Surgical Outcomes of Early Versus Late Onset Glaucoma Associated with Sturge-Weber Syndrome.

PURPOSE: To compare long-term surgical outcomes of glaucoma associated with Sturge-Weber syndrome (SWS) in eyes with early and late onset disease. METHODS: Medical records of children with glaucoma associated with SWS who underwent surgical treatment between January 1990 and December 2018 were reviewed. Those diagnosed ≤2 years of age were categorized as early onset while those who were diagnosed >2 years of age were late onset. Failure was defined as intraocular pressure (IOP) >21 mm Hg or reduced <20% below baseline on two consecutive follow-up visits after 3 months, IOP ≤5 mm Hg on two consecutive follow-up visits, reoperation for glaucoma or a complication, or loss of light perception. RESULTS: Forty three eyes of 36 children were studied, including 26 eyes in early onset group and 17 eyes in late onset group. The early onset group more frequently presented with buphthalmos, corneal edema and Haab's striae while late onset group had higher baseline IOP, larger cup-to-disc ratio and longer axial length. The most commonly performed primary surgery was trabeculotomy (50%) in early onset group and tube shunt implantation (71%) in late onset group. The cumulative probability of failure after 5 years follow-up was 50.6% in early onset group and 50.9% in late onset group (P=0.56). Postoperative complications occurred in 3 eyes (12%) in early onset group and 11 eyes (65%) in late onset group (P<0.001). CONCLUSION: Early and late onset SWS glaucoma may represent two entities with different pathogenetic mechanisms, clinical presentations, primary surgical choices and outcomes, though this needs corroboration in future studies.

Chitosan-nanoclay embolic material for catheter-directed arterial embolization.

Minimally invasive transcatheter embolization is a common nonsurgical procedure in interventional radiology. It is used for the deliberate occlusion of blood vessels for the treatment of disease or injured vasculature, including vascular malformation and malignant/benign tumors. Here, we introduce a gel embolic agent comprising chitosan nanofibers and nanoclay with excellent catheter injectability and tunable mechanical properties for embolization. The properties of the gel were optimized by varying the ratio between each individual component and also adjusting the total solid content. The rheological studies confirm the shear thinning property and gel nature of the developed gel as well as their recoverability. Injection force was measured to record the force required to pass the embolic gel through a clinically relevant catheter, evaluating for practicality of hand-injection. Theoretical predicted injection force was calculated to reduce the development time and to enhance the physician's experience. The stability of occlusion was also tested in vitro by monitoring the pressure required to displace the gel. The engineered gels exhibited sterility, hemocompatibility and cell biocompatibility, highlighting their potential for transcatheter embolization.

Protocolized Natriuresis-Guided Decongestion Improves Diuretic Response: The Multicenter ENACT-HF Study.

BACKGROUND: The use of urinary sodium to guide diuretics in acute heart failure is recommended by experts and the most recent European Society of Cardiology guidelines. However, there are limited data to support this recommendation. The ENACT-HF study (Efficacy of a Standardized Diuretic Protocol in Acute Heart Failure) investigated the feasibility and efficacy of a standardized natriuresis-guided diuretic protocol in patients with acute heart failure and signs of volume overload. METHODS: ENACT-HF was an international, multicenter, open-label, pragmatic, 2-phase study, comparing the current standard of care of each center with a standardized diuretic protocol, including urinary sodium to guide therapy. The primary end point was natriuresis after 1 day. Secondary end points included cumulative natriuresis and diuresis after 2 days of treatment, length of stay, and in-hospital mortality. All end points were adjusted for baseline differences between both treatment arms. RESULTS: Four hundred one patients from 29 centers in 18 countries worldwide were included in the study. The natriuresis after 1 day was significantly higher in the protocol arm compared with the standard of care arm (282 versus 174 mmol; adjusted mean ratio, 1.64; P<0.001). After 2 days, the natriuresis remained higher in the protocol arm (538 versus 365 mmol; adjusted mean ratio, 1.52; P<0.001), with a significantly higher diuresis (5776 versus 4381 mL; adjusted mean ratio, 1.33; P<0.001). The protocol arm had a shorter length of stay (5.8 versus 7.0 days; adjusted mean ratio, 0.87; P=0.036). In-hospital mortality was low and did not significantly differ between the 2 arms (1.4% versus 2.0%; P=0.852). CONCLUSIONS: A standardized natriuresis-guided diuretic protocol to guide decongestion in acute heart failure was feasible, safe, and resulted in higher natriuresis and diuresis, as well as a shorter length of stay.

