Foramen ovale electrode investigation in the era of SEEG: Results and a reappraisal.

INTRODUCTION: Patients with medication-resistant disabling epilepsy should be considered for potential epilepsy surgery. If noninvasive techniques are unable to identify the location of the seizure onset zone (SOZ), it becomes necessary to consider intracranial investigations. Stereo-electroencephalography (SEEG) is currently the preferred method for such monitoring, however foramen ovale (FO) electrodes offer a less invasive alternative that may be suitable in certain situations. Previous studies have demonstrated the effectiveness of FO electrodes in suspected mesial temporal epilepsy, nevertheless, increased experience with FO electrode use could further enhance their safety and efficacy. Therefore, we conducted an analysis of recent FO electrode investigations to assess their utility in surgical decision making, post resection outcomes, and complication rates. METHODS: We conducted a retrospective analysis of 61 patients who underwent FO placement at Mass General Brigham between 2009 and 2020. Patient and seizure characteristics, preoperative investigation data, and seizures outcomes were collected. In addition, identified predictors of FO utility using logistic regression. RESULTS: A total of 61 patients were identified. FO evaluation localized the SOZ in 56 % of patients. Complications were encountered in 1.6 % of patients. Subsequent surgical resection was pursued by 49 % of patients, with 56 % becoming seizure free, and 67 % having favorable seizure outcomes at last follow-up. Multivariate analysis identified younger patients with a higher number of preoperative ASMs as more likely to undergo subsequent treatment, however, these features were not predictive features of SOZ localization, seizure freedom, or favorable seizure outcomes. In patients with bitemporal or cross-over onsets on scalp EEG, FO was able to identify the SOZ in 79 %, whereas in patients with discordant or unclear onset, the rates were 71 % and 45 %, respectively. CONCLUSION: In a contemporary cohort, FO electrode placement had a low complication rate and a high utility primarily in cases of unclear laterality of mesial temporal onsets or discordance between scalp EEG and other pre-FO investigation data in cases of suspected mesial temporal onsets.

Cost modelling rehabilitation in the home for reconditioning in the Australian context.

BACKGROUND: Inpatient rehabilitation services are challenged by increasing demand. Where appropriate, a shift in service models towards more community-oriented approaches may improve efficiency. We aimed to estimate the hypothetical cost of delivering a consensus-based rehabilitation in the home (RITH) model as hospital substitution for patients requiring reconditioning following medical illness, surgery or treatment for cancer, compared to the cost of inpatient rehabilitation. METHODS: Data were drawn from the following sources: the results of a Delphi survey with health professionals working in the field of rehabilitation in Australia; publicly available data and reports; and the expert opinion of the project team. Delphi survey data were analysed descriptively. The costing model was developed using assumptions based on the sources described above and was restricted to the Australian National Subacute and Non-Acute Patient Classification (AN-SNAP) classes 4AR1 to 4AR4, which comprise around 73% of all reconditioning episodes in Australia. RITH cost modelling estimates were compared to the known cost of inpatient rehabilitation. Where weighted averages are provided, these were determined based on the modelled number of inpatient reconditioning episodes per annum that might be substitutable by RITH. RESULTS: The cost modelling estimated the weighted average cost of a RITH reconditioning episode (which mirrors an inpatient reconditioning episode in intensity and duration) for AN-SNAP classes 4AR1 to 4AR4, to be A$11,371, which is 28.1% less than the equivalent weighted average public inpatient cost (of A$15,820). This represents hypothetical savings of A$4,449 per RITH reconditioning substituted episode of care. CONCLUSIONS: The hypothetical cost of a model of RITH which would provide patients with as comprehensive a rehabilitation service as received in inpatient rehabilitation, has been determined. Findings suggest potential cost savings to the public hospital sector. Future research should focus on trials which compare actual clinical and cost outcomes of RITH for patients in the reconditioning impairment category, to inpatient rehabilitation.

Mid- and long-term outcomes after surgical correction of subaortic stenosis: a 27-year experience.

