Cholesterol 24-hydroxylase: an enzyme of cholesterol turnover in the brain.

Cholesterol 24-hydroxylase is a highly conserved cytochrome P450 that is responsible for the majority of cholesterol turnover in the vertebrate central nervous system. The enzyme is expressed in neurons, including hippocampal and cortical neurons that are important for learning and memory formation. Disruption of the cholesterol 24-hydroxylase gene in the mouse reduces both cholesterol turnover and synthesis in the brain but does not alter steady-state levels of cholesterol in the tissue. The decline in synthesis reduces the flow of metabolites through the cholesterol biosynthetic pathway, of which one, geranylgeraniol diphosphate, is required for learning in the whole animal and for synaptic plasticity in vitro. This review focuses on how the link between cholesterol metabolism and higher-order brain function was experimentally established.

Endoscopic ultrasound-guided balloon-occluded gastrojejunostomy bypass, duodenal stent or laparoscopic gastrojejunostomy for unresectable malignant gastric outlet obstruction.

OBJECTIVES: Malignant gastric outlet obstruction (GOO) can be relieved by either laparoscopic gastrojejunostomy (LGJ), endoscopic stenting (SEMS) or endoscopic ultrasound-guided gastrojejunostomy (endoscopic ultrasound-guided balloon-occluded gastrojejunostomy bypass; EPASS). This study aimed to compare the outcomes of the three treatment methods. METHODS: This was a retrospective study of patients who suffered from malignant GOO between January 2012 to November 2020 that received either EPASS, LGJ or SEMS. The outcomes included the technical and clinical success, 30-day adverse events and mortality, pre and post stenting GOO scores (GOOSs), stent patency and causes of stent dysfunction. RESULTS: One hundred and fourteen patients were included (30 EPASS, 35 LGJ, 49 SEMS). The technical success of EPASS, LGJ and SEMS were 93.3%, 100%, 100% (P = 0.058) and clinical success rates were 93.3%, 80%, 87.8% (P = 0.276), respectively. Procedural time was longest for the LGJ group (P < 0.001). The EPASS group had the shortest hospital stay (EPASS 1.5 [1-17], LGJ 7 [2-44], SEMS 5 [2-46] days, P < 0.001). EPASS group also had the lowest rates of recurrent obstruction (EPASS 3.3%, LGJ 17.1%, SEMS 36.7%, P = 0.002) and re-intervention (EPASS 3.3%, LGJ 17.1%, SEMS 26.5%, P = 0.031). The 1-month GOOS was highest in the EPASS group (EPASS 3 [1-3], LGJ 3 [0-3], SEMS 2 [0-3], P = 0.028). CONCLUSION: Endoscopic ultrasound-guided gastrojejunostomy was associated with better clinical outcomes then the other two procedures. The procedure may be the best option provided that the expertise is available.

Multipoint fixation with vascularised fibular bone graft and myotomy for atlanto-axial instability in cervical dystonia: a case report.

Spinal instability is a challenging condition to manage in patients with cervical dystonia. Standard surgical stabilisation approaches may fail to cope with additional stress forces created by spasmodic muscles leading to construct failure either in the immediate or late post-operative period. Long-term stabilisation relies on the management of dystonic symptoms and adjunctive strategies to increase fusion success rate. We discuss the management of a challenging patient with translational C1/2 instability who had three metalwork failures with standard occipito-cervical fixation techniques within a 12 month period. A combined surgical approach using multipoint fixation, sternocleidomastoid myotomy and a vascularised fibular occiput-C2 bone graft successfully prevented further metalwork failure at over 2 years follow up.

Hydrolytically Degradable Microgels with Tunable Mechanical Properties Modulate the Host Immune Response.

