Characteristics and outcomes of patients with COVID-19 at high risk of disease progression receiving sotrovimab, oral antivirals, or no treatment: a retrospective cohort study.

BACKGROUND: The clinical benefit of coronavirus disease 2019 (COVID-19) treatments against new circulating variants remains unclear. We sought to describe characteristics and clinical outcomes of highest risk patients with COVID-19 receiving early COVID-19 treatments in Scotland. METHODS: Retrospective cohort study of non-hospitalized patients diagnosed with COVID-19 from December 1, 2021-October 25, 2022, using Scottish administrative health data. We included adult patients who met ≥ 1 of the National Health Service highest risk criteria for early COVID-19 treatment and received outpatient treatment with sotrovimab, nirmatrelvir/ritonavir or molnupiravir, or no early COVID-19 treatment. Index date was defined as the earliest of COVID-19 diagnosis or early COVID-19 treatment. Baseline characteristics and acute clinical outcomes in the 28 days following index were reported. Values of ≤ 5 were suppressed. RESULTS: In total, 2548 patients were included (492: sotrovimab, 276: nirmatrelvir/ritonavir, 71: molnupiravir, and 1709: eligible highest risk untreated). Patients aged ≥ 75 years accounted for 6.9% (n = 34/492), 21.0% (n = 58/276), 16.9% (n = 12/71) and 13.2% (n = 225/1709) of the cohorts, respectively. Advanced renal disease was reported in 6.7% (n = 33/492) of sotrovimab-treated and 4.7% (n = 81/1709) of untreated patients, and ≤ 5 nirmatrelvir/ritonavir-treated and molnupiravir-treated patients. All-cause hospitalizations were experienced by 5.3% (n = 25/476) of sotrovimab-treated patients, 6.9% (n = 12/175) of nirmatrelvir/ritonavir-treated patients, ≤ 5 (suppressed number) molnupiravir-treated patients and 13.3% (n = 216/1622) of untreated patients. There were no deaths in the treated cohorts; mortality was 4.3% (n = 70/1622) among untreated patients. CONCLUSIONS: Sotrovimab was often used by patients who were aged < 75 years. Among patients receiving early COVID-19 treatment, proportions of 28-day all-cause hospitalization and death were low.

Characteristics and outcomes of patients with COVID-19 at high risk of disease progression receiving sotrovimab, oral antivirals or no treatment in England: a retrospective cohort study.

OBJECTIVE: To describe characteristics and acute clinical outcomes for patients with COVID-19 treated with sotrovimab, nirmatrelvir/ritonavir or molnupiravir, or untreated patients at highest risk per National Health Service (NHS) criteria. METHODS: Retrospective study of non-hospitalized patients between 1 December 2021 and 31 May 2022, using data from the Discover-NOW dataset (North-West London). Included patients were aged ≥12 years and treated with sotrovimab, nirmatrelvir/ritonavir or molnupiravir, or untreated but expected to be eligible for early treatment per NHS highest-risk criteria. COVID-19-related and all-cause hospitalizations were reported for 28 days from COVID-19 diagnosis (index). Subgroup analyses were conducted in patients with advanced renal disease, those aged 18-64 and ≥65 years, and by period of Omicron BA.1, BA.2 and BA.5 (post-hoc exploratory) predominance. RESULTS: Overall, 1503 treated and 4044 eligible high-risk untreated patients were included. A high proportion of patients on sotrovimab had advanced renal disease (29.3%), ≥3 high-risk comorbidities (47.6%) and were aged ≥65 years (36.9%). Five of 696 (0.7%) patients on sotrovimab, <5/337 (0.3-1.2%) on nirmatrelvir/ritonavir, 10/470 (2.1%) on molnupiravir and 114/4044 (2.8%) untreated patients were hospitalized with COVID-19. Similar results were observed across all subgroups. The proportion of patients dying within 28 days of the index period was similarly low across all cohorts (<2%). CONCLUSION: Patients receiving sotrovimab appeared to show evidence of multiple high-risk comorbidities. Low hospitalization rates were observed for all treated cohorts across subgroups and periods of predominant variants of concern. These results require confirmation with comparative effectiveness analyses adjusting for differences in underlying patient characteristics.

