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Purpose: To evaluate outcomes of patients who underwent rhegmatogenous retinal detachment repair and were started on oral curcumin for proliferative vitreoretinopathy (PVR) prevention., Methods: Retrospective, observational case series of eyes of patients undergoing high-risk rhegmatogenous retinal detachment repair that was started on curcumin postoperatively. Recommended dosage was 500 mg twice daily for 30 days followed by 500 mg daily for 60 days. The primary outcome was recurrent PVR-related rhegmatogenous retinal detachment within 6 months and a single-surgery retinal reattachment rate. Secondary outcomes included epiretinal membrane formation, visual acuity, and curcumin safety profile., Results: Thirty-two eyes of 31 patients met the study inclusion criteria. Postoperatively, 2 eyes developed a PVR-related detachment (6.3%), and 2 eyes redetached due to new breaks without PVR (6.3%). Overall, single-surgery retinal reattachment rate was 87.5%. Single-surgery retinal reattachment rate without silicone oil was 92.6% (25/27). Of the 12 cases with Grade C PVR-related retinal detachment, the single-surgery retinal reattachment rate was 91.7%. Postoperatively, 7 eyes developed an epiretinal membrane (21.9%), of which 3 underwent epiretinal membrane removal (9.4%). No patient had gastrointestinal upset or anemia., Conclusion: This proof-of-concept clinical study suggests that oral curcumin is well tolerated and warrants further investigation for its potential to reduce the risk of PVR after rhegmatogenous retinal detachment repair in eyes at higher risk of PVR.

Background/purpose: To evaluate the status of the posterior vitreous hyaloid on presenting optical coherence tomography images of the macula and its relationship to clinical characteristics, treatment patterns, and outcomes in eyes with central retinal vein occlusion., Methods: This is a retrospective longitudinal cohort study of consecutive patients with acute, treatment-naive central retinal vein occlusion diagnosed between 2009 and 2021 who had at least 12 months of follow-up. Clinical characteristics, treatment patterns, and outcomes were analyzed between eyes stratified based on the presence or absence of a complete posterior vitreous detachment (PVD) on optical coherence tomography at presentation., Results: Of 102 acute, treatment-naive central retinal vein occlusions identified, 52 (51%) had complete PVD at presentation and 50 (49%) did not. Central subfield thickness was significantly lower in those with complete PVD (12 months: 284.9 ± 122.9 µ m vs. 426.8 ± 286.4 µ m, P < 0.001; last follow-up: 278 ± 127.9 vs. 372.8 ± 191.0 µ m, P = 0.022). One-year intravitreal injection burden was significantly less for those with a complete PVD than those without (5.1 ± 3.6 injections vs. 6.7 ± 3.3 injections, P = 0.013)., Conclusion: Central retinal vein occlusion with complete PVD on presentation had significantly lower central subfield thickness and 1-year injection burden. Assessment of the vitreomacular interface in central retinal vein occlusion may serve as a prognostic imaging biomarker.

