Effects of Balanced Versus Saline-based Solutions on Acute Kidney Injury in Off-pump Coronary Artery Bypass Surgery: A Randomized Controlled Trial.

OBJECTIVES: To determine whether balanced solutions can reduce the incidence of acute kidney injury after off-pump coronary artery bypass surgery compared with saline. DESIGN: Randomized controlled trial. SETTING: Single tertiary care center. PARTICIPANTS: Patients who underwent off-pump coronary artery bypass surgery between June 2014 and July 2020. INTERVENTIONS: Balanced solution-based chloride-restrictive intravenous fluid strategy. MEASUREMENTS AND MAIN RESULTS: The primary outcome was acute kidney injury within 7 postoperative days, as defined by the 2012 Kidney Disease: Improving Global Outcomes Clinical Practice Guideline. The incidence of acute kidney injury was 4.4% (8/180) in the balanced group and 7.3% (13/178) in the saline group. The difference was not statistically significant (risk difference, -2.86%; 95% confidence interval [CI], -7.72% to 2.01%; risk ratio, 0.61, 95% CI, 0.26 to 1.43; p = 0.35). Compared with the balanced group, the saline group had higher levels of intraoperative serum chloride and lower base excess, which resulted in a lower pH. CONCLUSIONS: In patients undergoing off-pump bypass surgery with a normal estimated glomerular filtration rate, the intraoperative balanced solution-based chloride-restrictive intravenous fluid administration strategy did not decrease the rate of postoperative acute kidney injury compared with the saline-based chloride-liberal intravenous fluid administration strategy.

A dynamic flow fetal membrane organ-on-a-chip system for modeling the effects of amniotic fluid motion.

Fetal membrane (amniochorion), the innermost lining of the intrauterine cavity, surround the fetus and enclose amniotic fluid. Unlike unidirectional blood flow, amniotic fluid subtly rocks back and forth, and thus, the innermost amnion epithelial cells are continuously exposed to low levels of shear stress from fluid undulation. Here, we tested the impact of fluid motion on amnion epithelial cells (AECs) as a bearer of force impact and their potential vulnerability to cytopathologic changes that can destabilize fetal membrane functions. A previously developed amnion membrane (AM) organ-on-chip (OOC) was utilized but with dynamic flow to culture human fetal amnion membrane cells. The applied flow was modulated to perfuse culture media back and forth for 48 h to mimic fluid motion. A static culture condition was used as a negative control, and oxidative stress (OS) condition was used as a positive control representing pathophysiological changes. The impacts of fluidic motion were evaluated by measuring cell viability, cellular transition, and inflammation. Additionally, scanning electron microscopy (SEM) imaging was performed to observe microvilli formation. The results show that regardless of the applied flow rate, AECs and AMCs maintained their viability, morphology, innate meta-state, and low production of pro-inflammatory cytokines. E-cadherin expression and microvilli formation in the AECs were upregulated in a flow rate-dependent fashion; however, this did not impact cellular morphology or cellular transition or inflammation. OS treatment induced a mesenchymal morphology, significantly higher vimentin to cytokeratin 18 (CK-18) ratio, and pro-inflammatory cytokine production in AECs, whereas AMCs did not respond in any significant manner. Fluid motion and shear stress, if any, did not impact AEC cell function and did not cause inflammation. Thus, when using an amnion membrane OOC model, the inclusion of a dynamic flow environment is not necessary to mimic in utero physiologic cellular conditions of an amnion membrane.

Thrombogenic Risk Assessment of Transcatheter Prosthetic Heart Valves Using a Fluid-Structure Interaction Approach.