Apigenin-6-C-glucoside ameliorates MASLD in rodent models via selective agonism of adiponectin receptor 2.

Adiponectin plays key roles in energy metabolism and ameliorates inflammation, oxidative stress, and mitochondrial dysfunction via its primary receptors, adiponectin receptors -1 and 2 (AdipoR1 and AdipoR2). Systemic depletion of adiponectin causes various metabolic disorders, including MASLD; however adiponectin supplementation is not yet achievable owing to its large size and oligomerization-associated complexities. Small-molecule AdipoR agonists, thus, may provide viable therapeutic options against metabolic disorders. Using a novel luciferase reporter-based assay here, we have identified Apigenin-6-C-glucoside (ACG), but not apigenin, as a specific agonist for the liver-rich AdipoR isoform, AdipoR2 (EC50: 384 pM) with >10000X preference over AdipoR1. Immunoblot analysis in HEK-293 overexpressing AdipoR2 or HepG2 and PLC/PRF/5 liver cell lines revealed rapid AMPK, p38 activation and induction of typical AdipoR targets PGC-1α and PPARα by ACG at a pharmacologically relevant concentration of 100 nM (reported cMax in mouse; 297 nM). ACG-mediated AdipoR2 activation culminated in a favorable modulation of key metabolic events, including decreased inflammation, oxidative stress, mitochondrial dysfunction, de novo lipogenesis, and increased fatty acid ß-oxidation as determined by immunoblotting, QRT-PCR and extracellular flux analysis. AdipoR2 depletion or AMPK/p38 inhibition dampened these effects. The in vitro results were recapitulated in two different murine models of MASLD, where ACG at 10 mg/kg body weight robustly reduced hepatic steatosis, fibrosis, proinflammatory macrophage numbers, and increased hepatic glycogen content. Together, using in vitro experiments and rodent models, we demonstrate a proof-of-concept for AdipoR2 as a therapeutic target for MASLD and provide novel chemicobiological insights for the generation of translation-worthy pharmacological agents.

Real-world effectiveness of sotrovimab in preventing hospitalization and mortality in high-risk patients with COVID-19 in the United States: A cohort study from the Mayo Clinic electronic health records.

BACKGROUND: To describe outcomes of high-risk patients with coronavirus disease 2019 (COVID-19) treated with sotrovimab, other monoclonal antibodies (mAbs), or antivirals, and patients who did not receive early COVID-19 treatment. We also evaluate the comparative effectiveness of sotrovimab versus no treatment in preventing severe clinical outcomes. METHODS: This observational retrospective cohort study analyzed Mayo Clinic electronic health records. Non-hospitalized adult patients diagnosed with COVID-19 from May 26, 2021 and April 23, 2022 and at high risk of COVID-19 progression were eligible. The primary outcome was 29-day all-cause hospitalization and/or death. Outcomes were described for patients treated with sotrovimab, other mAbs, or antivirals, and eligible but untreated patients, and compared between sotrovimab-treated and propensity score (PS)-matched untreated cohorts. RESULTS: We included 35,485 patients (sotrovimab, 1369; other mAbs, 6488; antivirals, 133; high-risk untreated, 27,495). A low proportion of patients treated with sotrovimab (n = 33/1369, 2.4%), other mAbs (n = 147/6488, 2.3%), or antivirals (n = 2/133, 1.5%) experienced all-cause hospitalization or death. Among high-risk untreated patients, the percentage of all-cause hospitalization or death was 3.3% (n = 910/27,495). In the PS-matched analysis, 2.5% (n = 21/854) of sotrovimab-treated patients experienced all-cause hospitalization and/or death versus 2.8% (n = 48/1708) of untreated patients (difference, -0.4%; p = 0.66). Significantly fewer sotrovimab-treated patients required intensive care unit admission (0.5% vs 1.8%; difference, -1.3%; p = 0.002) or respiratory support (3.5% vs 8.7%; difference, -5.2%; p < 0.001). CONCLUSIONS: There was no significant difference in the proportion of sotrovimab-treated and PS-matched untreated patients experiencing 29-day all-cause hospitalization or mortality, although significantly fewer sotrovimab-treated patients required intensive care unit admission or respiratory support.

HIF Stabilizer Desidustat Protects against Complement-Mediated Diseases.

