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BACKGROUND Higher-volume centers for pancreatic cancer surgeries have been shown to have improved outcomes such as length of stay. We examined how centralization of pancreatic cancer care within a regional integrated healthcare system improves overall survival. METHODS We conducted a retrospective study of 1621 patients treated for pancreatic cancer from February 2010 to December 2018. Care was consolidated into 4 Centers of Excellence (COE) in surgery, medical oncology, and other specialties. Descriptive statistics, bivariate analysis, Chi-square tests, and Kaplan-Meier analysis were performed. RESULTS Neoadjuvant chemotherapy use rose from 10% to 31% (p

Background: Colorectal cancer is the fourth most diagnosed malignancy worldwide and surgery is one of the cornerstones of the treatment strategy. Near-infrared (NIR) fluorescence imaging is a new and upcoming technique, which uses an NIR fluorescent agent combined with a specialised camera that can detect light in the NIR range. It aims for more precise surgery with improved oncological outcomes and a reduction in complications by improving discrimination between different structures.Methods: A systematic search was conducted in the Embase, Medline and Cochrane databases with search terms corresponding to 'fluorescence-guided surgery', 'colorectal surgery', and 'colorectal cancer' to identify all relevant trials.Results: The following clinical applications of fluorescence guided surgery for colorectal cancer were identified and discussed: (1) tumour imaging, (2) sentinel lymph node imaging, (3) imaging of distant metastases, (4) imaging of vital structures, (5) imaging of perfusion. Both experimental and FDA/EMA approved fluorescent agents are debated. Furthermore, promising future modalities are discussed.Conclusion: Fluorescence-guided surgery for colorectal cancer is a rapidly evolving field. The first studies show additional value of this technique regarding change in surgical management. Future trials should focus on patient related outcomes such as complication rates, disease free survival, and overall survival. (C) 2021 The Authors. Published by Elsevier Ltd.

STAT3 signaling has been shown to regulate cellular function and cytokine production in the tumor microenvironment (TME). Within the head and neck squamous cell carcinoma (HNSCC) TME, we previously showed that therapeutic targeting of STAT3 in combination with radiation resulted in improved tumor growth delay. However, given the independent regulatory effects STAT3 has on anti-tumor immunity, we aimed to decipher the effects of individually targeting STAT3 in the cancer cell, regulatory T cells (Tregs), and natural killer (NK) cell compartments in driving tumor growth and resistance to therapy in HNSCCs. We utilized a CRISPR knockout system for genetic deletion of STAT3 within the cancer cell as well as two genetic knockout mouse models, FoxP3-Cre/STAT3 fl and NKp46-Cre/STAT3 fl, for Tregs and NK cell targeting, respectively. Our data revealed differences in development of resistance to treatment with STAT3 CRISPR knockout in the cancer cell, driven by differential recruitment of immune cells. Knockout of STAT3 in Tregs overcomes this resistance and results in Treg reprogramming and recruitment and activation of antigen-presenting cells. In contrast, knockout of STAT3 in the NK cell compartment results in NK cell inactivation and acceleration of tumor growth. These data underscore the complex interplay between the cancer cell and the immune TME and carry significant implications for drug targeting and design of combination approaches in HNSCCs.

Background: Despite advances in surgery and pharmacotherapy, there remains significant residual ischemic risk after coronary artery bypass grafting surgery. Methods: In REDUCE-IT (Reduction of Cardiovascular Events With Icosapent Ethyl–Intervention Trial), a multicenter, placebo-controlled, double-blind trial, statin-treated patients with controlled low-density lipoprotein cholesterol and mild to moderate hypertriglyceridemia were randomized to 4 g daily of icosapent ethyl or placebo. They experienced a 25% reduction in risk of a primary efficacy end point (composite of cardiovascular death, myocardial infarction, stroke, coronary revascularization, or hospitalization for unstable angina) and a 26% reduction in risk of a key secondary efficacy end point (composite of cardiovascular death, myocardial infarction, or stroke) when compared with placebo. The current analysis reports on the subgroup of patients from the trial with a history of coronary artery bypass grafting. Results: Of the 8179 patients randomized in REDUCE-IT, a total of 1837 (22.5%) had a history of coronary artery bypass grafting, with 897 patients randomized to icosapent ethyl and 940 to placebo. Baseline characteristics were similar between treatment groups. Randomization to icosapent ethyl was associated with a significant reduction in the primary end point (hazard ratio [HR], 0.76 [95% CI, 0.63–0.92]; P =0.004), in the key secondary end point (HR, 0.69 [95% CI, 0.56–0.87]; P =0.001), and in total (first plus subsequent or recurrent) ischemic events (rate ratio, 0.64 [95% CI, 0.50–0.81]; P =0.0002) compared with placebo. This yielded an absolute risk reduction of 6.2% (95% CI, 2.3%–10.2%) in first events, with a number needed to treat of 16 (95% CI, 10–44) during a median follow-up time of 4.8 years. Safety findings were similar to the overall study: beyond an increased rate of atrial fibrillation/flutter requiring hospitalization for at least 24 hours (5.0% vs 3.1%; P =0.03) and a nonsignificant increase in bleeding, occurrences of adverse events were comparable between groups. Conclusions: In REDUCE-IT patients with a history of coronary artery bypass grafting, treatment with icosapent ethyl was associated with significant reductions in first and recurrent ischemic events. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT01492361.

To evaluate the effectiveness of netarsudil in combination with other ocular hypotensive agents in patients with open-angle glaucoma (OAG) or ocular hypertension (OHT).Retrospective cohort study.All patients with OAG or OHT with netarsudil added to a regimen of at least 1 other ocular hypotensive agent between March 2018 and March 2019.Subjects with at least 2 baseline intraocular pressure (IOP) measurements on the same medication regimen before initiation of netarsudil were included. Subjects were excluded if they experienced other changes in their ocular hypotensive medication regimen.Change in IOP after initiation of netarsudil was assessed using linear mixed-effect models. Kaplan-Meier survival analysis was used to evaluate the time to discontinuation of netarsudil for any reason.Netarsudil was prescribed for 191 eyes of 138 patients. All of these subjects were included in the analysis of adverse effects. Twelve subjects discontinued netarsudil before the first follow-up visit because of adverse effects, leaving 175 eyes of 126 patients with at least 1 follow-up visit while using netarsudil included in the effectiveness analysis. The mean baseline IOP ± standard deviation was 17.1 ± 5.2 mmHg on a median of 2 ocular hypotensive medications. Including all observations on the same medication regimen after the addition of netarsudil, the mean IOP was 15.0 ± 4.5 mmHg, with a mean reduction of 2.2 mmHg (P0.001). A reduction in IOP was observed in eyes on 1 (2.0 mmHg, P0.001), 2 (1.0 mmHg, P = 0.12), 3 (3.0 mmHg, P0.001), and 4 (2.9 mmHg, P = 0.002) medications at baseline. A sustained ≥ 20% IOP reduction was observed in 16.2% of 123 eyes with at least 2 observations on treatment with netarsudil. Of the 138 subjects who were treated with netarsudil, 26.8% discontinued it because of adverse effects. The median time to discontinuation of netarsudil for any reason was 88 days.This study demonstrates a modest reduction in IOP is achievable with netarsudil in patients with OAG or OHT who are taking as many as 4 ocular hypotensive medications. The incidence of discontinuation due to adverse effects or inadequate efficacy was high.

