Anti-CRISPRs: Protein Inhibitors of CRISPR-Cas Systems.

Clustered regularly interspaced short palindromic repeats (CRISPR) together with their accompanying cas (CRISPR-associated) genes are found frequently in bacteria and archaea, serving to defend against invading foreign DNA, such as viral genomes. CRISPR-Cas systems provide a uniquely powerful defense because they can adapt to newly encountered genomes. The adaptive ability of these systems has been exploited, leading to their development as highly effective tools for genome editing. The widespread use of CRISPR-Cas systems has driven a need for methods to control their activity. This review focuses on anti-CRISPRs (Acrs), proteins produced by viruses and other mobile genetic elements that can potently inhibit CRISPR-Cas systems. Discovered in 2013, there are now 54 distinct families of these proteins described, and the functional mechanisms of more than a dozen have been characterized in molecular detail. The investigation of Acrs is leading to a variety of practical applications and is providing exciting new insight into the biology of CRISPR-Cas systems.

Naturally Occurring Off-Switches for CRISPR-Cas9.

CRISPR-Cas9 technology would be enhanced by the ability to inhibit Cas9 function spatially, temporally, or conditionally. Previously, we discovered small proteins encoded by bacteriophages that inhibit the CRISPR-Cas systems of their host bacteria. These "anti-CRISPRs" were specific to type I CRISPR-Cas systems that do not employ the Cas9 protein. We posited that nature would also yield Cas9 inhibitors in response to the evolutionary arms race between bacteriophages and their hosts. Here, we report the discovery of three distinct families of anti-CRISPRs that specifically inhibit the CRISPR-Cas9 system of Neisseria meningitidis. We show that these proteins bind directly to N. meningitidis Cas9 (NmeCas9) and can be used as potent inhibitors of genome editing by this system in human cells. These anti-CRISPR proteins now enable "off-switches" for CRISPR-Cas9 activity and provide a genetically encodable means to inhibit CRISPR-Cas9 genome editing in eukaryotes. VIDEO ABSTRACT.

Molecular mechanism of anion permeation through aquaporin 6.

Aquaporins (AQPs) are recognized as transmembrane water channels that facilitate selective water permeation through their monomeric pores. Among the AQP family, AQP6 has an intriguing characteristic as an anion channel, which is allosterically controlled by pH conditions and is eliminated by a single amino acid mutation. However, the molecular mechanism of anion permeation through AQP6 remains unclear. Using molecular dynamics simulations in the presence of a transmembrane voltage utilizing an ion concentration gradient, we show that chloride ions permeate through the pore corresponding to the central axis of the AQP6 homotetramer. Under low pH conditions, a subtle opening of the hydrophobic selectivity filter (SF), located near the extracellular part of the central pore, becomes wetted and enables anion permeation. Our simulations also indicate that a single mutation (N63G) in human AQP6, located at the central pore, significantly reduces anion conduction, consistent with experimental data. Moreover, we demonstrate that the pH-sensing mechanism in which the protonation of H184 and H189 under low pH conditions allosterically triggers the gating of the SF region. These results suggest a unique pH-dependent allosteric anion permeation mechanism in AQP6 and could clarify the role of the central pore in some of the AQP tetramers.

Weighting estimation in the cause-specific Cox regression with partially missing causes of failure.

Complex diseases are often analyzed using disease subtypes classified by multiple biomarkers to study pathogenic heterogeneity. In such molecular pathological epidemiology research, we consider a weighted Cox proportional hazard model to evaluate the effect of exposures on various disease subtypes under competing-risk settings in the presence of partially or completely missing biomarkers. The asymptotic properties of the inverse and augmented inverse probability-weighted estimating equation methods are studied with a general pattern of missing data. Simulation studies have been conducted to demonstrate the double robustness of the estimators. For illustration, we applied this method to examine the association between pack-years of smoking before the age of 30 and the incidence of colorectal cancer subtypes defined by a combination of four tumor molecular biomarkers (statuses of microsatellite instability, CpG island methylator phenotype, BRAF mutation, and KRAS mutation) in the Nurses' Health Study cohort.

