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Radiation therapy is effective for cancer treatment but may also result in collateral soft tissue contracture, contour deformities, and non-healing wounds. Autologous fat transfer has been described to improve tissue architecture and function of radiation-induced fibrosis and these effects may be augmented by enrichment with specific adipose-derived stromal cells (ASCs) with enhanced angiogenic potential. CD34+CD146+, CD34+CD146-, or CD34+ unfractionated (UF) human ASCs were isolated by flow cytometry and used to supplement human lipoaspirate placed beneath the scalp of irradiated mice. Volume retention was followed radiographically and fat grafts as well as overlying soft tissue were harvested after eight weeks for histologic and biomechanical analyses. Radiographic evaluation revealed the highest volume retention in fat grafts supplemented with CD34+CD146+ ASCs, and these grafts were also found to have greater histologic integrity than other groups. Irradiated skin overlying CD34+CD146+ ASC-enriched grafts was significantly more vascularized than other treatment groups, had significantly less dermal thickness and collagen deposition, and the greatest improvement in fibrillin staining and return of elasticity. Radiation therapy obliterates vascularity and contributes to scarring and loss of tissue function. ASC-enrichment of fat grafts with CD34+CD146+ ASCs not only enhances fat graft vascularization and retention, but also significantly promotes improvement in overlying radiation-injured soft tissue. This regenerative effect on skin is highly promising for patients with impaired wound healing and deformities following radiotherapy. This article is protected by copyright. All rights reserved.

To evaluate the efficacy and safety profile of netarsudil 0.02% ophthalmic solution in a tertiary glaucoma referral center. This retrospective cohort study included patients with glaucoma initiated on netarsudil 0.02% at a single institution from November 2017 to September 2018. Demographic and clinical data were collected, including intraocular pressure (IOP) and drug side effects at baseline and 1-, 3-, and 6-month follow-up visits. A total of 340 eyes of 233 patients were included; mean ± SD patient age was 69.1 ± 12.5 years. One hundred twenty (48%) eyes experienced ≥ 20% decreases in IOP at the 1-month study visit; this effect was maintained through the 6-month visit. IOP-lowering effects in patients using ≥ 3 topical glaucoma medications were similar (all p > 0.1). Eighteen (7.4%) and 7 (2.9%) patients experienced increases in IOP of ≥ 3 and ≥ 5 mmHg, respectively. Across all study visits, conjunctival hyperemia was noted at a rate of 27.6%, and though frequently reported, complaints of blurred vision (31.1%) did not manifest in significant worsening of visual acuity. The rate of drug discontinuation due to insufficient IOP-lowering and side effects was 15.6% and 24.8%, respectively. Twenty-nine (11.4%) and 82 (32.3%) eyes required additional medical and surgical/laser intervention, respectively. Commonly used as the last-line medical therapy in this case series, netarsudil safely and significantly reduced IOP in patients with glaucoma, even in those using ≥ 3 glaucoma medications. Increases in IOP of ≥ 3 mmHg occurred in a small number of patients. Subjective vision changes and conjunctival hyperemia were the most frequently reported side effects.

This study aimed to evaluate the risk of sustained life-threatening ventricular tachyarrhythmias (VTAs) after hospitalization for heart failure (HHF).HHF is common among patients with an implantable cardioverter-defibrillator (ICD).We analyzed all 5,511 ICD patients enrolled in the landmark MADIT (Multicenter Automatic Defibrillator Implantation Trial) and RAID (Ranolazine in High-Risk Patients With Implanted Cardioverter-Defibrillator) trials. Multivariate Cox regression was used to evaluate the association of in-trial HHF occurrence with the risk of subsequent VTA and the composite end point of VTA or cardiac death.Mean age was 64 ± 11 years, 23% were women, 62% were ischemic, and 40% had cardiac resynchronization therapy with defibrillators. The 3-year cumulative rate of VTA subsequent to HHF was significantly higher than the corresponding rate without HHF (44% vs. 24%, respectively; p 0.001). After multivariable adjustment, time-dependent HHF was shown to be associated with a 79% increased risk for VTA and a 2.9-fold increased risk for VTA/cardiac death (p 0.001 for both). In-trial development of atrial tachyarrhythmia (ATA) was also identified as an independent risk factor for the VTA and VTA/cardiac death end points (hazard ratio [HR]: 1.59 and 1.43, respectively; p ≤ 0.001 for both) but did not affect the association of HHF with VTA. Subgroup analysis demonstrated that the association of HHF with the risk of subsequent VTA was maintained among risk subsets categorized by age, sex, history of ATA, and implantation indication, but was significantly more pronounced among patients with nonischemic versus ischemic cardiomyopathy (HR: 2.54 and 1.43, respectively; p for interaction = 0.017).HHF is a powerful risk factor for subsequent VTA in patients implanted with an ICD. These data may be used for improved risk stratification in this population.

Purpose: To compare the outcomes of iStent vs. iStent inject implantation combined with phacoemulsification. Methods: This single center retrospective comparative case series included subjects with open angle glaucoma who underwent iStent or iStent inject implantation combined with phacoemulsification with ≥1 year follow-up. The main outcome measures were in-group and between-group changes in intraocular pressure (IOP) and medication number, proportion of eyes that achieved IOP ≤15 mmHg, and surgical success defined as 20% IOP reduction from baseline at 6/12 months. Univariate/multivariate regression analyses were done to identify predictors of surgical failure. Results: One hundred ninety-seven eyes of 148 patients were included (122 iStent, 75 iStent inject). Both groups achieved significant IOP and medication reduction at months 6/12 (P < 0.05). At month 6, IOP was significantly lower in iStent inject vs. iStent eyes (P = 0.003), but the difference was insignificant by month 12 (P = 0.172). Medication number was comparable in both groups at months 6/12 (P > 0.05). More iStent inject eyes achieved IOP ≤15 mmHg at month 6 (P = 0.003) and 12 (P = 0.047). Surgical success was comparable in both groups at months 6/12 (P > 0.05). Kaplan–Meier survival analysis showed similar cumulative rate of surgical failure at year-1 in both groups (P = 0.644). The multivariate model identified older age (P = 0.017) and lower baseline IOP (P = 0.002) as the strongest predictors of surgical failure. Conclusion: Compared to iStent, iStent inject achieved lower IOP at month 6 and higher proportion of eyes achieved IOP ≤15 mmHg at month 6/12. However, surgical success was similar in both groups. Predictors of surgical failure were older age and lower baseline IOP rather than the stent type.

Purpose To assess the incidence of glaucoma surgery cancellations, as well as their characteristics, underlying reasons, resultant surgical delay, and estimated lost potential reimbursement, at a tertiary eye hospital. Design Retrospective observational study of planned surgical procedures of 4 glaucoma specialists at a tertiary eye center over a 2-year period (May 2017–May 2019). An additional prospective survey of patients was conducted. Participants Patients who canceled glaucoma surgeries. Methods Demographics and clinical information were recorded from the electronic medical record. A brief phone survey was implemented to determine the reason for cancellation and whether the patient rescheduled. Lost reimbursement was estimated assuming Medicare reimbursement rates for each procedure based on facility fee, surgeon fee, and anesthesia fee. Main Outcome Measures Reasons for surgical cancellation, delay related to surgical cancellations, and annual lost reimbursement potential. Results One hundred twenty-three of 1384 glaucoma surgeries (8.9%) to be performed by 4 glaucoma specialists at Wills Eye Hospital during the 2-year study period were canceled. Among those canceled, the mean age ± standard deviation (SD) of the patients was 70.3 ± 14.4 years and 51% were men. Of the cancellations, 56.9% were made within 1 day of the planned date of surgery and 96.7% were canceled within 7 days. Of the reasons for surgical cancellation, 28% were considered preventable, 50% were considered unpreventable, and 23% were categorized as “no reason given.” Most of the surgeries eventually were performed-to-date (64.2%); the mean ± SD delay in surgery was 63.4 ± 68.6 days. The 3 most common preventable reasons for cancellation were lack of transportation (34%), lack of timely clearance (26%), and insurance-related issues (14%). Assuming Medicare reimbursement rates, the estimated annual lost potential reimbursement from surgical cancellations of the 4 glaucoma specialists was $208 306. Conclusions This study highlights a significant number of cancellations in a glaucoma practice, most of which occurred within 1 day of planned surgery. Minimizing preventable causes of cancellations could decrease the likelihood of surgical delays as well as lost reimbursement. Further comparison with patients who successfully underwent surgery performed without delay may identify predictive factors or interventions that could decrease the number of surgical cancellations.

