Responsive neurostimulation as a treatment for super-refractory focal status epilepticus: a systematic review and case series.

OBJECTIVE: Super-refractory status epilepticus (SRSE) has high rates of morbidity and mortality. Few published studies have investigated neurostimulation treatment options in the setting of SRSE. This systematic literature review and series of 10 cases investigated the safety and efficacy of implanting and activating the responsive neurostimulation (RNS) system acutely during SRSE and discusses the rationale for lead placement and selection of stimulation parameters. METHODS: Through a literature search (of databases and American Epilepsy Society abstracts that were last searched on March 1, 2023) and direct contact with the manufacturer of the RNS system, 10 total cases were identified that utilized RNS acutely during SE (9 SRSE cases and 1 case of refractory SE [RSE]). Nine centers obtained IRB approval for retrospective chart review and completed data collection forms. A tenth case had published data from a case report that were referenced in this study. Data from the collection forms and the published case report were compiled in Excel. RESULTS: All 10 cases presented with focal SE: 9 with SRSE and 1 with RSE. Etiology varied from known lesion (focal cortical dysplasia in 7 cases and recurrent meningioma in 1) to unknown (2 cases, with 1 presenting with new-onset refractory focal SE [NORSE]). Seven of 10 cases exited SRSE after RNS placement and activation, with a time frame ranging from 1 to 27 days. Two patients died of complications due to ongoing SRSE. Another patient's SE never resolved but was subclinical. One of 10 cases had a device-related significant adverse event (trace hemorrhage), which did not require intervention. There was 1 reported recurrence of SE after discharge among the cases in which SRSE resolved up to the defined endpoint. CONCLUSIONS: This case series offers preliminary evidence that RNS is a safe and potentially effective treatment option for SRSE in patients with 1-2 well-defined seizure-onset zone(s) who meet the eligibility criteria for RNS. The unique features of RNS offer multiple benefits in the SRSE setting, including real-time electrocorticography to supplement scalp EEG for monitoring SRSE progress and response to treatment, as well as numerous stimulation options. Further research is indicated to investigate the optimal stimulation settings in this unique clinical scenario.

Intersectionality and COVID-19: Academic Medicine Faculty's Lived Experiences of Well-Being, Workload, and Productivity During the Pandemic.

Purpose: The aim of this study was to utilize an intersectional framework to examine academic faculty's lived experiences during COVID-19. Specifically, we set out to: (1) describe the multiple intersectional identities (e.g., gender, race/ethnicity, rank, caregiver status, disability status) represented by the faculty, (2) examine potential disparities in well-being, workload, and productivity linked to these intersectional factors, and (3) identify qualitative themes endorsed by faculty as they relate to lived experiences during COVID-19. Methods: This was a cross-sectional mixed-methods research study. The Center for Women in Medicine and Science (CWIMS) at the University of Minnesota developed and implemented a survey between February-June of 2021 in response to national reports of disparities in the impacts of COVID-19 on faculty with lived experiences from multiple intersections. Results: There were 291 full-time faculty who participated in the study. Quantitative findings indicated that faculty with multiple intersectional identities (e.g., woman+assistant professor+caregiver+underrepresented in medicine) reported greater depression symptoms, work/family conflict, and stress in contrast to faculty with fewer intersectional identities. Furthermore, faculty with more intersectional identities reported higher clinical workloads and service responsibilities and lower productivity with regard to research article submissions, publications, and grant submissions in contrast to faculty with fewer intersectional identities. Qualitative findings supported quantitative findings and broadened understanding of potential underlying reasons. Conclusions: Findings confirm anecdotal evidence that faculty with lived experiences from multiple intersections may be disproportionately experiencing negative outcomes from the pandemic. These findings can inform decisions about how to address these disparities moving into the next several years with regard to promotion and tenure, burnout and well-being, and faculty retention in academic medical settings. Given these findings, it is also important to intentionally plan responses for future public health crises to prevent continued disparities for faculty with multiple intersectional identities.

Diagnosis and management of elevated intracranial pressure in the emergency department.