Background and Objective: Prosthetic heart valve interventions such as TAVR have surged over the past decade, but the associated complication of long-term, life-threatening thrombotic events continues to undermine patient outcomes. Thus, improving thrombogenic risk analysis of TAVR devices is crucial. In vitro studies for thrombogenicity are typically difficult to perform. However, revised ISO testing standards include computational testing for thrombogenic risk assessment of cardiovascular implants. We present a fluid-structure interaction (FSI) approach for assessing thrombogenic risk of prosthetic heart valves. Methods: An FSI framework was implemented via the incompressible computational fluid dynamics multi-physics solver of the Ansys LS-DYNA software. The numerical modeling approach for flow analysis was validated by comparing the derived flow rate of the 29-mm CoreValve device from benchtop testing and orifice areas of commercial TAVR valves in the literature to in silico results. Thrombogenic risk was analyzed by computing stress accumulation (SA) on virtual platelets seeded in the flow fields via Ansys EnSight. The integrated FSI-thrombogenicity methodology was subsequently employed to examine hemodynamics and thrombogenic risk of TAVR devices with two approaches: 1) engineering optimization and 2) clinical assessment. Results: The simulated effective orifice areas of the commercial devices were in the range reported in the literature. The flow rates from the in vitro flow testing matched well with the in silico results. The approach was used to analyze the effect of various TAVR leaflet designs on hemodynamics. Platelets experienced different magnitudes of SA along their trajectories as they flowed past each design. Post-TAVR deployment hemodynamics in patient-specific bicuspid aortic valve anatomies revealed varying degrees of thrombogenic risk for these patients, despite being clinically defined as "mild" paravalvular leak. Conclusions: Our methodology can be used to improve the thromboresistance of prosthetic valves from the initial design stage to the clinic. It allows for unparalleled optimization of devices, uncovering key TAVR leaflet design parameters that can be used to mitigate thrombogenic risk, in addition to patient-specific modeling to evaluate device performance. This work demonstrates the utility of advanced in silico analysis of TAVR devices that can be utilized for thrombogenic risk assessment of other blood recirculating devices.

Tear Fluid as a Matrix for Biomonitoring Environmental and Chemical Exposures.

PURPOSE: Exposures to hazardous chemicals have been linked to many detrimental health effects and it is therefore critical to have effective biomonitoring methods to better evaluate key environmental exposures that increase the risk of chronic disease and death. Traditional biomonitoring utilizing blood and urine is limited due to the specialized skills and invasiveness of collecting these fluid samples. This systematic review focuses on tear fluid, which is largely under-researched, as a promising complementary matrix to the traditional fluids used for biomonitoring. The objective is to evaluate the practicability of using human tear fluid for biomonitoring environmental exposures, highlighting potential pitfalls and opportunities. RECENT FINDING: Tear fluid biomonitoring represents a promising method for assessing exposures because it can be collected with minimal invasiveness and tears contain exposure markers from both the external and internal environments. Tear fluid uniquely interfaces with the external environment at the air-tear interface, providing a surface for airborne chemicals to diffuse into the ocular environment and interact with biomolecules. Tear fluid also contains molecules from the internal environment that have travelled from the blood to tears by crossing the blood-tear barrier. This review demonstrates that tear fluid can be used to identify hazardous chemicals from the external environment and differentiate exposure groups.

Changes in cerebrospinal fluid proteome of patients with tick-borne encephalitis.

Tick-borne encephalitis (TBE) is one of the main diseases transmitted by ticks, the incidence of which is increasing. Moreover, its diagnosis and therapy are often long and difficult according to nonspecific symptoms and complex etiology. This study aimed to observe changes in the proteome of cerebrospinal fluid from TBE patients. Cerebrospinal fluid (CSF) of TBE patients (n = 20) and healthy individuals (n = 10) was analyzed using a proteomic approach (QExactiveHF-Orbitrap mass spectrometer) and zymography. Obtained results show that in CSF of TBE patients, the top-upregulated proteins are involved in pro-inflammatory reaction (interleukins), as well as antioxidant/protective response (peroxiredoxins, heat shock proteins). Moreover, changes in the proteome of CSF are not only the result of this disease development, but they can also be an indicator of its course. This mainly applies to proteins involved in proteolysis including serpins and metalloproteinases, whose activity is proportional to the length of patients' convalescence. The obtained proteomic data strongly direct attention to the changes caused by the development of TBE to antioxidant, pro-inflammatory, and proteolytic proteins, knowledge about which can significantly contribute to faster and more accurate diagnosis of various clinical forms of TBE.