Hydrogel microparticles (microgels) are an attractive approach for therapeutic delivery because of their modularity, injectability, and enhanced integration with the host tissue. Multiple microgel fabrication strategies and chemistries have been implemented, yet manipulation of microgel degradability and its effect on in vivo tissue responses remains underexplored. Here, the authors report a facile method to synthesize microgels crosslinked with ester-containing junctions to afford tunable degradation kinetics. Monodisperse microgels of maleimide-functionalized poly(ethylene-glycol) are generated using droplet microfluidics crosslinked with thiol-terminated, ester-containing molecules. Tunable mechanics are achievable based on the ratio of degradable to nondegradable crosslinkers in the continuous phase. Degradation in an aqueous medium leads to microgel deformation based on swelling and a decrease in elastic modulus. Furthermore, degradation byproducts are cytocompatible and do not cause monocytic cell activation under noninflammatory conditions. These injectable microgels possess time-dependent degradation on the order of weeks in vivo. Lastly, the evaluation of tissue responses in a subcutaneous dorsal pocket shows a dynamic type-1 like immune response to the synthetic microgels, driven by interferon gamma (IFN-γ ) expression, which can be moderated by tuning the degradation properties. Collectively, this study demonstrates the development of a hydrolytic microgel platform that can be adapted to desired host tissue immune responses.

Seven phenotypes of varus osteoarthritic knees can be identified in the coronal plane.

PURPOSE: Recommendations for resecting distal femur and proximal tibia in mechanical and anatomical alignment techniques are standardized. Kinematic alignment propagates individualizing resection planes. Whether significant variation exists, to warrant departure from standardized resection planes, has not been shown thus far in a large cohort of knees and with a wide range of varus deformity. The null hypothesis of this study was that there was no phenotypic variation in varus osteoarthritic knees. The aim of this paper was to determine whether distinct phenotypes could be identified, based on variations in coronal femoral and tibial morphology, which could aid in surgical planning and categorizing varus knees for future studies. METHODS: 2129 full-leg weightbearing radiographs were analyzed (1704 preoperative; 425 of contralateral arthritic knee). Measurements made were of HKA (hip-knee-ankle angle), VCA (valgus correction angle), mLDFA (lateral mechanical distal femoral angle), aLDFA (lateral anatomical distal femoral angle), MPTA (medial proximal tibial angle), MNSA (medial neck shaft angle), TAMA (angle between tibial mechanical and anatomical axes), and TPDR (percentage length of tibia proximal to extra-articular deformity). RESULTS: Seven distinct types were identified covering 2021 knees, reducible to 4 broad phenotypes: 11% were Type 1 'Neutral' knees showing values close to reported normal knees (mean VCA 5.5°, mLDFA 87°, aLDFA 81°). 38% were Type 2 'Intra-articular varus' with medial intra-articular bone loss (mean mLDFA 90.9°, MPTA 85.4°, VCA of 5.7°). 41% were Type 3 'Extra-articular varus' with extra-articular deformity (EAD). Type 3a had proximal tibial EAD; Type 3b had tibial diaphyseal EAD; Type 3c had femoral EAD (mean VCA 8.7°, HKA 166°), and severe medial bone loss (mean mLDFA 92°, MPTA 83°). 9% were Type 4 'Valgoid type' with features of valgus knees: Type 4a had medial femoral bowing (mean VCA 2.9°); Type 4b had significant distal femoral valgus (mean mLDFA 85.3°, aLDFA 78.6°). CONCLUSIONS: The null hypothesis that there was no phenotypic variation in varus osteoarthritic knees was rejected as considerable variation was found in coronal morphology of femur and tibia. Four broad phenotypic groups could be identified. Plane of the knee joint articular surface was quite variable. This has relevance to planning and performance of corrective osteotomies, unicompartmental and total knee arthroplasty. LEVEL OF EVIDENCE: III, retrospective cohort study.

Factors associated with endometrial cancer and hyperplasia among middle-aged and older Hispanics.