BACKGROUND: Elevated intracranial pressure is a devastating complication of catastrophic brain injury. Intracranial hypertension is commonly seen in neurologic injury secondary to traumatic brain injuries. Uncontrolled pressures can lead to permanent neurologic damage, but acute medical management is often overlooked when pursuing surgical management options that may not always be indicated. DISCUSSION: Traumatic brain injury is the leading cause of death in patients with severe neurologic injury. Diagnosing elevated intracranial pressures is imperative in initiating prompt treatment to reduce secondary central nervous system injury, morbidity, and mortality. Although the initial injury to the brain is typically irreversible, intracranial pressure control can assist in salvaging the remaining brain tissue from additional damage. We will discuss the initial medical and surgical management of traumatic brain injury to prevent further neurologic deterioration and reduce mortality. CONCLUSION: Recent literature has reported several methods to detect elevated intracranial pressure easily and studies describing multiple treatment modalities. These investigations suggest that early detection and timely treatment of intracranial hypertension are beneficial in reducing mortality.

Work, Parenting, and Well-being: An International Survey of Neurologists During the COVID-19 Pandemic.

Background and Objectives: COVID-19 reframed the relationship between work and home and, in general, made both more difficult-especially for parents. We hypothesized that, among neurologists, the effects of the pandemic on productivity and on well-being would be greater on those with children than on those without children and that the effects would be greater on women with children than on men with children. Methods: We conducted an international electronic survey launched by the Practice Current section of the American Academy of Neurology. The survey included questions on demographics (self-identified gender, number of children and elderly dependents, childcare support, and country and state when applicable), workflow changes because of COVID-19, impacted domains, and productivity and well-being using the Likert scale. Counts are presented as descriptive statistics. Statistical analysis was performed using Mann-Whitney U and Kruskal-Wallis tests. Results: We collected 243 fully completed surveys from providers in all continents with high representation of the United States (76%), providers who identified as women (71.6%), and neurologists with children (91%) among respondents. A majority worked remotely (28% fully, 43% mix). Neurologists reported decreased academic productivity (72%), work benefits (65%), and time for writing (48%). These findings were more prominent in respondents with children and among women practicing outside of the United States. Increased pressure from productivity expectations and lack of time for family were reported by 47% and 41% of respondents, respectively. Discussion: The disruption from the COVID-19 pandemic affected academic productivity and decreased the well-being of neurologists in general and of neurologists with children more drastically. This could potentially hinder the promotion and retention of junior neurologists who were juggling life and work during the pandemic outbreak and its recurrent surges.

Bedside Flexible Cystoscopy-Guided Ureteric Stent Insertion for Early Control of Sepsis.

Sepsis is a life-threatening condition that needs the clinician to act quickly and swiftly in order to provide the best medical outcome for the patient. Sepsis can lead to multi-organ dysfunction, which is not only a risk to life but also utilizes multiple resources within the healthcare services. The management of any infection is reliant on two major factors: antimicrobial therapy and source control. We present two cases where source control, in the form of a ureteric stent insertion, was performed at bedside via the use of flexible cystoscopy to provide source control in the management of a septic patient.

EEG Correlates of Spikes in Intracranial Pressure Caused by Transient Ventriculoperitoneal Shunt Malfunction.

SUMMARY: A 30-year-old man with recurrent headaches and seizure-like activity and a 26-year-old woman with worsening headaches were admitted to the hospital. Both had ventriculoperitoneal shunts and history of several shunt revisions for congenital hydrocephalus. The ventricle size visualized on computed tomography scans was unremarkable, and shunt series were negative in both cases. Both patients began to present with brief periods of unresponsiveness, and video electroencephalography at that time showed periods of diffuse delta slowing. Lumbar punctures revealed increased opening pressures. Despite normal imaging and shunt series, both patients ultimately had increased intracranial pressure caused by shunt malfunction. This series demonstrates the difficulty of diagnosing potential transient increases in intracranial pressure based on standard-of-care diagnostics/examination and the potentially critical role for EEG in the identification of shunt malfunction.

Subcutaneous delivery of FGF21 mRNA therapy reverses obesity, insulin resistance, and hepatic steatosis in diet-induced obese mice.