Correlation of amniotic fluid inflammatory markers with preterm birth: a meta-analysis.

BACKGROUND: The relationship between amniotic fluid inflammatory biomarkers and preterm birth in second- or third-trimester pregnancy has been a focus, and understanding the correlation between these markers and preterm birth is important for early identification and intervention in preterm birth. The aim of this study was to explore potential inflammatory biomarkers in second- or third-trimester pregnancy amniotic fluid associated with preterm birth. METHODS: On November 30, 2023, we searched literature involved the influence of second- or third-trimester pregnancy amniotic fluid inflammatory biomarkers on preterm birth through PubMed, Web of Science, Embase, Scope, CNKI, WanFang, VIP and China Biomedical Databases. The search languages were Chinese and English. Included outcomes indexes were combined utility analysis via R software. RESULTS: A total of 11 articles were included in the combined utility analysis. This combined analysis revealed significant differences in several inflammatory biomarkers in amniotic fluid between the two groups (MD = 6.87, 95%CI: 0.26 - 13.47, P < 0.01); the difference in amniotic fluid IL-6 between the two groups (MD = 5.73, 95%CI: 3.13-8.32, P < 0.01); the difference in amniotic fluid IL-10 between the two groups (MD = 0.11, 95%CI: -3.26-3.48, P < 0.01); the difference in amniotic fluid CRP between the two groups (MD = 21.34, 95%CI: 11.69-30.89, P < 0.01); the difference in amniotic fluid MCP-1 between the two groups (MD = 312.14, 95%CI: 211.34-412.97, P < 0.01); the difference in the amniotic fluid MMP-9 between the two groups (MD = 0.86, 95%CI: -0.10-1.82, P < 0.01); and the difference in TNF-α in amniotic fluid between the two groups (MD = 22.78, 95%CI: -5.05-50.61, P < 0.01). CONCLUSIONS: The inflammatory biomarkers IL-1ß, IL-6, IL-10, CRP, TNFα, MCP-1 and MMP-9 in the amniotic fluid of patients in the second- or third-trimester pregnancy were all correlated with preterm birth.

The premature foetus has many serious complications in the near and long term because of the immature organs, which is related to the long-term incidence of cerebral palsy, developmental delay and retinopathy of prematurity, which is the main cause of perinatal foetal death. Preterm birth cases are accompanied by infection of pathogenic microorganisms in amniotic cavity, which then leads to inflammatory reaction in amniotic cavity. However, research on the correlation between inflammatory markers and preterm birth has shown certain complexity and differences. The results of this meta-analysis show that the inflammatory biomarkers interleukin-1 beta (IL-1ß), interleukin-6 (IL-6) and interleukin-10 (IL-10), C-reactive protein (CRP), tumour necrosis factor-alpha (TNF-α), monocyte chemoattractant protein-1 (MCP-1) and matrix metalloproteinase-9 (MMP-9) in amniotic fluid of patients in the second- or third-trimester pregnancy are significant between the preterm birth group and the control group, and the expression level of inflammatory factors in amniotic fluid of patients in the preterm birth group is elevated, thus suggesting that these inflammatory factors may be able to predict preterm birth.

Intraoperative fluid management is not predictive of AKI in major pancreatic surgery: a retrospective cohort study.