Objective To describe reoperations that occurred within 90 days of minimally invasive glaucoma surgery (MIGS) at a single institution over a 30-month period. Setting Tertiary care hospital. Design Retrospective case series. Methods Charts of adult patients who underwent trabecular microbypass stents, gel microstents, and goniotomy procedures (including gonioscopy-assisted transluminal trabeculotomy) from October 1, 2017, to March 15, 2020, at Wills Eye Hospital were examined. Outcome measures were unanticipated reoperations within the first 90 days after MIGS procedures and the complications that led to these reoperations. Results A total of 448 MIGS procedures were performed on 436 eyes of 348 patients over a 30-month period by 6 glaucoma surgeons. Of these, 206 (46.0%) were trabecular microbypass stents (198 iStent/iStent inject and 8 Hydrus), 152 (33.9%) were gel microstents, and 90 (20.1%) were goniotomy procedures. Combined phacoemulsification took place in 256 eyes (58.7%). Reoperation within 90 days took place in 23 (5.3%) of 436 eyes, including 16 (10.5%) of 152 eyes in the gel microstent group, 4 (2.0%) of 198 eyes in iStent/iStent inject group, and 3 (3.3%) of 90 eyes in the goniotomy group. Indications for reoperation were elevated intraocular pressure (IOP) in 16 (69.6%) of 23 eyes, gel microstent tip exposure with wound leakage in 3 (13.0%) of 23 eyes, and early gel microstent encapsulation without elevated IOP in 1 (4.3%) of 23 eyes. Two (8.7%) of 23 eyes required reoperation for intraocular lens complications, whereas 1 (4.3%) of 23 eyes had elevated IOP and aphakia requiring reoperation. Conclusions The rate of reoperation within the first 90 days after MIGS was low. Elevated IOP and complications associated with gel microstents were the main indications for reoperation.

Context Cancer pain prevalence is high despite well-established international guidelines on pain management and improved accessibility to treatment. Inadequate cancer pain management can be attributed to barriers related to patients, health care professionals, and health care system. Objectives To identify patient-related barriers to effective cancer pain management in a diverse multicultural developing country. Design A cross-sectional survey study was carried out using Brief Pain Inventory—Short Form to measure effectiveness of pain management and Barriers Questionnaire II to explore patient-related barriers to effective pain management. Setting/Participants Patients on strong opioids treated in a comprehensive cancer unit of a public hospital in Sarawak, Malaysia. Results Among 133 subjects surveyed, 66% reported no pain or mild pain, 34% moderate pain, and 10% severe pain. Despite good pain control, 71% of patients still reported moderate-to-severe interference with daily activities. Fatalism scored the highest median Barriers Questionnaire II score among the four domains of patient-related barriers followed by harmful effects, physiological effects, and communication factor. Conclusion Cancer pain is generally well controlled with more than half of patients reporting mild pain. However, degree of interference with daily activities is still high despite good cancer pain control. Fatalistic mentality need to be addressed for effective cancer pain management. Further studies on health care professional-related barriers and health system-related barriers are urgently needed to provide a comprehensive approach of holistic pain management.

Context Severe hypoglycemia with neuroglycopenia, termed post-bariatric hypoglycemia (PBH). typically occurs postprandially, but it is also reported after activity or mid-nocturnally. Objective To quantify glycemia, glycemic variability, and magnitude/duration of low sensor glucose (SG) values in patients with PBH after Roux-en-Y gastric bypass (PBH-RYGB). Methods This retrospective analysis of data from an academic medical center included individuals with PBH-RYGB (n = 40), reactive hypoglycemia without gastrointestinal surgery (Non-Surg Hypo, n = 20), prediabetes (Pre-DM, n = 14), newly diagnosed T2D (n = 5), and healthy controls (HC, n = 38). Masked continuous glucose monitoring (Dexcom G4) was used to assess patterns over 24 hours, daytime (6 am–midnight) and nighttime (midnight–6 am). Prespecified measures included mean and median SG, variability, and percent time at thresholds of sensor glucose. Results Mean and median SG were similar for PBH-RYGB and HC (mean: 99.8 ± 18.6 vs 96.9 ± 10.2 mg/dL; median: 93.0 ± 14.8 vs 94.5 ± 7.4 mg/dL). PBH-RYGB had a higher coefficient of variation (27.3 ± 6.8 vs 17.9 ± 2.4%, P 2-fold greater time with SG Conclusion Patients with PBH-RYGB experience higher glycemic variability and frequency of SG

The current ST-elevation myocardial infarction (STEMI) vs. non-STEMI (NSTEMI) paradigm prevents some NSTEMI patients with acute coronary occlusion from receiving emergent reperfusion, in spite of their known increased mortality compared with NSTEMI without occlusion. We have proposed a new paradigm known as occlusion MI vs. nonocclusion MI (OMI vs. NOMI).We aimed to compare the two paradigms within a single population. We hypothesized that STEMI(-) OMI would have characteristics similar to STEMI(+) OMI but longer time to catheterization.We performed a retrospective review of a prospectively collected acute coronary syndrome population. OMI was defined as an acute culprit and either TIMI 0-2 flow or TIMI 3 flow plus peak troponin T 1.0 ng/mL. We collected electrocardiograms, demographic characteristics, laboratory results, angiographic data, and outcomes.Among 467 patients, there were 108 OMIs, with only 60% (67 of 108) meeting STEMI criteria. Median peak troponin T for the STEMI(+) OMI, STEMI(-) OMI, and no occlusion groups were 3.78 (interquartile range [IQR] 2.18-7.63), 1.87 (IQR 1.12-5.48), and 0.00 (IQR 0.00-0.08). Median time from arrival to catheterization was 41 min (IQR 23-86 min) for STEMI(+) OMI compared with 437 min (IQR 85-1590 min) for STEMI(-) OMI (p 0.001). STEMI(+) OMI was more likely than STEMI(-) OMI to undergo catheterization within 90 min (76% vs. 28%; p 0.001).STEMI(-) OMI patients had significant delays to catheterization but adverse outcomes more similar to STEMI(+) OMI than those with no occlusion. These data support the OMI/NOMI paradigm and the importance of further research into emergent reperfusion for STEMI(-) OMI.

Microinvasive glaucoma surgeries (MIGSs) are new surgical procedures for treatment of glaucoma. They aim to safely and effectively reduce intraocular pressure (IOP) with minimal trauma to the eye and less complications. The first-generation iStent is the first approved ab interno MIGS implant for management of open-angle glaucoma. It works by allowing aqueous humor to drain directly from the anterior chamber into Schlemm canal bypassing the trabecular meshwork, the major site of outflow resistance. The second-generation iStent inject is the smallest available trabecular device that occupies less than 0.5 mm. It is designed to facilitate the surgical technique and allow simultaneous implantation of 2 stents, aiming for more IOP reduction. This review examines publications about the iStent inject, focusing on the device's efficacy, safety, and comparison with the first generation iStent. Both devices were found to be a safe and effective tool in management of open-angle glaucoma.