Immunotherapeutic approach to reduce senescent cells and alleviate senescence-associated secretory phenotype in mice.

Accumulation of senescent cells (SNCs) with a senescence-associated secretory phenotype (SASP) has been implicated as a major source of chronic sterile inflammation leading to many age-related pathologies. Herein, we provide evidence that a bifunctional immunotherapeutic, HCW9218, with capabilities of neutralizing TGF-ß and stimulating immune cells, can be safely administered systemically to reduce SNCs and alleviate SASP in mice. In the diabetic db/db mouse model, subcutaneous administration of HCW9218 reduced senescent islet ß cells and SASP resulting in improved glucose tolerance, insulin resistance, and aging index. In naturally aged mice, subcutaneous administration of HCW9218 durably reduced the level of SNCs and SASP, leading to lower expression of pro-inflammatory genes in peripheral organs. HCW9218 treatment also reverted the pattern of key regulatory circadian gene expression in aged mice to levels observed in young mice and impacted genes associated with metabolism and fibrosis in the liver. Single-nucleus RNA Sequencing analysis further revealed that HCW9218 treatment differentially changed the transcriptomic landscape of hepatocyte subtypes involving metabolic, signaling, cell-cycle, and senescence-associated pathways in naturally aged mice. Long-term survival studies also showed that HCW9218 treatment improved physical performance without compromising the health span of naturally aged mice. Thus, HCW9218 represents a novel immunotherapeutic approach and a clinically promising new class of senotherapeutic agents targeting cellular senescence-associated diseases.

A novel interleukin-2-based fusion molecule, HCW9302, differentially promotes regulatory T cell expansion to treat atherosclerosis in mice.

Atherosclerosis is a chronic inflammatory disease caused by deposition of oxidative low-density lipoprotein (LDL) in the arterial intima which triggers the innate immune response through myeloid cells such as macrophages. Regulatory T cells (Tregs) play an important role in controlling the progression or regression of atherosclerosis by resolving macrophage-mediated inflammatory functions. Interleukin-2 (IL-2) signaling is essential for homeostasis of Tregs. Since recombinant IL-2 has an unfavorable pharmacokinetic profile limiting its therapeutic use, we constructed a fusion protein, designated HCW9302, containing two IL-2 domains linked by an extracellular tissue factor domain. We found that HCW9302 exhibited a longer serum half-life with an approximately 1000-fold higher affinity for the IL-2Rα than IL-2. HCW9302 could be administered to mice at a dosing range that expanded and activated Tregs but not CD4+ effector T cells. In an ApoE-/- mouse model, HCW9302 treatment curtailed the progression of atherosclerosis through Treg activation and expansion, M2 macrophage polarization and myeloid-derived suppressor cell induction. HCW9302 treatment also lessened inflammatory responses in the aorta. Thus, HCW9302 is a potential therapeutic agent to expand and activate Tregs for treatment of inflammatory and autoimmune diseases.

Incidence, outcomes, and risk of surgical failure after development of early hypotony following Aurolab aqueous drainage implant surgery.

Purpose: To report the incidence, outcomes, and risk of surgical failure after early postoperative hypotony following Aurolab Aqueous Drainage Implant (AADI) surgery for adult and pediatric refractory glaucoma. Methods: Medical records of patients who underwent AADI between January 2013 and March 2017 with a minimum of 2-years follow-up were retrospectively reviewed. Early postoperative hypotony was defined as IOP ≤5 mmHg within the first 3 months after AADI. Surgical failure of AADI was defined as IOP >21 mmHg or reduced <20% below baseline on two consecutive follow-up visits after 3 months, IOP ≤5 mmHg on two consecutive follow-up visits after 3 months, reoperation for glaucoma or a complication, or loss of light perception vision. Results: Early postoperative hypotony was seen in 15/213 eyes (7%) in the adult group and in 6/101 eyes (6%) in the pediatric group. The onset of hypotony was significantly earlier in the pediatric group (median = 39 days post AADI, IQR = 20-58 days) compared with adult eyes (median = 51 days post AADI, IQR = 30-72 days) (P = 0.02). Eyes with early postoperative hypotony did not have an increased risk of cumulative surgical failure as compared with eyes without hypotony in both adult (33.3% vs. 23.7%; P = 0.48) and pediatric (33.3% vs. 13.7%; P = 0.16) refractory glaucoma. All eyes recovered from hypotony, though one adult eye developed retinal detachment and one pediatric eye developed corneal decompensation and lost vision. Conclusion: Early postoperative hypotony was an infrequent complication post AADI and occurred earlier in pediatric eyes. Early postoperative hypotony did not increase risk of surgical failure up to 2 years.