Background: Sodium-glucose cotransporter 2 inhibitors reduce the risk of heart failure hospitalization and cardiovascular death in patients with heart failure and reduced ejection fraction (HFrEF). However, their effects on cardiac structure and function in HFrEF are uncertain., Methods: We designed a multicenter, randomized, double-blind, placebo-controlled trial (the SUGAR-DM-HF trial [Studies of Empagliflozin and Its Cardiovascular, Renal and Metabolic Effects in Patients With Diabetes Mellitus, or Prediabetes, and Heart Failure]) to investigate the cardiac effects of empagliflozin in patients in New York Heart Association functional class II to IV with a left ventricular (LV) ejection fraction ≤40% and type 2 diabetes or prediabetes. Patients were randomly assigned 1:1 to empagliflozin 10 mg once daily or placebo, stratified by age (<65 and ≥65 years) and glycemic status (diabetes or prediabetes). The coprimary outcomes were change from baseline to 36 weeks in LV end-systolic volume indexed to body surface area and LV global longitudinal strain both measured using cardiovascular magnetic resonance. Secondary efficacy outcomes included other cardiovascular magnetic resonance measures (LV end-diastolic volume index, LV ejection fraction), diuretic intensification, symptoms (Kansas City Cardiomyopathy Questionnaire Total Symptom Score, 6-minute walk distance, B-lines on lung ultrasound, and biomarkers (including N-terminal pro-B-type natriuretic peptide)., Results: From April 2018 to August 2019, 105 patients were randomly assigned: mean age 68.7 (SD, 11.1) years, 77 (73.3%) male, 82 (78.1%) diabetes and 23 (21.9%) prediabetes, mean LV ejection fraction 32.5% (9.8%), and 81 (77.1%) New York Heart Association II and 24 (22.9%) New York Heart Association III. Patients received standard treatment for HFrEF. In comparison with placebo, empagliflozin reduced LV end-systolic volume index by 6.0 (95% CI, -10.8 to -1.2) mL/m 2 ( P =0.015). There was no difference in LV global longitudinal strain. Empagliflozin reduced LV end-diastolic volume index by 8.2 (95% CI, -13.7 to -2.6) mL/m 2 ( P =0.0042) and reduced N-terminal pro-B-type natriuretic peptide by 28% (2%-47%), P =0.038. There were no between-group differences in other cardiovascular magnetic resonance measures, diuretic intensification, Kansas City Cardiomyopathy Questionnaire Total Symptom Score, 6-minute walk distance, or B-lines., Conclusions: The sodium-glucose cotransporter 2 inhibitor empagliflozin reduced LV volumes in patients with HFrEF and type 2 diabetes or prediabetes. Favorable reverse LV remodeling may be a mechanism by which sodium-glucose cotransporter 2 inhibitors reduce heart failure hospitalization and mortality in HFrEF. Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT03485092.

Background: The authors describe the preclinical pharmacological properties of GAL-021, a novel peripheral chemoreceptor modulator., Methods: The ventilatory effects of GAL-021 were characterized using tracheal pneumotachometry (n = 4 to 6), plethysmography (n = 5 to 6), arterial blood gas analyses (n = 6 to 11), and nasal capnography (n = 3 to 4) in naive animals and those subjected to morphine-induced respiratory depression. Morphine analgesia in rats was evaluated by tail-flick test (n = 6). Carotid body involvement in GAL-021 ventilatory effects was assessed by comparing responses in intact and carotid sinus nerve-transected rats. Hemodynamic effects of GAL-021 were evaluated in urethane-anesthetized rats (n = 7). The pharmacological profile of GAL-021 in vitro was investigated using radioligand binding, enzyme inhibition, and cellular electrophysiology assays., Results: GAL-021 given intravenously stimulated ventilation and/or attenuated opiate-induced respiratory depression in rats, mice, and nonhuman primates, without decreasing morphine analgesia in rats. GAL-021 did not alter mean arterial pressure but produced a modest increase in heart rate. Ventilatory stimulation in rats was attenuated by carotid sinus nerve transection. GAL-021 inhibited KCa1.1 in GH3 cells, and the evoked ventilatory stimulation was attenuated in Slo1 mice lacking the pore-forming α-subunit of the KCa1.1 channel., Conclusions: GAL-021 behaved as a breathing control modulator in rodents and nonhuman primates and diminished opioid-induced respiratory depression without compromising opioid analgesia. It acted predominantly at the carotid body, in part by inhibiting KCa1.1 channels. Its preclinical profile qualified the compound to enter clinical trials to assess effects on breathing control disorders such as drug (opioid)-induced respiratory depression and sleep apnea.

