Successful Sequential Liver and Isolated Intestine Transplantation for Mitochondrial Neurogastrointestinal Encephalopathy Syndrome: A Case Report.

BACKGROUND Mitochondrial neurogastrointestinal encephalopathy syndrome (MNGIE) is an autosomal recessive disease caused by thymidine phosphorylase deficiency leading to progressive gastrointestinal dysmotility, cachexia, ptosis, ophthalmoparesis, peripheral neuropathy and leukoencephalopathy. Although liver transplantation corrects thymidine phosphorylase deficiency, intestinal deficiency of the enzyme persists. Retrospective chart review was carried out to obtain clinical, biochemical, and pathological details. CASE REPORT We present a case of liver and subsequent intestine transplant in a 28-year-old man with MNGIE syndrome with gastrointestinal dysmotility, inability to walk, leukoencephalopathy, ptosis, cachexia, and elevated serum thymidine. To halt progression of neurologic deficit, he first received a left-lobe partial liver transplantation. Although his motor deficit improved, gastrointestinal dysmotility persisted, requiring total parenteral nutrition. After exhaustive intestinal rehabilitation, he was listed for intestine transplantation. Two-and-half years after liver transplantation, he received an intestine transplant. At 4 years after LT and 20 months after the intestine transplant, he remains off parenteral nutrition and is slowly gaining weight. CONCLUSIONS This is the first reported case of mitochondrial neurogastrointestinal encephalomyopathy to undergo successful sequential liver and intestine transplantation.

Methylated ctDNA Quantification: Noninvasive Approach to Monitoring Hepatocellular Carcinoma Burden.

BACKGROUND: Noninvasive, precision monitoring of hepatocellular carcinoma (HCC) treatment efficacy would greatly facilitate personalized therapy and improve patient outcomes. We hypothesize that quantifying methylated circulating tumor DNA (ctDNA) can be used to effectively monitor HCC burden without the need for biopsy. STUDY DESIGN: Blood samples were collected from 25 patients, 21 with HCC and 4 with benign liver masses, at various timepoints throughout the course of treatment at a high-volume academic medical center. Quantification of methylated ctDNA molecules assessed CpG sites on more than 550 preselected cancer-specific amplicons. The tumor methylation score (TMS) was calculated by measuring the difference between the amount of methylation in the plasma and buffy coat with a normal cutoff value of 120 or less. RESULTS: Among 10 patients with surgical HCC (5 surgical resections and 5 liver transplants), TMS revealed a statistically significant, rapid postoperative decline in 9. One patient who had a persistently elevated TMS on postoperative day 1 was subsequently found to have had metastatic disease. Patients in the negative control cohort all had normal-range pre- and postoperative TMS. Preoperative TMS correlated moderately with tumor burden on pathology (Spearman r = 0.54) of surgical specimens. From 11 subjects undergoing systemic therapy or Y90 radioembolization, analysis of 16 time periods demonstrated that the change in TMS (ΔTMS) was better associated with tumor progression than the change in Δalpha-fetoprotein (area under the curve 0.800 and 0.783, respectively). A composite score combining ΔTMS and Δalpha-fetoprotein further improved performance for detecting tumor progression with an area under the curve of 0.892. CONCLUSIONS: These findings indicate that ctDNA methylation scores can effectively evaluate changes in tumor burden without the need for tumor biopsy.

Effect of transcranial direct current stimulation on the functionality of 40 Hz auditory steady state response brain network: graph theory approach.