Outcomes of the Aurolab aqueous drainage implant and trabeculectomy with mitomycin C in iridocorneal endothelial syndrome.

PURPOSE: To compare the surgical outcomes of the Aurolab aqueous drainage implant (AADI) and trabeculectomy with mitomycin C (MMC) in patients with glaucoma secondary to iridocorneal endothelial (ICE) syndrome. MATERIALS AND METHODS: This retrospective comparative case series included 41 eyes of 41 patients with ICE syndrome and glaucoma who underwent either a trabeculectomy with MMC (n = 20) or AADI surgery (n = 21) with a minimum of 2 years follow-up. Outcome measures included intraocular pressure (IOP), the use of glaucoma medications, visual acuity, additional surgical interventions, and surgical complications. Surgical failure was defined as IOP > 21 mmHg or reduced < 20% from baseline, IOP ≤ 5 mmHg, reoperation for glaucoma or a complication, or loss of light perception vision. RESULTS: The cumulative probability of failure at 2 years was 50% in the trabeculectomy group (95%CI = 31-83%) and 24% in the AADI group (95%CI = 11-48%) (p = 0.09). The IOP was consistently lower in the AADI group compared with the trabeculectomy group at 6 months and thereafter. Surgical complications occurred in 13 eyes (65%) in the trabeculectomy group and 12 eyes (57%) in the AADI group (p = 0.71). Reoperations for glaucoma or complications were performed in 12 eyes (60%) in the trabeculectomy group and 5 patients (24%) in the tube group (p = 0.06). Cox proportional hazards showed that AADI had a 53% lower risk of failure at 2 years (p = 0.18; HR = 0.47; 95%CI = 0.16-1.40). CONCLUSION: AADI surgery achieved lower mean IOPs than trabeculectomy with MMC in managing glaucoma secondary to ICE syndrome. A trend toward lower rates of surgical failure and reoperations for glaucoma and complications was observed following AADI placement compared with trabeculectomy with MMC in eyes with ICE syndrome.

Long-term surgical outcomes of Aurolab aqueous drainage implant in pediatric eyes with primary congenital glaucoma versus aphakic glaucoma.

PURPOSE: To compare the outcomes of the Aurolab aqueous drainage implant (AADI) placed in eyes with refractory primary congenital glaucoma (PCG) versus aphakic glaucoma (APG). DESIGN: Retrospective comparative interventional case series. METHODS: Case files of consecutive eyes with PCG or APG that underwent AADI surgery between January 2013 and December 2016 and had a minimum 4 years follow-up were extracted from a computerised database. Failure was defined as intraocular pressure (IOP)>21 mm Hg or reduced<20% below baseline on two consecutive follow-up visits after 3 months, IOP≤5 mm Hg on two consecutive follow-up visits after 3 months, reoperation for glaucoma or a complication, or loss of light perception. RESULTS: Eighty-nine eyes underwent AADI placement, including 42 eyes (47%) with PCG and 47 eyes (53%) with APG. Both groups were comparable at baseline. At 1 year, the APG group had lower mean IOP (13.6±8.1 mm Hg vs 17.6±7.5 mm Hg, p=0.02) with use of fewer IOP-lowering medications (0.8±1.0 vs 1.5±1.0, p=0.01) than the PCG group. The cumulative failure rate at 4 years was 57% (95% CI 43% to 72%) in PCG versus 40% (95% CI 28% to 56%) in the APG eyes (p=0.11). Eyes with PCG had greater tube-related complications (48% vs 38%, p=0.07) and number of reoperations (40% vs 32%, p=0.02) compared with eyes with APG. CONCLUSIONS: Eyes with APG had relatively better outcomes after AADI placement compared with PCG during 4 years of follow-up. Reoperations accounted for more than 70% of the failures.

Intermediate-term outcomes of the Aurolab aqueous drainage implant in neovascular glaucoma.