PURPOSE OF REVIEW The aim of this study was to provide a comprehensive summary of in-vivo imaging techniques of the aqueous outflow system and discuss its role in improving our understanding of glaucoma pathogenesis and management. RECENT FINDINGS Our understanding of the aqueous outflow system is largely derived from ex-vivo studies. Recent innovations in imaging technology and techniques enable in-vivo evaluation of the conventional outflow system in real-time. Optical coherence tomography allows for noninvasive, high-resolution, volumetric imaging of ocular tissues. Dynamic structural changes have been observed at the trabecular meshwork and Schlemm's canal. In parallel, aqueous angiography using injected tracers show a similar dynamism with variable and pulsatile flow signals. SUMMARY In-vivo imaging enable real-time evaluation of the conventional aqueous outflow pathway. This emerging field shows great promise to expand our understanding of the pathogenesis and treatment of glaucoma.

Although the first case of tumor-to-tumor metastasis was reported over a century ago, it remains a rare occurrence. We report a rare case of metastatic infiltrating lobular carcinoma involving clear cell renal cell carcinoma, as well as offer a brief literature review.

Ocular trauma is a significant cause of blindness worldwide, particularly if associated with glaucoma. Direct damage from blunt or penetrating trauma, bleeding, inflammation, lens-related problems, orbital and brain vascular pathologies related to trauma, and chemical injuries may increase intraocular pressure and lead to traumatic glaucoma. Treatment may be as simple as eliminating the underlying cause in some conditions or management can be challenging, depending on the mechanism of damage. If proper management is not undertaken, visual outcomes can be poor. We discuss a broad spectrum of trauma-related mechanisms of intraocular pressure elevation, as well as their management.

Selective laser trabeculoplasty (SLT) is a common procedure to lower intraocular pressure (IOP) in patients with glaucoma. However, reports are conflicting regarding what factors contribute to SLT success. The purpose of this study was to determine predictors of SLT success.Retrospective case series.All patients treated with SLT between January 1, 2012, and June 30, 2018.Baseline, demographic, procedural, and ophthalmic examination data were recorded at the time of first SLT treatment. Intraocular pressure and medication data were recorded at all follow-up visits.Selective laser trabeculoplasty success was defined as IOP decrease of 20% or more from baseline at the 3-month, 6-month, and 12-month follow-up visits. Eyes were considered to have failed and were censored when additional SLT or glaucoma surgery was performed. Patients were excluded if they had less than 3 months of follow-up.A total of 997 eyes from 677 patients were included in the study. Mean age was 70.2±11.5 years. Selective laser trabeculoplasty success was achieved in 227 eyes (22.8%), whereas 770 eyes (77.2%) did not meet success criteria. Intraocular pressure before SLT was 21.9±5.2 mmHg while taking 2.0±1.2 medications in eyes with successful SLT, compared with 19.0±5.0 mmHg (P0.0001) while taking 2.1±1.3 medications (P = 0.52) in eyes with SLT failure. At the 1-year follow-up, mean IOP in eyes with SLT success was 14.7±3.2 mmHg with 2.0±1.2 medications, compared with 16.3±4.7 mmHg (P = 0.008) with a mean of 1.9±1.3 medications (P = 0.37) in eyes with SLT failure. Eyes with SLT success more often showed greater angle pigment (P = 0.03). Age, glaucoma severity, total SLT power, type of glaucoma, severity of glaucoma, visual field mean defect, and retinal nerve fiber layer thickness were not found to correlate with success. No difference was found between the rate of success based on treatments before SLT, whether surgical or medical.In this large cohort of eyes undergoing SLT, greater IOP and angle pigment before SLT correlated positively with SLT success. Age, total SLT power, severity of glaucoma, and prior treatments were not associated with SLT success or failure.

The pathophysiology of microhemorrhages in the context of cerebral amyloid angiopathy (CAA) remains poorly understood. Here we used in vivo two-photon microscopy in aged APP/PS1 mice with mild-to-moderate CAA to assess the formation of microhemorrhages and their spatial relationship with vascular Aβ depositions in the surrounding microvascular network. Mice with chronic cranial windows were intravenously injected with fluorescent dextran to visualize the vessels and a fluorescently labeled anti-fibrin antibody to visualize microhemorrhages. Focal vessel irradiations resulted in extravascular fibrin-positive clots at individual rupture sites that remained visible for weeks. Spontaneous extravascular fibrin-positive clots were more often observed in 19-month-old transgenic APP/PS1 mice compared to their wild-type littermate controls ( p = 0.039), after heparin administration. In the transgenic mice, these spontaneous leakage sites frequently occurred at arteriolar segments without CAA at bifurcations or vessel bends. These findings suggest that the presence of vascular Aβ per se does not directly predispose vessels to leak, but that complex flow dynamics within CAA-affected vascular networks likely play a role. Our in vivo approach for the detection of individual spontaneous leakage sites may be used in longitudinal studies aimed to assess structural and functional alterations at the single-vessel level leading up to microhemorrhage formation.

Peripheral nerve field stimulation (PNfS) has emerged as a viable neuromodulatory therapy in the treatment of refractory pain. Although the technology surrounding percutaneous electrical stimulation is not novel, recent advancements help to explain its increased utilization. Treatment success is most often aligned with the identification of the correct patient, as well as the selection and placement of the leads and implantable pulse generators. PNfS carries less risk of complications compared to other neuromodulatory procedures, but lead migration, erosion, infection, or mechanical issues with the device may occur.

Background Occlusion myocardial infarctions (OMIs) of the posterolateral walls are commonly missed by ST‐segment–elevation myocardial infarction (STEMI) criteria, with >50% of patients with circumflex occlusion not receiving emergent reperfusion and experiencing increased mortality. ST‐segment depression maximal in leads V1–V4 (STDmaxV1–4) has been suggested as an indicator of posterior OMI. Methods and Results We retrospectively reviewed a high‐risk population with acute coronary syndrome. OMI was defined from prior studies as a culprit lesion with TIMI (Thrombolysis in Myocardial Infarction) 0 to 2 flow or TIMI 3 flow plus peak troponin T >1.0 ng/mL or troponin I >10 ng/mL. STEMI was defined by the Fourth Universal Definition of Myocardial Infarction. ECGs were interpreted blinded to outcomes. Among 808 patients, there were 265 OMIs, 108 (41%) meeting STEMI criteria. A total of 118 (15%) patients had “suspected ischemic” STDmaxV1–4, of whom 106 (90%) had an acute culprit lesion, 99 (84%) had OMI, and 95 (81%) underwent percutaneous coronary intervention. Suspected ischemic STDmaxV1–4 had 97% specificity and 37% sensitivity for OMI. Of the 99 OMIs detected by STDmaxV1–4, 34% had P =0.028). Conclusions Among patients with high‐risk acute coronary syndrome, the specificity of ischemic STDmaxV1–4 was 97% for OMI and 96% for OMI requiring emergent percutaneous coronary intervention. STEMI criteria missed half of OMIs detected by STDmaxV1–4. Ischemic STDmaxV1–V4 in acute coronary syndrome should be considered OMI until proven otherwise.

Background Age-specific incidence of acute myocarditis/pericarditis in adolescents following Comirnaty vaccination in Asia is lacking. This study aimed to study the clinical characteristics and incidence of acute myocarditis/pericarditis among Hong Kong adolescents following Comirnaty vaccination. Methods This is a population cohort study in Hong Kong that monitored adverse events following immunization through a pharmacovigilance system for coronavirus disease 2019 (COVID-19) vaccines. All adolescents aged between 12 and 17 years following Comirnaty vaccination were monitored under the COVID-19 vaccine adverse event response and evaluation program. The clinical characteristics and overall incidence of acute myocarditis/pericarditis in adolescents following Comirnaty vaccination were analyzed. Results Between 14 June 2021 and 4 September 2021, 33 Chinese adolescents who developed acute myocarditis/pericarditis following Comirnaty vaccination were identified. In total, 29 (87.88%) were male and 4 (12.12%) were female, with a median age of 15.25 years. And 27 (81.82%) and 6 (18.18%) cases developed acute myocarditis/pericarditis after receiving the second and first dose, respectively. All cases are mild and required only conservative management. The overall incidence of acute myocarditis/pericarditis was 18.52 (95% confidence interval [CI], 11.67–29.01) per 100 000 persons vaccinated. The incidence after the first and second doses were 3.37 (95% CI, 1.12–9.51) and 21.22 (95% CI, 13.78–32.28 per 100 000 persons vaccinated, respectively. Among male adolescents, the incidence after the first and second doses were 5.57 (95% CI, 2.38–12.53) and 37.32 (95% CI, 26.98–51.25) per 100 000 persons vaccinated. Conclusions There is a significant increase in the risk of acute myocarditis/pericarditis following Comirnaty vaccination among Chinese male adolescents, especially after the second dose.