OBJECTIVE: While disparities in endometrial hyperplasia and endometrial cancer are well documented in Blacks and Whites, limited information exists for Hispanics. The objective is to describe the patient characteristics associated with endometrial hyperplasia symptoms, endometrial hyperplasia with atypia and endometrial cancer, and assess factors contributing to racial/ethnic differences in disease outcomes. METHODS: This single-center, retrospective study included women aged ≥50 years with ≥ two encounters for endometrial hyperplasia symptoms, endometrial hyperplasia with atypia and endometrial cancer between 2012 and 2016. Multivariate logistic regression models evaluated the predictors of endometrial cancer and hyperplasia. RESULTS: We included 19,865 women (4749 endometrial hyperplasia symptoms, 71 endometrial hyperplasias with atypia, 201 endometrial cancers) with mean age of 60.45 years (SD 9.94). The odds of endometrial hyperplasia symptoms were higher in non-Hispanic Blacks (Odds Ratio [OR] 1.56, 95% Confidence Interval [CI] 1.20-1.72), Hispanics (OR 1.35, 95% CI 1.22-1.49), family history of female cancer (OR 1.25, 95% CI 1.12-1.39), hypertension (OR 1.24, 95% CI 1.14-1.35), and birth control use (OR 1.29, 95% CI 1.15-1.43). Odds of endometrial cancer and atypical hyperplasia increased for ages 60-64 (OR 7.95, 95% CI 3.26-19.37; OR 3.66, 95% 1.01-13.22) and being obese (OR 1.61, 95% CI 1.08-2.41; OR: 6.60, 95% CI 2.32-18.83). Odds of endometrial cancer increased with diabetes (OR 1.68, 95% CI 1.22-2.32). CONCLUSION(S): Patients with obesity and diabetes had increased odds of endometrial cancer and hyperplasia with atypia. Further study is needed to understand the exogenous estrogen effect contributing to the increased incidence among Hispanics.

Ocular Point-of-Care Ultrasound: Description of Intermediate Uveitis in an Adolescent Female.

ABSTRACT: Ocular point-of-care ultrasound has been used to assess for intraocular pathology, including retinal and vitreous detachment. We describe a pediatric patient whose initial point-of-care ultrasound examination appeared to be consistent with bilateral posterior vitreous detachment but who was ultimately diagnosed with intermediate uveitis.

WiMonitor: Continuous Long-Term Human Vitality Monitoring Using Commodity Wi-Fi Devices.

For a large population of elderly who live alone, a continuous long-term daily monitoring system is critical and imminently needed to enhance the quality of their lives. Continuous monitoring of vitality information (i.e., which area the elder is staying in, the motion state and activity intensity of an elder) is essential for elderly care. In this paper, we use existing commodity Wi-Fi devices to design and implement a long-term device-free human daily vitality system, WiMonitor. Our system can continuously capture the target's vitality information in a multi-room home environment without compromising the privacy of the target. In a continuous 22-day experiment, WiMonitor successfully captures the human vitality information accurately. We believe our system can provide valuable long-term monitoring data for both researchers and health care personnel.

Primary Prophylaxis Patterns for Hepatic Encephalopathy in Patients with Liver Cirrhosis: What are the Current Prescribing Trends in Specialty Practice?

INTRODUCTION: Hepatic encephalopathy (HE) is a significant complication of severe chronic liver insufficiency characterized by altered sensorium, motor, and cognitive dysfunction. This was a cross-sectional multicenter, epidemiological study to understand the prescribing pattern for primary prophylaxis of overt HE (OHE) in patients with cirrhosis in India. METHODS: The study was conducted at eight centers across different geographical regions of India. A total of 200 patients (100%) were screened, of which 197 (98.50%) met all the inclusion criteria. The prescribing pattern of the physicians was studied by calculating the percentage (subject to availability of sufficient data) of OHE-naïve patients with cirrhosis who were prescribed with different classes of drugs as primary prophylaxis of HE (such as lactulose, rifaximin, neomycin, sodium benzoate, and L-ornithine L- aspartate). The risk factors responsible for initiation of primary prophylaxis of HE was also determined. RESULTS: All the 197 patients (100%) were prescribed with prophylactic treatment. The factors that were considered by treating physicians to pose a risk for precipitating OHE for which prophylaxis was initiated were constipation in 111 (56.35%), infections in 51 (25.89%) and gastrointestinal bleeding in 35 (17.77%). Of the total 197 patients, 122 (61.93%) patients were prescribed a monotherapy, and 75 (38.07%) were prescribed a combination therapy. Of the patients on combination therapy, 68 (34.52%) patients were prescribed with two primary prophylaxis agents (dual therapy), and seven (3.55%) patients were prescribed with three primary prophylaxis agents (triple therapy). Lactulose was the most commonly prescribed agent for primary prophylaxis, followed by rifaximin. CONCLUSION: These findings may guide recommendations on primary prophylaxis for OHE in patients with liver cirrhosis that may help reduce the occurrence of first episode of overt HE, and thereby prevent subsequent cognitive impairment in these patients.

