or CCNU (median survival 5.8 vs. 1.5 years; BCNU/CCNU vs other treatments; respectively). AKT subtyping advances previous approaches by revealing additional subgroups with unique clinical and molecular features. Evidence indicates it is a predictive marker for response to BCNU or CCNU and PI3K/AKT/mTOR pathway inhibitors. We anticipate Akt subtyping may help stratify patients for clinical trials and augment discovery of class-specific therapeutic targets.

An in vitro and in vivo validation of a novel monitor for intracuff pressure in cuffed endotracheal tubes.

BACKGROUND: The clinical practice of pediatric anesthesiology has changed with increasing use of cuffed endotracheal tubes (cETTs) in infants and children. To limit the risk of tracheal mucosal damage, regular monitoring of intracuff pressure (CP) is necessary. This study evaluates the efficacy and accuracy of a novel syringe device that provides a digital readout of the CP. METHODS: The study was conducted in two phases. In phase 1, an in vitro study, cETTs of sizes 4.0, 5.0, and 6.0 mm ID were placed into polyvinylchloride tubing of appropriate sizes. The cuffs were then inflated, and the CP was measured simultaneously using the syringe device and a manometer. In phase 2, an in vivo study on 200 pediatric patients, the syringe device and the manometer were simultaneously attached to the pilot balloon to measure the CP following endotracheal intubation. Statistical analysis included linear regression analysis and Bland-Altman comparison. RESULTS: Linear regression analysis of the in vitro study demonstrated an R2 value of 0.9989. Bias and precision were -1.92 ± 0.62 with 95% level of agreement (LOA) ranging from -3.13 to -0.72. For the in vivo study, the linear regression analysis demonstrated an R2 value of 0.9943. The bias and precision were -0.53 ± 0.68 with 95% LOA ranging from -1.86 to 0.81. CONCLUSION: The study has demonstrated clinically acceptable correlation between the CPs obtained from the standard manometer and the syringe device both in vitro and in vivo. This device is a simple, reliable, portable, and affordable method to monitor CP.