Background Intraprostatic inflammation is frequently observed in the prostate and linked to prostatic diseases, including prostatitis, benign prostatic hyperplasia (BPH), and cancer. The etiology of prostate diseases is unclear. Periodontal diseases are associated with an increased risk of prostate diseases. In men, chronic prostatitis and moderate/severe periodontitis have significantly elevated serum prostate-specific antigen (PSA) levels. Treatment of periodontal disease reduced PSA levels in men. The presence of periodontal pathogens deoxyribonucleic acid (DNA) was identified in the prostate fluid of prostatitis patients. These pathogenic bacteria might have the potential to trigger prostatitis progressing to prostatic adenocarcinoma. The mechanism(s) explaining the etiology of association between periodontal disease and prostate cancer remains unclear. However, the presence of periodontal pathogens has not been analyzed in the prostate gland. Objective To identify and compare the presence of specific periodontal pathogens in the areas of BPH, inflammation, and cancer of the prostate glands diagnosed with malignancy. Materials and methods Whole-mount radical prostatectomy sections from men (n=30) were identified for BPH, inflammation, and cancer areas and marked for tissue procurement. The tissues were subjected to DNA isolation and analysis of microbial DNA and total bacterial load for the following pathogens, including Porphyromonas gingivalis strain ATCC 33277, Prevotella intermedia strain B422, Treponema denticola strain 35405, Fusobacterium nucleatum subsp. fusiform strain, Tannerella forsythia strain ATCC 43037, and Campylobacter​​​​​​​ rectus strain ATCC 33238performed real-time PCR. The universal bacterial primer pairs were used to detect genomic DNA (gDNA) from the total bacteria present in the samples. All species-specific primers were designed to target the variable regions of the 16S ribosomal RNA (rRNA). Data were analyzed using the 2-ΔΔCT method, statistically validated using unpaired t-test and ANOVA test. Results A total of 90 samples of prostate tissue specimens were analyzed for periodontal pathogens; only one pathogen (F. nucleatum subsp. fusiform strain ATCC 51190) showed a significant difference compared to the expression of S. epidermidis (internal control). In particular, F. nucleatum expression was 9, 11.9, and 10.3-fold higher in BPH, inflammation, and cancer, respectively, at p-value 0.05). Similarly, there was no significant difference between F. nucleatum (folder change) among the three areas (p-valve>0.05). Conclusion Fusobacterium nucleatum is identified in the prostates that harbor cancer, chronic inflammation, and BPH.

The coronavirus disease 2019 (COVID-19) pandemic had significant impact on research directions and productivity in the past year. Despite these challenges, since 2020, >2,500 peer-reviewed articles in pancreatic islet biology have been published. These include updates on the roles of isocitrate dehydrogenase, pyruvate kinase, and incretin hormones in insulin secretion, as well as the discovery of Inceptor and signaling by circulating RNAs. 2020 also brought advancements in in vivo and in vitro models, including a new transgenic mouse for assessing β-cell proliferation, a pancreas-on-a-chip to study glucose-stimulated insulin secretion, and successful genetic editing of primary human islet cells. Islet biologists evaluated the functionality of stem cell-derived islet-like cells coated with semi-permeable biomaterials to prevent autoimmune attack, revealing the importance of cell maturation following transplantation. Prompted by observations that COVID-19 symptoms can worsen for people with obesity or diabetes, researchers examined how islets are directly affected by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Herein, we highlight novel functional insights, technologies and therapeutic approaches emerging between March 2020 and July 2021, written for both scientific and lay audiences. We also include a response to these advancements from patient stakeholders, to help lend broader perspective to developments and challenges in islet research., Graphical abstract

The iron chelator, deferoxamine (DFO), has been shown to potentially improve dermal radiation‐induced fibrosis (RIF) in mice through increased angiogenesis and reduced oxidative damage. This preclinical study evaluated the efficacy of two DFO administration modalities, transdermal delivery and direct injection, as well as temporal treatment strategies in relation to radiation therapy to address collateral soft tissue fibrosis. The dorsum of CD‐1 nude mice received 30 Gy radiation, and DFO (3 mg) was administered daily via patch or injection. Treatment regimens were prophylactic, during acute recovery, post‐recovery, or continuously throughout the experiment (n = 5 per condition). Measures included ROS‐detection, histology, biomechanics and vascularity changes. Compared with irradiated control skin, DFO treatment decreased oxidative damage, dermal thickness and collagen content, and increased skin elasticity and vascularity. Metrics of improvement in irradiated skin were most pronounced with continuous transdermal delivery of DFO. In summary, DFO administration reduces dermal fibrosis induced by radiation. Although both treatment modalities were efficacious, the transdermal delivery showed greater effect than injection for each temporal treatment strategy. Interestingly, the continuous patch group was more similar to normal skin than to irradiated control skin by most measures, highlighting a promising approach to address detrimental collateral soft tissue injury following radiation therapy.

IntroductionSudden cardiac death (SCD) is the leading cause of death in patients with myocardial infarction (MI) and can be prevented by the implantable cardioverter defibrillator (ICD). Currently, risk stratification for SCD and decision on ICD implantation are based solely on impaired left ventricular ejection fraction (LVEF). However, this strategy leads to over- and under-treatment of patients because LVEF alone is insufficient for accurate assessment of prognosis. Thus, there is a need for better risk stratification. This is the study protocol for developing and validating a prediction model for risk of SCD in patients with prior MI.Methods and AnalysisThe EU funded PROFID project will analyse 23 datasets from Europe, Israel and the US (∼225,000 observations). The datasets include patients with prior MI or ischemic cardiomyopathy with reduced LVEFEthics and disseminationLocal ethical approval was obtained. The final model will be disseminated through scientific publications and a web-calculator. Statistical code will be published through open-source repositories.

Purpose: Fat grafting is known to rejuvenate and improve fibrosis in irradiated skin, but the underlying mechanisms behind these effects are poorly understood. We have previously identified the Engrailed-1 fibroblast sub-population as having a role in post-natal dorsal skin fibrosis in mice. Using a radiation model to the scalp of Engrailed-1 mice, we sought to better understand the regenerative effects of fat grafting in irradiated tissue. Methods: Adult (60-day old) En1Cre;R26mTmG transgenic mice (n=5) underwent total body irradiation with 9 Gy for immunodepletion. Mice were then immediately reconstituted with 2 million nucleated bone marrow cells from donor NSG(NOD.CB17-Prkdcsscid/J) mice via retro-orbital injections. Reconstitution was confirmed with fluorescence-activated cell sorting (FACS) 2 weeks after whole body irradiation. Mice scalps were then irradiated with 5 Gy every other day for 12 days (30 Gy total) and allowed to recover for 4 weeks to facilitate fibrotic conversion. Irradiated scalps were grafted with 200μL of fresh human lipoaspirate. Graph retention was measured in-vivo for 8 weeks using Micro-Computed Tomography Scanner (Bruker SkyScan 1726™) and scalp skin was harvest for histology. Results: Two weeks post bone-marrow transplant, >90% of circulating hematopoietic cells (CD45+) cells in En1Cre;R26mTmG reporter mice were non-fluorescent, signifying successful reconstitution. Volumetric analysis of fat grafting in-vivo was performed using 3-dimensional reconstruction. At 8 weeks post-grafting, 4 of the 5 grafts demonstrated >50% graft retention, confirming successful grafting. Histological sections of scalp skin 8 weeks post-grafting demonstrated significantly less En1+GFP cells compared to non-grafted scalp skin, signifying less presence of En1+ fibroblasts. Furthermore, histology demonstrated significantly less dermal thickening, epidermal thinning, and collagen deposition and disorganization in fat grafted irradiated scalp skin compared to non-grafted scalp skin. Conclusion: Fat grafting mitigates radiation-induced fibrosis in scalp skin by decreasing collagen deposition, remodeling collagen formation, decreasing epidermal thinning, and reducing presence of pro-fibrotic fibroblast sub-populations.