Complement cascade is a defence mechanism useful for eliminating pathogenic microorganisms and damaged cells. However, activation of alternative complement system can also cause inflammation and promote kidney and retinal disease progression. Inflammation causes tissue hypoxia, which induces hypoxia-inducible factor (HIF) and HIF helps the body to adapt to inflammation. In this study, we investigated the effect of HIF stabilizer desidustat in complement-mediated diseases. Oral administration of desidustat (15 mg/kg) was effective to reduce the kidney injury in mice that was induced by either lipopolysaccharide (LPS), doxorubicin or bovine serum albumin (BSA)-overload. Complement activation-induced membrane attack complex (MAC) formation and factor B activity were also reduced by desidustat treatment. In addition, desidustat was effective against membranous nephropathy caused by cationic BSA and retinal degeneration induced by sodium iodate in mice. C3-deposition, proteinuria, malondialdehyde, and interleukin-1ß were decreased and superoxide dismutase was increased by desidustat treatment in cBSA-induced membranous nephropathy. Desidustat specifically inhibited alternative complement system, without affecting the lectin-, or classical complement pathway. This effect appears to be mediated by inhibition of factor B. These data demonstrate the potential therapeutic value of HIF stabilization by desidustat in treatment of complement-mediated diseases.

Health Status and Mental Health of Transgender and Gender-Diverse Adults.

This cross-sectional study examines self-reported poor or fair health status, frequent mental distress, and depression among transgender and gender-diverse respondents compared with cisgender respondents to the 2014 to 2022 Behavioral Risk Factor Surveillance System.

A Clinical Course of Repeated Supratherapeutic Ingestion of Acetaminophen.

Acute liver failure (ALF) exemplifies a rapid decline in liver function among individuals with previously healthy livers, often manifesting through symptoms such as jaundice, confusion, and potentially life-threatening complications. Timely medical intervention, and, in severe instances, liver transplantation, are essential for enhancing outcomes and averting further deterioration. While the causes of ALF are multifaceted, in developed nations, it predominantly arises from drug-induced liver injury. Treatment primarily revolves around supportive measures, with severe cases necessitating liver transplantation. In instances where acute overdose with acetaminophen serves as the instigating factor, N-acetylcysteine (NAC) emerges as a pivotal component of management, as indicated by the Rumack-Matthew nomogram. The Rumack-Matthew nomogram guides treatment for acetaminophen overdose by correlating serum levels with the risk of liver damage. If levels exceed a set threshold, NAC is administered to prevent toxicity by replenishing glutathione. The decision to administer NAC is typically guided by this clinical tool, which aids healthcare providers in determining the appropriate course of action. NAC assumes a critical role in ameliorating the detrimental effects of acetaminophen overdose, particularly in averting liver damage, thus holding significant importance in patient care and recovery. While chronic acetaminophen overdose cases leading to ALF may also benefit from NAC, the supporting evidence remains weak. In this context, we present a case of ALF stemming from chronic acetaminophen ingestion, managed with NAC when liver transplantation was not a viable option.

The Relationship Between Serum Albumin Levels and Sepsis in Patients Admitted to a Tertiary Care Center in India.

Introduction Sepsis poses a significant threat in Indian hospitals, with high mortality rates and complications. This study explores the correlation between serum albumin levels and sepsis outcomes in an intensive care unit (ICU) setting. The challenges of diagnosing tropical infections further complicate sepsis management in India. Methodology A longitudinal study was conducted at Vinayaka Mission's Kirupananda Variyar Medical College and Hospital, Salem, India. Adult patients admitted between July 2020 and March 2021 with sepsis were included. Serum albumin levels, demographic data, and clinical outcomes were analyzed. The study used a convenient sampling technique with a sample size of 102 patients. Results Among the 102 patients in the ICU, 22 have expired and the mortality rate in the study was 21.6%. Hypoalbuminemia was present in 56.9% (n = 58) of the patients. The mortality rate is higher among the sepsis patients with the occurrence of hypoalbuminemia (29.3%) compared to patients without hypoalbuminemia (11.4%) and the difference in proportion between the two groups was statistically significant (p-value = 0.029). The requirement of vasopressor support is higher among sepsis patients with the occurrence of hypoalbuminemia (56.9%) compared to patients without hypoalbuminemia (27.3%). The chi-square test reveals that the difference in proportion between the two groups was statistically significant (p-value = 0.005). No substantial impact on systemic inflammatory response scores, readmission to ICU, or progression to chronic illness was observed based on albumin levels. Conclusion This study underscores the predictive value of hypoalbuminemia in sepsis outcomes. Patients with decreased albumin levels showed higher mortality rates and increased vasopressor usage. While albumin levels did not significantly influence certain parameters, hypoalbuminemia may serve as an indicator of severity and adverse prognosis in sepsis, emphasizing the need for further research and tailored interventions.