Introduction: Measuring whole-brain networks of the 40 Hz auditory steady state response (ASSR) is a promising approach to describe the after-effects of transcranial direct current stimulation (tDCS). The main objective of this study was to evaluate the effect of tDCS on the brain network of 40 Hz ASSR in healthy adult males using graph theory. The second objective was to identify a population in which tDCS effectively modulates the brain network of 40 Hz ASSR. Methods: This study used a randomized, sham-controlled, double-blinded crossover approach. Twenty-five adult males (20-24 years old) completed two sessions at least 1 month apart. The participants underwent cathodal or sham tDCS of the dorsolateral prefrontal cortex, after which 40 Hz ASSR was measured using magnetoencephalography. After the signal sources were mapped onto the Desikan-Killiany brain atlas, the statistical relationships between localized activities were evaluated in terms of the debiased weighted phase lag index (dbWPLI). Weighted and undirected graphs were constructed for the tDCS and sham conditions based on the dbWPLI. Weighted characteristic path lengths and clustering coefficients were then measured and compared between the tDCS and sham conditions using mixed linear models. Results: The characteristic path length was significantly lower post-tDCS simulation (p = 0.04) than after sham stimulation. This indicates that after tDCS simulation, the whole-brain networks of 40 Hz ASSR show a significant functional integration. Simple linear regression showed a higher characteristic path length at baseline, which was associated with a larger reduction in characteristic path length after tDCS. Hence, a pronounced effect of tDCS is expected for those who have a less functionally integrated network of 40 Hz ASSR. Discussion: Given that the healthy brain is functionally integrated, we conclude that tDCS could effectively normalize less functionally integrated brain networks rather than enhance functional integration.

Low vs Standard-Dose Indocyanine Green in the Identification of Biliary Anatomy Using Near-Infrared Fluorescence Imaging: A Multicenter Randomized Controlled Trial.

BACKGROUND: Near-infrared fluorescence imaging using intravenous indocyanine green (ICG) facilitates intraoperative identification of biliary anatomy. We hypothesize that a much lower dose of ICG than the standard decreases hepatic and background fluorescence and improves bile duct visualization. STUDY DESIGN: In this multicenter randomized controlled trial, 55 adult patients undergoing laparoscopic cholecystectomy were randomized to low-dose (0.05 mg) or standard-dose (2.5 mg) ICG preoperatively on the day of surgery. A quantitative assessment was performed on recorded videos from the operation using ImageJ software to quantify the fluorescence intensity of the bile duct, liver, and surrounding/background fat. Operating surgeons blinded to ICG dose provided a qualitative assessment of various aspects of the visualization of the extrahepatic biliary tree comparing near-infrared fluorescence to standard visible light imaging using a scale of 1 to 5 (1, unsatisfactory; 5, excellent). Quantitative and qualitative scores were compared between the groups to determine any significant differences between the doses. RESULTS: The bile duct-to-liver and bile duct-to-background fat fluorescence intensity ratios were significantly higher for the low-dose group compared with the standard-dose group (3.6 vs 0.68, p < 0.0001; and 7.5 vs 3.3, p < 0.0001, respectively). Low-dose ICG had a slightly higher (ie better) mean score on the qualitative assessment compared to the standard dose, although the differences were not statistically significant. CONCLUSIONS: Low-dose ICG leads to quantitative improvement of biliary visualization using near-infrared fluorescence imaging by minimizing liver fluorescence; this further facilitates routine use during hepatobiliary operations.

Alterations in brain networks in children with sub-threshold autism spectrum disorder: A magnetoencephalography study.

Individuals with sub-threshold autism spectrum disorder (ASD) are those who have social communication difficulties but do not meet the full ASD diagnostic criteria. ASD is associated with an atypical brain network; however, no studies have focused on sub-threshold ASD. Here, we used the graph approach to investigate alterations in the brain networks of children with sub-threshold ASD, independent of a clinical diagnosis. Graph theory is an effective approach for characterizing the properties of complex networks on a large scale. Forty-six children with ASD and 31 typically developing children were divided into three groups (i.e., ASD-Unlikely, ASD-Possible, and ASD-Probable groups) according to their Social Responsiveness Scale scores. We quantified magnetoencephalographic signals using a graph-theoretic index, the phase lag index, for every frequency band. Resultantly, the ASD-Probable group had significantly lower small-worldness (SW) in the delta, theta, and beta bands than the ASD-Unlikely group. Notably, the ASD-Possible group exhibited significantly higher SW than the ASD-Probable group and significantly lower SW than the ASD-Unlikely group in the delta band only. To our knowledge, this was the first report of the atypical brain network associated with sub-threshold ASD. Our findings indicate that magnetoencephalographic signals using graph theory may be useful in detecting sub-threshold ASD.

Development and Characterization of Human Primary Cholangiocarcinoma Cell Lines.