Adenosine, an endogenous purine nucleoside, is a well-known actor of the immune system and the inflammatory response both in physiologic and pathologic conditions. By acting upon particular, G-protein coupled adenosine receptors, i.e., A1, A2- a & b, and A3 receptors mediate a variety of intracellular and immunomodulatory actions. Several studies have elucidated Adenosine's effect and its up-and downstream molecules and enzymes on the anti-tumor response against several types of cancers. We have also targeted a couple of molecules to manipulate this pathway and get the immune system's desired response in our previous experiences. Besides, the outgrowth of the studies on ocular Adenosine in recent years has significantly enhanced the knowledge about Adenosine and its role in ocular immunology and the inflammatory response of the eye. Glaucoma is the second leading cause of blindness globally, and the recent application of Adenosine and its derivatives has shown the critical role of the adenosine pathway in its pathophysiology. However, despite a very promising background, the phase III clinical trial of Trabodenoson failed to achieve the non-inferiority goals of the study. In this review, we discuss different aspects of the abovementioned pathway in ophthalmology and ocular immunology; following a brief evaluation of the current immunotherapeutic strategies, we try to elucidate the links between cancer immunotherapy and glaucoma in order to introduce novel therapeutic targets for glaucoma.

Pancreatic islets adapt to insulin resistance of pregnancy by up regulating β-cell mass and increasing insulin secretion. Previously, using a transgenic mouse with global, heterozygous deletion of prolactin receptor (Prlr+/−), we found Prlr signaling is important for this adaptation. However, since Prlr is expressed in tissues outside of islets as well as within islets and prolactin signaling affects β-cell development, to understand β-cell-specific effect of prolactin signaling in pregnancy, we generated a transgenic mouse with an inducible conditional deletion of Prlr from β-cells. Here, we found that β-cell-specific Prlr reduction in adult mice led to elevated blood glucose, lowed β-cell mass and blunted in vivo glucose-stimulated insulin secretion during pregnancy. When we compared gene expression profile of islets from transgenic mice with global (Prlr+/−) versus β-cell-specific Prlr reduction (βPrlR+/−), we found 95 differentially expressed gene, most of them down regulated in the Prlr+/− mice in comparison to the βPrlR+/− mice, and many of these genes regulate apoptosis, synaptic vesicle function and neuronal development. Importantly, we found that islets from pregnant Prlr+/− mice are more vulnerable to glucolipotoxicity-induced apoptosis than islets from pregnant βPrlR+/− mice. These observations suggest that down regulation of prolactin action during pregnancy in non-β-cells secondarily and negatively affect β-cell gene expression, and increased β-cell susceptibility to external insults.

Forward genetic screen, typically performed in invertebrates or mammalian cell lines, has been instrumental in discovering genes essential for neural function. In this issue of Neuron, Wertz et al. (2020) demonstrate the first viral-mediated, genome-wide screen to identify neuroprotective genes in wild-type and Huntington's disease (HD) mouse brains.

A 32-year-old-woman presented with traumatic facial injuries from a horseback riding incident. She was found to have a Glasgow Coma Score of 3T, left eyelid ptosis with a fixed-dilated pupil and a flaccid right upper extremity. CT angiogram of the head showed complex craniofacial injuries, including a transverse fracture transecting the clivus and the left petrous temporal bone, with SAH in the suprasellar cistern. There was a bilateral engorgement of the superior ophthalmic veins, suggestive of bilateral CCF formations. Digital subtraction angiography (DSA) showed a left petrocavernous internal carotid artery dissection (ICAD). MRI of the brain demonstrated multiple embolic infarcts in the left middle cerebral artery (MCA) territory, despite therapeutic anticoagulation with heparin. Follow-up DSA 1 week later showed bilateral multifocal internal carotid artery (ICA) and vertebral artery dissections, bilateral direct CCFs and cavernous ICA PAs. Because of progressing morphological distortion (figure 1), a flexible LVIS Jr. stent was placed at the anterior genu of the left cavernous ICA to provide a scaffold for the more rigid 3.5×20.0 mm self-expanding Wingspan stent (petrous ICA to distal cavernous ICA), covering the neck of the PA followed by its coil embolisation. Five days after coiling, a 5 mm residual sac was noted in the PA with extension of the left ICAD up to the ICA terminus (figure 2). The latter was treated with another 3.5×23.0 mm LVIS Jr. stent (from left the M1 MCA up to the dural junction of the left ICA). Eleven days after coiling, the PA had increased up to 15×14 mm and was treated with three PED …

Retroperitoneal haemorrhage is a rare but potentially life-threatening event. It may occur either spontaneously or secondary to percutaneous vascular access procedures, trauma, or ruptured aortic, iliac, or mesenteric aneurysms. As a result, the clinical presentation is variable. Computed tomography and/or angiography are vital for diagnosis. Management may range from conservative treatment for stable patients to emergency laparotomy or embolization for catastrophic haemorrhage. Direct percutaneous puncture of a deep intra-abdominal pseudoaneurysm is an accepted but infrequently performed technique due to a number of diagnostic and technical challenges. We describe the successful percutaneous transabdominal angioembolization of a superior mesenteric artery rupture in a 77-year-old woman with a large retroperitoneal haematoma. This was performed after a conventional femoral transarterial approach was unsuccessful.

Introduction: Reduction of intraocular pressure (IOP) is the only known modifiable risk factor for prevention and treatment of glaucoma. Rho-kinase (ROCK) inhibitors are a new class of glau...

To assess the effects of surgeon-related factors on laser peripheral iridotomy (LPI) outcomes by comparing residents and glaucoma specialists, and to look for demographic and clinical predictive factors associated with LPI complications.Retrospective cohort study.Patients who underwent LPI performed by a resident physician were included as cases, and patients who underwent LPI performed by a glaucoma specialist were included as controls. In patients who underwent multiple sessions of laser therapy, only the information from the first session of each eye was included in the study.Demographic and clinical information were gathered from the pre-LPI, 1-week, 1-month, and 3-month follow-up visits. The following information was recorded from the LPI session: total laser energy, presence of bleeding, and post-laser intraocular pressure (IOP). Information gathered from the follow-up visits included visual acuity (VA), IOP, hyphema, and need to repeat LPI. A logistic regression analysis with modification for rare events was used to examine the relationship between the dependent variables and the group, adjusted for the clinical and demographic characteristics of patients.The LPI procedure parameters (total energy), postoperative VA and IOP, risk for complications, and need for re-treatment were compared between groups using odds ratio (OR) measurements.A total of 333 eyes were included in the study. The residents used statistically significant higher total energy compared with the glaucoma specialists' group (P0.001). After adjusting for demographic characteristics, antiplatelet/anticoagulant use, and laser energy parameters, we found that the patients of the residents group had a significantly increased likelihood for re-treatment within 3 months (OR, 3.38; 95% confidence interval [CI], 1.31-8.73) and anterior chamber bleeding (OR, 7.48; 95% CI, 1.07-52.02).Although LPI is an effective and minimally invasive procedure, evidence shows that a higher level of experience leads to clinically and statistically significant better outcomes.