Factors to predict recurrence after epidural blood patch in patients with spontaneous intracranial hypotension.

OBJECTIVES: This study aimed to identify predictors for the recurrence of spontaneous intracranial hypotension (SIH) after epidural blood patch (EBP). BACKGROUND: Epidural blood patch is the main treatment option for SIH; however, the characteristics of patients who experience relapse after successful EBP treatment for SIH remain understudied. METHODS: In this exploratory, retrospective, case-control study, we included 19 patients with SIH recurrence after EBP and 36 age- and sex-matched patients without recurrence from a single tertiary medical institution. We analyzed clinical characteristics, neuroimaging findings, and volume changes in intracranial structures after EBP treatment. Machine learning methods were utilized to predict the recurrence of SIH after EBP treatment. RESULTS: There were no significant differences in clinical features between the recurrence and no-recurrence groups. Among brain magnetic resonance imaging signs, diffuse pachymeningeal enhancement and cerebral venous dilatation were more prominent in the recurrence group than no-recurrence group after EBP (14/19 [73%] vs. eight of 36 [22%] patients, p = 0.001; 11/19 [57%] vs. seven of 36 [19%] patients, p = 0.010, respectively). The midbrain-pons angle decreased in the recurrence group compared to the no-recurrence group after EBP, at a mean (standard deviation [SD]) of -12.0 [16.7] vs. +1.8[18.3]° (p = 0.048). In volumetric analysis, volume changes after EBP were smaller in the recurrence group than in the no-recurrence group in intracranial cerebrospinal fluid (mean [SD] -11.6 [15.3] vs. +4.8 [17.1] mL, p = 0.001) and ventricles (mean [SD] +1.0 [2.0] vs. +2.0 [2.5] mL, p = 0.003). Notably, the random forest classifier indicated that the model constructed with brain volumetry was more accurate in discriminating SIH recurrence (area under the curve = 0.80 vs. 0.52). CONCLUSION: Our study suggests that volumetric analysis of intracranial structures may aid in predicting recurrence after EBP treatment in patients with SIH.

Structural studies of a bacterial condensin complex reveal ATP-dependent disruption of intersubunit interactions.

Condensins are key mediators of chromosome condensation across organisms. Like other condensins, the bacterial MukBEF condensin complex consists of an SMC family protein dimer containing two ATPase head domains, MukB, and two interacting subunits, MukE and MukF. We report complete structural views of the intersubunit interactions of this condensin along with ensuing studies that reveal a role for the ATPase activity of MukB. MukE and MukF together form an elongated dimeric frame, and MukF's C-terminal winged-helix domains (C-WHDs) bind MukB heads to constitute closed ring-like structures. Surprisingly, one of the two bound C-WHDs is forced to detach upon ATP-mediated engagement of MukB heads. This detachment reaction depends on the linker segment preceding the C-WHD, and mutations on the linker restrict cell growth. Thus ATP-dependent transient disruption of the MukB-MukF interaction, which creates openings in condensin ring structures, is likely to be a critical feature of the functional mechanism of condensins.

Application of conformational space annealing to the protein structure modeling using cryo-EM maps.

Conformational space annealing (CSA), a global optimization method, has been applied to various protein structure modeling tasks. In this paper, we applied CSA to the cryo-EM structure modeling task by combining the python subroutine of CSA (PyCSA) and the fast relax (FastRelax) protocol of PyRosetta. Refinement of initial structures generated from two methods, rigid fitting of predicted structures to the Cryo-EM map and de novo protein modeling by tracing the Cryo-EM map, was performed by CSA. In the refinement of the rigid-fitted structures, the final models showed that CSA can generate reliable atomic structures of proteins, even when large movements of protein domains were required. In the de novo modeling case, although the overall structural qualities of the final models were rather dependent on the initial models, the final models generated by CSA showed improved MolProbity scores and cross-correlation coefficients to the maps. These results suggest that CSA can accomplish flexible fitting and refinement together by sampling diverse conformations effectively and thus can be utilized for cryo-EM structure modeling.