Patient- and Clinician-Reported Outcomes for Tirbanibulin in Actinic Keratosis in Clinical Practice Across the United States (PROAK).

BACKGROUND: The Patient-Reported Outcomes in Actinic Keratosis (PROAK) study evaluated patient- and clinician-reported outcomes (PRO; ClinRO) during 24 weeks of follow-up among adult patients with actinic keratosis (AK) on the face or scalp who were administered tirbanibulin 1% ointment in real-world community practices in the United States.  Methods: Quality of life (QoL) was assessed by Skindex-16 at week (W) 8. Additionally, effectiveness (Investigator Global Assessment [IGA]), PRO and ClinRO (Treatment Satisfaction Questionnaire for Medication and Expert Panel Questionnaire), safety, and tolerability were assessed at W8 and W24. RESULTS: The safety population included 300 patients; the full analysis set included 290 patients (278 patients at W24). At W8, a statistically significant difference (P<0.03) was observed for Skindex-16 domains in all assessed subgroups. Clinicians and patients reported high global satisfaction (mean [SD] scores of 74.9 [23.9] and 72.0 [24.6], respectively) at W24. Overall skin appearance improved from baseline to W24 (83.6% clinicians; 78.5% patients). IGA success (IGA score of 0-1) was achieved by 71.9% of patients at W24 with a similar % at W8 (73.8%) suggesting a stable effectiveness over time. About 5% of patients reported at least one adverse event, 4% reported at least one serious adverse event and no patients reported serious adverse drug reactions. At W8, the most frequently reported local skin reactions were mild/moderate erythema (47.6%) and flaking/scaling (49.6%). CONCLUSIONS: Treatment with tirbanibulin demonstrated effectiveness in the management of AK lesions and a favorable safety and tolerability profile. Furthermore, QoL was improved as early as W8, and both patients and clinicians reported high levels of treatment satisfaction, independently of patients' characteristics. J Drugs Dermatol. 2024;23(5):338-346. doi:10.36849/JDD.8264.

Updates from the International League Against Epilepsy Classification of Epilepsy (2017) and Focal Cortical Dysplasias (2022): Imaging Phenotype and Genetic Characterization.

The International League Against Epilepsy (ILAE) is an organization of 120 national chapters providing the most widely accepted and updated guidelines on epilepsy. In 2022, the ILAE Task Force revised the prior (2011) classification of focal cortical dysplasias to incorporate and update clinicopathologic and genetic information, with the aim to provide an objective classification scheme. New molecular-genetic information has led to the concept of "integrated diagnosis" on the same lines as brain tumors, with a multilayered diagnostic model providing a phenotype-genotype integration. Major changes in the new update were made to type II focal cortical dysplasias, apart from identification of new entities, such as mild malformations of cortical development and cortical malformation with oligodendroglial hyperplasia. No major changes were made to type I and III focal cortical dysplasias, given the lack of significant new genetic information. This review provides the latest update on changes to the classification of focal cortical dysplasias with discussion about the new entities. The ILAE in 2017 updated the classification of seizure and epilepsy with 3 levels of diagnosis, including seizure type, epilepsy type, and epilepsy syndrome, which are also briefly discussed here.

Massive infected pancreatic necrosis in an 8-year-old: Endoscopic management.

Pancreatitis is a condition much more commonly found in adults, but when diagnosed in the pediatric population, is often due to medications, congenital pathology, and critical illness. This patient had previously undergone treatment with 6-mercaptopurine and presented with pancreatitis that eventually worsened to a walled-off necrotic collection with paracolic extensions reaching the pelvis. Given clinical worsening with development of shock, procedural options for source control were weighed with gastroenterology, pediatric surgery, and interventional radiology, before pancreatic necrosectomy was determined to be the treatment of choice, given the adjacency of the collection to the stomach. A total of three separate endoscopic pancreatic necrosectomy procedures were performed and the patient s clinical status improved greatly, with vast improvement later seen on outpatient imaging. This successful treatment course argues for the efficacy of pancreatic necrosectomy even in very large walled off collections, and most importantly, lead to a positive outcome in this young patient.