BACKGROUND: Pancreatic surgery is associated with a significant risk for acute kidney injury (AKI) and clinically relevant postoperative pancreatic fistula (CR-POPF). This investigation evaluated the impact of intraoperative volume administration, vasopressor therapy, and blood pressure management on the primary outcome of AKI and the secondary outcome of a CR-POPF after pancreatic surgery. METHODS: This retrospective single-center cohort investigated 200 consecutive pancreatic surgeries (January 2018-December 2021). Patients were categorized for the presence/absence of AKI (Kidney Disease Improving Global Outcomes) and CR-POPF. After univariate analysis, multivariable models were constructed to control for the univariate cofactor differences in the primary and secondary outcomes. RESULTS: AKI was identified in 20 patients (10%) with significant univariate differences in demographics (body mass index and gender), comorbidities, indices of chronic renal insufficiency, and an increased AKI Risk score. Surgical characteristics, intraoperative fluid, vasopressor, and blood pressure management were similar in patients with and without AKI. Patients with AKI had increased blood loss, lower urine output, and packed red blood cell administration. After multivariate analysis, male gender (OR = 7.9, 95% C.I. 1.8-35.1) and the AKI Risk score (OR = 6.3, 95% C.I. 2.4-16.4) were associated with the development of AKI (p < 0.001). Intraoperative and postoperative volume, vasopressor administration, and intraoperative hypotension had no significant impact in the multivariate analysis. CR-POPF occurred in 23 patients (11.9%) with no significant contributing factors in the multivariate analysis. Patients who developed AKI or a CR-POPF had an increase in surgical complications, length of stay, discharge to a skilled nursing facility, and mortality. CONCLUSION: In this analysis, intraoperative volume administration, vasopressor therapy, and a blood pressure < 55 mmHg for more than 10 min were not associated with an increased risk of AKI. After multivariate analysis, male gender and an elevated AKI Risk score were associated with an increased likelihood of AKI.

Comparative evaluation of the diagnostic and prognostic performance of CNSide™ versus standard cytology for leptomeningeal disease.

Background: This retrospective study compares the real-world performance of cerebrospinal fluid (CSF) CNSide™ versus cytology in leptomeningeal disease (LMD). Methods: Consecutive patients with suspected LMD who underwent lumbar punctures for CSF cytology and CNSide™ from January 2020 to December 2022 were reviewed. LMD was classified by EANO criteria. Descriptive statistics, confusion matrix, Kaplan-Meier curves, and Cox proportional regression were used. Results: Median age for 87 evaluable patients was 63 years (range: 23-93); 82 (94%) met EANO criteria for possible/probable/confirmed LMD (EANO/LMD). The commonest primary cancers were breast (36,44.0%) and lung (34,41.5%). Primary lung harbored actionable mutations in 18 (53.0%); primary breast expressed hormone receptors in 27 (75%), and HER2 amplification in 8 (22%). Uncontrolled systemic disease was detected in 35 (40%), while 25 (46%) received systemic therapy with medium/high CNS penetrance at LMD diagnosis. The median time from initial cancer to LMD diagnosis was 31 months (range: 13-73). LMD was confirmed by CSF cytology in 23/82 (28%), all identified by CNSide™. CNSide™ identified 13 additional cases (36/82, 43.9%), increasing diagnostic yield by 56.5%. Median overall survival (mOS) was 31 weeks (95%CI: 21-43), significantly worse for CNSide™ positive versus negative: 4.0 versus 16.0 weeks, respectively (HR = 0.50, P = .010). While survival since LMD diagnosis did not differ by histology, time to LMD diagnosis from initial cancer diagnosis was longer for breast (48.5 months, IQR: 30.0-87.5) versus lung (8 months, IQR:0.5-16.0) cohorts. mOS was longer for patients eligible for intrathecal chemotherapy (HR: 0.189, 95%CI: 0.053-0.672, P = .010). Conclusions: This retrospective, real-world analysis of CNSide™ showed increased sensitivity versus cytology and provided clinically relevant molecular CSF analyses.

Anaplastic Multiple Myeloma With a Novel Proliferation of Pleomorphic Binuclear Plasma Cells.

This study describes an unusual case of multiple myeloma that progressed to anaplastic multiple myeloma in the pleural fluid. The Wright-stained cytospin of the pleural fluid showed a predominant population of mononuclear plasma cells with pleomorphic nuclei, characterized by both small and large nuclei, which is typical of anaplastic multiple myeloma. However, there were also more binuclear plasma cells with pleomorphic nuclei. Morphometric analysis showed that the mean nuclear length was 1.9-fold and 2.3-fold higher in the large nuclei compared to the small nuclei for the mononuclear plasma cells and binuclear plasma cells, respectively (p<0.001). The patient received B cell maturation antigen chimeric antigen receptor T cell (CAR-T) therapy for relapsed disease, with a significant reduction of the serum monoclonal paraprotein level at day 51 post-therapy. Pathologists should be aware that pleomorphic binuclear plasma cells can be part of the morphologic spectrum in anaplastic multiple myeloma.