Background Dorsal root ganglion (DRG) stimulation, an invasive method of neuromodulation, and transcranial direct current stimulation (tDCS), a non-invasive method of altering cortical excitability, have both proven effective in relieving chronic pain. Objective We employed a randomized, sham-controlled crossover study design to investigate whether single-session tDCS would have an additive therapeutic effect alongside DRG stimulation (DRGS) in the treatment of chronic pain. Methods Sixteen neuropathic pain patients who were previously implanted with DRG stimulators were recruited. Baseline pain scores were established with DRGS-OFF. Pain scores were then recorded with DRGS-ON, after paired sham tDCS stimulation, and after paired active anodal tDCS (a-tDCS) stimulation. For active tDCS, patients were randomized to ‘MEG (magnetoencephalography) localized’ tDCS or contralateral motor cortex (M1) tDCS for 30 min. EEG recordings and evaluations of tDCS adverse effects were also collected. Results All participants reported the interventions to be tolerable with no significant adverse effects during the session. Paired DRGS/active tDCS resulted in a significant reduction in pain scores compared to paired DRGS-ON/sham tDCS or DRGS alone. There was no difference in the additive effect of M1 vs. MEG-localized tDCS. Significant augmentation of beta activity was observed between DRGS-OFF and DRGS-ON conditions, as well as between paired DRGS-ON/sham tDCS and paired DRGS-ON/active tDCS. Conclusion Our results indicate that a single session of tDCS alongside DRGS is safe and can significantly reduce pain acutely in neuropathic pain patients. Paired invasive/non-invasive neuromodulation is a promising new treatment strategy for pain management and should be evaluated further to assess long-term benefits.

The incidence of internal carotid artery (ICA) injury associated with endoscopic endonasal approaches to the pituitary is less than 1%. While parent vessel sacrifice has historically been the choice of treatment, vessel-preserving endovascular techniques have been reported. Although flow diversion offers endoluminal reconstruction, its major limitation is the delay in obtaining complete occlusion. We describe the use of a combined Pipeline embolization device (PED) with endoscopic endonasal repair using a fascia lata/muscle graft to treat an iatrogenic ICA pseudoaneurysm and report long-term radiographic follow-up. Further investigation into the utility of directed endoscopic endonasal repair of iatrogenic pseudoaneurysms initially treated with PED is necessary, especially given the need of post-PED anticoagulation and the rate of permanent neurological deficit after ICA sacrifice.

ObjectiveLiver biopsy is still needed for fibrosis staging in many patients with non-alcoholic fatty liver disease. The aims of this study were to evaluate the individual diagnostic performance of liver stiffness measurement by vibration controlled transient elastography (LSM-VCTE), Fibrosis-4 Index (FIB-4) and NAFLD (non-alcoholic fatty liver disease) Fibrosis Score (NFS) and to derive diagnostic strategies that could reduce the need for liver biopsies.DesignIndividual patient data meta-analysis of studies evaluating LSM-VCTE against liver histology was conducted. FIB-4 and NFS were computed where possible. Sensitivity, specificity and area under the receiver operating curve (AUROC) were calculated. Biomarkers were assessed individually and in sequential combinations.ResultsData were included from 37 primary studies (n=5735; 45% women; median age: 54 years; median body mass index: 30 kg/m2; 33% had type 2 diabetes; 30% had advanced fibrosis). AUROCs of individual LSM-VCTE, FIB-4 and NFS for advanced fibrosis were 0.85, 0.76 and 0.73. Sequential combination of FIB-4 cut-offs (ConclusionSequential combinations of markers with a lower cut-off to rule-out advanced fibrosis and a higher cut-off to rule-in cirrhosis can reduce the need for liver biopsies.

Background & Aims Progression of chronic liver disease (CLD) to liver cirrhosis and liver cancer is a major global cause of morbidity and mortality. Treatment options capable of inhibiting progression of liver fibrosis when etiological treatment of CLD is not available or fails have yet to be established. We investigated the role of serine/threonine kinase p70 ribosomal protein S6 kinase (p70S6K) as checkpoint of fibrogenesis in hepatic stellate cells (HSCs) and as target for the treatment of liver fibrosis. Approach & Results Immunohistochemistry was used to assess p70S6K expression in liver resection specimen. Primary human or murine HSCs from wild-type or p70S6K–/– mice as well as LX-2 cells were used for in vitro experiments. Specific small interfering RNA or CEP-1347 were used to silence or inhibit p70S6K and assess its functional relevance in viability, contraction and migration assays, fluorescence-activated cell sorting, and Western blot. These results were validated in vivo by a chemical model of fibrogenesis using wild-type and p70S6K–/– mice. Expression of p70S6K was significantly increased in human cirrhotic vs noncirrhotic liver-tissue and progressively increased in vitro through activation of primary human HSCs. Conversely, p70S6K induced fibrogenic activation of HSCs in different models, including the small interfering RNA–based silencing of p70S6K in HSC lines, experiments with p70S6K–/– cells, and the pharmacological inhibition of p70S6K by CEP-1347. These findings were validated in vivo as p70S6K–/– mice developed significantly less fibrosis upon exposure to CCl4. Conclusions We establish p70S6K as a checkpoint of fibrogenesis in vitro and in vivo and CEP-1347 as potential treatment option that can safely be used for long-term treatment., Graphical abstract

Objective Drug-induced liver injury (DILI) is a leading cause of acute liver failure (ALF). Predictors for orthotopic liver transplantation (OLT) or death in drug-induced ALF (DI-ALF) are scarce. Methods In total 33 of 346 patients recruited for our prospective study on potentially hepatotoxic drugs had ALF. DILI diagnosis was based on Roussel Uclaf Causality Assessment Method (RUCAM) score and expert opinion. Area under the receiver operating characteristic (AUROC) curve, Youden's index and positive and negative likelihood ratios were calculated to identify the best performing predictive markers and scores for OLT or death. Results Poor outcome was associated with lower baseline platelet counts and cholinesterase (CHE) levels, higher International Normalized Ratio (INR) levels and Model for End-Stage Liver Disease (MELD) scores. Yet, AUROC reached a maximum of only 0.71-0.75 for either of those laboratory markers or the MELD score. Notably however, combinations of those scores were highly discriminatory, in particular INR/(CHE*platelet count) and MELD/(CHE*platelet count), showing an AUROC of 0.91, a positive likelihood ratios of 13.78 and a negative likelihood ratios of 0.08. Conclusion While baseline MELD score, INR, CHE, and platelet counts had limited potential to discriminate between DI-ALF with survival or poor outcome, their combinations were highly associated with OLT or death in patients with DI-ALF.

BACKGROUND Little is known about the epidemiology of allergic contact dermatitis in the aging US population. OBJECTIVE The aim of this study was to describe patch test results in a cohort of older adult patients evaluated in a patch testing clinic in a tertiary medical center. METHODS This study was a retrospective analysis of patch test results of adults 65 years and older from February 2013 to December 2019. RESULTS Data from a total of 169 patients 65 years and older were analyzed. Of these patients, 84.6% (143/169) had 1 or more positive reactions on patch testing, 84.6% (121/143) of which were felt to be clinically relevant and received a final diagnosis of allergic contact dermatitis. The most common allergen categories were fragrances (30.1%), preservatives (20.8%), metals (11.0%), medicaments (8.3%), and textile dyes (6.5%). The most common individual allergens were Myroxylon pereirae resin (balsam of Peru), hydroperoxide of linalool, methylisothiazolinone, nickel sulfate, and fragrance mix I. Personal products were by far the most common presumed source of allergen exposure. CONCLUSIONS Allergic contact dermatitis is a common diagnosis in the older adult population, and patch testing with allergen avoidance counseling can be an important diagnostic step and potential cure for this allergic condition.