Urinary tract infection after radiation therapy or radical prostatectomy on the prognosis of patients with prostate cancer: a population-based study.

BACKGROUND: We aimed to assess the trends in urinary tract infections (UTIs) and prognosis of patients with prostate cancer after radical prostatectomy (RP) and radiation therapy (RT) as definitive treatment options. METHODS: The data of patients diagnosed with prostate cancer between 2007 and 2016 were collected from the National Health Insurance Service database. The incidence of UTIs was evaluated in patients treated with RT, open/laparoscopic RP, and robot-assisted RP. The proportional hazard assumption test was performed using the scaled Schoenfeld residuals based on a multivariable Cox proportional hazard model. Kaplan-Meier analysis were performed to assess survival. RESULTS: A total of 28,887 patients were treated with definitive treatment. In the acute phase (< 3 months), UTIs were more frequent in RP than in RT; in the chronic phase (> 12 months), UTIs were more frequent in RT than in RP. In the early follow-up period, the risk of UTIs was higher in the open/laparoscopic RP group (aHR, 1.63; 95% CI, 1.44-1.83; p < 0.001) and the robot-assisted RP group (aHR, 1.26; 95% CI, 1.11-1.43; p < 0.001), compared to the RT group. The robot-assisted RP group had a lower risk of UTIs than the open/laparoscopic RP group in the early (aHR, 0.77; 95% CI, 0.77-0.78; p < 0.001) and late (aHR, 0.90; 95% CI, 0.89-0.91; p < 0.001) follow-up periods. In patients with UTI, Charlson Comorbidity Index score, primary treatment, age at UTI diagnosis, type of UTI, hospitalization, and sepsis from UTI were risk factors for overall survival. CONCLUSIONS: In patients treated with RP or RT, the incidence of UTIs was higher than that in the general population. RP posed a higher risk of UTIs than RT did in early follow-up period. Robot-assisted RP had a lower risk of UTIs than open/laparoscopic RP group in total period. UTI characteristics might be related to poor prognosis.

Measurement of level of consciousness by AVPU scale assessment system based on automated video and speech recognition technology.

OBJECTIVE: To develop an alert/verbal/painful/unresponsive (AVPU) scale assessment system based on automated video and speech recognition technology (AVPU-AVSR) that can automatically assess a patient's level of consciousness and evaluate its performance through clinical simulation. METHODS: We developed an AVPU-AVSR system with a whole-body camera, face camera, and microphone. The AVPU-AVSR system automatically extracted essential audiovisual features to assess the AVPU score from the recorded video files. Arm movement, pain stimulus, and eyes-open state were extracted using a rule-based approach using landmarks estimated from pre-trained pose and face estimation models. Verbal stimuli were extracted using a pre-trained speech-recognition model. Simulations of a physician examining the consciousness of 12 simulated patients for 16 simulation scenarios (4 for each of "Alert", "Verbal", "Painful", and "Unresponsive") were conducted under the AVPU-AVSR system. The accuracy, sensitivity, and specificity of the AVPU-AVSR system were assessed. RESULTS: A total of 192 cases with 12 simulated patients were assessed using the AVPU-AVSR system with a multi-class accuracy of 0.95 (95% confidence interval [CI] (0.92-0.98). The sensitivity and specificity (95% CIs) for detecting impaired consciousness were 1.00 (0.97-1.00) and 0.88 (0.75-0.95), respectively. The sensitivity and specificity of each extracted feature ranged from 0.88 to 1.00 and 0.98 to 1.00. CONCLUSIONS: The AVPU-AVSR system showed good accuracy in assessing consciousness levels in a clinical simulation and has the potential to be implemented in clinical practice to automatically assess mental status.

Spatial summation of thermal sensitivity is limited to small areas: Comparisons of the forehead, forearm, abdomen, and foot.