Cholangiocarcinoma (CCA) is the second most common primary liver tumor and is associated with late diagnosis, limited treatment options, and a 5-year survival rate of around 30%. CCA cell lines were first established in 1971, and since then, only 70 to 80 CCA cell lines have been established. These cell lines have been essential in basic and translational research to understand and identify novel mechanistic pathways, biomarkers, and disease-specific genes. Each CCA cell line has unique characteristics, reflecting a specific genotype, sex-related properties, and patient-related signatures, making them scientifically and commercially valuable. CCA cell lines are crucial in the use of novel technologies, such as three-dimensional organoid models, which help to model the tumor microenvironment and cell-to-cell crosstalk between tumor-neighboring cells. This review highlights crucial information on CCA cell lines, including: i) type of CCA (eg, intra- or extrahepatic), ii) isolation source (eg, primary tumor or xenograft), iii) chemical digestion method (eg, trypsin or collagenase), iv) cell-sorting method (colony isolation or removal of fibroblasts), v) maintenance-medium choice (eg, RPMI or Dulbecco's modified Eagle's medium), vi) cell morphology (eg, spindle or polygonal shape), and vii) doubling time of cells.

Trans-Pacific class transmission over a standard cladding ultralow-loss 4-core fiber.

The total capacity of optical submarine cable systems as a global communication infrastructure must be continuously enlarged. Multi-core fibers (MCFs) have been studied as methods to maximize the total cable capacity under electrical power and cable space limitations. In particular, standard cladding MCFs, which are expected to have high productivity and mechanical reliability, are attractive for early deployment in submarine cable systems. In this paper, we demonstrate high-capacity trans-Pacific class transmission using standard cladding uncoupled 4-core fibers, achieving a transmission capacity of 55.94 Tbit/s over 12,040 km. In addition, based on the results of this and our previous coupled MCF transmission experiments, we summarize the characteristics of coupled and uncoupled MCFs applied to optical submarine cable systems.

Liver Transplantation in Recipients With Class III Obesity: Posttransplant Outcomes and Weight Gain.

BACKGROUND: There has been a dramatic increase in obesity in the United States. Several studies have reported conflicting results for the impact of obesity on outcomes of liver transplantation (LT). This study aims to assess the impact of obesity on LT and changes in body mass index (BMI) after transplantation. METHODS: All adult LTs performed at Indiana University between 2001 and 2018 were reviewed. BMIs of recipients were subdivided into 6 categories. Survival outcomes were compared across the subgroup. BMI was followed up in a cohort of patients from 2008 to 2018. RESULTS: Among 2024 patients, 25% were in class I obesity, 9.3% were in class II obesity, and 1.1% were in class III obesity. There was no significant difference in patient and graft survival at 10-y follow-up with respect to BMI. Among 1004 patients in the subgroup, BMI of all groups except the underweight group declined in the first 3 mo postoperatively; however, the BMI of all groups except the class III obesity group returned to the pre-LT level by 2 y and reached a plateau by 5 y. In the class III obesity group, there was a significant increase in body weight at 5 y. CONCLUSIONS: Class III obesity was not associated with higher mortality in our cohort. Because our cohort is small, it may be underpowered to detect a smaller difference in outcome. From our observation, obesity should not be considered a contraindication for LT. Post-LT interventions are required to prevent significant weight gain for the class III obesity group.

A common variant of CNTNAP2 is associated with sub-threshold autistic traits and intellectual disability.

Sub-threshold autistic traits are common in the general population. Children with sub-threshold autistic traits have difficulties with social adaptation. Contactin-associated protein-like 2 (CNTNAP2) is associated with the development of Autism spectrum disorder (ASD) and the single-nucleotide polymorphism rs2710102 (G/A) of CNTNAP2 is suggested to contribute to sub-threshold social impairments and intellectual disabilities. We recruited 67 children with Autistic disorder (AD) (49 boys, 18 girls, aged 38-98 months) and 57 typically developing (TD) children (34 boys, 23 girls, aged 53-90 months). We assessed the participants' intelligence and social reciprocity using the Kaufman Assessment Battery for Children (K-ABC) and the Social Responsiveness Scale (SRS), respectively. Genomic DNA was extracted from the buccal mucosa and genotyped for rs2710102. A chi-square test revealed a significant association between genotype and group [χ2(2) = 6.56, p = 0.038]. When a co-dominant model was assumed, the results from linear regression models demonstrated that TD children with A-carriers (AA + AG) presented higher SRS T-scores [t(55) = 2.11, p = 0.039] and lower simultaneous processing scale scores of K-ABC [t(55) = -2.19, p = 0.032] than those with GG homozygotes. These associations were not significant in children with ASD. TD children with the rs2710102 A-allele may have more sub-threshold autistic traits than those with GG homozygotes, reflected in higher SRS scores and lower simultaneous processing scale scores. These results support the use of genetic evidence to detect sub-threshold autistic traits.