Comparative effectiveness of sotrovimab versus no treatment in non-hospitalised high-risk COVID-19 patients in north west London: a retrospective cohort study.

BACKGROUND: We assessed the effectiveness of sotrovimab vs no early COVID-19 treatment in highest-risk COVID-19 patients during Omicron predominance. METHODS: Retrospective cohort study using the Discover dataset in North West London. Included patients were non-hospitalised, aged ≥12 years and met ≥1 National Health Service highest-risk criterion for sotrovimab treatment. We used Cox proportional hazards models to compare HRs of 28-day COVID-19-related hospitalisation/death between highest-risk sotrovimab-treated and untreated patients. Age, renal disease and Omicron subvariant subgroup analyses were performed. RESULTS: We included 599 sotrovimab-treated patients and 5191 untreated patients. Compared with untreated patients, the risk of COVID-19 hospitalisation/death (HR 0.50, 95% CI 0.24, 1.06; p=0.07) and the risk of COVID-19 hospitalisation (HR 0.43, 95% CI 0.18, 1.00; p=0.051) were both lower in the sotrovimab-treated group; however, statistical significance was not reached. In the ≥65 years and renal disease subgroups, sotrovimab was associated with a significantly reduced risk of COVID-19 hospitalisation, by 89% (HR 0.11, 95% CI 0.02, 0.82; p=0.03) and 82% (HR 0.18, 95% CI 0.05, 0.62; p=0.007), respectively. CONCLUSIONS: Risk of COVID-19 hospitalisation in sotrovimab-treated patients aged ≥65 years and with renal disease was significantly lower compared with untreated patients. Overall, risk of hospitalisation was also lower for sotrovimab-treated patients, but statistical significance was not reached.

Characteristics and outcomes of COVID-19 patients presumed to be treated with sotrovimab in NHS hospitals in England.

BACKGROUND: The impact of the constantly evolving severe acute respiratory syndrome coronavirus 2 on the effectiveness of early coronavirus disease 2019 (COVID-19) treatments is unclear. Here, we report characteristics and acute clinical outcomes of patients with COVID-19 treated with a monoclonal antibody (mAb; presumed to be sotrovimab) across six distinct periods covering the emergence and predominance of Omicron subvariants (BA.1, BA.2, and BA.5) in England. METHODS: Retrospective cohort study using data from the Hospital Episode Statistics database from January 1-July 31, 2022. Included patients received a mAb delivered by a National Health Service (NHS) hospital as a day-case, for which the primary diagnosis was COVID-19. Patients were presumed to have received sotrovimab based on NHS data showing that 99.98% of COVID-19-mAb-treated individuals received sotrovimab during the study period. COVID-19-attributable hospitalizations were reported overall and across six distinct periods of Omicron subvariant prevalence. Subgroup analyses were conducted in patients with severe renal disease and active cancer. RESULTS: Among a total of 10,096 patients, 1.0% (n = 96) had a COVID-19-attributable hospitalization, 4.6% (n = 465) had a hospital visit due to any cause, and 0.3% (n = 27) died due to any cause during the acute period. COVID-19-attributable hospitalization rates were consistent among subgroups, and no significant differences were observed across periods of Omicron subvariant predominance. CONCLUSIONS: Levels of COVID-19-attributable hospitalizations and deaths were low in mAb-treated patients and among subgroups. Similar hospitalization rates were observed whilst Omicron BA.1, BA.2, and BA.5 were predominant, despite reported reductions in in vitro neutralization activity of sotrovimab against BA.2 and BA.5.

Assessing the Performance of Artificial Intelligence Models: Insights from the American Society of Functional Neuroradiology Artificial Intelligence Competition.