The purpose of the present study was to examine if spatial summation in thermal sensitivity exists when stimulating areas larger than about 1% of body surface area (BSA) (approximately 200 cm2). We hypothesized that spatial summation would exist within a limited area and the effect would be insignificant for over the 1%BSA. Fifteen young males participated in this study and we measured their warmth and hot sensation thresholds on the four body regions (the forehead, forearm, abdomen, and instep) using the three sizes of radiant film heaters (10 × 10, 15 × 15, and 20 × 20 cm2 heating film area). The heating panel was kept at a distance of 10 cm from the skin and the surface temperature of the heating panel increased by 1 °C·s-1. The results showed that warmth and hot sensation thresholds were higher for the 100 cm2 condition than the 225 or 400 cm2 conditions (P < 0.05), but no differences were found between the 225 and 400 cm2 conditions. Secondly, the instep was most insensitive to the gradual increase of radiant heat among the four body regions for all three stimulating film sizes, even though the hot threshold was lowest for the instep because the initial foot temperature was lower than other skin temperatures. In summary, spatial summation in thermal sensitivity was found for the 100 and 225 cm 2 conditions, but not for the 225 and 400 cm2 conditions. These results suggest that spatial summation exists but limited to small stimulating areas, smaller than approximately 1% BSA.

Cutaneous warmth and hotness thresholds to radiation heat exposure at a distance of 10 cm from 17 body regions.

The purpose of the present study was to evaluate body regional differences in cutaneous warmth and hotness thresholds in relation to radiant heat exposure. Fourteen male subjects participated in this study (age: 25 ± 5 y, height: 176.6 ± 5.5 cm, body weight: 70 ± 5.8 kg). Cutaneous warmth and hotness thresholds were measured on the forehead, neck, chest, abdomen, upper back, lower back, upper arm, forearm, palm, back of hand, front thigh, shin, top of foot, buttock, back thigh, calf, and sole. The forehead (34.8 ± 0.2 °C), lower back (34.1 ± 1.2 °C) and palm (34.3 ± 0.7 °C) had the highest warmth thresholds, whereas the foot (29.8 ± 1.9 °C) and sole (28.0 ± 2.1 °C) had the lowest values among the 17 regions (P<0.001). Higher warmth thresholds were related to higher initial skin temperatures (Tsk) (r=0.972, P<0.001). Increases in Tsk for detecting warmth sensation were smaller for the lower back with a rise of 0.2 ± 0.4 °C and the abdomen (0.3 ± 0.3 °C) than for the buttock (0.9 ± 0.8 °C) and sole (0.8 ± 0.6 °C) (P<0.05). Increases in Tsk for detecting hotness sensation ranged from 0.5 to 1.5 °C. Warmth and hotness thresholds on the abdomen or sole had significant relationships with body mass index, indicating that the overweight are less sensitive to detecting radiant heat on the abdomen or sole. Thermal thresholds from radiant heat exposure of 100 cm2 were lower than the values from conductive heat exposure of 6.25 cm2, which might be explained by the effect of spatial summation.

Uncertainty Evaluation for the Quantification of Urinary Amphetamine and 4-Hydroxyamphetamine Using Liquid Chromatography-Tandem Mass Spectrometry: Comparison of the Guide to the Expression of Uncertainty in Measurement Approach and the Monte Carlo Method with R.

Estimating the measurement uncertainty (MU) is becoming increasingly mandatory in analytical toxicology. This study evaluates the uncertainty in the quantitative determination of urinary amphetamine (AP) and 4-hydroxyamphetamine (4HA) using a liquid chromatography-tandem mass spectrometry (LC-MS/MS) method based on the dilute-and-shoot approach. Urine sample dilution, preparation of calibrators, calibration curve, and method repeatability were identified as the sources of uncertainty. To evaluate the MU, the Guide to the Expression of Uncertainty in Measurement (GUM) approach and the Monte Carlo method (MCM) were compared using the R programming language. The MCM afforded a smaller coverage interval for both AP (94.83, 104.74) and 4HA (10.52, 12.14) than that produced by the GUM (AP (92.06, 107.41) and 4HA (10.21, 12.45)). The GUM approach offers an underestimated coverage interval for Type A evaluation, whereas the MCM provides an exact coverage interval under an abnormal probability distribution of the measurand. The MCM is useful in complex settings where the measurand is combined with numerous distributions because it is generated from the uncertainties of input quantities based on the propagation of the distribution. Therefore, the MCM is more practical than the GUM for evaluating the MU of urinary AP and 4HA concentrations using LC-MS/MS.