OBJECTIVES: We reviewed the mid- and long-term surgical outcomes of patients with subaortic stenosis (SAS). METHODS: Patients operated for SAS from April 1990 to August 2016 were reviewed retrospectively. Patients with major associations such as aortic arch obstruction were excluded. Time to reintervention and predictors of recurrence were assessed using Kaplan-Meier analysis, log-rank test and uni/multivariable Cox regression. RESULTS: 120 patients at a median age of 4.7 years (interquartile range 2.9, 8.1) underwent primary operation (median peak preoperative left ventricular outflow tract gradient 52.5 mmHg, interquartile range 40, 70) involving fibrous tissue excision (n = 120) with septal myectomy (93%; n = 112) as the procedure of choice.At median follow-up of 13 years (interquartile range 7, 18), freedom from reintervention at 1, 3, 5 and 10 years was 99% (95% confidence interval 94%, 99%), 94% (87%, 97%), 93% (86%, 96%) and 90% (82%, 94%), respectively. Recurrence occurred in 18% (n = 20) with 15 patients undergoing reinterventions, 13 of whom required radical reoperation. Multivariable analysis revealed higher preoperative peak left ventricular outflow tract gradient (hazard risk 1.06, confidence interval 1.03, 1.09, P < 0.001), and presence of bicuspid aortic valve (hazard risk 14.13, confidence interval 3.32, 60.1, P < 0.001) as predictors for reintervention. Mild/moderate aortic regurgitation occurred in 49% (n = 55) of patients at the most recent follow-up. CONCLUSIONS: Reintervention for recurrent SAS is common, predicted by higher preoperative peak left ventricular outflow tract gradient, and presence of bicuspid aortic valve, and frequently involves a radical procedure. Aortic regurgitation is a major consequence of SAS, but its severity usually remains low. CLINICAL REGISTRATION NUMBER: SCHN HREC reference number 2019/ETH02729, approved on 09 July 2019.

The complexities underlying epilepsy in people with glioblastoma.

Seizures are among the most common clinical signs in people with glioblastoma. Advances over the past 5 years, including new clinical trial data, have increased the understanding of why some individuals with glioblastoma are susceptible to seizures, how seizures manifest clinically, and what implications seizures have for patient management. The pathophysiology of epilepsy in people with glioblastoma relates to a combination of intrinsic epileptogenicity of tumour tissue, alterations in the tumour and peritumoural microenvironment, and the physical and functional disturbance of adjacent brain structures. Successful management of epilepsy in people with glioblastoma remains challenging; factors such as drug-drug interactions between cancer therapies and antiseizure medications, and medication side-effects, can affect seizure outcomes and quality of life. Advances in novel therapies provide some promise for people with glioblastoma; however, the effects of these therapies on seizures are yet to be fully determined. Looking forward, insights into electrical activity as a driver of tumour cell growth and the intrinsic hyperexcitability of tumour tissue might represent useful targets for treatment and disease modification. There is a pressing need for large randomised clinical trials in this field.

Developing a model for rehabilitation in the home as hospital substitution for patients requiring reconditioning: a Delphi survey in Australia.

BACKGROUND: Reconditioning for patients who have experienced functional decline following medical illness, surgery or treatment for cancer accounts for approximately 26% of all reported inpatient rehabilitation episodes in Australia. Rehabilitation in the home (RITH) has the potential to offer a cost-effective, high-quality alternative for appropriate patients, helping to reduce pressure on the acute care sector. This study sought to gain consensus on a model for RITH as hospital substitution for patients requiring reconditioning. METHODS: A multidisciplinary group of health professionals working in the rehabilitation field was identified from across Australia and invited to participate in a three-round online Delphi survey. Survey items followed the patient journey, and also included items on practitioner roles, clinical governance, and budgetary considerations. Survey items mostly comprised statements seeking agreement on 5-point Likert scales (strongly agree to strongly disagree). Free text boxes allowed participants to qualify item answers or make comments. Analysis of quantitative data used descriptive statistics; qualitative data informed question content in subsequent survey rounds or were used in understanding item responses. RESULTS: One-hundred and ninety-eight health professionals received an invitation to participate. Of these, 131/198 (66%) completed round 1, 101/131 (77%) completed round 2, and 78/101 (77%) completed round 3. Consensus (defined as ≥ 70% agreement or disagreement) was achieved on over 130 statements. These related to the RITH patient journey (including patient assessment and development of the care plan, case management and program provision, and patient and program outcomes); clinical governance and budgetary considerations; and included items for initial patient screening, patient eligibility and case manager roles. A consensus-based model for RITH was developed, comprising five key steps and the actions within each. CONCLUSIONS: Strong support amongst survey participants was found for RITH as hospital substitution to be widely available for appropriate patients needing reconditioning. Supportive legislative and payment systems, mechanisms that allow for the integration of primary care, and appropriate clinical governance frameworks for RITH are required, if broad implementation is to be achieved. Studies comparing clinical outcomes and cost-benefit of RITH to inpatient rehabilitation for patients requiring reconditioning are also needed.