Purpose To describe the clinical characteristics, surgical outcomes, and management recommendations in patients with traumatic rhegmatogenous retinal detachment (RRD) resulting from self-injurious behavior (SIB). Design International, multicenter, retrospective, interventional case series. Participants Patients with SIB from 23 centers with RRD in at least 1 eye. Methods Clinical histories, preoperative assessment, surgical details, postoperative management, behavioral intervention, and follow-up examination findings were reviewed. Main Outcome Measures The rate of single-surgery anatomic success (SSAS) was the primary outcome. Other outcomes included new RRD in formerly attached eyes, final retinal reattachment, and final visual acuity. Results One hundred seven eyes with RRDs were included from 78 patients. Fifty-four percent of patients had bilateral RRD or phthisis bulbi in the fellow eye at final follow-up. The most common systemic diagnoses were autism spectrum disorder (35.9%) and trisomy 21 (21.8%) and the most common behavior was face hitting (74.4%). The average follow-up time was 3.3 ± 2.8 years, and surgical outcomes for operable eyes were restricted to patients with at least 3 months of follow-up (81 eyes). Primary initial surgeries were vitrectomy alone (33.3%), primary scleral buckle (SB; 26.9%), and vitrectomy with SB (39.7%), and 5 prophylactic SBs were placed. Twenty-three eyes (21.5%) with RRDs were inoperable. The SSAS was 23.1% without tamponade (37.2% if including silicone oil), and final reattachment was attained in 80% (36.3% without silicone oil tamponade). Funnel-configured RRD (P = 0.006) and the presence of grade C proliferative vitreoretinopathy (P = 0.002) correlated with re-detachment. The use of an SB predicted the final attachment rate during the initial surgery (P = 0.005) or at any surgery (P = 0.008. These associations held if restricting to 64 patients with ≥12 months followup. Anatomic reattachment correlated with better visual acuity (P Conclusions RRD resulting from SIB poses therapeutic challenges because of limited patient cooperation, bilateral involvement, chronicity, and ongoing trauma in vulnerable and neglected patients. The surgical success rates were some of the lowest in the modern retinal detachment literature. The use of an SB may result in better outcomes, and visual function can be restored in some patients.

Background Catatonia is an often underdiagnosed diagnosis in the pediatric population that carries substantial morbidity and mortality. Early recognition of catatonia is important, especially whenit presents with autonomic abnormalities to ensure timely initiation of treatment. Treatment of catatonia is well established, especially the use of GABAergic agents such as benzodiazepines. Although the use of high potency cannabis has been associated with multiple neuropsychiatric sequelae, the relationship between vaporized cannabis use and catatonia has not been previously described. Case Presentations We report two cases of malignant catatonia in adolescent males with psychiatric histories significant for trauma and depression, and a recent history of vaporized marijuana use. These adolescents presented to the pediatric emergency room with classic symptoms of catatonia including psychomotor and behavioral disturbances. Both patients had evidence of autonomic dysfunction including hypertension, tachycardia, and mydriasis, and in one case, even evidence of cardiac ischemia. Laboratory and imaging workups for both patients were otherwise unremarkable. Both patients had resolution of symptoms following the administration of lorazepam. Conclusions These cases represent the first reported instances of pediatric malignant catatonia secondary to vaporized cannabis use. Given the increasing popularity of vaporized cannabis use among adolescents, malignant catatonia should be on the differential in a pediatric patient presenting with psychomotor disturbances and autonomic instability. Further research is needed to quantify the risk of catatonia secondary to vaporized cannabis use.

Objective To assess outcomes after surgery for vestibular schwannoma in patients over 70 years of age. Study design Retrospective chart review. Setting Two tertiary otology and neurotology centers. Patients and interventions Patients undergoing primary surgery for vestibular schwannoma between 2007 and 2018. Main outcome measures Postoperative complications and surgical outcomes. Results A total of 452 patients met inclusion criteria, 31 of whom (6.9%) were over 70 years of age. Age ranged from 18 to 90 years with a mean of 53 years. Elderly patients were more likely to have pre-existing hypertension (58.1% versus 34.0%, p = 0.007) and diabetes mellitus (19.4% versus 7.4%, p = 0.02). Elderly patients were less likely to undergo gross total resections of their tumors (35.5% versus 60.6%, p = 0.05) although they were not statistically significantly more likely to undergo subtotal ( 0.05). Elderly patients were also less likely to undergo second stage procedures (0% versus 9.5%, p = 0.04). There were no significant differences between elderly and non-elderly patients in the rates of any complications, ultimate facial nerve function, or duration of surgery. No patients over 70 years of age expired within 1 year of surgery. Conclusions Conservative surgery for vestibular schwannoma in appropriately selected elderly patients is appropriate and safe, given adequate consideration to risk-benefit analysis and goals of care.

Objective: This study describes the peri-operative results, safety, and functional outcomes of transurethral resection of the prostate (TURP) performed in men with benign prostatic hyperplasia [or hypertrophy; (BPH)] and a prostate gland volume ≥100 cc. Materials and Methods: A retrospective analysis of a cohort of patients undergoing TURP at a single institution over four years was undertaken. Patients with known prostate cancer were excluded. Clinical outcomes were between men with a prostate volume of ≥100 cc and men with a prostate volume

Fetuses with intrauterine growth restriction (IUGR) have high concentrations of catecholamines, which lowers the insulin secretion and glucose uptake. Here, we studied the effect of hypercatecholaminemia on glucose metabolism in sheep fetuses with placental insufficiency-induced IUGR. Norepinephrine concentrations are elevated throughout late gestation in IUGR fetuses but not in IUGR fetuses with a bilateral adrenal demedullation (IAD) at 0.65 of gestation. Euglycemic (EC) and hyperinsulinemic–euglycemic (HEC) clamps were performed in control, intact-IUGR, and IAD fetuses at 0.87 of gestation. Compared to controls, basal oxygen, glucose, and insulin concentrations were lower in IUGR groups. Norepinephrine concentrations were five-fold higher in IUGR fetuses than in IAD fetuses. During the EC, rates of glucose entry (GER, umbilical + exogenous), glucose utilization (GUR), and glucose oxidation (GOR) were greater in IUGR groups than in controls. In IUGR and IAD fetuses with euglycemia and euinsulinemia, glucose production rates (GPR) remained elevated. During the HEC, GER and GOR were not different among groups. In IUGR and IAD fetuses, GURs were 40% greater than in controls, which paralleled the sustained GPR despite hyperinsulinemia. Glucose-stimulated insulin concentrations were augmented in IAD fetuses compared to IUGR fetuses. Fetal weights were not different between IUGR groups but were less than controls. Regardless of norepinephrine concentrations, IUGR fetuses not only develop greater peripheral insulin sensitivity for glucose utilization but also develop hepatic insulin resistance because GPR was maintained and unaffected by euglycemia or hyperinsulinemia. These findings show that adaptation in glucose metabolism of IUGR fetuses are independent of catecholamines, which implicate that hypoxemia and hypoglycemia cause the metabolic responses.

There are limited data to inform risk of readmission and short-term mortality in musculoskeletal oncology. The goal of this study was to identify factors independently associated with 30-day readmission and 90-day mortality following surgical resection of osteosarcoma. We retrospectively reviewed patients (n = 5293) following surgical resection of primary osteosarcoma in the National Cancer Database (2004–2015). Univariate and multivariate methods were used to correlate variables with readmission and short-term mortality. Of 210 readmissions (3.97%), risk factors independently associated with unplanned 30-day readmission included comorbidity burden (odds ratio [OR] 2.4, p = 0.042), Medicare insurance (OR 1.9, p = 0.021), and axial skeleton location (OR 1.5, p = 0.029). A total of 91 patients died within 90 days of their surgery (1.84%). Risk factors independently associated with mortality included age (hazard ratio 1.1, p < 0.001), increasing comorbidity burden (OR 6.6, p = 0.001), higher grade (OR 1.7, p = 0.007), increasing tumor size (OR 2.2, p = 0.03), metastatic disease at presentation (OR 8.5, p < 0.001), and amputation (OR 2.0, p = 0.04). Chemotherapy was associated with a decreased risk of short-term mortality (p < 0.001). Several trends were clear: insurance status, tumor location and comorbidity burden were independently associated with readmission rates, while age, amputation, grade, tumor size, metastatic disease, and comorbidity burden were independently associated with short-term mortality.