Fibroblast growth factor 21 (FGF21) is a promising therapeutic agent for treatment of type 2 diabetes (T2D) and non-alcoholic steatohepatitis (NASH). We show that therapeutic levels of FGF21 were achieved following subcutaneous (s.c.) administration of mRNA encoding human FGF21 proteins. The efficacy of mRNA was assessed following 2-weeks repeated s.c. dosing in diet-induced obese (DIO), mice which resulted in marked decreases in body weight, plasma insulin levels, and hepatic steatosis. Pharmacokinetic/pharmacodynamic (PK/PD) modelling of several studies in both lean and DIO mice showed that mRNA encoding human proteins provided improved therapeutic coverage over recombinant dosed proteins in vivo. This study is the first example of s.c. mRNA therapy showing pre-clinical efficacy in a disease-relevant model, thus, showing the potential for this modality in the treatment of chronic diseases, including T2D and NASH.

An Easy Solution for Difficult Urethral Catheter: Three-Way Urethral Catheter Insertion Using a Guidewire Technique.

Urethral catheter insertion is a skill taught to all medical students but often not practised for a multitude of reasons. The difficult catheter can be a clinical nightmare for the junior doctor, especially on call, and can lead to significant mortality and morbidity with suboptimal repeated attempts. The incorporation of a soft-tipped hydrophilic guidewire technique for the insertion of a two-way urethral catheter has been described in the literature and has the potential to reduce the morbidity and mortality of patients by making the insertion of a catheter less traumatic. Here, we propose and describe the insertion of a three-way urethral catheter, performed using the technique employed for the insertion of a two-way urinary catheter via the use of a hydrophilic guidewire, with similar outcomes. A hydrophilic soft-tipped guidewire to insert a three-way urethral catheter can be used in the wards, in the emergency department, and in a theatre setting. The district hospital in which this method was employed demonstrated a 100% success rate in the insertion of a urethral catheter (N = 15), with 26% of cases (four patients out of 15) having a three-way urethral catheter inserted using the soft-tipped hydrophilic guidewire method. Follow-ups of these patients showed that there were no complications or adverse effects experienced by the patients. The use of a soft-tipped guidewire approach to insert a difficult urethral catheter can reduce the financial burden on the healthcare system by eliminating costs due to harm/trauma caused by repeated unsuccessful urethral catheter attempts or those attempts that have been performed suboptimally and have led to potential patient harm. The use of a hydrophilic guidewire-assisted technique to insert a three-way urinary catheter is a safe and easy option for those who have had repeated unsuccessful attempts. The hydrophilic guidewire approach has the potential to reduce morbidity and mortality associated with urethral catheterisation and improve patient safety.

Subarachnoid hemorrhage in the emergency department.

BACKGROUND: Subarachnoid hemorrhage accounts for more than 30,000 cases of stroke annually in North America and encompasses a 4.4% mortality rate. Since a vast number of subarachnoid hemorrhage cases present in a younger population and can range from benign to severe, an accurate diagnosis is imperative to avoid premature morbidity and mortality. Here, we present a straightforward approach to evaluating, risk stratifying, and managing subarachnoid hemorrhages in the emergency department for the emergency medicine physician. DISCUSSION: The diversities of symptom presentation should be considered before proceeding with diagnostic modalities for subarachnoid hemorrhage. Once a subarachnoid hemorrhage is suspected, a computed tomography of the head with the assistance of the Ottawa subarachnoid hemorrhage rule should be utilized as an initial diagnostic measure. If further investigation is needed, a CT angiography of the head or a lumbar puncture can be considered keeping risks and limitations in mind. Initiating timely treatment is essential following diagnosis to help mitigate future complications. Risk tools can be used to assess the complications for which the patient is at greatest. CONCLUSION: Subarachnoid hemorrhages are frequently misdiagnosed; therefore, we believe it is imperative to address the diagnosis and initiation of early management in the emergency medicine department to minimize poor outcomes in the future.