Early removal of biflanged metal stents in the management of pancreatic walled-off necrosis: a prospective study.

BACKGROUND AND STUDY AIMS: Dedicated stents placed under endoscopic ultrasound (EUS) guidance have shown promise for the management of pancreatic walled-off necrosis (WON). A long duration of stent placement may increase the risk of adverse events. We prospectively evaluated the effects of (i) early removal of biflanged metal stents (BFMSs) and (ii) additional stenting of the pancreatic duct with plastic stents in patients with ductal leaks, on the risk of WON recurrence. PATIENTS AND METHODS: Symptomatic patients with pancreatic WON underwent EUS-guided BFMS placement, followed by necrosectomy, when required, from Day 3. A 5 Fr plastic stent was placed in patients with ductal leak. BFMS was removed when the WON cavity had collapsed completely. Patients were followed up at 3-month intervals. RESULTS: BFMS placement was successful in all 88 patients. A total of 64 patients (72.7 %) underwent necrosectomy (median 3 sessions). All BFMSs were removed at a median of 3.5 weeks (range 3 - 17 weeks). Ductal disconnection and leak occurred in 53/87 (60.9 %) and 61/87 (70.1 %) patients, respectively. A 5 Fr stent was placed in 56/61 patients (91.8 %) with ductal leak. Overall, 22 patients (25.0 %) had adverse events (17 mild, 1 moderate, 3 severe, 1 fatal). Recurrence was noted in 8/88 (9.1 %) at a median follow-up of 22 months. The recurrence rate was higher in patients with ductal disconnection than in those without (13.2 % vs. 2.9 %; P = 0.08), and was similar in patients with vs. without pancreatic duct stenting (7.1 % vs. 12.9 %; P = 0.44). Seven recurrences (87.5 %) partially regressed on follow-up and did not require therapy; in one case, drainage with a plastic stent was performed. CONCLUSIONS: Short-term BFMS placement is an effective therapy for pancreatic WON. The majority of recurrences developed in patients with ductal disconnection and did not require therapy. Additional pancreatic duct stents probably do not influence the recurrence rate.

Outcomes after endoscopic dilation of laryngotracheal stenosis: an analysis of ACS-NSQIP.

IMPORTANCE: Endoscopic management of pediatric subglottic stenosis (SGS) is common, however no multi-institutional studies have assessed its perioperative outcomes. The American College of Surgeon's National Surgical Quality Improvement Program - Pediatric (ACS-NSQIP-P) represents a source of such data. DESIGN: Current procedural terminology (CPT) codes were queried for endoscopic or open airway reconstruction in the ACS-NSQIP-P Public Use File (PUF). Demographics and 30-day events were abstracted to compare open to endoscopic techniques and to assess for risk factors for varied outcomes after endoscopic dilation. SETTING: National database. PARTICIPANTS: Patients with data reported in the 2015 ACS-NSQIP-P PUF. MEASUREMENTS: Length of stay (LOS), 30-day rates of reintubation, readmission and reoperation. RESULTS: 171 endoscopic and 116 open procedures were identified. Mean age at endoscopic and open procedures was 4.1 (SEM = 0.37) and 5.4 years (SEM = 0.40) respectively. Mean LOS was shorter after endoscopic procedures (5.5 days, SEM = 1.13 vs. 11.3 days SEM = 1.01, p = 0.0003). Open procedures had higher rates of reintubation (OR = 7.41, p = .026) and reoperation (OR = 3.09, p = .009). In patients undergoing endoscopic dilation, children <1 year were more likely to require readmission (OR=4.21, p=0.03) and reoperation (OR=4.39, p=0.03) when compared to older children. CONCLUSION: Open airway reconstruction is associated with longer LOS and increased reintubations and reoperations, suggesting a possible opportunity to improve value in healthcare in the appropriately selected patient. Reoperations and readmissions following endoscopic dilation are more prevalent in children less than one year.