The risk of subsequent surgery following bowel resection for Crohn's disease in a national cohort of 19 207 patients.

AIM: Surgery is required for most patients with Crohn's disease (CD) and further surgery may be necessary if medical treatment fails to control disease activity. The aim of this study was to characterize the risk of, and factors associated with, further surgery following a first resection for Crohn's disease. METHODS: Hospital Episode Statistics from England were examined to identify patients with CD and a first recorded bowel resection between 2007 and 2016. Multivariable logistic regression was used to examine risk factors for further resectional surgery within 5 years. Prevalence-adjusted surgical rates for index CD surgery over the study period were calculated. RESULTS: In total, 19 207 patients (median age 39 years, interquartile range 27-53 years; 55% women) with CD underwent a first recorded resection during the study period. 3141 (16%) underwent a further operation during the study period. The median time to further surgery was 2.4 (interquartile range 1.2-4.6) years. 3% of CD patients had further surgery within 1 year, 14% by 5 years and 23% by 10 years. Older age (≥58), index laparoscopic surgery and index elective surgery (adjusted OR 0.65, 95% CI 0.54-0.77; 0.77, 0.67-0.88; and 0.77, 0.69-0.85; respectively) were associated with a reduced risk of further surgery by 5 years. Prior surgery for perianal disease (1.60, 1.37-1.87), an extraintestinal manifestation of CD (1.51, 1.22-1.86) and index surgery in a high-volume centre for CD surgery (1.20, 1.02-1.40) were associated with an increased risk of further surgery by 5 years. A 25% relative and 0.3% absolute reduction in prevalence-adjusted index surgery rates for CD was observed over the study period. CONCLUSIONS: Further surgery following an index operation is common in CD. This risk was particularly seen in patients with perianal disease, extraintestinal manifestations and those who underwent index surgery in a high-volume centre.

mRNA vaccines induce rapid antibody responses in mice.

mRNA vaccines can be developed and produced quickly, making them prime candidates for immediate outbreak responses. Furthermore, clinical trials have demonstrated rapid protection following mRNA vaccination. Thus, we sought to investigate how quickly mRNA vaccines elicit antibody responses compared to other vaccine modalities. We first compared the immune kinetics of mRNA and DNA vaccines expressing SARS-CoV-2 spike in mice. We observed rapid induction of antigen-specific binding and neutralizing antibodies by day 5 following mRNA (4 µg/mouse), but not DNA (50 µg/mouse), immunization. Comparing innate responses hours post immunization, the mRNA vaccine induced increased levels of IL-5, IL-6, and MCP-1 cytokines which maybe promoting humoral responses downstream. We then evaluated the immune kinetics of an HIV-1 mRNA vaccine in comparison to DNA, protein, and rhesus adenovirus 52 (RhAd52) vaccines of the same HIV-1 envelope antigen in mice. Again, induction of envelope-specific antibodies was observed by day 5 following mRNA vaccination, whereas antibodies were detected by day 7-14 following DNA, protein, and RhAd52 vaccination. Thus, eliciting rapid humoral immunity may be a unique and advantageous property of mRNA vaccines for controlling infectious disease outbreaks.

Australian inpatient cancer rehabilitation as seen by patients receiving care pre and post intervention: Insights into unmet needs in the cancer and rehabilitation journey.

OBJECTIVE: The objective of this study is to explore both the negative and positive lived experiences of cancer survivors during specialist inpatient rehabilitation programmes. METHODS: This phenomenological study explored the negative and positive perspectives of cancer survivors with residual disability, during their inpatient rehabilitation. Semi-structured interviews conducted with 22 inpatients on admission and discharge were analysed using the protocols of Interpretative Phenomenological Analysis. RESULTS: Experiences of inpatient cancer rehabilitation were not independent of the whole cancer trajectory. Rather, for these inpatients, processing and ruminating upon challenges to self from the moment of cancer diagnosis and throughout treatments indicated that more emotional and psychosocial support may be useful throughout cancer rehabilitation and the whole cancer trajectory. CONCLUSION: Understanding the concurrent sources of psychological distress and growth in these cancer survivors as they recover from life changing events provides a unique consumer evaluation of an inpatient cancer rehabilitation service and the overall cancer experience. This study has implications for developing insight into the impact that the cancer trajectory has on the individual and reinforces the importance of a holistic approach to rehabilitation that includes a supported mind, body and spirit appreciation of healing.