PURPOSE: To assess the outcomes of the non-valved Aurolab aqueous drainage implant (AADI) in neovascular glaucoma (NVG). METHODS: Data of consecutive patients with NVG who underwent AADI and had a minimum follow-up of 2 years were included. The primary outcome measure was the cumulative rate of surgical failure defined as intraocular pressure (IOP) >21 mm Hg or reduced <20% below baseline, IOP ≤5 mm Hg, reoperation for glaucoma or a complication, or loss of light perception vision. RESULTS: We included 85 eyes of 85 patients with NVG, with a mean age of 61.2±9.3 years. The most common aetiologies were proliferative diabetic retinopathy (n=43) and central retinal vein occlusion (n=24). The mean IOP decreased from 36.8±12.5 mm Hg at baseline to 15.8±7.5 mm Hg at 2-year follow-up (p<0.001) and the number of IOP-lowering medications reduced from 3.4±0.8 to 1.5±1.1 (p<0.001). The cumulative rate of failure increased from 3.1% (95% CI 1.1% to 11.8%) at 1 year to 33.8% (95% CI 20.4% to 52.5%) at 2 years. Multivariable analysis showed that eyes with open angles had a lower risk of failure (HR 0.17, 95% CI 0.10 to 1.03, p=0.09). The logarithm of minimum angle of resolution visual acuity declined from 0.98±0.7 to 1.8±1.0 at 2 years (p<0.001). CONCLUSION: Approximately one-third of NVG eyes that received the AADI failed after 2 years of follow-up similar to other series. Early AADI implantation at the open angle stage of NVG may yield better results.

Short-term surgical outcomes of twin-site combined phaco-emulsification and mitomycin-C augmented trabeculectomy in pseudo-exfoliation glaucoma versus primary open-angle glaucoma.

Purpose: To compare the short-term outcomes of combined phaco-emulsification with posterior chamber intra-ocular lens and mitomycin augmented trabeculectomy in patients with pseudo-exfoliation glaucoma (PXFG) versus primary open-angle glaucoma (POAG). Methods: A total of 144 eyes of 144 patients were enrolled in this prospective interventional comparative study, 72 each of which had PXFG and POAG, respectively. All patients underwent twin-site combined phaco-trabeculectomy at a tertiary eye center in India between December 2017 and December 2018 and were followed up for a period of 12 months. The main outcome measures were intra-ocular pressure (IOP), best corrected visual acuity (BCVA), total surgical time, rate of intra-operative and post-operative complications, and the number of ocular hypotensive medications needed. Success rates were determined via Kaplan-Meier survival analysis. Results: The mean age was 63.9 ± 7.9 years in the POAG group and 66.4 ± 6.8 years in the PXFG group (P - 0.04). The baseline BCVA, IOP, and cup-disc ratio were comparable between two groups. Intra-operative complications and post-operative outcomes were comparable between the two groups. There was a significant drop in anti-glaucoma medications in both groups. Six patients, three (4.2%) in each group, were lost to follow-up after 6 months. Three patients (4.2%) in PXFG needed additional glaucoma intervention for controlling IOP, one patient needed a non-valved glaucoma drainage device, and two patients required diode cyclo-photocoagulation within the follow-up period. Conclusion: Patients with PXFG had a longer surgical time than POAG. Similar success and complication rates were observed following combined twin-site phaco-trabeculectomy in both POAG and PXFG at 1 year. Combined glaucoma surgery resulted in good IOP control, improvement in BCVA, and lower requirement of ocular hypotensives in both the groups.

Intermediate-term outcomes of combined phacoemulsification and Aurolab aqueous drainage implant in eyes with refractory glaucoma and coexistent cataract.