Predicting older adults who return to the hospital or die within 30†days of emergency department care using the ISAR tool: subjective versus objective risk factors.

BACKGROUND: We sought to evaluate the ability of the Identification of Seniors At Risk (ISAR) tool to differentiate between older adult patients having a poor outcome within 30 days of emergency department (ED) care and those who do not. We compare prognostic accuracy of subjective versus objective risk factors. METHODS: 202 community-dwelling patients age 65 years and older presenting to two EDs were prospectively enrolled. Participants completed the six-question ISAR and objective testing (cognition, ambulation, vision). We reviewed electronic medical records for current medications, hospitalisations in the past six months, ED disposition, length of hospital stay, subsequent ED visits or inpatient admissions or death at 30 days. Participants were given a point for each risk factor present; subjective and objective risk factors were scored separately. We tested ability of individual risk factors and scores to predict a composite outcome of subsequent ED visit, postdischarge hospitalisation or death by day 30 after the index ED visit. We computed receiver operating curve area under the curves (AUC) to determine tool discrimination. RESULTS: 23% of participants had a poor 30-day outcome. The optimum subjective ISAR cut-off score for screening was ≥2, which was present in 84% of participants, had a sensitivity of 91% and specificity of 19%. Using the subjective ISAR tool, the AUC was 0.66. The optimum objective ISAR-related risk cut-off score for screening was ≥3, which was present in 82% of participants, had a sensitivity of 87% and specificity of 40%. Using the objective ISAR-related tool, the AUC was 0.69. CONCLUSIONS: The self-reported ISAR tool did not discriminate well between older adults with or without 30-day hospital revisit or death. An optimum score of ≥2 would identify many older adults at no apparent increased risk of poor outcomes at 30 days. Using objective ISAR-related risk factors did not improve overall discrimination.

Life-threatening upper gastrointestinal bleeding due to gastric Dieulafoy's lesion: Successful minimally-invasive management.

Dieulafoy's lesion (DL) is a relatively rare, but potentially life-threatening condition. It accounts for 1-2% of acute gastrointestinal bleedings. Its serious nature makes it necessary for early diagnosis and treatment. This is a case report of a patient who presented with life-threatening haematemesis due to gastric Dieulafoy's that was successfully treated laparoscopically after failed endotherapy.

Biographical sketch: Jason Brice.

This article is a biographical sketch of retired British neurosurgeon Jason Brice, who is a pioneer of deep brain stimulation and helped establish the Wessex Neurological Centre.

Delayed post-operative haemorrhage after carmustine wafer implantation: a case series from two UK centres.

OBJECT: Significant haemorrhage following intracranial tumour resection may occur in 1-2% of cases and the majority occur within the first few hours post-operatively. Implantation of carmustine wafers has been associated with increased operative site complications in some series, but post-operative haematoma is not routinely reported. We analyzed the characteristics of post-operative haemorrhage after carmustine wafer insertion. METHODS: We performed a retrospective audit of surgical site haematoma after tumour resection and insertion of carmustine wafers in two neurosurgical units in the UK (University Hospital of North Staffordshire, Stoke-on-Trent, March 2003 - July 2012; Wessex Neurological Centre, Southampton, October 2005 - January 2013). RESULTS: During the specified time periods, carmustine wafers were inserted in 181 operations in 177 patients. We identified acute operative site haematomas after carmustine wafer insertion in 8 (4.4%) patients. All presented in a delayed fashion on or after Day 2 post-operatively. In contrast, acute operative site haematoma was present in 4/491 (0.81%) of patients who underwent resection without gliadel wafer insertion. CONCLUSIONS: In contrast to the expected timing of bleeding following intracranial tumour resection, all carmustine wafer patients who experienced haemorrhage presented in a delayed fashion on or after Day 2 post-operatively. The causative factors for universally delayed post-operative haematoma after carmustine wafer insertion are unclear and further studies are required to characterize this phenomenon.