BACKGROUND AND PURPOSE: Artificial intelligence (AI) models in radiology are frequently developed and validated using datasets from a single institution and are rarely tested on independent, external datasets, raising questions about their generalizability and applicability in clinical practice. The American Society of Functional Neuroradiology (ASFNR) organized a multi-center AI competition to evaluate the proficiency of developed models in identifying various pathologies on NCCT, assessing age-based normality and estimating medical urgency. MATERIALS AND METHODS: In total, 1201 anonymized, full-head NCCT clinical scans from five institutions were pooled to form the dataset. The dataset encompassed normal studies as well as pathologies including acute ischemic stroke, intracranial hemorrhage, traumatic brain injury, and mass effect (detection of these-task 1). NCCTs were also assessed to determine if findings were consistent with expected brain changes for the patient's age (task 2: age-based normality assessment) and to identify any abnormalities requiring immediate medical attention (task 3: evaluation of findings for urgent intervention). Five neuroradiologists labeled each NCCT, with consensus interpretations serving as the ground truth. The competition was announced online, inviting academic institutions and companies. Independent central analysis assessed each model's performance. Accuracy, sensitivity, specificity, positive and negative predictive values, and receiver operating characteristic (ROC) curves were generated for each AI model, along with the area under the ROC curve (AUROC). RESULTS: 1177 studies were processed by four teams. The median age of patients was 62, with an interquartile range of 33. 19 teams from various academic institutions registered for the competition. Of these, four teams submitted their final results. No commercial entities participated in the competition. For task 1, AUROCs ranged from 0.49 to 0.59. For task 2, two teams completed the task with AUROC values of 0.57 and 0.52. For task 3, teams had little to no agreement with the ground truth. CONCLUSIONS: To assess the performance of AI models in real-world clinical scenarios, we analyzed their performance in the ASFNR AI Competition. The first ASFNR Competition underscored the gap between expectation and reality; the models largely fell short in their assessments. As the integration of AI tools into clinical workflows increases, neuroradiologists must carefully recognize the capabilities, constraints, and consistency of these technologies. Before institutions adopt these algorithms, thorough validation is essential to ensure acceptable levels of performance in clinical settings.ABBREVIATIONS: AI = artificial intelligence; ASFNR = American Society of Functional Neuroradiology; AUROC = area under the receiver operating characteristic curve; DICOM = Digital Imaging and Communications in Medicine; GEE = generalized estimation equation; IQR = interquartile range; NPV = negative predictive value; PPV = positive predictive value; ROC = receiver operating characteristic; TBI = traumatic brain injury.

Beta-blockers or Placebo for Primary Prophylaxis (BOPPP) of oesophageal varices: study protocol for a randomised controlled trial.

BACKGROUND: Liver disease is within the top five causes of premature death in adults. Deaths caused by complications of cirrhosis continue to rise, whilst deaths related to other non-liver disease areas are declining. Portal hypertension is the primary sequelae of cirrhosis and is associated with the development of variceal haemorrhage, ascites, hepatic encephalopathy and infection, collectively termed hepatic decompensation, which leads to hospitalisation and mortality. It remains uncertain whether administering a non-selective beta-blocker (NSBB), specifically carvedilol, at an earlier stage, i.e. when oesophageal varices are small, can prevent VH and reduce all-cause decompensation (ACD). METHODS/DESIGN: The BOPPP trial is a pragmatic, multicentre, placebo-controlled, triple-blinded, randomised controlled trial (RCT) in England, Scotland, Wales and Northern Ireland. Patients aged 18 years or older with cirrhosis and small oesophageal varices that have never bled will be recruited, subject to exclusion criteria. The trial aims to enrol 740 patients across 55 hospitals in the UK. Patients are allocated randomly on a 1:1 ratio to receive either carvedilol 6.25 mg (a NSBB) or a matched placebo, once or twice daily, for 36 months, to attain adequate power to determine the effectiveness of carvedilol in preventing or reducing ACD. The primary outcome is the time to first decompensating event. It is a composite primary outcome made up of variceal haemorrhage (VH, new or worsening ascites, new or worsening hepatic encephalopathy (HE), spontaneous bacterial peritonitis (SBP), hepatorenal syndrome, an increase in Child-Pugh grade by 1 grade or MELD score by 5 points, and liver-related mortality. Secondary outcomes include progression to medium or large oesophageal varices, development of gastric, duodenal, or ectopic varices, participant quality of life, healthcare costs and transplant-free survival. DISCUSSION: The BOPPP trial aims to investigate the clinical and cost-effectiveness of carvedilol in patients with cirrhosis and small oesophageal varices to determine whether this non-selective beta-blocker can prevent or reduce hepatic decompensation. There is clinical equipoise on whether intervening in cirrhosis, at an earlier stage of portal hypertension, with NSBB therapy is beneficial. Should the trial yield a positive result, we anticipate that the administration and use of carvedilol will become widespread with pathways developed to standardise the administration of the medication in primary care. ETHICS AND DISSEMINATION: The trial has been approved by the National Health Service (NHS) Research Ethics Committee (REC) (reference number: 19/YH/0015). The results of the trial will be submitted for publication in a peer-reviewed scientific journal. Participants will be informed of the results via the BOPPP website ( www.boppp-trial.org ) and partners in the British Liver Trust (BLT) organisation. TRIAL REGISTRATION: EUDRACT reference number: 2018-002509-78. ISRCTN reference number: ISRCTN10324656. Registered on April 24 2019.