Immunogenicity of the UK group B meningococcal vaccine (4CMenB) schedule against groups B and C meningococcal strains (Sched3): outcomes of a multicentre, open-label, randomised controlled trial.

BACKGROUND: The use of the multicomponent meningococcal vaccine 4CMenB in the UK schedule at 2, 4, and 12 months of age has been shown to be 59·1% effective at preventing invasive group B meningococcal disease. Here, we report the first data on the immunogenicity of this reduced-dose schedule to help to interpret this effectiveness estimate. METHODS: In this multicentre, parallel-group, open-label, randomised clinical trial, infants aged up to 13 weeks due to receive their primary immunisations were recruited via child health database mailouts in Oxfordshire and via general practice surgeries in Gloucestershire and Hertfordshire. Infants were randomly assigned (1:1) with permuted block randomisation to receive a 2 + 1 (2, 4, and 12 months; group 1) or 1 + 1 (3 and 12 months; group 2) schedule of the 13-valent pneumococcal conjugate vaccine (PCV13). All infants also received 4CMenB at 2, 4, and 12 months of age, and had blood samples taken at 5 and 13 months. Participants and clinical trial staff were not masked to treatment allocation. Proportions of participants with human complement serum bactericidal antibody (hSBA) titres of at least 4 were determined for group B meningococcus (MenB) reference strains 5/99 (Neisserial Adhesin A [NadA]), NZ98/254 (porin A), and 44/76-SL (factor H binding protein [fHbp]). Geometric mean titres (GMTs) with 95% CIs were also calculated, and concomitant vaccine responses (group C meningococcus [MenC], Haemophilus influenzae b [Hib], tetanus, diphtheria, and pertussis) were compared between groups. The primary outcome was PCV13 immunogenicity, with 4CMenB immunogenicity and reactogenicity as secondary outcomes. All individuals by randomised group with a laboratory result were included in the analysis. The study is registered on the EudraCT clinical trials database, 2015-000817-32, and ClinicalTrials.gov, NCT02482636, and is complete. FINDINGS: Between Sept 22, 2015, and Nov 1, 2017, of 376 infants screened, 213 were enrolled (106 in group 1 and 107 in group 2). 204 samples post-primary immunisation and 180 post-boost were available for analysis. The proportion of participants with hSBA of at least 4 was similar in the two study groups. For strain 5/99, all participants developed hSBA titres above 4 in both groups and at both timepoints. For strain 44/76-SL, these proportions were 95·3% (95% CI 88·5-98·7) or above post-priming (82 of 86 participants in group 1), and 92·4% (84·2-97·2) or above post-boost (73 of 79 participants in group 1). For strain NZ98/254, these proportions were 86·5% (78·0-92·6) or above post-priming (83 of 96 participants in group 2) and 88·6% (79·5-94·7) or above post-boost (70 of 79 participants in group 1). The MenC rabbit complement serum bactericidal antibody (rSBA) titre in group 1 was significantly higher than in group 2 (888·3 vs 540·4; p=0·025). There was no significant difference in geometric mean concentrations between groups 1 and 2 for diphtheria, tetanus, Hib, and pertussis post-boost. A very small number of children did not have a protective response against 44/76-SL and NZ98/254. Local and systemic reactions were similar between the two groups, apart from the 3 month timepoint when one group received an extra dose of PCV13 and recorded more systemic reactions. INTERPRETATION: These data support the recent change to the licensed European schedule for 4CMenB to add an infant 2 + 1 schedule, as used in the routine UK vaccine programme with an effectiveness of 59·1%. When compared with historical data, our data do not suggest that effectiveness would be higher with a 3 + 1 schedule, however a suboptimal boost response for bactericidal antibodies against vaccine antigen fHbp suggests a need for ongoing surveillance for vaccine breakthroughs due to fHbp-matched strains. Changing from a 2 + 1 to a 1 + 1 schedule for PCV13 for the UK is unlikely to affect protection against diphtheria, tetanus, and Hib, however an unexpected reduction in bactericidal antibodies against MenC seen with the new schedule suggests that ongoing surveillance for re-emergent MenC disease is important. FUNDING: Bill & Melinda Gates Foundation and the National Institute for Health Research.