The use of artificial dermal substitutes for repair of the donor site following harvesting of a radial forearm free flap: A systematic review.

BACKGROUND: Artificial dermal substitutes (ADMs) have been trialled to improve outcomes at the donor site following the harvesting of a radial forearm free flap (RFFF). This systematic review compares donor site aesthetic and functional outcomes, with the use of an ADM versus conventional practice. METHODS: The databases Medline, Embase, Cochrane Library, Web of Science (Core Collection), and Scopus were searched for retrospective, prospective, and case-control studies and randomised control trials (RCTs) involving any ADM. Studies with adult patients having undergone RFFF harvesting and donor site repair with an ADM, commenting on appropriate clinical outcomes and without high risk of bias, were included. Direction-of-effect analysis was performed on relevant groupings of studies since heterogeneity in outcome measurement precluded meta-analyses. RESULTS: Across eight non-comparative studies included, 132 patients had donor site coverage with AlloDerm™, Integra™, Matriderm™, or Rapiderm. Across 11 comparative studies included, 240 patients had donor site coverage with fish-skin matrix, AlloDerm™, amniotic membrane, MegaDerm™, Hyalomatrix, Integra™, or Matriderm™. Five out of 11 comparative studies demonstrated superior aesthetic outcomes with ADMs according to at least one aesthetic metric compared to controls, whilst 6/11 demonstrated superior functional outcomes with ADMs. No study demonstrated poorer aesthetic or functional outcomes with an ADM compared to conventional practice. CONCLUSIONS: In summary, the lack of studies reporting poorer outcomes with them compared to conventional practices, and a cumulative effect direction in their favour, provide strong indications in support of the use of AlloDerm™, Integra™, or Matriderm™ grafts. Further comparative studies, including RCTs, are needed to reinforce these initial indications.

Pediatric Airway Balloon Dilation: Urge for Safety Redesign.

Airway balloons are widely used by otolaryngologists to treat laryngotracheal stenosis. We review an adverse event and interventions that may prevent similar occurrences. There are no other reports of similar incidents in the Food and Drug Administration Manufacturer and User Facility Device Experience. We implore Acclarent to redesign their airway balloon device to prevent accidental airway irrigation.

Can ChatGPT help patients answer their otolaryngology questions?

Background: Over the past year, the world has been captivated by the potential of artificial intelligence (AI). The appetite for AI in science, specifically healthcare is huge. It is imperative to understand the credibility of large language models in assisting the public in medical queries. Objective: To evaluate the ability of ChatGPT to provide reasonably accurate answers to public queries within the domain of Otolaryngology. Methods: Two board-certified otolaryngologists (HZ, RS) inputted 30 text-based patient queries into the ChatGPT-3.5 model. ChatGPT responses were rated by physicians on a scale (accurate, partially accurate, incorrect), while a similar 3-point scale involving confidence was given to layperson reviewers. Demographic data involving gender and education level was recorded for the public reviewers. Inter-rater agreement percentage was based on binomial distribution for calculating the 95% confidence intervals and performing significance tests. Statistical significance was defined as p < .05 for two-sided tests. Results: In testing patient queries, both Otolaryngology physicians found that ChatGPT answered 98.3% of questions correctly, but only 79.8% (range 51.7%-100%) of patients were confident that the AI model was accurate in its responses (corrected agreement = 0.682; p < .001). Among the layperson responses, the corrected coefficient was of moderate agreement (0.571; p < .001). No correlation was noted among age, gender, or education level for the layperson responses. Conclusion: ChatGPT is highly accurate in responding to questions posed by the public with regards to Otolaryngology from a physician standpoint. Public reviewers were not fully confident in believing the AI model, with subjective concerns related to less trust in AI answers compared to physician explanation. Larger evaluations with a representative public sample and broader medical questions should immediately be conducted by appropriate organizations, governing bodies, and/or governmental agencies to instill public confidence in AI and ChatGPT as a medical resource. Level of Evidence: 4.