Robotic-assisted total knee arthroplasty (RA-TKA) was introduced to improve limb alignment, component positioning, soft-tissue balance and to minimize surgical outliers. This study investigates perioperative outcomes, complications, and early patient-reported outcome measures (PROMs) of one imageless RA-TKA system compared to conventional method TKA (CM-TKA) at 24-month follow-up. This multi-surgeon retrospective cohort analysis compared 111 imageless RA-TKA patients to 110 CM-TKA patients (n = 221). Basic demographic information, intraoperative and postoperative data, and PROMs, including the functional score of the Knee Society Score (KSS-FS), The Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), and the Short Form 12 Mental and Physical scores (SF-12M and P), were collected and recorded preoperatively, at 3-, 12- and 24-months postoperatively. Range of motion (ROM), estimated blood loss (EBL), surgical duration, and complications were also collected. There were no baseline patient demographic differences between groups. EBL (240 vs. 190 mL, p

Cancer pain is common and challenging to manage - it is estimated that approximately 30% of cancer patients have pain that is not adequately controlled by analgesia. This paper discusses safe and effective neuroablative treatment options for refractory cancer pain. Current management of cancer pain predominantly focuses on the use of medications, resulting in a relative loss of knowledge of these surgical techniques and the erosion of the skills required to perform them. Here, we review surgical methods of modulating various points of the neural axis with the aim to expand the knowledge base of those managing cancer pain. Integration of neuroablative approaches may lead to higher rates of pain relief, and the opportunity to dose reduce analgesic agents with potential deleterious side effects. With an ever-increasing population of cancer patients, it is essential that neurosurgeons maintain or train in these techniques in tandem with the oncological multi-disciplinary team.

Objective Acute hyperglycemia during myocardial infarction worsens outcomes in part by inflammatory mechanisms. Pulsed ultrasound has anti-inflammatory potential in bone healing and neuromodulation. We hypothesized that pulsed ultrasound would attenuate the hyperglycemic exacerbation of myocardial ischemia–reperfusion injury via the cholinergic anti-inflammatory pathway. Methods Acute hyperglycemia was induced in wild-type C57BL6 or acetylcholine-receptor knockout (α7nAChR-/-) mice by intraperitoneal injection of glucose. Pulsed ultrasound (frequency 7 MHz, bursting mechanical index 1.2, duration 1 second, repeated every 6 seconds for 2 minutes, 20-second total exposure) was performed at the spleen or neck after glucose injection. Separate mice underwent vagotomy before treatment. The left coronary artery was occluded for 20 minutes, followed by 60 minutes of reperfusion. The primary end point was infarct size in explanted hearts. Results Splenic pulsed ultrasound significantly decreased infarct size in wild-type C57BL6 mice exposed to acute hyperglycemia and myocardial ischemia–reperfusion injury (5.2% ± 4.4% vs 16.9% ± 12.5% of risk region, P = .013). Knockout of α7nAChR abrogated the beneficial effect of splenic pulsed ultrasound (22.2% ± 12.1%, P = .79 vs control). Neck pulsed ultrasound attenuated the hyperglycemic exacerbation of myocardial infarct size (3.5% ± 4.8%, P = .004 vs control); however, the cardioprotective effect disappeared in mice that underwent vagotomy. Plasma acetylcholine, β2 adrenergic receptor, and phosphorylated Akt levels were increased after splenic pulsed ultrasound treatment. Conclusions Pulsed ultrasound treatment of the spleen or neck attenuated the hyperglycemic exacerbation of myocardial ischemia–reperfusion injury leading to a 3-fold decrease in infarct size. Pulsed ultrasound may provide cardioprotection via the cholinergic anti-inflammatory pathway and could be a promising new nonpharmacologic, noninvasive therapy to reduce infarct size during acute myocardial infarction and improve patient outcomes.

Psychotic patients with a lifetime history of cannabis use generally show better cognitive functioning than other psychotic patients. Some authors suggest that cannabis-using patients may have been less cognitively impaired and less socially withdrawn in their premorbid life. Using a dataset comprising 948 patients with first-episode psychosis (FEP) and 1313 population controls across 6 countries, we examined the extent to which IQ and both early academic (Academic Factor [AF]) and social adjustment (Social Factor [SF]) are related to the lifetime frequency of cannabis use in both patients and controls. We expected a higher IQ and a better premorbid social adjustment in psychotic patients who had ever used cannabis compared to patients without any history of use. We did not expect such differences in controls. In both patients and controls, IQ was 3 points higher among occasional-users than in never-users (mean difference [Mdiff] = 2.9, 95% CI = [1.2, 4.7]). Both cases and control daily-users had lower AF compared to occasional (Mdiff = −0.3, 95% CI = [−0.5; −0.2]) and never-users (Mdiff = −0.4, 95% CI = [−0.6; −0.2]). Finally, patient occasional (Mdiff = 0.3, 95% CI = [0.1; 0.5]) and daily-users (Mdiff = 0.4, 95% CI = [0.2; 0.6]) had better SF than their never-using counterparts. This difference was not present in controls (Fgroup*frequency(2, 2205) = 4.995, P = .007). Our findings suggest that the better premorbid social functioning of FEP with a history of cannabis use may have contributed to their likelihood to begin using cannabis, exposing them to its reported risk-increasing effects for Psychotic Disorders.

Face-processing deficits, while not required for the diagnosis of Autism Spectrum Disorder (ASD), have been associated with impaired social skills—a core feature of ASD; however, the strength and prevalence of this relationship remains unclear. Across 445 participants from the NIMH Data Archive, we examined the relationship between Benton Face Recognition Test (BFRT) performance and Autism Diagnostic Observation Schedule-Social Affect (ADOS-SA) scores. Lower BFRT scores (worse face-processing performance) were associated with higher ADOS-SA scores (higher ASD severity)–a relationship that held after controlling for other factors associated with face processing, i.e., age, sex, and IQ. These findings underscore the utility of face discrimination, not just recognition of facial emotion, as a key covariate for the severity of symptoms that characterize ASD.

Chronic rhinosinusitis with nasal polyps (CRSwNP) represents a challenging disease entity with significant rates of recurrence following appropriate medical and surgical therapy. Recent approval of targeted biologics in CRSwNP compels deeper understanding of underlying disease pathophysiology. Both of the approved biologics for CRSwNP modulate the type 2 inflammatory pathway, and the majority of drugs in the clinical trials pathway are similarly targeted. However, there remain multiple other pathogenic mechanisms relevant to CRSwNP for which targeted therapeutics already exist in other inflammatory diseases that have not been studied directly. In this article we summarize pathogenic mechanisms of interest in CRSwNP and discuss the results of ongoing clinical studies of targeted therapeutics in CRSwNP and other related human inflammatory diseases.

Background Clinicians express concern that they may be unaware of important information contained in voluminous scanned and other outside documents contained in electronic health records (EHRs). An example is “unrecognized EHR risk factor information,” defined as risk factors for heritable cancer that exist within a patient's EHR but are not known by current treating providers. In a related study using manual EHR chart review, we found that half of the women whose EHR contained risk factor information meet criteria for further genetic risk evaluation for heritable forms of breast and ovarian cancer. They were not referred for genetic counseling. Objectives The purpose of this study was to compare the use of automated methods (optical character recognition with natural language processing) versus human review in their ability to identify risk factors for heritable breast and ovarian cancer within EHR scanned documents. Methods We evaluated the accuracy of the chart review by comparing our criterion standard (physician chart review) versus an automated method involving Amazon's Textract service (Amazon.com, Seattle, Washington, United States), a clinical language annotation modeling and processing toolkit (CLAMP) (Center for Computational Biomedicine at The University of Texas Health Science, Houston, Texas, United States), and a custom-written Java application. Results We found that automated methods identified most cancer risk factor information that would otherwise require clinician manual review and therefore is at risk of being missed. Conclusion The use of automated methods for identification of heritable risk factors within EHRs may provide an accurate yet rapid review of patients' past medical histories. These methods could be further strengthened via improved analysis of handwritten notes, tables, and colloquial phrases.