PURPOSE: To investigate the efficacy and safety of non-valved Aurolab aqueous drainage implant (AADI) surgery combined with phacoemulsification in eyes with refractory glaucoma and coexistent cataract. METHODS: Included patients of 18 years or older who underwent combined AADI-Phacoemulsification from June 2015 to January 2017 with at least 12 months of consecutive follow-up. The best-corrected visual acuity, intraocular pressure (IOP), and the number of IOP-lowering medications were recorded at baseline, 2 weeks, 1, 3, 6, 12, 18, and 24 months. Cumulative probability of success was defined as IOP < 18 mmHg or 30% reduction from the baseline at two consecutive postoperative visits after 3-months. Loss of light perception or reoperation for uncontrolled glaucoma or a complication was considered failure apart from IOP criteria. RESULTS: Seventeen eyes of 17 patients with a mean follow-up of 22.6 ± 4.0 months were included. Baseline IOP and ocular hypotensive drugs reduced significantly from 27.9 ± 7.6 mmHg to 14.0 ± 3.0 mmHg (p < 0.001) and 3.24 ± 0.7 to 1.33 ± 1.1 (p = 0.001), respectively, at 24 months. Cumulative probability of qualified success was 71.4% (95% Confidence Interval [CI] 40.6-88.2%) at 3 months and was maintained from 6 months onwards at 64.3% (95% CI 34.3-83.3%), up to 2 years. Intravitreal steroid was injected in one eye (5.9%) of chronic cystoid macular edema, and tube repositioning was done in another for focal corneal decompensation. CONCLUSIONS: Combined AADI-Phacoemulsification surgery is a safe and effective option in providing favorable visual and IOP outcomes at an affordable cost in eyes with refractory glaucoma and coexistent cataract.

Continued Increase in Cost of Care Despite Decrease in Stay After Posterior Spinal Fusion for Adolescent Idiopathic Scoliosis.

INTRODUCTION: Previous studies have demonstrated decreased hospital length of stay (LOS) for children undergoing posterior spinal fusion (PSF) for adolescent idiopathic scoliosis (AIS). METHODS: Hospitalization event data from the Kids Inpatient Database were queried for all PSF events for AIS performed in 2009, 2012, and 2016 using diagnosis and surgical codes. Data were subdivided into two groups: pre-enhanced recovery after surgery (ERAS) (2009 and 2012) and post-ERAS (2016). The primary outcome variables were LOS and total treatment charge (adjusted for 2020 inflation). Univariate and multivariate analysis were performed to identify differences in outcome variables. RESULTS: A total of 12,010 unique hospitalization events were identified, 74% female, mean 14.3 years. There was a decrease in LOS (pre-ERAS: 5.4 ± 4.0 versus 4.3 ± 3.2 days, P < 0.0001) with an increase in adjusted total treatment charge (pre-ERAS $193,544.4 ± $108,116.1 versus $200,469.1 ± $110,112.6; P = 0.0013). Pre-ERAS, male sex, smaller hospital, and non-Medicaid insurance were predictive of longer LOS, whereas pre-ERAS, older age, non-White race, male sex, hospital outside the Northeast, and non-Medicaid insurance were predictive of higher treatment costs. DISCUSSION: There continues to be a significant decrease in LOS for PSF hospitalization events for AIS; however, total treatment charges continue to rise. Future research should investigate potential factors influencing total treatment charges after PSF for AIS.

Management of a recurrent encapsulated bleb with a cost-effective non-valved glaucoma drainage device.

Despite the advancements in the surgical management of glaucoma, childhood glaucoma remains a challenging surgical disease worldwide. An early adolescent boy with primary congenital glaucoma, status after glaucoma drainage device (GDD) implantation, on maximum medical therapy, was presented with a swelling in the superotemporal orbital region. The patient had undergone an uneventful GDD implantation 2 years prior to presentation. A similar swelling, which was diagnosed to be a Tenon's cyst, had been excised on three earlier occasions. Given that the repeat capsular excision would also have the same likelihood of failure, and poor intraocular pressure control, a non-valved, cost-effective Aurolab aqueous drainage implant (AADI, Aurolab, Madurai, India) implantation was done inferonasally. In this patient, AADI proved to be a safe and effective alternative for the known GDDs.

Retinal detachment in eyes treated with Aurolab aqueous drainage implant for refractory glaucoma - Incidence and outcomes.

Purpose: To analyze the incidence of rhegmatogenous retinal detachment (RRD) in patients who have undergone prior Aurolab aqueous drainage implant (AADI) surgery and report outcomes in terms of anatomic, visual acuity, and intraocular pressure (IOP) findings. Methods: Case records of all patients who underwent RRD repair after AADI surgery from 2013 to 2019 were retrospectively analyzed. Data collected included patient demographics, ocular examination findings at all visits including IOP and best-corrected visual acuity (BCVA) and clinical findings related to RRD both at baseline and postoperatively. Results: Ten eyes of nine patients were included in study. The mean age of patients was 28.2 years (median: 15 years, range: 6-83 years). Mean duration between AADI and RRD was 14 months (median 2.5 months; range 2 days-72 months). All eyes underwent pars plana vitrectomy with silicon oil injection. The preoperative LogMAR BCVA (logarithm of the minimum angle of resolution) was 2.52 ± 0.15 which improved to 2.29 ± 0.58 at final follow-up; however, only one eye had vision ≥ 20/400 largely due to recurrent RRD and advanced glaucomatous disc damage. Postoperatively retina was attached in 6 eyes (60%) and IOP was ≤ 21 mmHg in 5 out of 6 eyes with anatomic success. Conclusion: The incidence of RRD following AADI was found to be 0.86% in our study. Pars plana vitrectomy (PPV) with silicon oil tamponade was the preferred approach in the management of these eyes with IOP being well controlled post PPV. However, visual acuity outcomes were largely unsatisfactory due to recurrent RRD and preexisting advanced glaucoma.