Heat strain of Japanese firefighters wearing personal protective equipment: a review for developing a test method.

The aim of this review was to develop a test method for the evaluation of heat strain for structural firefighters wearing personal protective equipment (PPE) in Japan. We analysed a series of our laboratory's questionnaires and experimental studies and reviewed international standards on test methods. We investigated the actual average working conditions (total firefighting time on one incidence, working time with full PPE, maximum temperature and humidity during firefighting) at structural firefighting site in Japan by conducting a large-scale questionnaire survey of Japanese firefighters. We discussed test subjects (firefighters vs. non-firefighters; body size; physical fitness), exercise intensity (absolutes vs. relative; light vs. heavy) and duration, experimental temperature and relative humidity, experimental clothing items including station uniforms (shorts vs. long), and measurement variables (physiological and subjective responses), and suggested a standard test method to evaluate the heat strain of firefighters in hot and humid environments.Practitioner summary: We reviewed studies on human wear trials of firefighting personal protective equipment (PPE) in hot environments and suggested a standard test method to evaluate the heat strain of firefighters. The test method can be internationally utilised to examine the comfort functions and heat stress of PPE in hot, humid environments.

The illness-death model for family studies.

Family studies involve the selection of affected individuals from a disease registry who provide right-truncated ages of disease onset. Coarsened disease histories are then obtained from consenting family members, either through examining medical records, retrospective reporting, or clinical examination. Methods for dealing with such biased sampling schemes are available for continuous, binary, and failure time responses, but methods for more complex life history processes are less developed. We consider a simple joint model for clustered illness-death processes which we formulate to study covariate effects on the marginal intensity for disease onset and to study the within-family dependence in disease onset times. We construct likelihoods and composite likelihoods for family data obtained from biased sampling schemes. In settings where the disease is rare and data are insufficient to fit the model of interest, we show how auxiliary data can augment the composite likelihood to facilitate estimation. We apply the proposed methods to analyze data from a family study of psoriatic arthritis carried out at the University of Toronto Psoriatic Arthritis Registry.

Estimation and inference for the population attributable risk in the presence of misclassification.

Because it describes the proportion of disease cases that could be prevented if an exposure were entirely eliminated from a target population as a result of an intervention, estimation of the population attributable risk (PAR) has become an important goal of public health research. In epidemiologic studies, categorical covariates are often misclassified. We present methods for obtaining point and interval estimates of the PAR and the partial PAR (pPAR) in the presence of misclassification, filling an important existing gap in public health evaluation methods. We use a likelihood-based approach to estimate parameters in the models for the disease and for the misclassification process, under main study/internal validation study and main study/external validation study designs, and various plausible assumptions about transportability. We assessed the finite sample perf ormance of this method via a simulation study, and used it to obtain corrected point and interval estimates of the pPAR for high red meat intake and alcohol intake in relation to colorectal cancer incidence in the HPFS, where we found that the estimated pPAR for the two risk factors increased by up to 317% after correcting for bias due to misclassification.

Risk of Metachronous Colorectal Advanced Neoplasia and Cancer in Patients With 3-4 Nonadvanced Adenomas at Index Colonoscopy: A Systematic Review and Meta-Analysis.