With a 5-year recurrence rate of 30-78%, urothelial cell carcinoma (UCC) rates amongst the highest of all solid malignancies. Consequently, after transurethral resection, patients are subjugated to life-long endoscopic surveillance. A multimodal near-infrared (NIR) fluorescence-based imaging strategy can improve diagnosis, resection and surveillance, hence increasing quality of life.Methods: Expression of urokinase plasminogen activator receptor (uPAR) and epithelial cell adhesion molecule (EpCAM) are determined on paraffin-embedded human UCC using immunohistochemistry and on UCC cell lines by flow cytometry. MNPR-101, a humanised monoclonal antibody targeting uPAR is conjugated to IRDye800CW and binding is validated in vitro using surface plasmon resonance and cell-based binding assays. In vivo NIR fluorescence and photoacoustic three-dimensional (3D) imaging are performed with subcutaneously growing human UM-UC-31uc2 cells in BALB/c-nude mice. The translational potential is confirmed in a metastasising UM-UC-31uc2 orthotopic mouse model. InfliximabIRDye800CW and rituximab-IRDye800CW are used as controls.Results: UCCs show prominent uPAR expression at the tumour-stroma interface and EpCAM on epithelial cells. uPAR and EpCAM are expressed by 6/7 and 4/7 UCC cell lines, respectively. In vitro, MNPR-101-IRDye800CW has a picomolar affinity for domain 2-3 of uPAR. In vivo fluorescence imaging with MNPR-101-IRDye800CW, specifically delineates both subcutaneous and orthotopic tumours with tumour-to-background ratios reaching as high as 6.8, differing significantly from controls (p < 0.0001). Photoacoustic 3D in depth imaging confirms the homogenous distribution of MNPR-101-IRDye800CW through the tumour.Conclusions: MNPR-101-IRDye800CW is suitable for multimodal imaging of UCC, awaiting clinical translation. (C) 2021 The Author(s). Published by Elsevier Ltd.

BackgroundCarcinoembryonic antigen is overexpressed in colorectal cancer (CRC), making it an optimal target for fluorescence imaging. A phase I/II study was designed to determine the optimal imaging dose of SGM-101 for intraoperative fluorescence imaging of primary and recurrent CRC.MethodsPatients were included and received a single dose of SGM-101 at least 24 h before surgery. Patients who received routine anticancer therapy (i.e., radiotherapy or chemotherapy) also were eligible. A dedicated near-infrared imaging system was used for real-time fluorescence imaging during surgery. Safety assessments were performed and SGM-101 efficacy was evaluated per dose level to determine the most optimal imaging dose.ResultsThirty-seven patients with CRC were included in the analysis. Fluorescence was visible in all primary and recurrent tumors. In seven patients, no fluorescence was seen; all were confirmed as pathological complete responses after neoadjuvant therapy. Two tumors showed false-positive fluorescence. In the 37 patients, a total of 97 lesions were excised. The highest mean intraoperative tumor-to-background ratio (TBR) of 1.9 (p = 0.019) was seen in the 10-mg dose. This dose showed a sensitivity of 96%, specificity of 63%, and negative predictive value of 94%. Nine patients (24%) had a surgical plan alteration based on fluorescence, with additional malignant lesions detected in six patients.ConclusionsThe optimal imaging dose was established at 10 mg 4 days before surgery. The results accentuate the potential of SGM-101 and designated a promising base for the multinational phase III study, which enrolled the first patients in June 2019.

Ovarian cancer is one of the most common diseases of the female reproductive system. The aim of this study was the investigation of the antitumor cisplatin effect on ascitic fluid tumor cells in the ovarian cancer experimental model by digital cytomorphometry and cell bioinformatic analysis. Female Wistar rats were inoculated by ovarian cancer strain. After ovarian cancer transplantation rats were divided into two groups: control group—without cisplatin treatment, the experimental group—under cisplatin treatment. The ascitic fluid was taken on the 9-th day after tumor cell inoculation. Digital cytomorphometric and cytobioinformatic analysis were used to study ascitic fluid cancer cell morphofunctional changes under cisplatin treatment. Digital cytomorphometric characteristics of rat ovarian cancer ascitic cells were obtained. Tumor cells were classified into four groups according to their geometric size: small, medium, large, “gigantic”. The algorithm and the computer program based on tumor cell morphometric characteristics were created to calculate such cell bioinformatic characteristic as information redundancy coefficient R. Three parameters were determined as the criteria of cisplatin effect on cancer cells: cell number, nuclear/cytoplasmic ratio, R-value. Data obtained suggest that cisplatin reduces the total cell number, the nuclear/cytoplasmic ratio and R-value thus indicates a decrease in cellular resistance and adaptive potential. The digital cytomorphometry and bioinformatics could be recommended as a testing system in the experimental or clinical study.

Introduction and Objective The potential of metamizole to cause drug-induced liver injury (DILI) has received increasing attention. We investigated the distinguishing features of a case series comprising 32 patients with suspected metamizole-induced DILI. Methods For the current analysis, 32 of 238 patients with DILI included in our prospective study on drugs potentially causing DILI were included. Diagnosis of DILI was based on expert opinion and RUCAM (Roussel Uclaf Causality Assessment Method) score and supported by an in vitro test using monocyte-derived hepatocyte-like cells. Results Suspected metamizole-DILI was characterised by a female predominance, hepatocellular pattern of injury, high proportion of antinuclear antibody positivity, and predominance of eosinophilic cell infiltration and necrosis in the histopathological analysis. With 22%, a high proportion of these metamizole-associated liver injury cases developed acute liver failure, which was characterised by a longer latency of metamizole use and more pronounced liver biochemistry abnormalities at onset and peak levels. Furthermore, jaundice was a common finding in the metamizole-associated liver injury cases with 66% presenting with peak bilirubin levels of 3 mg/dL or higher, which was associated with a worse outcome and a higher frequency of acute liver failure. Conclusions Our analysis of a well-characterised DILI cohort further supports the potential of metamizole causing DILI and provides important features for the establishment of a signature pattern of liver injury observed in patients treated with metamizole. Clinical Trial Registration ClinicalTrials.gov: NCT 02353455. Supplementary Information The online version contains supplementary material available at 10.1007/s40264-021-01049-z.

Background & Aims: Bacterial infections can trigger the development of organ failure(s) and acute-on-chronic liver failure (ACLF). Geographic variations in bacteriology and clinical practice could lead to worldwide differences in ACLF epidemiology, phenotypes and associated outcomes. Herein, we aimed to evaluate regional differences in bacterial infection-related ACLF in patients with cirrhosis admitted to hospital. Methods: This post hoc analysis included 1,175 patients with decompensated cirrhosis (with bacterial infection on admission or nosocomial infection) from 6 geographic regions worldwide. Clinical, laboratory and microbiological data were collected from the diagnosis of infection. Patients were followed-up for organ failure(s) and ACLF development according to the EASL-CLIF criteria from enrolment to discharge/death. Results: A total of 333 patients (28%) had ACLF at diagnosis of infection, while 230 patients developed ACLF after diagnosis of infection, resulting in an overall rate of bacterial infection related-ACLF of 48%, with rates differing amongst different geographic regions (38% in Southern Europe vs. 75% in the Indian subcontinent). Bacterial infection related-ACLF more frequently developed in younger patients (55 ± 13 vs. 58 ± 14 years), males (73% vs. 62%), patients with alcohol-related cirrhosis (59% vs. 45%) and those with a higher baseline MELD score (25 ± 11 vs. 16 ± 5) (all p