Kidney Transplantation for Erdheim-Chester Disease.

Erdheim-Chester disease is a rare inflammatory disease that infiltrates skeletal and extra-skeletal tissue. Chronic kidney disease (CKD) in Erdheim-Chester disease is usually attributed to retroperitoneal lesions that lead to urologic obstruction and hydronephrosis. In this report, we describe a patient diagnosed with Erdheim-Chester disease who eventually developed end-stage kidney disease (ESKD). After complete remission of Erdheim-Chester disease by vemurafenib therapy and 2 years of hemodialysis, the patient underwent a deceased donor kidney transplantation with basiliximab induction and tacrolimus/mycophenolic acid maintenance. After conversion of mycophenolic acid to azathioprine due to cost, acute cellular rejection had occurred, and he was treated with steroid therapy. The patient remained in complete remission from Erdheim-Chester disease and dialysis-free 16 months after transplant. Kidney transplantation is another treatment option for those patients with Erdheim-Chester disease who suffer from renal failure in the setting of complete remission.

Adolescents' Acceptance of Long-Acting Reversible Contraception After an Educational Intervention in the Emergency Department: A Randomized Controlled Trial.

INTRODUCTION: Adolescents who seek care in the emergency department (ED) are a cohort at increased risk of unintended pregnancy. Although adolescents are interested in learning about pregnancy prevention in the ED, there is a lack of effective educational interventions in this setting. Long-acting reversible contraceptives (LARC) are highly effective and safe in teens, yet are underutilized. This study assessed contraception use among adolescents in the ED and evaluated the impact of an educational video on their interest in and uptake of LARCs. METHODS: We conducted a two-arm randomized controlled trial on a convenience sample of sexually active females 14 to 21 years old in an urban pediatric ED. Participants were randomized to an educational video or standard care. All participants completed a survey and were given an informational card about affiliated teen clinics with the option to schedule an appointment. We assessed pre-post mean differences between control and intervention participants and pre-post differences among intervention participants. Participants were followed three months after their ED visit to examine use of contraception. RESULTS: A total of 79 females were enrolled (42 control and 37 intervention). The mean age was 17 years, and most were youth of color. The proportion of participants with a prior pregnancy was 18%. Almost all participants reported wanting to avoid pregnancy, yet 18% reported not using contraception at last intercourse. At baseline, 17.7% of participants were somewhat or very interested in the intrauterine device (IUD) or implant. After watching the video, 42.3% were somewhat or very interested in the IUD and 35.7% in the implant. Among those who watched the video, there were significant increases in interest in using an IUD or implant (p<.001). Compared to controls, adolescents who watched the video were also significantly more likely to report wanting an IUD (p<0.001) or implant (p=0.002). A total of 46% were reached for follow-up. Of these, 16% had initiated a LARC method after their ED visit (p=NS). CONCLUSION: Most adolescent females in the ED want to avoid pregnancy, but are using ineffective methods of contraception. A brief educational video on LARCs was acceptable to adolescents and feasible to implement in a busy urban ED setting. Adolescents who watched the video had significantly greater interest in using LARCs, but no demonstrated change in actual adoption of contraception.

Insulinoma as a Potential Insidious Presenter in Medical Refractory Epilepsy.

BACKGROUND: Insulinoma as a cause of epileptic seizure has been thoroughly described but often not considered in differentials for previously established diagnoses of seizure disorder. Hypoglycemic symptoms can mimic neurological disorders such as epilepsy. CASE PRESENTATION: A 52-year-old woman presented with a history of epilepsy on anti-epileptic drugs (AEDs) developed repeated episodes consisting of seizures and neuropsychiatric symptoms with no predisposing factors for epilepsy at age 52. She had received full AED treatment before the possibility of hypoglycemia was considered. Following a clinical diagnosis of insulinoma, distal pancreatectomy was performed, and her seizures did not occur again. CONCLUSION: The early diagnosis of insulinoma requires vigilance, not only for hypoglycemia in patients with neuropsychiatric symptoms, but also for the possible masking effects of a history of epilepsy and preceding AED usage.