Noninvasive Detection of Hippocampal Epileptiform Activity on Scalp Electroencephalogram.

Importance: The hippocampus is a highly epileptogenic brain region, yet over 90% of hippocampal epileptiform activity (HEA) cannot be identified on scalp electroencephalogram (EEG) by human experts. Currently, detection of HEA requires intracranial electrodes, which limits our understanding of the role of HEA in brain diseases. Objective: To develop and validate a machine learning algorithm that accurately detects HEA from a standard scalp EEG, without the need for intracranial electrodes. Design, Setting, and Participants: In this diagnostic study, conducted from 2008 to 2021, EEG data were used from patients with temporal lobe epilepsy (TLE) and healthy controls (HCs) to train and validate a deep neural network, HEAnet, to detect HEA on scalp EEG. Participants were evaluated at tertiary-level epilepsy centers at 2 academic hospitals: Massachusetts General Hospital (MGH) or Brigham and Women's Hospital (BWH). Included in the study were patients aged 12 to 78 years with a clinical diagnosis of TLE and HCs without epilepsy. Patients with TLE and HCs with a history of intracranial surgery were excluded from the study. Exposures: Simultaneous intracranial EEG and/or scalp EEG. Main Outcomes and Measures: Performance was assessed using cross-validated areas under the receiver operating characteristic curve (AUC ROC) and precision-recall curve (AUC PR) and additional clinically relevant metrics. Results: HEAnet was trained and validated using data sets that were derived from a convenience sample of 141 eligible participants (97 with TLE and 44 HCs without epilepsy) whose retrospective EEG data were readily available. Data set 1 included the simultaneous scalp EEG and intracranial electrode recordings of 51 patients with TLE (mean [SD] age, 40.7 [15.9] years; 30 men [59%]) at MGH. An automatically generated training data set with 972 095 positive HEA examples was created, in addition to a held-out expert-annotated testing data set with 22 762 positive HEA examples. HEAnet's performance was validated on 2 independent scalp EEG data sets: (1) data set 2 (at MGH; 24 patients with TLE and 20 HCs; mean [SD] age, 42.3 [16.2] years; 17 men [39%]) and (2) data set 3 (at BWH; 22 patients with TLE and 24 HCs; mean [SD] age, 43.0 [14.4] years; 20 men [43%]). For single-event detection of HEA on data set 1, HEAnet achieved a mean (SD) AUC ROC of 0.89 (0.01) and a mean (SD) AUC PR of 0.39 (0.03). On external validation with data sets 2 and 3, HEAnet accurately distinguished TLE from HC (AUC ROC of 0.88 and 0.95, respectively) and predicted epilepsy lateralization with 100% and 92% accuracy, respectively. HEAnet tracked dynamic changes in HEA in response to seizure medication adjustments and performed comparably with human experts in diagnosing TLE from 1-hour scalp EEG recordings, diagnosing TLE in several individuals that experts missed. Without reducing specificity, addition of HEAnet to human expert EEG review increased sensitivity for diagnosing TLE in humans from 50% to 58% to 63% to 67%. Conclusions and Relevance: Results of this diagnostic study suggest that HEAnet provides a novel, noninvasive, quantitative, and clinically relevant biomarker of hippocampal hyperexcitability in humans.

Aura Type and Outcome After Anterior Temporal Lobectomy.