Simple SummaryNear-infrared imaging of tumors during surgery facilitates the oncologic surgeon to distinguish malignant from healthy tissue. The technique is based on fluorescent tracers binding to tumor biomarkers on malignant cells. Currently, there are no clinically available fluorescent tracers that specifically target soft tissue sarcomas. This review searched the literature to find candidate biomarkers for soft tissue sarcomas, based on clinically used therapeutic antibodies. The search revealed 7 biomarkers: TEM1, VEGFR-1, EGFR, VEGFR-2, IGF-1R, PDGFR alpha, and CD40. These biomarkers are abundantly present on soft tissue sarcoma tumor cells and are already being targeted with humanized monoclonal antibodies. The conjugation of these antibodies with a fluorescent dye will yield in specific tracers for image-guided surgery of soft tissue sarcomas to improve the success rates of tumor resections.Surgery is the mainstay of treatment for localized soft tissue sarcomas (STS). The curative treatment highly depends on complete tumor resection, as positive margins are associated with local recurrence (LR) and prognosis. However, determining the tumor margin during surgery is challenging. Real-time tumor-specific imaging can facilitate complete resection by visualizing tumor tissue during surgery. Unfortunately, STS specific tracers are presently not clinically available. In this review, STS-associated cell surface-expressed biomarkers, which are currently already clinically targeted with monoclonal antibodies for therapeutic purposes, are evaluated for their use in near-infrared fluorescence (NIRF) imaging of STS. Clinically targeted biomarkers in STS were extracted from clinical trial registers and a PubMed search was performed. Data on biomarker characteristics, sample size, percentage of biomarker-positive STS samples, pattern of biomarker expression, biomarker internalization features, and previous applications of the biomarker in imaging were extracted. The biomarkers were ranked utilizing a previously described scoring system. Eleven cell surface-expressed biomarkers were identified from which 7 were selected as potential biomarkers for NIRF imaging: TEM1, VEGFR-1, EGFR, VEGFR-2, IGF-1R, PDGFR alpha, and CD40. Promising biomarkers in common and aggressive STS subtypes are TEM1 for myxofibrosarcoma, TEM1, and PDGFR alpha for undifferentiated soft tissue sarcoma and EGFR for synovial sarcoma.

Purpose Childhood stricturing Crohn’s disease (CD) has significant morbidity. Interventions including resection, stricturoplasty and endoscopic balloon dilatation (EBD) are often required. Optimal intervention modality and timing, and use of adjuvant medical therapies, remains unclear. We aim to review the therapies used in paediatric stricturing CD. Methods A systematic review in accordance with PRISMA was performed (PROSPERO: CRD42020164464). Demographics, stricture features, interventions and outcomes were extracted. Results Fourteen studies were selected, including 177 patients (183 strictures). Strictures presented at 40.6 months (range 14–108) following CD diagnosis. Medical therapy was used in 142 patients for an average of 20.4 months (2–36), with a complete response in 11 (8%). Interventions were undertaken in 138 patients: 53 (38%) resections, 39 (28%) stricturoplasties, and 17 (12%) EBD. Complications occurred in 11% of resections, versus 15% stricturoplasties, versus 6% EBD (p = 0.223). At a median follow-up of 1.9 years (interquartile range 1.2–2.4) pooled stricture recurrence was 22%. Resection had 9% recurrence, versus 38% stricturoplasty, versus 47% EBD (p Conclusions Resection is associated with a low incidence of recurrence and complications. There remains a paucity of evidence regarding adjuvant medical therapy and the role of EBD. We propose a minimum reported dataset for interventions in paediatric stricturing CD.

The purpose of this study was to describe the incidence of subsidence in patients with AO/OTA 41 (tibial plateau) fractures which were repaired with a novel fenestrated screw system to used to deliver CaPO4 bone substitute material to fill the subchondral void and support the articular reduction. Patients with unicondylar and bicondylar tibial plateau fractures were treated according to the usual technique of two surgeons. After fixation, the Zimmer Biomet N-Force Fixation System®, a fenestrated screw that allows for the injection of bone substitute was placed and used for injection of the proprietary calcium phosphate bone graft substitute into the subchondral void. For all included patients, demographic information, operative data, radiographs, and clinic notes were reviewed. Patients were considered to have articular subsidence if one or more of two observations were made when comparing post-operative to their most recent clinic radiographs: > 2 mm change in the distance between the screw and the lowest point of the tibial plateau, > 2 mm change in the distance between the screw and the most superior aspect of the plate. Data were analyzed to determine if there were any identifiable risk factors for complication, reoperation, or subsidence using logistic regression. Statistical significance was set at p

Background Life-threatening hemorrhage from extremity injuries can be effectively controlled in the prehospital environment through direct pressure, wound packing, and the use of tourniquets. Early tourniquet application has been prioritized for rapid control of severe extremity hemorrhage and is a cornerstone of prehospital trauma resuscitation guidelines. Emergency physicians must be knowledgeable regarding the initial assessment and appropriate management of patients who present with a prehospital tourniquet in place. Discussion An interdisciplinary group of experts including emergency physicians, trauma surgeons, and tactical and Emergency Medical Services physicians collaborated to develop a stepwise approach to the assessment and removal (discontinuation) of an extremity tourniquet in the emergency department after being placed in the prehospital setting. We have developed a best-practices guideline to serve as a resource to aid the emergency physician in how to safely remove a tourniquet. The guideline contains five steps that include: 1) Determine how long the tourniquet has been in place; 2) Evaluate for contraindications to tourniquet removal; 3) Prepare for tourniquet removal; 4) Release the tourniquet; and 5) Monitor and reassess the patient. Conclusion These steps outlined will help emergency medicine clinicians appropriately evaluate and manage patients presenting with tourniquets in place. Tourniquet removal should be performed in a systematic manner with plans in place to immediately address complications.

Introduction: People suffering from fibromyalgia syndrome report various difficulties in emotional processing, possibly resulting from changes in bodily perception (interoception). In our study, we investigated the relationships between interoceptive sensibility (IS) and two disease-relevant emotional components (alexithymia and emotion regulation) in fibromyalgia sufferers compared to healthy individuals. Methods: Fifty-five fibromyalgia sufferers and 55 healthy individuals, matched with regard to age and gender, participated in our cross-sectional study. All participants completed the following self-report measures: the Multidimensional Assessment of Interoceptive Awareness, the Toronto Alexithymia Scale, and the Emotion Regulation Skills Questionnaire. Depression and anxiety scores served as confounding variables. Results: Fibromyalgia sufferers reported a stronger tendency to note as well as to avoid (unpleasant) body sensations. IS and psychopathology each explained about thirty percent of the variance in emotion regulation in fibromyalgia sufferers. Alexithymia was related to IS and emotion regulation in controls but not in fibromyalgia sufferers. Conclusion: Disturbances in interoception could be seen as the starting point of emotional difficulties in people with fibromyalgia. Following the fear-avoidance-model, experiential avoidance may restrict patients’ ability to adaptively regulate emotional states, possibly initiating a vicious cycle of psychological distress and pain.

Aim: To compare safety (immunogenicity) and efficacy of a biosimilar insulin GP-Lis25 and a reference insulin Ly-Lis25 (Humalog Mix 25) in Type 2 diabetes mellitus (T2D) patients. Materials & methods: This randomized open-label, 26-week clinical trial enrolled 210 T2D patients, randomized 1:1 to twice-daily GP-Lis25 or Ly-Lis25. The primary end point was immune response at 26th week. Noninferiority margin for HbA1c was 0.4%. Results: Immune response frequency was similar in GP-Lis25 and Ly-Lis25 groups both at week 12 (p = 0.651) and 26 (p = 0.164). The difference of HbA1c change at week 26 was (95% CI) 0.01 (-0.27–0.28)%. Fasting plasma glucose, seven-point glucose profile and insulin dose were similar between groups. Safety did not differ between groups. Conclusion: GP-Lis25 and Ly-Lis25 demonstrated similar safety and efficacy. ClincalTrials.gov identifier: NCT04023344 .