Real-Time Optimal Synthetic Inversion Recovery Image Selection (RT-OSIRIS) for Deep Brain Stimulation Targeting.

Deep brain stimulation (DBS) is a method of electrical neuromodulation used to treat a variety of neuropsychiatric conditions including essential tremor, Parkinson's disease, epilepsy, and obsessive-compulsive disorder. The procedure requires precise placement of electrodes such that the electrical contacts lie within or in close proximity to specific target nuclei and tracts located deep within the brain. DBS electrode trajectory planning has become increasingly dependent on direct targeting with the need for precise visualization of targets. MRI is the primary tool for direct visualization, and this has led to the development of numerous sequences to aid in visualization of different targets. Synthetic inversion recovery images, specified by an inversion time parameter, can be generated from T1 relaxation maps, and this represents a promising method for modifying the contrast of deep brain structures to accentuate target areas using a single acquisition. However, there is currently no accessible method for dynamically adjusting the inversion time parameter and observing the effects in real-time in order to choose the optimal value. In this work, we examine three different approaches to implementing an application for real-time optimal synthetic inversion recovery image selection and evaluate them based on their ability to display continually-updated synthetic inversion recovery images as the user modifies the inversion time parameter. These methods include continuously computing the inversion recovery equation at each voxel in the image volume, limiting the computation only to the voxels of the orthogonal slices currently displayed on screen, or using a series of lookup tables with precomputed solutions to the inversion recovery equation. We find the latter implementation provides for the quickest display updates both when modifying the inversion time and when scrolling through the image. We introduce a publicly available cross-platform application built around this conclusion. We also briefly discuss other details of the implementations and considerations for extensions to other use cases.

Delayed Postoperative Intracerebral Hemorrhage Associated With Oral Multikinase Inhibitor Therapy for Cancer: A Case Report.

Regorafenib is a multikinase inhibitor with anti-vascular endothelial growth factor receptor (VEGF) activity used as an antiangiogenic agent for metastatic colorectal cancer treatment and has been studied as a potential therapeutic agent for several other cancer treatments. Adverse reactions commonly reported with the use of regorafenib and similar oral multikinase inhibitors include hemorrhage, gastrointestinal fistulas, hypertension, and incomplete wound healing. We report a case of a 59-year-old man with metastatic colorectal adenocarcinoma post-colostomy on regorafenib treatment presenting to the emergency department with altered mental status. MRI showed a left frontoparietal mass, which was resected with a left frontal craniotomy. Postoperative MRI showed a resection cavity without significant hemorrhage. He had been prescribed regorafenib preceding his hospitalization, which was continued after admission before surgery and on postoperative day 1. Thirty-two hours after surgery, the patient exhibited sudden right-sided facial droop and right arm weakness. Imaging revealed an acute intraparenchymal hemorrhage within and adjacent to the tumor resection bed, which was managed conservatively. The patient was subsequently discharged to an inpatient rehabilitation facility. The unusual timing of the hemorrhage suggests that the hemorrhage was due to adverse effects of regorafenib. Patients undergoing neurosurgery should have regorafenib discontinued in preparation for surgery. Similar management should be considered for other anti-VEGF medications to avoid serious complications.