Aramchol, an oral stearoyl-coenzyme-A-desaturase-1 inhibitor, has been shown to reduce hepatic fat content in patients with primary nonalcoholic fatty liver disease (NAFLD); however, its effect in patients with human immunodeficiency virus (HIV)-associated NAFLD is unknown. The aramchol for HIV-associated NAFLD and lipodystrophy (ARRIVE) trial was a double-blind, randomized, investigator-initiated, placebo-controlled trial to test the efficacy of 12 weeks of treatment with aramchol versus placebo in HIV-associated NAFLD. Fifty patients with HIV-associated NAFLD, defined by magnetic resonance imaging (MRI)-proton density fat fraction (PDFF) ≥5%, were randomized to receive either aramchol 600 mg daily (n = 25) or placebo (n = 25) for 12 weeks. The primary endpoint was a change in hepatic fat as measured by MRI-PDFF in colocalized regions of interest. Secondary endpoints included changes in liver stiffness using magnetic resonance elastography (MRE) and vibration-controlled transient elastography (VCTE), and exploratory endpoints included changes in total-body fat and muscle depots on dual-energy X-ray absorptiometry (DXA), whole-body MRI, and cardiac MRI. The mean (± standard deviation) of age and body mass index were 48.2 ± 10.3 years and 30.7 ± 4.6 kg/m2 , respectively. There was no difference in the reduction in mean MRI-PDFF between the aramchol group at -1.3% (baseline MRI-PDFF 15.6% versus end-of-treatment MRI-PDFF 14.4%, P = 0.24) and the placebo group at -1.4% (baseline MRI-PDFF 13.3% versus end-of-treatment MRI-PDFF 11.9%, P = 0.26). There was no difference in the relative decline in mean MRI-PDFF between the aramchol and placebo groups (6.8% versus 1.1%, P = 0.68). There were no differences in MRE-derived and VCTE-derived liver stiffness and whole-body (fat and muscle) composition analysis by MRI or DXA. Compared to baseline, end-of-treatment aminotransferases were lower in the aramchol group but not in the placebo arm. There were no significant adverse events. Conclusion: Aramchol, over a 12-week period, did not reduce hepatic fat or change body fat and muscle composition by using MRI-based assessment in patients with HIV-associated NAFLD (clinicaltrials.gov ID:NCT02684591).

Emre Firlar,1,2 Meagan Ouy,1 Leigha Covnot,1 Yuan Xing,3 Daniel Lee,1,4 Alessandro Chan,1,4 Yi He,3 Boao Song,2 Solomon Afelik,4 Yong Wang,3 Reza Shahbazian-Yassar,2 Jose Oberholzer,1,3 Tolou Shokuhfar1 1Department of Bioengineering, University of Illinois at Chicago, Chicago, IL, USA; 2University of Illinois at Chicago, Department of Mechanical and Industrial Engineering, Chicago, IL, USA; 3University of Virginia, Department of Surgery, Charlottesville, VA, USA; 4University of Illinois at Chicago, Department of Surgery, Chicago, IL, USA Background: Islet cell transplantation is one of the key treatments for type 1 diabetes. Understanding the mechanisms of insulin fusion and exocytosis are of utmost importance for the improvement of the current islet cell transplantation and treatment of diabetes. These phenomena have not been fully evaluated due either to the lack of proper dynamic imaging, or the lack of proper cell preservation during imaging at nanoscales. Methods: By maintaining the native environment of pancreatic β-cells between two graphene monolayer sheets, we were able to monitor the subcellular events using in situ graphene liquid cell (GLC)-transmission electron microscopy (TEM) with both high temporal and high spatial resolution. Results: For the first time, the nucleation and growth of insulin particles until the later stages of fusion were imaged at nanometer scales. The release of insulin from plasma membrane involves the degradation of plasma membrane and drastic reductions in the shorter axis of the insulin particles. Sequential exocytosis results indicated the nucleation, growth and attachment of the new insulin particles to the already anchored ones, which is thermodynamically favorable due to the reduction in total surface, further reducing the Gibbs free energy. The retraction of the already anchored insulin toward the cell is also monitored for the first time live at nanoscale resolution. Conclusion: Investigation of insulin granule dynamics in β-cells can be investigated via GLC-TEM. Our findings with this technology open new realms for the development of novel drugs on pathological pancreatic β-cells, because this approach facilitates observing the effects of the stimuli on the live cells and insulin granules. Keywords: transmission electron microscopy, graphene liquid cell, insulin secretion, exocytosis

The prevalence of endophthalmitis after minimally invasive glaucoma surgery (MIGS) in this large 5-year series was 0.13% [0.04% – 0.30%]. All cases were associated with implantable devices. Outcomes were variable.

Highlights • Acute coronary occlusions without ST elevation criteria suffer double mortality without reperfusion. • ECG findings other than ST elevation criteria can identify occlusion myocardial infarction sooner and more accurately. • Our results justify further research to evaluate the external validity of advanced ECG interpretation., Objective In the STEMI paradigm of Acute Myocardial Infarction (AMI), many NSTEMI patients have unrecognized acute coronary occlusion MI (OMI), may not receive emergent reperfusion, and have higher mortality than NSTEMI patients without occlusion. We have proposed a new OMI vs. Non-Occlusion MI (NOMI) paradigm shift. We sought to compare the diagnostic accuracy of OMI ECG findings vs. formal STEMI criteria for the diagnosis of OMI. We hypothesized that blinded interpretation for predefined OMI ECG findings would be more accurate than STEMI criteria for the diagnosis of OMI. Methods We performed a retrospective case-control study of patients with suspected acute coronary syndrome. The primary definition of OMI was either 1) acute TIMI 0–2 flow culprit or 2) TIMI 3 flow culprit with peak troponin T ≥1.0 ng/mL or I ≥10.0 ng/mL. Results 808 patients were included, of whom 49% had AMI (33% OMI; 16% NOMI). Sensitivity, specificity, and accuracy of STEMI criteria vs Interpreter 1 using OMI ECG findings among 808 patients were 41% vs 86%, 94% vs 91%, and 77% vs 89%, and for Interpreter 2 among 250 patients were 36% vs 80%, 91% vs 92%, and 76% vs 89%. STEMI(−) OMI patients had similar infarct size and mortality as STEMI(+) OMI patients, but greater delays to angiography. Conclusions Blinded interpretation using predefined OMI ECG findings was superior to STEMI criteria for the ECG diagnosis of Occlusion MI. These data support further investigation into the OMI vs. NOMI paradigm and suggest that STEMI(−) OMI patients could be identified rapidly and noninvasively for emergent reperfusion using more accurate ECG interpretation.

While ultrasound is often the preferred imaging modality for suspected acute cholecystitis (AC), CT is often the first line study when patients are being evaluated for abdominal pain. The diagnostic value of CT in the setting of AC is controversial, given the prevalent use of additional imaging. To evaluate the positive predictive value (PPV) of CT for diagnosing acute cholecystitis (AC) when used as a first line imaging study for evaluating abdominal pain and assess if additional imaging with ultrasound studies provides additional clinically useful information. Abnormal gallbladder findings in CT imaging studies were queried in a retrospective study over a 25-month period within a large urban health system. Sonographic (US) studies performed within 72 h of the initial CT were also included. Outcomes were determined by surgical pathology, fluid analysis, and clinical outcomes. Cases were stratified by the interpreting radiologist’s subjective confidence level of diagnosing AC, and the PPVs were compared between cases using CT without US and cases with both CT and US. Of the 468 CT studies meeting criteria, 192 were read as concerning for AC. PPV of CT was 44.7% without US and 50.5% when US was positive, which amounted to an insignificant gain (p = 0.41). When subdividing by confidence level, high-confidence positive CTs demonstrated no significant difference without ultrasound (80%) compared to with ultrasound (75%). Less confident reads in CT demonstrated potential gain from ultrasound; in the case of a “probable” CT impression, PPV increased from 45% without US to 90% with a high-confidence ultrasound impression. Based on current practice within a large health system, CT examinations with high suspicion for AC demonstrated little gain from follow-up ultrasound. However, ultrasound may be of benefit when CT interpretations are less confident but still suspicious for AC.