OBJECTIVE Review surgical outcomes of stapedectomy for otosclerosis in patients with Meniere's disease. STUDY DESIGN Retrospective case review. SETTING Tertiary referral center. PATIENTS Patients with otosclerosis and Meniere's disease undergoing stapedectomy between 2010 and 2017. INTERVENTION Stapedectomy. MAIN OUTCOME MEASURES Pre- and postoperative hearing and complications. Hearing was measured by air conduction (AC) and bone conduction (BC) pure-tone frequency, pure-tone averages (PTA), air-bone gap (ABG), and word recognition scores (WRS). RESULTS Among 1,499 patients with otosclerosis, the incidence of concomitant Meniere's disease was 1.7%. Fifteen patients with otosclerosis and Meniere's disease underwent stapedectomy, 12 primary and three revisions. Mean AC PTA was 43 dB preoperatively, and 25 dB postoperatively (p = 0.0007), while the ABG improved on average from 20 to 5 dB (p = 0.0001). There was no significant difference in BC PTA or WRS postoperatively. Two patients experienced fluctuation of hearing in the postoperative period, one of which resolved with a course of steroids. The mean follow-up time was 41 months. CONCLUSIONS In patients with otosclerosis and Meniere's disease, stapedectomy provides excellent hearing outcomes in a majority of patients. As is characteristic of Meniere's disease, some patients will continue to experience fluctuating hearing postoperatively, which may progress to severe sensorineural hearing loss. Meniere's disease may not be an absolute contraindication to stapes surgery.

Management of symptomatic brain metastases often includes surgical resection with postoperative radiotherapy. Postoperative whole-brain radiotherapy (WBRT) improves intracranial control but detrimentally impacts quality of life and neurocognition. We sought to characterize the use in the United States of postoperative stereotactic radiosurgery (SRS), an evolving standard-of-care associated with reduced cognitive effects.With the MarketScan Commercial Claims and Encounters Database from 2007 to 2015, we identified patients aged 18-65 years treated with resection of a brain metastasis followed by SRS or WBRT within 60 days of surgery. Logistic regression estimated associations between co-variables (treatment year, age, sex, geographic region, place of service, insurance type, disease histology, comorbidity score, and median area household income and educational attainment) and SRS receipt.Of 4007 patients included, 1506 (37.6%) received SRS and 2501 (62.4%) received WBRT. Postoperative SRS increased from 16.5% (2007-2008) to 56.8% (2014-2015). Patients residing in areas with a median household income or an educational attainment below 50th percentile were significantly less likely to receive SRS after controlling for treatment year and other demographic characteristics (P0.01). Factors associated with greater odds of receiving SRS included younger age, female sex, melanoma histology, Western region location, hospital-based facility, and high-deductible health plan enrollment (P0.05 for each).Postoperative SRS for brain metastases has increased from 2007 to 2015, with the majority of patients now receiving SRS over WBRT. Patients in areas of lower socioeconomic class were less likely to receive SRS, warranting further investigation of barriers to SRS adoption.

Objectives: To describe audiologic outcomes following hydroxyapatite bone cement fixation of stapedotomy prostheses. Methods: A retrospective case review at a tertiary neurotology referral center was performed of patients undergoing primary or revision stapedotomy between 2010 and 2017. Patients with hydroxyapatite bone cement fixation of stapes prostheses were assessed. Pre- and postoperative hearing was compared, consisting of air conduction (AC) and bone conduction (BC) pure-tone averages (PTA), air-bone gap (ABG), and word recognition scores (WRS). Short and long-term outcomes were assessed. Results: Forty-six patients with otosclerosis underwent stapedotomy with bone cement fixation: 21 primary cases and 25 revision cases, with an average follow-up time of 17 months. Mean AC PTA was 56 dB preoperatively, and 34 dB postoperatively ( P < .0001), while the ABG improved on average from 27 dB to 9 dB ( P < .0001). There was no significant difference in postoperative ABG between primary and revision stapes surgery (6 dB vs 10 dB, P = .07). These results persisted through long-term follow-up in a subgroup of patients with significantly longer follow-up time (mean 44 months). There was no significant change in BC PTA or word recognition scores. Three patients underwent subsequent revisions, one patient developed sensorineural hearing loss. Conclusion: Stapedotomy with bone cement fixation of the prosthesis provides excellent hearing outcomes in both primary and revision treatment of otosclerosis. Results are consistent and stable through long-term follow-up. The use of bone cement should be incorporated into the surgical armamentarium of the otologist for the prevention and treatment of loose-wire syndrome and incus necrosis.

Guttate psoriasis is an eruptive variant of plaque psoriasis. Systemic therapy of guttate psoriasis has been inconsistently effective. Given that guttate psoriasis and plaque psoriasis share several immunopathogenic features, we hypothesized that antibodies targeting interleukin-17 (IL-17) would be effective in the treatment of guttate psoriasis. Here we present a series of 3 patients with guttate psoriasis successfully treated with ixekizumab, a monoclonal antibody against IL-17A.

In cardiac amyloidosis (CA), amyloid infiltration results in increased left ventricular (LV) mass disproportionate to electrocardiographic (EKG) voltage. We assessed the relationship between LV mass–voltage ratio with subsequent heart failure hospitalization (HHF) and mortality in CA. Patients with confirmed CA and comprehensive cardiovascular magnetic resonance (CMR) and EKG exams were included. CMR-derived LV mass was indexed to body surface area. EKG voltage was assessed using Sokolow, Cornell, and Limb–voltage criteria. The optimal LV mass–voltage ratio for predicting outcomes was determined using receiver operating characteristic curve analysis. The relationship between LV mass–voltage ratio and HHF was assessed using Cox proportional hazards analysis adjusting for significant covariates. A total of 85 patients (mean 69 ± 11 years, 22% female) were included, 42 with transthyretin and 43 with light chain CA. At a median of 3.4-year follow-up, 49% of patients experienced HHF and 60% had died. In unadjusted analysis, Cornell LV mass–voltage ratio was significantly associated with HHF (HR, 1.05; 95% CI 1.02–1.09, p = 0.001) and mortality (HR, 1.05; 95% CI 1.02–1.07, p = 0.001). Using ROC curve analysis, the optimal cutoff value for Cornell LV mass–voltage ratio to predict HHF was 6.7 gm/m2/mV. After adjusting for age, NYHA class, BNP, ECV, and LVEF, a Cornell LV mass–voltage ratio > 6.7 gm/m2/mV was significantly associated with HHF (HR 2.25, 95% CI 1.09–4.61; p = 0.03) but not mortality. Indexed LV mass–voltage ratio is associated with subsequent HHF and may be a useful prognostic marker in cardiac amyloidosis.

Objective Deep brain stimulation (DBS) is a treatment option for refractory chronic cluster headache (CCH). Despite several recent prospective case series reporting a good outcome, the effectiveness and the optimal stimulation target of DBS for CCH remain unclear. We aimed to obtain precise estimates and predictors of long-term pain relief in an individual patient data meta-analysis. Furthermore, we aimed to construct a probabilistic stimulation map of effective DBS. Methods We invited investigators of published cohorts of patients undergoing DBS for CCH, identified by a systematic review of MEDLINE from inception to Febuary 15, 2019, to provide individual patient data on baseline covariates, pre- and postoperative headache scores at median (12-month) and long-term follow-up, in addition to individual imaging data to obtain individual electrode positions. We calculated a stimulation map using voxel-wise statistical analysis. We used multiple regression analysis to estimate predictors of pain relief. Results Among 40 patients from four different cohorts representing ~50% of all previously published cases, we found a significant 77% mean reduction in headache attack frequency over a mean follow-up of 44 months, with an overall response rate of 75%. Positive outcome was not associated with baseline covariates. We identified 2 hotspots of stimulation covering the midbrain ventral and retrorubral tegmentum. Interpretation This study supports the hypothesis that DBS provides long-term pain relief for the majority of CCH patients. Our stimulation map of the region of influence of therapeutic DBS identified an optimal anatomical target site that can help surgeons to guide their surgical planning in the future. ANN NEUROL 2020;88:956-969.