Health literacy among cancer survivors: Results from the 2016 behavioral risk factor surveillance system survey.

ABSTRACT: Health literacy is a set of knowledge and skills that enables individuals to obtain, communicate, process and understand information, and services to make appropriate health decisions and to successfully navigate the health care system. Health literacy is important to quality of cancer survivorship care and patient self-management of their disease.We examined health literacy among cancer survivors, using data from the 2016 Behavioral Risk Factor Surveillance System. We compared health literacy across various demographic and socioeconomic groups and estimated the adjusted odds in favor of low health literacy for these characteristics.We found that about 16% of the cancer survivors had low health literacy. The prevalence was higher among Hispanic and Black individuals, and among those with poor health status, low income and educational attainment.A sizeable percentage of cancer survivors have low health literacy which is likely to complicate their ability to self-manage their disease and navigate the health care system for optimal care. In order to ensure the quality and appropriateness of cancer survivorship care, effective interventions are needed to address low health literacy in these populations.

An analytical model of population level chronic conditions and COVID-19 related hospitalization in the United States.

BACKGROUND: The surge in the COVID-19 related hospitalization has been straining the US health system. COVID-19 patients with underlying chronic conditions have a disproportionately higher risk of hospitalization and intensive care unit (ICU) admission. We developed a retrospective analytical model of COVID-19 related hospitalizations and ICU admissions linked to each of the three major chronic conditions - hypertension, diabetes, and cardiovascular diseases (CVD). METHODS: Based on the differential probability of hospitalization of the COVID-19 patients with and without a chronic condition, we estimate a baseline cumulative hospitalization rate and ICU admission rate using the population level chronic condition prevalence from the 2019 Behavioral Risk Factor Surveillance System survey. Next, we estimate the hospitalization and ICU admission rates under an alternative scenario of a lower prevalence of the same chronic condition, aligned with the World Health Organization target of 25% relative reduction of prevalence by 2025. We then compare the outcomes of the baseline and the alternative scenarios. RESULTS: We estimate that the lower prevalence of hypertension would have lowered the cumulative hospitalization and ICU admission rates by more than 2.5%. The lower prevalence of diabetes and CVD would lower the cumulative hospitalization rate by 0.6% and 1.4% respectively. The decrease in the rates would have been relatively higher among Black and elderly (age 55+). CONCLUSIONS: Our model, thus, provides evidence on the importance of prevention, control, and management of chronic conditions to lessen the overwhelming financial and public health burden on the health system during a pandemic like the COVID-19.

Immunotherapeutic HCW9218 augments anti-tumor activity of chemotherapy via NK cell-mediated reduction of therapy-induced senescent cells.

Therapy induced senescence (TIS) in tumors and TIS cancer cells secrete proinflammatory senescence-associated secretory phenotype (SASP) factors. SASP factors promote TIS cancer cells to re-enter the growth cycle with stemness characteristics, resulting in chemo-resistance and disease relapse. Herein, we show that the immunotherapeutic HCW9218, comprising transforming growth factor-ß (TGF-ß) receptor II and interleukin (IL)-15/IL-15 receptor α domains, enhances metabolic and cytotoxic activities of immune cells and reduces TIS tumor cells in vivo to improve the efficacy of docetaxel and gemcitabine plus nab-paclitaxel against B16F10 melanoma and SW1990 pancreatic tumors, respectively. Mechanistically, HCW9218 treatment reduces the immunosuppressive tumor microenvironment and enhances immune cell infiltration and cytotoxicity in the tumors to eliminate TIS cancer cells. Immuno-depletion analysis suggests that HCW9218-activated natural killer cells play a pivotal role in TIS cancer cell removal. HCW9218 treatment following docetaxel chemotherapy further enhances efficacy of tumor antigen-specific and anti-programmed death-ligand 1 (PD-L1) antibodies in B16F10 tumor-bearing mice. We also show that HCW9218 treatment decreases TIS cells and lowers SASP factors in off-target tissues caused by chemotherapy of tumor-bearing mice. Collectively, HCW9218 has the potential to significantly enhance anti-tumor efficacy of chemotherapy, therapeutic antibodies, and checkpoint blockade by eliminating TIS cancer cells while reducing TIS-mediated proinflammatory side effects in normal tissues.