INTRODUCTION: This systematic review and meta-analysis evaluated the available evidence on the risk of metachronous advanced neoplasia (AN) and colorectal cancer (CRC) in patients with 3-4 nonadvanced adenomas (NAAs). METHODS: We searched MEDLINE, EMBASE, and Cochrane Library databases up to January 2021 for studies evaluating metachronous AN and CRC risk by comparing 3 groups (1-2 vs 3-4 vs ≥5 NAAs) at index colonoscopy. The estimates for risk of metachronous AN and CRC were evaluated using random-effects models. RESULTS: Fifteen studies (n = 36,375) were included. The risk of metachronous AN was significantly higher in the 3-4 NAAs group than in the 1-2 NAAs group (relative risk [RR] 1.264, 95% confidence interval [CI] 1.053-1.518, P = 0.012; I2 = 0%); there was no difference between the ≥ 5 NAAs and 3-4 NAAs groups (RR 1.962, 95% CI 0.972-3.958, P = 0.060; I2 = 68%). The risks of metachronous CRC between the 1-2 NAAs and 3-4 NAAs groups (RR 2.663, 95% CI 0.391-18.128, P = 0.317; I2 = 0%) or the 3-4 NAAs and ≥ 5 NAAs groups (RR 1.148, 95% CI 0.142-9.290, P = 0.897; I2 = 0%) were not significantly different. DISCUSSION: Although the risk of metachronous AN was greater in the 3-4 NAAs group than in the 1-2 NAAs group, the risk of metachronous AN and CRC between the 3-4 NAAs and ≥ 5 NAAs groups was not different. This suggests that further studies on metachronous AN and CRC risk in the 3-4 NAAs group are warranted to confirm a firm ≥5-year interval surveillance colonoscopy.

Small sessile serrated polyps might not be at a higher risk for future advanced neoplasia than low-risk adenomas or polyp-free groups.

BACKGROUND: Polypectomy surveillance colonoscopy is recommended according to the risk stratification of initially removed polyps. This study aimed to evaluate the risk of advanced neoplasia following low-risk SSPs compared with that following LRAs and polyp-free groups. MATERIALS AND METHODS: From September 2013 to August 2017, asymptomatic Koreans aged 50-75 years who underwent surveillance colonoscopy post-baseline colonoscopy were enrolled. The 1314 participants who met the study design criteria were stratified into three groups according to the presence of LRAs or low-risk SSPs. The rate of advanced neoplasia was then compared between groups by surveillance colonoscopy. RESULTS: A total of 1314 participants were classified according to baseline colonoscopy findings: no polyp (n = 551), LRA (n = 707), and low-risk SSP (n = 56). All participants underwent surveillance colonoscopy after an average of 28.1 ± 8.7 months. The rate of advanced neoplasia at surveillance was not different between groups: no polyp group (13/551, 2.4%), LRA group (27/707, 3.8%), and low-risk SSP group (0/56, 0%). The LRA group exhibited a significantly higher rate of low- and high-risk polyps (47.5, 13.4%) than did the no polyp (35.6, 7.4%, p < .001, p = .001), but no significant differences to the low-risk SSP group (35.7, 7.1%, p = .117, p = .253), respectively. CONCLUSIONS: Patients with low-risk SSPs were not at a higher risk of advanced neoplasia than LRA patients, even in the polyp-free group. We suggest that surveillance colonoscopy after the removal of low-risk SSPs is not required more often than for LRAs.

Comparative analysis of background EEG activity based on MRI findings in neonatal hypoxic-ischemic encephalopathy: a standardized, low-resolution, brain electromagnetic tomography (sLORETA) study.