Background: T2-Weighted MRI reveals myocardial edema and enables estimation of the ischemic area at risk and myocardial salvage in patients with acute myocardial infarction (MI). We compared the diagnostic accuracy of a new bright-blood T2-weighted with a standard black blood T2-weighted MRI in patients with acute MI., Methods and Results: A breath-hold, bright-blood T2-weighted, Acquisition for Cardiac Unified T2 Edema pulse sequence with normalization for coil sensitivity and a breath-hold T2 dark-blood short tau inversion recovery sequence were used to depict the area at risk in 54 consecutive acute MI patients. Infarct size was measured on gadolinium late contrast enhancement images. Compared with dark-blood T2-weighted MRI, consensus agreements between independent observers for identification of myocardial edema were higher with bright-blood T2-weighted MRI when evaluated per patient (P<0.001) and per segment of left ventricle (P<0.001). Compared with bright-blood T2-weighted MRI, dark-blood T2-weighted MRI underestimated the area at risk compared with infarct size (P<0.001). The 95% limits of agreement for interobserver agreements for the ischemic area at risk and myocardial salvage were wider with dark-blood T2-weighted MRI than with bright-blood T2-weighted MRI. Bright blood enabled more accurate identification of the culprit coronary artery with correct identification in 94% of cases compared with 61% for dark blood (P<0.001)., Conclusions: Bright-blood T2-weighted MRI has higher diagnostic accuracy than dark-blood T2-weighted MRI. Additionally, dark-blood T2-weighted MRI may underestimate area at risk and myocardial salvage.

Objectives: To evaluate whether the level and duration of increased blood lactate levels are associated with daily Sequential Organ Failure Assessment (SOFA) scores and organ subscores and to evaluate these associations during the early and late phases of the intensive care unit stay., Design: Retrospective observational study., Setting: Mixed intensive care unit of a university hospital., Patients: 134 heterogeneous intensive care unit patients., Interventions: None., Measurements and Main Results: We calculated the area under the lactate curve above 2.0 mmol/L (lactateAUC>2). Daily SOFA scores were collected during the first 28 days of intensive care unit stay to calculate initial (day 1), maximal, total and mean scores. Daily lactateAUC>2 values were related to both daily SOFA scores and organ subscores using mixed-model analysis of variance. This was also done separately during the early (<2.75 days) and late (>2.75 days) phase of the intensive care unit stay.Compared with normolactatemic patients (n = 78), all median SOFA variables were higher in patients with hyperlactatemia (n = 56) (initial SOFA: 9 [interquartile range 4-12] vs. 4 [2-7]; maximal SOFA: 10 [5-13] vs. 5 [2-9]; total SOFA: 28 [10-70] vs. 9 [3-41]; mean SOFA: 7 [4-10] vs. 4 [2-6], all p < .001). The overall relationship between daily lactateAUC>2 and daily SOFA was an increase of 0.62 SOFA-points per 1 day.mmol/L of lactateAUC>2 (95% confidence interval, 0.41-0.81, p < .00001). During early intensive care unit stay, the relationship between lactateAUC>2 and SOFA was 1.01 (95% confidence interval, 0.53-1.50, p < .0005), and during late intensive care unit stay, this was reduced to 0.50 (95% confidence interval, 0.28-0.72, p < .0005). Respiratory (0.30, 0.22-0.38, p < .001) and coagulation (0.13, 0.09-0.18, p < .001) subscores were most strongly associated with lactateAUC>2., Conclusions: Blood lactate levels were strongly related to SOFA scores. This relationship was stronger during the early phase of intensive care unit stay, which provides additional indirect support for early resuscitation to prevent organ failure. The results confirm that hyperlactatemia can be considered as a warning signal for organ failure.

Background: The use of expanded criteria donors (ECDs) in cadaveric renal transplantation is increasing in the US. We assess the economic impact of the use of ECDs to the Medicare end stage renal disease program., Methods: The United Nations for Organ Sharing renal transplant registry was merged to Medicare claims data for 42,868 cadaveric renal transplants performed between 1991-1996 using USRDS identifiers. Only recipients for whom Medicare was the primary payer were considered, leaving 34,534 transplants. An ECD was defined as (1) age < or =5 or > or =55 years, (2) nonheart-beating donors, donor history of (3) hypertension or (4) diabetes. High-risk recipients (HRR) were age >60 years, or a retransplant. Medicare payments from the pretransplant dialysis period were projected forward to provide a financial "breakeven point" with transplantation., Results: There were 25,600 non-HRR transplants, with 5,718 (22%) using ECDs, and 8,934 HRR transplants, of which 2,200 (25%) used ECDs. The 5-year present value of payments for non-ECD/non-HRR donor/recipient pairings was $121,698 vs. $143,329 for ECD/non-HRR pairings (P<0.0001) and, similarly was $134,185 for non-ECD/HRR pairings vs. $165,716 for ECD/HRR pairings (P<0.0001). The break even point with hemodialysis ranged from 4.4 years for non-ECD/ non-HRR pairings to 13 years for the ECD/HRR combinations but was sensitive to small changes in graft survival. Transplantation was always less expensive than hemodialysis in the long run., Conclusions: The impact of ECDs on Medicare payments is most pronounced in high-risk recipients. Cadaveric renal transplantation is a cost-saving treatment strategy for the Medicare ESRD program regardless of recipient risk status or the use of ECDs.