The involvement of fibrosis as an underlying pathology in heart diseases is becoming increasingly clear. In recent years, fibrosis has been granted a causative role in heart diseases and is now emerging as a major contributor to Atrial Fibrillation (AF) pathogenesis. AF is the most common arrhythmia encountered in the clinic, but the substrate for AF is still being debated. Consensus in the field is a combination of cardiac tissue remodeling, inflammation and genetic predisposition. The extracellular matrix (ECM) is subject of growing investigation, since measuring circulatory biomarkers of ECM formation and degradation provides both diagnostic and prognostic information. However, fibrosis is not just fibrosis. Each specific collagen biomarker holds information on regulatory mechanisms, as well as information about which section of the ECM is being remodeled, providing a detailed description of cardiac tissue homeostasis. This review entails an overview of the implication of fibrosis in AF, the different collagens and their significance, and the potential of using biomarkers of ECM remodeling as tools for understanding AF pathogenesis and identifying patients at risk for further disease progression.

Fetal conditions associated with placental insufficiency and intrauterine growth restriction (IUGR) chronically elevate plasma norepinephrine (NE) concentrations. Our objective was to evaluate the effects of chronically elevated NE on insulin-stimulated glucose metabolism in normally grown, non-IUGR fetal sheep, which are independent of other IUGR-related reductions in nutrients and oxygen availability. After surgical placement of catheters, near-term fetuses received either a saline (control) or NE intravenous infusion with controlled euglycemia. In NE fetuses, plasma NE concentrations were 5.5-fold greater than controls, and fetal euglycemia was maintained with a maternal insulin infusion. Insulin secretion was blunted in NE fetuses during an intravenous glucose tolerance test. Weight-specific fluxes for glucose were measured during a euinsulinemic-euglycemic clamp (EEC) and a hyperinsulinemic-euglycemic clamp (HEC). Plasma glucose and insulin concentrations were not different between groups within each clamp, but insulin concentrations increased 10-fold between the EEC and the HEC. During the EEC, rates of glucose uptake (umbilical uptake + exogenous infusion) and glucose utilization were 47% and 35% lower ( P < 0.05) in NE fetuses compared with controls. During the HEC, rates of glucose uptake were 28% lower ( P < 0.05) in NE fetuses than controls. Glucose production was undetectable in either group, and glucose oxidation was unaffected by the NE infusion. These findings indicate that chronic exposure to high plasma NE concentrations lowers rates of net glucose uptake in the fetus without affecting glucose oxidation rates or initiating endogenous glucose production. Lower fetal glucose uptake was independent of insulin, which indicates insulin resistance as a consequence of chronically elevated NE.

BACKGROUND: Overactive bladder (OAB) is a common syndrome in the community characterised by unstable bladder contractions, resulting in urinary urgency, frequency and nocturia in the absence of detectable disease. Large studies suggest that >10% of the general population is symptomatic. OBJECTIVE: The aim of this article is to summarise the stepwise treatment for OAB that seeks to improve patient quality of life and reduce patient and health system costs. DISCUSSION: OAB is a diagnosis of exclusion that begins with a targeted history and examination of the urogenital system with the aim of assessing the burden of disease on the patient. First-line treatment comprises conservative measures including weight reduction, a decrease in exposure to bladder stimulants, fluid optimisation and pelvic floor exercises. Pharmacological treatments for OAB include anticholinergic medications such as oxybutynin. If the patient is unresponsive to pharmacological treatment, a review by a urology specialist is appropriate. Recommendations may include minimally invasive procedures such as intravesical botulinum toxin A injections, reserving the invasive procedures for patients in specific circumstances.

Background: Drug-induced liver injury caused by herbal and dietary supplements (HDS) has been an increasingly important phenomenon in recent years. Diagnosis is the major challenge. Definite causality assessment, especially in patients with concomitant prescription medicine or other potential causes of liver injury, can be impossible. Objectives: We investigated the usefulness of an in vitro test on the basis of peripheral monocytes of the individual patients in patients with acute liver injury consuming HDS. Method: Patients with acute liver injury who had been prospectively recruited by the University Hospital Munich (LMU, Munich) and the Chinese University of Hong Kong (CUHK) and who took at least 1 HDS were selected for this analysis. Diagnosis of drug-induced liver injury (DILI) was based on local expert adjudication, Roussel Uclaf Causality Assessment Method (RUCAM) score, and course of the disease and was supported by the monocyte-derived hepatocyte-like (MH) cell test. Results: We identified 47 patients with liver injury and intake of at least 1 HDS: 32 (68%) were diagnosed with DILI. HDS was determined as the causative agent in 28 out of those 32 patients. The MH cell test could correctly identify 29 out of those 32 DILI cases and showed false positive results in only 2 out of the 15 non-DILI patients. The MH cell test therefore reached a sensitivity and specificity of 90.6 and 86.7%, respectively, in patients with acute liver injury and HDS intake. Conclusions: Our data provide evidence that the MH cell test can be a useful tool to identify the role of HDS in causing DILI and therefore support causality assessment in patients consuming HDS.

Sorafenib represents the current standard of care for patients with advanced-stage hepatocellular carcinoma (HCC). However, acquired drug resistance occurs frequently during therapy and is accompanied by rapid tumor regrowth after sorafenib therapy termination. To identify the mechanism of this therapy-limiting growth resumption, we established robust sorafenib resistance HCC cell models that exhibited mitochondrial dysfunction and chemotherapeutic crossresistance. We found a rapid relapse of tumor cell proliferation after sorafenib withdrawal, which was caused by renewal of mitochondrial structures alongside a metabolic switch toward high electron transport system (ETS) activity. The translation-inhibiting antibiotic tigecycline impaired the biogenesis of mitochondrial DNA-encoded ETS subunits and limited the electron acceptor turnover required for glutamine oxidation. Thereby, tigecycline prevented the tumor relapse in vitro and in murine xenografts in vivo. These results offer a promising second-line therapeutic approach for advanced-stage HCC patients with progressive disease undergoing sorafenib therapy or treatment interruption due to severe adverse events.

Objective Abnormal pulmonary vasculature directly affects the development and progression of congenital diaphragmatic hernia (CDH)-associated pulmonary hypertension (PH). Though overarching structural and cellular changes in CDH-affected pulmonary arteries have been documented, the precise role of the extracellular matrix (ECM) in the pulmonary artery (PA) pathophysiology remains undefined. Here, we quantify the structural, compositional, and mechanical CDH-induced changes in the main and distal PA ECM and investigate the efficacy of mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) as a therapy to ameliorate pathological vascular ECM changes. Methods Pregnant Sprague-Dawley rodents were administered nitrofen to induce CDH-affected pulmonary vasculature in the offspring. A portion of CDH-affected pups was treated with intravenous infusion of MSC-EVs (1 × 1010 /mL) upon birth. A suite of histological, mechanical, and transmission electron microscopic analyses were utilized to characterize the PA ECM. Results The CDH model main PA presented significantly altered characteristics-including greater vessel thickness, greater lysyl oxidase (LOX) expression, and a relatively lower ultimate tensile strength of 13.6 MPa compared to control tissue (25.1 MPa), suggesting that CDH incurs ECM structural disorganization. MSC-EV treatment demonstrated the potential to reverse CDH-related changes, particularly through rapid inhibition of ECM remodeling enzymes (LOX and MMP-9). Additionally, MSC-EV treatment bolstered structural aspects of the PA ECM and mitigated pathological disorganization as exhibited by increased medial wall thickness and stiffness that, while not significantly altered, trends away from CDH-affected tissue. Conclusions These data demonstrate notable ECM remodeling in the CDH pulmonary vasculature, along with the capacity of MSC-EVs to attenuate pathological ECM remodeling, identifying MSC-EVs as a potentially efficacious therapeutic for CDH-associated pulmonary hypertension.