OBJECTIVE: Temporal lobe epilepsy (TLE) is one of the most common causes of medically refractory focal epilepsy. Anterior temporal lobectomy (ATL) leads to improved seizure control in patients with medically refractory TLE. Various auras are associated with TLE; however, the relationships between aura type and outcome after ATL are poorly understood. Our objective was to investigate the associations among clinical features, aura type, and seizure outcome after ATL. METHODS: The records of patients who underwent ATL between 1993 and 2016 at a single institution (N = 174) were retrospectively reviewed. Demographic and clinical variables were compared among aura types using analysis of variance and logistic regression analysis. A multiple regression analysis was conducted to determine whether aura type predicted seizure outcome after ATL. RESULTS: Mesial temporal sclerosis (MTS) on magnetic resonance imaging inversely correlated with cephalic auras (P = 0.0090). Affective auras (P = 0.014) and somatosensory auras (P = 0.021) were correlated with findings of MTS on pathology, whereas this finding was inversely correlated with the presence of auditory auras (P = 0.0056). On multiple regression analysis, predictors of worse seizure outcome after ATL were cephalic auras (P = 0.0048), gustatory auras (P = 0.029), visual auras (P = 0.049), and tonic-clonic seizures (P = 0.047). Fewer preoperative antiepileptic medications (P = 0.0032), and presence of multiple auras (P = 0.011) were associated with better outcome. CONCLUSIONS: Cephalic auras, gustatory auras, and visual auras were associated with worse seizure outcome after ATL.

Smartwatch helps detects lung cancer: Using personal technology to advance healthcare.

The prevalence of smartwatches and other wearable medical technology has been increasing yearly. These watches offer a sensitive tool for capturing cardiac dysrhythmias and can lead to patients seeking earlier medical advice. This case report highlights the importance of clinicians seeking and using the information provided by wearable medical technology which in this case resulted in both the timely treatment of non-sustained ventricular tachycardia and lung adenocarcinoma.

Preclinical characterization of AB-506, an inhibitor of HBV replication targeting the viral core protein.

AB-506, a small-molecule inhibitor targeting the HBV core protein, inhibits viral replication in vitro (HepAD38 cells: EC50 of 0.077 µM, CC50 > 25 µM) and in vivo (HBV mouse model: ∼3.0 log10 reductions in serum HBV DNA compared to the vehicle control). Binding of AB-506 to HBV core protein accelerates capsid assembly and inhibits HBV pgRNA encapsidation. Furthermore, AB-506 blocks cccDNA establishment in HBV-infected HepG2-hNTCP-C4 cells and primary human hepatocytes, leading to inhibition of viral RNA, HBsAg, and HBeAg production (EC50 from 0.64 µM to 1.92 µM). AB-506 demonstrated activity across HBV genotypes A-H and maintains antiviral activity against nucleos(t)ide analog-resistant variants in vitro. Evaluation of AB-506 against a panel of core variants showed that T33N/Q substitutions results in >200-fold increase in EC50 values, while L30F, L37Q, and I105T substitutions showed an 8 to 20-fold increase in EC50 values in comparison to the wild-type. In vitro combinations of AB-506 with NAs or an RNAi agent were additive to moderately synergistic. AB-506 exhibits good oral bioavailability, systemic exposure, and higher liver to plasma ratios in rodents, a pharmacokinetic profile supporting clinical development for chronic hepatitis B.

mRNA Vaccines Induce Rapid Antibody Responses in Mice.

mRNA vaccines can be developed and produced quickly, making them attractive for immediate outbreak responses. Furthermore, clinical trials have demonstrated rapid protection following mRNA vaccination. We sought to investigate how quickly mRNA vaccines elicit antibody responses compared to other vaccine modalities. We first examined immune kinetics of mRNA and DNA vaccines expressing SARS-CoV-2 spike in mice. We observed rapid induction of antigen-specific binding and neutralizing antibodies by day 5 following mRNA, but not DNA, immunization. The mRNA vaccine also induced increased levels of IL-5, IL-6 and MCP-1. We then evaluated immune kinetics of an HIV-1 mRNA vaccine in comparison to DNA, protein, and rhesus adenovirus 52 (RhAd52) vaccines with the same HIV-1 envelope antigen in mice. Induction of envelope-specific antibodies was observed by day 5 following mRNA vaccination, whereas antibodies were detected by day 7-14 following DNA, protein, and RhAd52 vaccination. Eliciting rapid humoral immunity may be an advantageous property of mRNA vaccines for controlling infectious disease outbreaks. IMPORTANCE: mRNA vaccines can be developed and produced in record time. Here we demonstrate induction of rapid antibody responses by mRNA vaccines encoding two different viral antigens by day 5 following immunization in mice. The rapid immune kinetics of mRNA vaccines can be an advantageous property that makes them well suited for rapid control of infectious disease outbreaks.

Host Poly(A) Polymerases PAPD5 and PAPD7 Provide Two Layers of Protection That Ensure the Integrity and Stability of Hepatitis B Virus RNA.