Endoscopic Endonasal Reconstruction of Intraoperative Cerebrospinal Fluid Leak in Different Skull base Regions: Outcomes, Meningitis and Risk Factors.

OBJECTIVE: Various non-vascularized or vascularized techniques have been adopted in endoscopic endonasal surgery (EES) for repairing intraoperative cerebrospinal fluid (CSF) leaks after tumor resection. Vascularized nasoseptal flaps (VNSF), free nasoseptal grafts (FNSG), free turbinate grafts (FTG), fascia lata and mashed muscle (FLMM) are frequently used. Outcomes of those grafts applied in the defects of different regions need to be clarified. METHODS: The data from a series of 162 patients with skull base tumor who underwent EES that had intraoperative CSF leak between Jan 2012 and Jan 2021 were retrospectively analyzed. The regions included anterior skull base (ASB), sellar region, clivus and infratemporal fossa (ITF). Repair failure rate (RFR), meningitis rate and associated risk factors were assessed. RESULTS: In total, 172 reconstructions were performed in 162 patients for the four sites of the skull base. There were 7 cases (4.3%) that had postoperative CSF leaks, which required second repair. The RFR for ASB, sellar region, clivus, and ITF was 2.6%, 2.2%, 16.7%, and 0%, respectively. The clivus defect was an independent risk factor for repair failure (P<0.01). The postoperative meningitis rate was 5.6%. Repair failure was an independent risk factor for meningitis (P < 0.01). CONCLUSIONS: VNSF, FNSG, FTG, FLMM are reliable autologous materials for repairing the dural defects in different regions during EES. Clivus reconstruction remains a great challenge, which had a higher RFR and meningitis rate. Repair failure is significantly associated with postoperative meningitis.

Partial adhesive small bowel obstruction due to peritoneal tuberculosis HIV/AIDS patient: A case report.

INTRODUCTION: Diagnosing peritoneal tuberculosis is challenging due to unspecific clinical manifestations, particularly in immunocompromised patients with HIV/AIDS and tuberculosis infections. PRESENTATION OF CASE: An Indonesian man, 26-years-old, complained of mid-abdominal colic and constipation. The patient's present state exhibited symptoms of weakness and paleness, oral candidiasis, a bloated abdomen, palpable discomfort, and shifting dullness. The ascitic fluid analysis showed increased ADA (709 U/L), and detected Mycobacterium tuberculosis using GeneXpert MTB/RIF. Radiographic examination from abdominal x-ray and CT scan revealed a small bowel obstruction. He received intestinal decompression, pain control, intravenous fluid resuscitation, and correction of electrolyte imbalance for small bowel obstruction without any indication for surgical intervention. He also receive first-line ATD for 2 months during intensive phase and 4 months for continuous phase. After a period of 2 weeks following the ATD administration, the patient began taking ARV medication on a daily basis. He showed a good prognosis 6 months following. DISCUSSION: The diagnosis of peritoneal tuberculosis is challenging due to its unspecific manifestation and some cases are identified when complications such as small bowel obstruction appear. The ADA test and GenExpert MTB/RIF are useful instruments for promptly diagnosing tuberculosis. It is suggested to use ARV treatment in individuals with HIV/AIDS who have peritoneal tuberculosis, starting 2 weeks following ATD treatments. CONCLUSION: Peritoneal tuberculosis with small bowel obstruction and HIV/AIDS infection is a rare case in which early diagnosis and monitoring play an important role in successful treatment.

Bioanalytical validation and clinical application of a liquid chromatography-tandem mass spectrometry method for the quantification of 3-orthomethyldopa, 5-hydroxytryptophan, 5-hydroxyindolacetic acid and homovanillic acid in human cerebrospinal fluid.