Atypical Resting State Functional Neural Network in Children With Autism Spectrum Disorder: Graph Theory Approach.

Measuring whole brain networks is a promising approach to extract features of autism spectrum disorder (ASD), a brain disorder of widespread regions. Objectives of this study were to evaluate properties of resting-state functional brain networks in children with and without ASD and to evaluate their relation with social impairment severity. Magnetoencephalographic (MEG) data were recorded for 21 children with ASD (7 girls, 60-89 months old) and for 25 typically developing (TD) control children (10 girls, 60-91 months old) in a resting state while gazing at a fixation cross. After signal sources were localized onto the Desikan-Killiany brain atlas, statistical relations between localized activities were found and evaluated in terms of the phase lag index. After brain networks were constructed and after matching with intelligence using a coarsened exact matching algorithm, ASD and TD graph theoretical measures were compared. We measured autism symptoms severity using the Social Responsiveness Scale and investigated its relation with altered small-worldness using linear regression models. Children with ASD were found to have significantly lower small-worldness in the beta band (p = 0.007) than TD children had. Lower small-worldness in the beta band of children with ASD was associated with higher Social Responsiveness Scale total t-scores (p = 0.047). Significant relations were also inferred for the Social Awareness (p = 0.008) and Social Cognition (p = 0.015) sub-scales. Results obtained using graph theory demonstrate a difference between children with and without ASD in MEG-derived resting-state functional brain networks, and the relation of that difference with social impairment. Combining graph theory and MEG might be a promising approach to establish a biological marker for ASD.

Spatial-light-modulator-based optical-fiber joint switch for few-mode multicore fibers.

To realize simplified cost-efficient optical networks with routing flexibility and scaling potential, a spatial-light-modulator-based optical-fiber joint switch for few-mode multicore fibers is proposed herein, which can route all spatial channels together as a unit. Numerical simulations and experiments were performed, and the results show that the signal paths for a 6-mode 19-core fiber can be simultaneously switched to the target output ports using the proposed method, and the mode-field patterns of the diffracted light can be maintained after joint switching. Further, the maximum port crosstalk can be reduced considerably from -11.6 to -25.1 dB by changing the position of the output port in the proposed method.

Epileptiform discharges relate to altered functional brain networks in autism spectrum disorders.

Many individuals with autism spectrum disorders have comorbid epilepsy. Even in the absence of observable seizures, interictal epileptiform discharges are common in individuals with autism spectrum disorders. However, how these interictal epileptiform discharges are related to autistic symptomatology remains unclear. This study used magnetoencephalography to investigate the relation between interictal epileptiform discharges and altered functional brain networks in children with autism spectrum disorders. Instead of particularly addressing individual brain regions, we specifically examine network properties. For this case-control study, we analysed 70 children with autism spectrum disorders (52 boys, 18 girls, 38-92 months old) and 19 typically developing children (16 boys, 3 girls, 48-88 months old). After assessing the participants' social reciprocity using the Social Responsiveness Scale, we constructed graphs of functional brain networks from frequency band separated task-free magnetoencephalography recordings. Nodes corresponded to Desikan-Killiany atlas-based 68 brain regions. Edges corresponded to phase lag index values between pairs of brain regions. To elucidate the effects of the existence of interictal epileptiform discharges on graph metrics, we matched each of three pairs from three groups (typically developing children, children with autism spectrum disorders who had interictal epileptiform discharges and those who did not) in terms of age and sex. We used a coarsened exact matching algorithm and applied adjusted regression analysis. We also investigated the relation between social reciprocity and the graph metric. Results show that, in children with autism spectrum disorders, the average clustering coefficient in the theta band was significantly higher in children who had interictal epileptiform discharges. Moreover, children with autism spectrum disorders who had no interictal epileptiform discharges had a significantly lower average clustering coefficient in the theta band than typically developing children had. However, the difference between typically developing children and children with autism spectrum disorder who had interictal epileptiform discharges was not significant. Furthermore, the higher average clustering coefficient in the theta band corresponded to severe autistic symptoms in children with autism spectrum disorder who had interictal epileptiform discharges. However, the association was not significant in children with autism spectrum disorders who had no interictal epileptiform discharge. In conclusion, results demonstrate that alteration of functional brain networks in children with autism spectrum disorders depends on the existence of interictal epileptiform discharges. Interictal epileptiform discharges might 'normalize' the deviation of altered brain networks in autism spectrum disorders, increasing the clustering coefficient. However, when the effect exceeds tolerance, it actually exacerbates autistic symptoms.