BACKGROUND: It is important to assess the degree of brain injury and predict long-term outcomes in neonates diagnosed with hypoxic-ischemic encephalopathy (HIE). However, routine studies, including magnetic resonance imaging (MRI) and conventional encephalography (EEG) or amplitude-integrated EEG (aEEG), have their own limitations in terms of availability and accuracy of evaluation. Recently, quantitative EEG (qEEG) has been shown to improve the predictive reliability of neonatal HIE and has been further refined with brain mapping techniques. METHODS: We investigated background EEG activities in 29 neonates with HIE who experienced therapeutic hypothermia, via qEEG using a distributed source model. MRI images were evaluated and classified into two groups (normal-to-mild injury vs moderate-to-severe injury), based on a scoring system. Non-parametric statistical analysis using standardized low-resolution brain electromagnetic tomography was performed to compare the current density distribution of four frequency bands (delta, theta, alpha, and beta) between the two groups. RESULTS: Electrical neuronal activities were significantly lower in the moderate-to-severe injury group compared with the normal-to-mild injury group. Background EEG activities in moderate-to-severe HIE were most significantly reduced in the temporal and parietal lobes. Quantitative EEG also revealed a decrease in background activity at all frequency bands, with a maximum in decrease in the delta component. The maximum difference in current density was found in the inferior parietal lobule of the right parietal lobe for the delta frequency band. CONCLUSIONS: Our study demonstrated quantitative and topographical changes in EEG in moderate-to-severe neonatal HIE. They also suggest possible implementation and evaluation of conventional EEG and aEEG in neonatal HIE. The findings have implications as biomarkers in the assessment of neonatal HIE.

Comparative analysis of background EEG activity in juvenile myoclonic epilepsy during valproic acid treatment: a standardized, low-resolution, brain electromagnetic tomography (sLORETA) study.

BACKGROUND: By definition, the background EEG is normal in juvenile myoclonic epilepsy (JME) patients and not accompanied by other developmental and cognitive problems. However, some recent studies using quantitative EEG (qEEG) reported abnormal changes in the background activity. QEEG investigation in patients undergoing anticonvulsant treatment might be a useful approach to explore the electrophysiology and anticonvulsant effects in JME. METHODS: We investigated background EEG activity changes in patients undergoing valproic acid (VPA) treatment using qEEG analysis in a distributed source model. In 17 children with JME, non-parametric statistical analysis using standardized low-resolution brain electromagnetic tomography was performed to compare the current density distribution of four frequency bands (delta, theta, alpha, and beta) between untreated and treated conditions. RESULTS: VPA reduced background EEG activity in the low-frequency (delta-theta) bands across the frontal, parieto-occipital, and limbic lobes (threshold log-F-ratio = ±1.414, p < 0.05; threshold log-F-ratio= ±1.465, p < 0.01). In the delta band, comparative analysis revealed significant current density differences in the occipital, parietal, and limbic lobes. In the theta band, the analysis revealed significant differences in the frontal, occipital, and limbic lobes. The maximal difference was found in the delta band in the cuneus of the left occipital lobe (log-F-ratio = -1.840) and the theta band in the medial frontal gyrus of the left frontal lobe (log-F-ratio = -1.610). CONCLUSIONS: This study demonstrated the anticonvulsant effects on the neural networks involved in JME. In addition, these findings suggested the focal features and the possibility of functional deficits in patients with JME.

Nondestructive versus advanced post-transplant lymphoproliferative disorder in a single-center pediatric kidney transplant population.

BACKGROUND: Pediatric kidney transplant recipients are at risk for the development of post-transplant lymphoproliferative disorders (PTLD), a group of potentially devastating diseases that present on a spectrum of severity ranging from nondestructive PTLD to more histologically destructive lesions. Currently, there is inadequate evidence to guide evaluation and management of nondestructive PTLD. METHODS: This is a single-center case series of pediatric kidney transplant recipients between January 1, 2008 and December 31, 2019, who were diagnosed with PTLD. The aim was to describe clinical characteristics, presentation, and management of nondestructive versus advanced PTLD. RESULTS: Eighteen patients were diagnosed with nondestructive PTLD and seven with more advanced PTLD histopathology. The majority (66.7%) of nondestructive PTLD patients (n = 16) presented with tonsillar hypertrophy and/or snoring and were managed conservatively, with minimal reduction in tacrolimus dose and no further evaluation. No patient progressed to more advanced PTLD. Advanced PTLD patients (n = 7) were more likely to present with fever, elevated creatinine, a new mass of gastrointestinal symptoms. They received workup with imaging and oncology consultation, and were managed with chemotherapy. CONCLUSIONS: Patients with nondestructive PTLD often present with symptoms of sleep-disordered breathing and can be managed conservatively with excellent clinical outcomes. More study is needed to guide care of this under-researched population.