Inherited disorders of monoamine neurotransmitters are a subset of inborn errors of metabolism affecting biochemical pathways of catecholamines, serotonin or their enzymatic cofactors. Usually, their clinical presentation is similar to those of other common neurological syndromes. For this reason, they are frequently under-recognized and misdiagnosed. Because cerebrospinal fluid concentration of catecholamine metabolites (3-orthomethyldopa and homovanillic acid) and serotonin metabolites (5-hydroxytryptophan and 5-hydroxyindolacetic acid) presents a direct correlation with their brain levels, analysis of this group of compounds is critical to reach an accurate diagnosis. Although there are several published liquid chromatography-based bioanalytical methods for the quantification of these compounds, most of them present disadvantages, making their application difficult to implement in routine clinical practice. In this study, a rapid and simple UHPLC-MS/MS method for simultaneous quantification of 3-orthomethyldopa, 5-hydroxytryptophan, 5-hydroxyindolacetic acid and homovanillic acid in human cerebrospinal fluid was validated. All the evaluated performance parameters, including linearity, carryover, accuracy and precision (within and between-day), lower limit of quantitation, recovery, matrix effect and stability under different conditions met the acceptance criteria from international guidelines. Additionally, 10 human cerebrospinal fluid samples collected via lumbar puncture from 10 pediatric patients were quantified using the validated method to assess its clinical application and diagnostic utility for inherited monoamine neurotransmitter metabolism.

Twenty percent human albumin solution fluid bolus administration therapy in patients after cardiac surgery-II: a multicentre randomised controlled trial.

PURPOSE: After cardiac surgery, fluid bolus therapy (FBT) with 20% human albumin may facilitate less fluid and vasopressor administration than FBT with crystalloids. We aimed to determine whether, after cardiac surgery, FBT with 20% albumin reduces the duration of vasopressor therapy compared with crystalloid FBT. METHODS: We conducted a multicentre, parallel-group, open-label, randomised clinical trial in six intensive care units (ICUs) involving cardiac surgery patients deemed to require FBT. We randomised 240 patients to receive up to 400 mL of 20% albumin/day as FBT, followed by 4% albumin for any subsequent FBT on that day, or to crystalloid FBT for at least the first 1000 mL, with use of crystalloid or 4% albumin FBT thereafter. The primary outcome was the cumulative duration of vasopressor therapy. Secondary outcomes included fluid balance. RESULTS: Of 480 randomised patients, 466 provided consent and contributed to the primary outcome (mean age 65 years; median EuroSCORE II 1.4). The cumulative median duration of vasopressor therapy was 7 (interquartile range [IQR] 0-19.6) hours with 20% albumin and 10.8 (IQR 0-22.8) hours with crystalloids (difference - 3.8 h, 95% confidence interval [CI] - 8 to 0.4; P = 0.08). Day one fluid balance was less with 20% albumin FBT (mean difference - 701 mL, 95% CI - 872 to - 530). CONCLUSIONS: In patients after cardiac surgery, when compared to a crystalloid-based FBT, 20% albumin FBT was associated with a reduced positive fluid balance but did not significantly reduce the duration of vasopressor therapy.

Cytology or Multiparameter Flow Cytometry Positivity in the Cerebrospinal Fluid Before Transplantation is Predictive of Poor Outcomes After Allotransplantation in Acute Myeloid Leukemia Patients.

INTRODUCTION: Central nervous system leukemia (CNSL) remains a serious complication in patients with acute myeloid leukemia (AML) and an ambiguous prognostic factor for those receiving allo-geneic hematopoiesis stem cell transplantation (allo-HSCT). It is unknown whether using more sensitive tools, such as multiparameter flow cytometry (MFC), to detect blasts in the cerebrospinal fluid (CSF) would have an impact on outcome. METHODS: We retrospectively analyzed the clinical outcomes of 1472 AML patients with or without cytology or MFC positivity in the CSF before transplantation. Abnormal CSF (CSF+) was detected via conventional cytology and MFC in 44 patients at any time after diagnosis. A control group of 175 CSF-normal (CSF-) patients was generated via propensity score matching (PSM) analyses according to sex, age at transplant, and white blood cell count at diagnosis. RESULTS: Compared to those in the CSF-negative group, the conventional cytology positive and MFC+ groups had comparable 8-year nonrelapse mortality (NRM) (4%, 4%, and 6%, p = 0.82), higher cumulative incidence of relapse (CIR) (14%, 31%, and 32%, p = 0.007), lower leukemia-free survival (LFS) (79%, 63%, and 64%, p = 0.024), and overall survival (OS) (83%, 63%, and 68%, p = 0.021), with no significant differences between the conventional cytology positive and MFC+ groups. Furthermore, multivariate analysis confirmed that CSF involvement was an independent factor affecting OS and LFS. CONCLUSION: Our results indicate that pretransplant CSF abnormalities are adverse factors independently affecting OS and LFS after allotransplantation in AML patients.