Invasive meningococcal disease in patients with complement deficiencies: a case series (2008-2017).

BACKGROUND: To describe patients with inherited and acquired complement deficiency who developed invasive meningococcal disease (IMD) in England over the last decade. METHODS: Public Health England conducts enhanced surveillance of IMD in England. We retrospectively identified patients with complement deficiency who developed IMD in England during 2008-2017 and retrieved information on their clinical presentation, vaccination status, medication history, recurrence of infection and outcomes, as well as characteristics of the infecting meningococcal strain. RESULTS: A total of 16 patients with 20 IMD episodes were identified, including four with two episodes. Six patients had inherited complement deficiencies, two had immune-mediated conditions associated with complement deficiency (glomerulonephritis and vasculitis), and eight others were on Eculizumab therapy, five for paroxysmal nocturnal haemoglobinuria and three for atypical haemolytic uraemic syndrome. Cultures were available for 7 of 11 episodes among those with inherited complement deficiencies/immune-mediated conditions and the predominant capsular group was Y (7/11), followed by B (3/11) and non-groupable (1/11) strains. Among patients receiving Eculizumab therapy, 3 of the 9 episodes were due to group B (3/9), three others were NG but genotypically group B, and one case each of groups E, W and Y. CONCLUSIONS: In England, complement deficiency is rare among IMD cases and includes inherited disorders of the late complement pathway, immune-mediated disorders associated with low complement levels and patients on Eculizumab therapy. IMD due to capsular group Y predominates in patient with inherited complement deficiency, whilst those on Eculizumab therapy develop IMD due to more diverse capsular groups including non-encapsulated strains.

Unique pattern of neutrophil migration and function during tumor progression.

Although neutrophils have been linked to the formation of the pre-metastatic niche, the mechanism of their migration to distant, uninvolved tissues has remained elusive. We report that bone marrow neutrophils from mice with early-stage cancer exhibited much more spontaneous migration than that of control neutrophils from tumor-free mice. These cells lacked immunosuppressive activity but had elevated rates of oxidative phosphorylation and glycolysis, and increased production of ATP, relative to that of control neutrophils. Their enhanced spontaneous migration was mediated by autocrine ATP signaling through purinergic receptors. In ectopic tumor models and late stages of cancer, bone marrow neutrophils demonstrated potent immunosuppressive activity. However, these cells had metabolic and migratory activity indistinguishable from that of control neutrophils. A similar pattern of migration was observed for neutrophils and polymorphonuclear myeloid-derived suppressor cells from patients with cancer. These results elucidate the dynamic changes that neutrophils undergo in cancer and demonstrate the mechanism of neutrophils' contribution to early tumor dissemination.

Defining the Anatomy of the Tendinous Intersections of the Rectus Abdominis Muscle and Their Clinical Implications in Functional Muscle Neurotization.

PURPOSE: Little is known about the definitive course of the tendinous intersections from anterior to posterior through the rectus abdominis (RA) muscle. The implications of a full thickness intersection may have effects on the ability to neurotize the RA. We hypothesized that these tendinous inscriptions would be fully adherent to the anterior rectus sheath, but there would be an incomplete penetrance into the posterior surface, thereby allowing for muscle fibers and neurovascular structures to run the entire course of the RA muscle. METHODS: Fifty-five cadaveric, hemiabdominal walls were evaluated. Measurements were taken of RA muscle thickness, depth of penetrance of the tendinous intersections, and intersection thickness. RESULTS: Of the 32 cadavers, 2 had 4 paired tendinous intersections and the remaining 30 cadavers had 3 paired tendinous intersections. Rectus abdominis muscle belly tended to be thicker at midbelly, between intersections than at the level of the corresponding intersection. A total of 168 tendinous intersections were assessed. Thirty (18%) of these inscriptions proved to be full thickness extending from anterior rectus sheath to posterior rectus sheath without any intervening muscle or neurovascular structures. Twenty-three (42%) of the 55 hemiabdomens assessed had at least one full-thickness tendinous intersection. CONCLUSIONS: The majority of RA muscles have 3 paired tendinous intersections. Most intersections are incomplete and only encompass the anterior rectus sheath. However, there may be a higher percentage of full-thickness intersections than previously appreciated and the clinical relevance behind these remains unclear.