Altered mental status is an independent predictor of mortality in hospitalized COVID-19 patients.

BACKGROUND/AIMS: Limited data exists on the outcomes of COVID-19 patients presenting with altered mental status (AMS). Hence, we studied the characteristics and outcomes of hospitalized COVID-19 patients who presented with AMS at our hospital in rural southwest Georgia. METHODS: Data from electronic medical records of all hospitalized COVID-19 patients from March 2, 2020, to June 17, 2020, were analyzed. Patients were divided in 2 groups, those presenting with and without AMS. Primary outcome of interest was in-hospital mortality. Secondary outcomes were needed for mechanical ventilation, need for intensive care unit (ICU) care, need for dialysis, and length of stay. All analyses were performed using SAS 9.4 and R 3.6.0. RESULTS: Out of 710 patients, 73 (10.3%) presented with AMS. Majority of the population was African American (83.4%). Patients with AMS were older and more likely to have hypertension, chronic kidney disease (CKD), cerebrovascular disease, and dementia. Patients with AMS were less likely to present with typical COVID-19 symptoms, including dyspnea, cough, fever, and gastrointestinal symptoms. Predictors of AMS included age ≥ 70 years, CKD, cerebrovascular disease, and dementia. After multivariable adjustment, patients with AMS had higher rates of in-hospital mortality (30.1% vs 14.8%, odds ratio (OR) 2.139, p = 0.019), ICU admission (43.8% vs 40.2%, OR 2.59, p < 0.001), and need for mechanical ventilation (27.4% vs 18.5%, OR 2.06, p = 0.023). Patients presenting with AMS had increased length of stay. CONCLUSIONS: Patients with COVID-19 presenting with AMS are less likely to have typical COVID-19 symptoms, and AMS is an independent predictor of in-hospital mortality, need for ICU admission, and need for mechanical ventilation.

Rationale and Design of the Efficacy of a Standardized Diuretic Protocol in Acute Heart Failure Study.

AIMS: Although acute heart failure (AHF) with volume overload is treated with loop diuretics, their dosing and type of administration are mainly based upon expert opinion. A recent position paper from the Heart Failure Association (HFA) proposed a step-wise pharmacologic diuretic strategy to increase the diuretic response and to achieve rapid decongestion. However, no study has evaluated this protocol prospectively. METHODS AND RESULTS: The Efficacy of a Standardized Diuretic Protocol in Acute Heart Failure (ENACT-HF) study is an international, multicentre, non-randomized, open-label, pragmatic study in AHF patients on chronic loop diuretic therapy, admitted to the hospital for intravenous loop diuretic therapy, aiming to enrol 500 patients. Inclusion criteria are as follows: at least one sign of volume overload (oedema, ascites, or pleural effusion), use ≥ 40 mg of furosemide or equivalent for >1 month, and a BNP > 250 ng/L or an N-terminal pro-B-type natriuretic peptide > 1000 pg/L. The study is designed in two sequential phases. During Phase 1, all centres will treat consecutive patients according to the local standard of care. In the Phase 2 of the study, all centres will implement a standardized diuretic protocol in the next cohort of consecutive patients. The protocol is based upon the recently published HFA algorithm on diuretic use and starts with intravenous administration of two times the oral home dose. It includes early assessment of diuretic response with a spot urinary sodium measurement after 2 h and urine output after 6 h. Diuretics will be tailored further based upon these measurements. The study is powered for its primary endpoint of natriuresis after 1 day and will be able to detect a 15% difference with 80% power. Secondary endpoints are natriuresis and diuresis after 2 days, change in congestion score, change in weight, in-hospital mortality, and length of hospitalization. CONCLUSIONS: The ENACT-HF study will investigate whether a step-wise diuretic approach, based upon early assessment of urinary sodium and urine output as proposed by the HFA, is feasible and able to improve decongestion in AHF with volume overload.