Noncanonical poly(A) polymerases PAPD5 and PAPD7 (PAPD5/7) stabilize hepatitis B virus (HBV) RNA via the interaction with the viral posttranscriptional regulatory element (PRE), representing new antiviral targets to control HBV RNA metabolism, hepatitis B surface antigen (HBsAg) production, and viral replication. Inhibitors targeting these proteins are being developed as antiviral therapies; therefore, it is important to understand how PAPD5/7 coordinate to stabilize HBV RNA. Here, we utilized a potent small-molecule AB-452 as a chemical probe, along with genetic analyses to dissect the individual roles of PAPD5/7 in HBV RNA stability. AB-452 inhibits PAPD5/7 enzymatic activities and reduces HBsAg both in vitro (50% effective concentration [EC50] ranged from 1.4 to 6.8 nM) and in vivo by 0.94 log10. Our genetic studies demonstrate that the stem-loop alpha sequence within PRE is essential for both maintaining HBV poly(A) tail integrity and determining sensitivity toward the inhibitory effect of AB-452. Although neither single knockout (KO) of PAPD5 nor PAPD7 reduces HBsAg RNA and protein production, PAPD5 KO does impair poly(A) tail integrity and confers partial resistance to AB-452. In contrast, PAPD7 KO did not result in any measurable changes within the HBV poly(A) tails, but cells with both PAPD5 and PAPD7 KO show reduced HBsAg production and conferred complete resistance to AB-452 treatment. Our results indicate that PAPD5 plays a dominant role in stabilizing viral RNA by protecting the integrity of its poly(A) tail, while PAPD7 serves as a second line of protection. These findings inform PAPD5-targeted therapeutic strategies and open avenues for further investigating PAPD5/7 in HBV replication. IMPORTANCE Chronic hepatitis B affects more than 250 million patients and is a major public health concern worldwide. HBsAg plays a central role in maintaining HBV persistence, and as such, therapies that aim at reducing HBsAg through destabilizing or degrading HBV RNA have been extensively investigated. Besides directly degrading HBV transcripts through antisense oligonucleotides or RNA silencing technologies, small-molecule compounds targeting host factors such as the noncanonical poly(A) polymerase PAPD5 and PAPD7 have been reported to interfere with HBV RNA metabolism. Herein, our antiviral and genetic studies using relevant HBV infection and replication models further characterize the interplays between the cis element within the viral sequence and the trans elements from the host factors. PAPD5/7-targeting inhibitors, with oral bioavailability, thus represent an opportunity to reduce HBsAg through destabilizing HBV RNA.

Targeted and Untargeted Metabolic Profiling to Discover Bioactive Compounds in Seaweeds and Hemp Using Gas and Liquid Chromatography-Mass Spectrometry.

Greenhouse gas emissions are a global problem facing the dairy/beef industry. Novel feed additives consisting of seaweeds and hemp containing bioactive compounds are theorized to reduce enteric methane emissions. In this study we aimed to investigate the metabolic profiles of brown, red and green seaweeds and hemp using gas chromatography and liquid chromatography mass spectrometry. We used targeted and untargeted approaches, quantifying known halomethanes and phenolics, as well as identifying potentially novel bioactive compounds with anti-methanogenic properties. The main findings were: (a) Asparagopsis taxiformis contained halomethanes, with high concentrations of bromoform (4200 µg/g DW), six volatile halocarbons were tentatively identified; (b) no halomethanes were detected in the other studied seaweeds nor in hemp; (c) high concentrations of lignans were measured in hemp; (d) a high numbers of sulfated phenolic acids and unidentified sulfuric acid-containing compounds were detected in all seaweeds; (e) flavonoid glucosides and glucuronides were mainly identified in hemp; and (f) the condensed tannin gallocatechin was tentatively identified in Fucus sp. Using the combined metabolomics approach, an overview and in-depth information on secondary metabolites were provided. Halomethanes of Asparagopsis sp. have already been shown to be anti-methanogenic; however, metabolic profiles of seaweeds such as Dictyota and Sargassum have also been shown to contain compounds that may have anti-methanogenic potential.

Outcomes Following Heterotopic Placement of Right Ventricle to Pulmonary Artery Conduits.