Endoscopic ultrasound-guided pancreatic fluid collection drainage: Where are we?

Pancreatic fluid collections (PFCs) result from injury to the pancreas from acute or chronic pancreatitis, surgery, or trauma. Management of these collections has evolved over the last 2 decades. The choice of interventions includes percutaneous, endoscopic, minimally invasive surgery, or a combined approach. Endoscopic drainage is the drainage of PFCs by creating an artificial communication between the collection and gastrointestinal lumen that is maintained by placing a stent across the fistulous tract. In this editorial, we endeavored to update the current status of endoscopic ultrasound-guided drainage of PFCs.

Widespread correction of brain pathology in feline alpha-mannosidosis by dose escalation of intracisternal AAV vector injection.

Alpha-mannosidosis is caused by a genetic deficiency of lysosomal alpha-mannosidase, leading to the widespread presence of storage lesions in the brain and other tissues. Enzyme replacement therapy is available but is not approved for treating the CNS, since the enzyme does not penetrate the blood-brain barrier. However, intellectual disability is a major manifestation of the disease; thus, a complimentary treatment is needed. While enzyme replacement therapy into the brain is technically feasible, it requires ports and frequent administration over time that are difficult to manage medically. Infusion of adeno-associated viral vectors into the cerebrospinal fluid is an attractive route for broadly targeting brain cells. We demonstrate here the widespread post-symptomatic correction of the globally distributed storage lesions by infusion of a high dose of AAV1-feline alpha-mannosidase (fMANB) into the CSF via the cisterna magna in the gyrencephalic alpha-mannosidosis cat brain. Significant improvements in clinical parameters occurred, and widespread global correction was documented pre-mortem by non-invasive magnetic resonance imaging. Postmortem analysis demonstrated high levels of MANB activity and reversal of lysosomal storage lesions throughout the brain. Thus, CSF treatment by adeno-associated viral vector gene therapy appears to be a suitable complement to systemic enzyme replacement therapy to potentially treat the whole patient.

A novel lumen-apposing metal stent for endoscopic drainage of symptomatic pancreatic fluid collections: a retrospective study.

Background and Objectives: Previous studies showed that lumen-apposing metal stent (LAMS) provides a feasible route to perform direct endoscopic necrosectomy. However, the high risk of bleeding and migration induced by the placement of LAMS attracted attention. The aim of this study was to evaluate the safety and effectiveness of a novel LAMS. Methods: In this retrospective study, we enrolled patients with symptomatic pancreatic fluid collections (PFCs) to perform EUS-guided drainage with a LAMS in our hospital. Evaluation variables included technical success rate, clinical success rate, and adverse events. Results: Thirty-two patients with a mean age of 41.38 ± 10.72 years (53.1% males) were included in our study, and the mean size of PFC was 10.06 ± 3.03 cm. Technical success rate and clinical success rate reached 96.9% and 93.8%, respectively. Stent migration occurred in 1 patient (3.1%), and no stent-induced bleeding occurred. The outcomes of using LAMS in 10 patients with pancreatic pseudocyst and 22 patients with walled-off necrosis were comparable. Compared with pancreatic pseudocyst, walled-off necrosis needed more direct endoscopic necrosectomy times to achieve resolution (P = 0.024). Conclusions: Our study showed that the novel LAMS is effective and safe for endoscopic drainage of PFCs with a relatively low rate of adverse events. Further large-scale multicenter studies are needed to confirm the present findings.