With continually improving treatment strategies and patient care, the overall mortality of cardiovascular disease (CVD) has been significantly reduced. However, this success is a double-edged sword, as many patients who survive cardiovascular complications will progress towards a chronic disorder over time. A family of adiponectin paralogs designated as C1q complement/tumor necrosis factor (TNF)-associated proteins (CTRPs) has been found to play a role in the development of CVD. CTRPs, which are comprised of 15 members, CTRP1 to CTRP15, are secreted from different organs/tissues and exhibit diverse functions, have attracted increasing attention because of their roles in maintaining inner homeostasis by regulating metabolism, inflammation, and immune surveillance. In particular, studies indicate that CTRPs participate in the progression of CVD, influencing its prognosis. This review aims to improve understanding of the role of CTRPs in the cardiovascular system by analyzing current knowledge. In particular, we examine the association of CTRPs with endothelial cell dysfunction, inflammation, and diabetes, which are the basis for development of CVD. Additionally, the recently emerged novel coronavirus (COVID-19), officially known as severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2), has been found to trigger severe cardiovascular injury in some patients, and evidence indicates that the mortality of COVID-19 is much higher in patients with CVD than without CVD. Understanding the relationship of CTRPs and the SARS-CoV-2-related damage to the cardiovascular system, as well as the potential mechanisms, will achieve a profound insight into a therapeutic strategy to effectively control CVD and reduce the mortality rate.

MicroRNAs (miRs) are relevant in biological processes, including human prostate cancer. In the present study, the role of miR-769-5p and its targets in prostate cancer were explored. Publicly available data on expression of genes, miRs and disease-free survival of patients with prostate cancer were analyzed along with RNAseq of transfected cell lines. miR-769-5p expression was inversely associated with patient survival and in vitro assays indicated that its inhibition reduced the proliferation and increased apoptosis of prostate cancer cells. miR-769-5p was revealed to target Rho GTPase activating protein 10 (ARHGAP10) and increased expression of ARHGAP10 in tumors was determined to be associated with a favorable prognosis regarding disease-free survival. Of note, ARHGAP10 is a purported tumor suppressor in ovarian cancer, where it inhibits cell division cycle 42 (CDC42) activity and increases apoptosis. Similar effects were observed in prostate cancer cells, where miR-769-5p inhibition increased ARHGAP10 and led to reduced CDC42 activity. Furthermore, miR-769-5p inhibition increased apoptosis, which was partly reversed by additional knockdown of ARHGAP10. These results suggested that miR-769-5p is an oncogene targeting ARHGAP10, which in turn is a candidate tumor suppressor in prostate cancer.

In Huntington’s disease (HD), the mutant Huntingtin (mHTT) is postulated to mediate template-based aggregation that can propagate across cells. It has been difficult to quantitatively detect such pathological seeding activities in patient biosamples, e.g. cerebrospinal fluids (CSF), and study their correlation with the disease manifestation. Here we developed a cell line expressing a domain-engineered mHTT-exon 1 reporter, which showed remarkably high sensitivity and specificity in detecting mHTT seeding species in HD patient biosamples. We showed that the seeding-competent mHTT species in HD CSF are significantly elevated upon disease onset and with the progression of neuropathological grades. Mechanistically, we showed that mHTT seeding activities in patient CSF could be ameliorated by the overexpression of chaperone DNAJB6 and by antibodies against the polyproline domain of mHTT. Together, our study developed a selective and scalable cell-based tool to investigate mHTT seeding activities in HD CSF, and demonstrated that the CSF mHTT seeding species are significantly associated with certain disease states. This seeding activity can be ameliorated by targeting specific domain or proteostatic pathway of mHTT, providing novel insights into such pathological activities.

Introduction: In the current STEMI paradigm of Acute Myocardial Infarction (AMI), many NonSTEMI patients have unrecognized acute coronary occlusion. Such patients do not receive emergent reperfusion and are known to have higher mortality than NSTEMI patients without occlusion. Thus, we have proposed a new Occlusion MI vs. Non-Occlusion MI (OMI vs. NOMI) paradigm. We sought to compare the diagnostic accuracy for OMI of blinded expert ECG interpretation vs. STEMI criteria advocated in the fourth Universal Definition of MI. We hypothesized that blinded expert ECG interpretation would be more accurate than STEMI criteria for the diagnosis of OMI, and that STEMI(-) OMI patients would have similar characteristics to STEMI(+) OMI but greater delays to cardiac catheterization. Methods: Retrospective case-control study of patients with suspected acute coronary syndrome, collecting demographics, laboratory results, ECGs, angiographic data, and outcomes. The primary definition of OMI was defined as either 1) acute TIMI 0-2 flow culprit or 2) TIMI 3 flow culprit with peak troponin T >1.0 ng/mL or troponin I >10.0 ng/mL. Results: 808 patients were included, of whom 49% had AMI (33% OMI; 16% NOMI). Sensitivity, specificity, and accuracy of STEMI criteria vs Expert 1 for OMI among all 808 patients were 41% vs 86%, 94% vs 91%, and 77% vs 89%, and for Expert 2 among 250 patients were 36% vs 80%, 91% vs 92%, and 76% vs 89%. When experts outperformed STEMI criteria (55% of OMI), they diagnosed OMI a median of 1.5 hours earlier than STEMI criteria. Seven key ECG findings were identified by experts as important signs of OMI in STEMI(-) cases. STEMI(-) OMI patients had similar infarct size and mortality as STEMI(+) OMI patients, but greater delays to angiography. Conclusions: Blinded expert ECG interpretation was superior to STEMI criteria for the ECG diagnosis of Occlusion MI. STEMI(-) OMI patients had greater delays to catheterization but similar outcomes to STEMI(+) OMI patients. These data support the OMI vs. NOMI paradigm and suggest that STEMI(-) OMI patients could be identified rapidly and noninvasively for emergent reperfusion using expert ECG interpretation.