Distal allograft pancreatectomy for graft salvage after pancreas transplantation.

Early pancreas allograft failure most commonly results from vascular thrombosis. Immediate surgical intervention may permit pancreas allograft salvage, typically requiring thrombectomy. In cases of partial allograft necrosis secondary to splenic arterial thrombosis, distal allograft pancreatectomy may allow salvage of at least half of the pancreas allograft with retention of function. We retrospectively reviewed four cases of simultaneous pancreas and kidney recipients who required distal allograft pancreatectomy for splenic artery thrombosis with necrosis of the distal pancreas. Three of the four maintained long-term allograft function with euglycemia independent of insulin at six months to six years of follow-up, and all patients continue to maintain normal renal allograft function. Early diagnosis and early intervention are essential in order to salvage the pancreas allograft in the case of thrombosis. Distal allograft pancreatectomy can be performed safely and result in excellent long-term outcomes in select patients.

Donor-recipient body size mismatch has no impact on outcomes after deceased donor whole liver transplantation: Role of donor liver size measurement.

The role of donor-recipient body size mismatch (DRSM) on outcomes after whole liver transplantation (LT) is not clearly defined. At our center, in presence of considerable DRSM, objective assessment of the donor liver by a radiology or intraoperative evaluation by procuring surgeon was incorporated. To evaluate the impact of DRSM on graft outcomes with this approach, adult deceased donor whole liver transplants between July 2001 and December 2017 at our center were studied. DRSM was considered when the donor-recipient body surface area (BSA) ratio (DR-BSAr) was either <0.69 or >1.25. There were 54 (3.2%) transplants with DR-BSAr <0.69 and 61 (3.6%) with DR-BSAr >1.25. One-year graft survival was 85% vs. 89% vs. 89%; (p = .64) for transplants with DR-BSArs of <0.69, 0.69-1.25, and >1.25, respectively. Early allograft dysfunction (EAD) (28% vs. 27% vs. 37%; p = .07), post-transplant coagulopathy, bilirubinemia, and renal function were also comparable. In conclusion, with the actual measurement of the donor liver and recipient abdominal cavity, significant DRSM did not have a negative impact on early and long-term outcomes. Routine measurement of donor liver size by radiology may be incorporated in liver allocation to improve utilization.

Impact of Recipient Age in Combined Liver-Kidney Transplantation: Caution Is Needed for Patients ≥70 Years.

Elderly recipients (≥70 y) account for 2.6% of all liver transplants (LTs) in the United States and have similar outcomes as younger recipients. Although the rate of elderly recipients in combined liver-kidney transplant (CLKT) is similar, limited data are available on how elderly recipients perform after CLKT. METHODS: We have previously shown excellent outcomes in CLKT using delayed kidney transplant (Indiana) Approach (mean kidney cold ischemia time = 53 ± 14 h). Between 2007 and 2018, 98 CLKTs were performed using the Indiana Approach at Indiana University (IU) and the data were retrospectively analyzed. Recipients were subgrouped based on their age: 18-45 (n = 16), 46-59 (n = 34), 60-69 (n = 40), and ≥70 years (n = 8). RESULTS: Overall, more elderly patients received LT at IU (5.2%) when compared nationally (2.6%). The rate of elderly recipients in CLKT at IU was 8.2% (versus 2% Scientific Registry of Transplant Recipient). Recipient and donor characteristics were comparable between all age groups except recipient age and duration of dialysis. Patient survival at 1 and 3 years was similar among younger age groups, whereas patient survival was significantly lower in elderly recipients at 1 (60%) and 3 years (40%) (P = 0.0077). Control analyses (replicating Scientific Registry of Transplant Recipient's survival stratification: 18-45, 46-64, ≥65 y) showed similar patient survival in all age groups. CONCLUSIONS: Although LT can be safely performed in elderly recipients, extreme caution is needed in CLKT due to the magnitude of operation.