BACKGROUND: We sought to evaluate the outcomes following right ventricle to pulmonary artery (RV-PA) conduit placement in pediatric patients, excluding those with a RV-PA conduit for the Ross procedure which is associated with improved conduit durability, partly related to its orthotopic position. METHODS: Outcomes for 119 patients who underwent RV-PA conduit placement at a single institution from January 2004 to December 2016 were reviewed. Primary outcome measures were reintervention-free survival (RFS) and overall survival. Survival analyses were performed using the Kaplan-Meier method, and risk factors associated with reintervention were evaluated. RESULTS: The median age at the time of conduit placement was 6 months (interquartile range, IQR: 1-14), and the median length of follow-up was 63 months (range: 0-156). During follow-up, 39 patients required conduit-related reintervention, while 6 patients died perioperatively with an overall survival of 90% at 10 years. Among the remaining 113 patients, the RFS at one, five, and ten years was 91% (84%-95%), 72% (60%-80%), and 33% (16%-50%), respectively. The median time to conduit replacement in the series was 43.5 months (IQR: 19.3-76.2). The use of a pulmonary homograft was associated with improved RFS (P = .03), and this was particularly pronounced in comparison with aortic homografts in neonates. Infection was the indication for replacement in only one patient. CONCLUSIONS: The majority of the conduits placed during the neonatal period required conduit replacement before the age of five years. Endocarditis was not a common indication for replacement. In neonates and infants, we prefer pulmonary homografts for most indications.

Endoscopic management of Barrett's dysplasia and early neoplasia: efficacy, safety and long-term outcomes in a UK tertiary centre.

BACKGROUND AND OBJECTIVES: Endoscopic mucosal resection (EMR) and radiofrequency ablation (RFA) are effective treatments for dysplastic Barrett's esophagus (BE). This study evaluates efficacy, durability and safety in a single high-volume UK tertiary centre with 15-years' experience. METHODS: Prospective data were collected from Nottingham University Hospitals 2004-2019 for endotherapy of dysplastic BE or intramucosal adenocarcinoma. Procedural outcome measures include complete resection, complications and surgery rates. Efficacy outcomes include complete remission of dysplasia (CR-D) and intestinal metaplasia (CR-IM), recurrence, treatment failure rates, durability of RFA, median follow up and tumor-associated mortality. RESULTS: A total of 319 lesions were resected; 671 RFAs were performed on 239 patients. Median age was 67 (±9.5) years, male:female ratio was 5:1 and median BE length was C3 [interquartile range (IQR): 6] M6 (IQR: 5). The most common lesion was Paris IIa (64%) with a median size of 10 mm (3-70). Final histology was adenocarcinoma in 50%. Complete resection rates were 96%. The multiband mucosectomy technique (91%) was most commonly used. The median number of RFA sessions was 3 (IQR: 2). The rates of CR-D and CR-IM were 90.4%% and 89.8% achieved after a median of 20.1 (IQR: 14) months. The most common complications: EMR was bleeding 2.2% and RFA was stricture (5.4%) requiring a median of 2 (range 1-7) dilatations. Median follow up post CR-IM/CR-D was 38 months (14-60). Metachronous lesions developed in 4.7% after CR-D and tumor-related mortality was 0.8%. Dysplasia and intestinal metaplasia-free survival at 5 years was 95 and 90%, respectively. CONCLUSION: BE endotherapy is minimally invasive, effective, safe and deliverable in a day-case setting.

Checkpoint inhibition through small molecule-induced internalization of programmed death-ligand 1.

Programmed death-ligand 1 is a glycoprotein expressed on antigen presenting cells, hepatocytes, and tumors which upon interaction with programmed death-1, results in inhibition of antigen-specific T cell responses. Here, we report a mechanism of inhibiting programmed death-ligand 1 through small molecule-induced dimerization and internalization. This represents a mechanism of checkpoint inhibition, which differentiates from anti-programmed death-ligand 1 antibodies which function through molecular disruption of the programmed death 1 interaction. Testing of programmed death ligand 1 small molecule inhibition in a humanized mouse model of colorectal cancer results in a significant reduction in tumor size and promotes T cell proliferation. In addition, antigen-specific T and B cell responses from patients with chronic hepatitis B infection are significantly elevated upon programmed death ligand 1 small molecule inhibitor treatment. Taken together, these data identify a mechanism of small molecule-induced programmed death ligand 1 internalization with potential therapeutic implications in oncology and chronic viral infections.