Background RECIST1 is commonly used to characterize intermediate outcomes for clinical trials in the context of solid tumors, and it is largely based on a standardized measure of tumor size known as the sum of longest diameters (SLD). In recent years, the FDA has granted accelerated approvals for several new compounds based on improvements in RECIST-based surrogate outcomes like overall response rate and progression-free survival.2 However, there are concerns regarding the robustness of these surrogate endpoints relative to overall survival (OS),3 4 and it is not known whether their prognostic value is similar across TKI, chemotherapy, and immunotherapy regimens. Methods We have developed a Bayesian meta-analytic joint model for longitudinal SLD and OS in order to predict Phase III outcomes from early Phase II data. We validated this model in extensive simulation studies. The model utilizes a generalized Stein-Fojo equation5 to characterize SLD over time in terms of 3 parameters: f (proportion of tumor that is treatment-susceptible), ks (the decay rate among susceptible cells), and kg (the growth rate among resistant cells). Two quantities [tumor shrinkage (f * ks) and tumor regrowth ((1-f) * kg)] are then associated with survival in the context of a proportional-hazards survival model. We estimated this model using Stan6 on a dataset of >6,000 subjects in 15 randomized clinical trials in advanced non-small cell lung cancer. Results Both tumor shrinkage and tumor regrowth were found to be associated with OS (HR for tumor shrinkage: median 0.51, 90% CrI 0.42 - 0.61; HR for tumor regrowth: median 1.24, 90% CrI 1.18 - 1.32). There is a stronger association between tumor shrinkage and OS among patients randomized to a PD-1/PD-L1 inhibitor, either as a monotherapy or in combination with a CTLA-4 inhibitor, than among patients in other trial arms (figure 1). By contrast, there were negligible differences across treatment classes in the association between tumor regrowth and OS. Conclusions Our results suggest that not all reductions in tumor size are equal. A patient with a certain degree of tumor shrinkage on the PD-1/PD-L1 inhibitor will have lower mortality risk than a patient with a similar degree of shrinkage on the other regimens evaluated. More research is needed to determine whether the result is unique to this particular PD-1/PD-L1 inhibitor, to determine what mechanisms of action mediate these treatment-specific effects, and to develop improved surrogate measures of treatment efficacy. References Eisenhauer EA, Therasse P, Bogaerts J, et al: New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer 2009;45:228–247. Of Health USD, Services H, Others: Clinical trial endpoints for the approval of non-small cell lung cancer drugs and biologics: guidance for Industry, 2015 Mandrekar SJ, An M-W, Meyers J, et al: Evaluation of Alternate Categorical Tumor Metrics and Cut Points for Response Categorization Using the RECIST 1.1 Data Warehouse. J Clin Orthod32:841–850, 2014 Blumenthal GM, Karuri SW, Zhang H, et al: Overall response rate, progression-free survival, and overall survival with targeted and standard therapies in advanced non-small-cell lung cancer: US Food and Drug Administration trial-level and patient-level analyses. J Clin Oncol33:1008–1014, 2015 Stein WD, Figg WD, Dahut W, et al: Tumor growth rates derived from data for patients in a clinical trial correlate strongly with patient survival: a novel strategy for evaluation of clinical trial data. Oncologist13:1046–1054, 2008 Carpenter B, Gelman A, Hoffman MD, et al: Stan: A probabilistic programming language [Internet]. jitc-2020-SITC2020.0277.pdf

Severe acidosis has significant adverse consequences on many aspects of human physiology. Most texts would argue that an arterial pH of less than 6.8 is not compatible with life...

Introduction: Immune checkpoint inhibitors (ICIs) are novel drugs that activate T cell-mediated anti-tumor response by blocking immune checkpoints such as PD-1 or CTLA-4, leading to improved cancer patient survival. Despite these benefits, ICIs can result in autoimmune side effects including fulminant myocarditis and heart failure. While ICI-induced myocarditis is characterized by myocardial T cell infiltration, the causal mechanisms remain unknown. We hypothesize that ICI-induced myocarditis is caused by cardiac-specific auto-antigens triggering clonal expansion of myocardial CD8+ T-cells, leading to T-cell mediated myocardial damage. Methods/Results: We have explored the ICI-induced inflammatory response in a mouse model of myocarditis induced by PD-1 knockout and in patients with ICI-induced myocarditis. PD-1 deficient-mice on a lupus-like autoimmune background (i.e. MRL/Pcd1-/- mice) develop spontaneous fatal myocarditis in 70% of animals by 5 weeks of age, with massive cardiac infiltration of CD8>CD4+ T-cells. Likewise, patients with ICI-induced myocarditis have CD8>CD4+ T-cell infiltrate in the heart. We have performed time-of-flight mass cytometry (CyTOF) to immunophenotype the T-cell subsets in the blood/myocardium of MRL/Pcd1-/- mice and in ICI-myocarditis patients. We have also conducted single cell sequencing of T-cell receptors (TCRs) from the blood +/- myocardial-derived T-cell samples of the mice and patients. Our preliminary results in ICI-myocarditis patients confirmed the previously reported CD8+ T-cell expansion in the blood and myocardium of myocarditis patients compared with healthy control. We are currently identifying candidate cardiac auto-antigen(s) responsible for this disease by performing Grouping Lymphocyte Interactions by Paratope Hotspots (GLIPH). Conclusion: Myocarditis is a serious and life-threatening complication of ICI treatment. By understanding the unique immune response present during ICI-induced myocarditis and the responsible cardiac auto-antigen(s) involved, we will pave the way for the development of adjuvant therapies that target these antigens and mitigate their deleterious effects.

Precis Baerveldt glaucoma drainage device demonstrated a greater reduction in intraocular pressure (IOP) than Ahmed in patients with uveitic glaucoma. The most common cause of failure was uncontrolled IOP in Ahmed and hypotony in the Baerveldt group. Purpose To compare the efficacy and safety of Ahmed and Baerveldt glaucoma drainage devices in uveitic glaucoma. Materials and methods The retrospective comparative study included patients with uveitic glaucoma who underwent Ahmed or Baerveldt glaucoma drainage device implantation with a minimum follow-up of 3 months. Success was defined as IOP ≥6 and ≤21 mm Hg and >20% reduction on 2 consecutive visits after the third month with (qualified success) or without (complete success) medications and no further glaucoma surgery or loss of vision. IOP, number of medications, visual acuity, complications, and interventions were compared between groups. Results In total, 137 eyes of 122 patients (67 Ahmed, 70 Baerveldt) were included. The preoperative IOP and number of medications in the Ahmed group (32.7±10.3 mm Hg; 4.1±1.3) were similar to Baerveldt (32.1±10.2 mm Hg; 4.3±1.3; P=0.73, 0.35). These at the last follow-up were (18.1±9.8 mm Hg; 2.1±1) in Ahmed and (12.7±6.9 mm Hg; 1.3±1.3) in Baerveldt groups (P=0.04, 0.01). The Baerveldt had greater IOP reduction (60.3% vs. 44.5%) and complete success rate (30% vs. 9%) with higher complication rate (51.4% vs. 20.9%) (all P≤0.05). The de novo glaucoma reoperation rate was 19% in the Ahmed group and 4% in the Baerveldt group (P=0.006). Hypotony resulted in failure in 7 eyes (10%) in the Baerveldt group and none in the Ahmed group (P=0.013). Conclusions Higher complete success rate and significantly greater reduction in mean IOP and number of medications were observed in the Baerveldt group, but with a higher rate of complications including hypotony.

This study analyzes the content quality and characteristics of the most popular and highly ranked search results on the internet related to glaucoma and medical cannabis (MC).Internet-based, cross-sectional study.Not applicable.Google and 2 social media platforms (Facebook, YouTube) were used to identify online information most accessible to patients. Search criteria included "glaucoma" AND "marijuana" or "cannabinoid" or "CBD." The top 20 Google search and YouTube results for each search term and the posts from the top 9 patient-based glaucoma Facebook groups were aggregated and analyzed using the search criteria.The quality of the content was graded by 2 independent graders using a previously validated Sandvik score and previously reported risk score. The differing values were resolved by a final grader. Additional analysis included whether the source was professional (by physician or medical organization) or shared an opinion on MC (pro, mixed, or against) use in glaucoma.This search resulted in an aggregate of 51 websites on Google, 126 posts from Facebook groups, and 37 videos on YouTube. The mean (± standard deviation) Sandvik score and risk score were 11.0 (±2.23), 10.2 (±1.12), 10.6 (±1.89) and 0.27 (±0.49), 0.46 (±0.62), 0.97 (±0.90) for Google, Facebook, and YouTube, respectively. Analysis of variance showed statistically significant differences in Sandvik (P = 0.01) and risk (P0.0001) scores across the 3 platforms. A significant portion of online material was pro-MC use in the setting of glaucoma (24% of Google, 59% of YouTube, and 21% of Facebook results). Professional content had a significantly higher content quality score and a lower risk score, and was less likely to recommend MC use in glaucoma.Despite American Academy of Ophthalmology, Canadian Ophthalmological Society, and American Glaucoma Society statements against MC use in patients with glaucoma, a significant portion of online material recommends its use. With the wide variation in quality and content of online information, it is important for physicians to be aware of the different platforms and opinions that are readily available to patients.