Lipid bodies containing oxidatively truncated lipids block antigen cross-presentation by dendritic cells in cancer.

Cross-presentation is a critical function of dendritic cells (DCs) required for induction of antitumor immune responses and success of cancer immunotherapy. It is established that tumor-associated DCs are defective in their ability to cross-present antigens. However, the mechanisms driving these defects are still unknown. We find that impaired cross-presentation in DCs is largely associated with defect in trafficking of peptide-MHC class I (pMHC) complexes to the cell surface. DCs in tumor-bearing hosts accumulate lipid bodies (LB) containing electrophilic oxidatively truncated (ox-tr) lipids. These ox-tr-LB, but not LB present in control DCs, covalently bind to chaperone heat shock protein 70. This interaction prevents the translocation of pMHC to cell surface by causing the accumulation of pMHC inside late endosomes/lysosomes. As a result, tumor-associated DCs are no longer able to stimulate adequate CD8 T cells responses. In conclusion, this study demonstrates a mechanism regulating cross-presentation in cancer and suggests potential therapeutic avenues.

Hereditary Colorectal Tumors: A Literature Review on MUTYH-Associated Polyposis.

MAP (MUTYH-associated polyposis) is a syndrome, described in 2002, which is associated with colorectal adenomas, with enhanced colorectal carcinogenesis. This review synthesizes the available literature on MAP and outlines its pathogenesis, association with colorectal tumorigenesis, screening, treatment, and the subtle differences between it and its close cousins-FAP and AFAP. The preponderance of data is collected using MAP guidelines. However, although AFAP and MAP appear similar, potentially important distinctions exist, warranting targeted diagnostic criteria and treatment approaches. We suggest that it may be prudent to screen for MAP earlier than in current clinical practice, as it has been shown that sequence variants are associated with more severe disease, presenting with an earlier onset of colorectal cancer. Finally, we issue a call-to-action for much-needed further data to establish clear clinical and diagnostic criteria.

A Novel Role for Programmed Cell Death Receptor Ligand-1 (PD-L1) in Sepsis-Induced Intestinal Dysfunction.

Studies imply that intestinal barrier dysfunction is a key contributor to morbid events associated with sepsis. Recently, co-inhibitory molecule, programmed death-ligand1 (PD-L1) has been shown to be involved in the regulation of intestinal immune tolerance and/or inflammation. Our previous studies showed that PD-L1 gene deficiency reduced sepsis-induced intestinal injury morphologically. However, it isn't known how PD-L1 expression impacts intestinal barrier dysfunction during sepsis. Here we tested the hypothesis that PD-L1 expressed on intestinal epithelial cells (IECs) has a role in sepsis-induced intestinal barrier dysfunction. To address this, C57BL/6 or PD-L1 gene knockout mice were subjected to experimental sepsis and PD-L1 expression, intestinal permeability, tissue cytokine levels were assessed. Subsequently, septic or non-septic patient colonic samples (assigned by pathology report) were immunohistochemically stained for PD-L1 I a blinded fashion. Finally, human Caco2 cells were used for in vitro studies. The results demonstrated that PD-L1 was constitutively expressed and sepsis significantly up-regulates PD-L1 in IECs from C57BL/6 mice. Concurrently, we observed an increased PD-L1 expression in colon tissue samples from septic patients. PD-L1 gene deficiency reduced ileal permeability, tissue levels of IL-6, TNF-α and MCP-1, and prevented ileal tight junction protein loss compared to WT after sepsis. Comparatively, while Caco2 cell monolayers responded to inflammatory cytokine stimulation also with elevated PD-L1 expression, increased monolayer permeability and altering/decreasing monolayer tight junction protein morphology/expression; these changes were reversed by PD-L1 blocking antibody. Together these data indicate that ligation of ICE PD-L1 plays a novel role in mediating the pathophysiology of sepsis-induced intestinal barrier dysfunction.