Different associations between intelligence and social cognition in children with and without autism spectrum disorders.

Autism spectrum disorders (ASD) are characterized by impaired social cognition and communication. In addition to social impairment, individuals with ASD often have intellectual disability. Intelligence is known to influence the phenotypic presentation of ASD. Nevertheless, the relation between intelligence and social reciprocity in people with ASD remains unclear, especially in childhood. To elucidate this relation, we analyzed 56 typically developing children (35 male, 21 female, aged 60-91 months) and 46 children with ASD (35 male, 11 female, aged 60-98 months) from university and affiliated hospitals. Their cognitive function was evaluated using the Kaufman Assessment Battery for Children. Their social cognition was assessed using the Social Responsiveness Scale. We used linear regression models to ascertain whether the associations between intelligence and social cognition of typically developing children and children with ASD are significantly different. Among the children with ASD, scores on the Kaufman Assessment Battery for Children correlated significantly with social cognition, indicating that higher intelligence is associated with better social cognition. For typically developing children, however, no significant correlation was found. One explanation might be that children with ASD fully use general intelligence for successful learning in social cognition, although extensive use of intelligence might not be necessary for TD children. Alternatively, autistic impairment in social cognition can be compensated by intelligence despite a persistent deficit in social cognition. In either case, when using the SRS as a quantitative phenotype measure for ASD, the influence of intelligence must be considered.

Isolated Intestine Transplantation for Autoimmune Enteropathy: A Case Report.

Autoimmune enteropathy is a rare disease characterized by chronic watery diarrhea, weight loss, and immune-mediated injury of the enterocolic mucosa. The clinicopathologic findings of this disease are variable, and timely diagnosis is challenging. It is usually managed medically. If medical management fails, surgical intervention is considered. This is a case report of a patient with autoimmune enteropathy mimicking collagenous enterocolitis. A 55-year-old man developed intestinal failure that manifested as profuse watery diarrhea, electrolyte disturbances, and weight loss. Initially, he was diagnosed with collagenous enterocolitis based on pathologic findings. Medical interventions were started, but the patient failed to show improvement. At 13 months after the onset of the disease, he was listed for isolated intestine transplantation (IITX) for intestinal failure. A healthy donor graft became available. IITX with chimney colostomy was performed. Based on the pathologic findings of the excised native small intestine, the patient was diagnosed with severe autoimmune enteropathy. The postoperative course was uneventful. By the third postoperative week, a full diet was tolerated and parenteral nutrition (PN) was weaned to end. He was discharged on postoperative day 34. Since discharge, he has been off PN, remaining on an enteral diet. This case is the first reported IITX performed on a patient with severe autoimmune enteropathy that was both curative and lifesaving. The present case confirms that IITX promptly restores gastrointestinal absorption in medically refractory autoimmune enteropathy. This observation provides clinicians with an effective treatment option in this challenging group of patients.

Weakly coupled 10-mode-division multiplexed transmission over 48-km few-mode fibers with real-time coherent MIMO receivers.

For weakly coupled mode-division multiplexed (MDM) transmission systems, we design and implement optical coherent receiver prototypes with real-time multiple-input multiple-output (MIMO) digital signal processing to equalize two degenerate linearly polarized modes with dual polarization. Using field programmable gate array circuits, we implement real-value 8 × 2 MIMO adaptive equalization with externally separated phase compensators based on the least mean square algorithm, which enables not only training equalization but also fast carrier-phase tracking. With the optical coherent MIMO receiver prototype, we demonstrate real-time weakly coupled 10 × MDM wavelength-division multiplexed dual-polarization quadrature phase shift keying transmission over 48-km few-mode fibers. This report shows a record number of multiplexed spatial modes, namely, 10 modes with dual polarization, in real-time MDM transmission experiments.