Background: Recently the United Network for Organ Sharing (UNOS) began a pilot study to evaluate prospectively the merits of an allocation of cadaveric kidneys based on broader classes of HLA antigens, called cross-reactive groups (CREG). The objectives of the pilot study consider patient outcomes, but not the potential economic impact of a CREG-based allocation. This study predicts the impact of a CREG-based local allocation of cadaveric kidneys on 3-year Medicare payments and graft survival., Methods: The UNOS renal transplant registry was merged to Medicare claims data for 1991-1997 by the United States Renal Data System. Average accumulated Medicare payments and graft survival up to 3 years posttransplant for first cadaveric renal transplant recipients were stratified by cross-reactive group mismatch categories. The economic impact was defined as the difference in average 3-year costs per transplant between the current and proposed allocation algorithms. Average 3-year costs were computed as a weighted average of costs, where the weights were the actual and predicted distributions of transplants across cross-reactive group categories., Results: Results suggest that an organ allocation based on cross-reactive group matching criteria would result in a 3-year cost savings of $1,231 (2%) per transplant, and an average 3-year graft survival improvement of 0.6%., Conclusions: Cost savings and graft survival improvements can be expected if CREG criteria were to replace current criteria in the current allocation policy for cadaveric kidneys, although the savings appear to be smaller than may be achievable through expanded HLA matching.

Background: We found previously that the clinical advantages of living donor (LD) renal transplantation lead to financial cost savings compared to either cadaveric donation (CAD) or dialysis. Here, we analyze the sources of the cost savings of LD versus CAD kidney transplantation., Methods: We used United States Renal Data System data to merge United Network for Organ Sharing registry information with Medicare claims data for 1991-1996. Information was available for 42,868 CAD and 13,754 LD transplants. More than 5 million Medicare payment records were analyzed. We calculated the difference in average payments made by Medicare for CAD and LD for services provided during the first posttransplant year., Results: Average total payments were $39,534 and $24,652 for CAD and LD, respectively (P<0.0001) during the first posttransplant year. The largest source of the difference in payments was in inpatient hospitals, representing $10,653.67 (P<0.0001). For patients who had Medicare as the primary payer, average transplant charges were significantly higher for CAD donation ($79,730 vs. $69,547, P<0.0001); average transplant payments demonstrated no statistical differences ($28,483 vs. $28,447, P = 0.858). Therefore, inferred profitability was significantly higher for LD., Conclusions: Medicare payments are remarkably lower for LD compared to CAD in every category. The single largest cost saving comes from inpatient hospital services. A portion of the savings from LD could be invested in programs to expand living kidney donation.

Background: The aim of this study was to compare the efficacy and safety of Thymoglobulin (a rabbit-derived polyclonal antibody) to Atgam (a horse-derived polyclonal antibody) for induction in adult renal transplant recipients., Methods: Transplant recipients (n=72) were randomized 2:1 in a double-blinded fashion to receive Thymoglobulin (n=48) at 1.5 mg/kg intravenously or Atgam (n=24) at 15 mg/kg intravenously, intraoperatively, then daily for at least 6 days. Recipients were observed for at least 1 year of follow-up., Results: By 1 year after transplantation, 4% of Thymoglobulin-treated patients experienced acute rejection compared with 25% of Atgam-treated patients (P=0.014). The rate of acute rejection was lower with Thymoglobulin than Atgam (relative risk=0.09; P=0.009). Rejection was less severe with Thymoglobulin than Atgam (P=0.02). No recurrent rejection occurred with Thymoglobulin compared with 33% with Atgam (P=NS). Patient survival was not different, but the composite end point of freedom from death, graft loss, or rejection, the "event-free survival," was superior with Thymoglobulin (94%) compared with Atgam (63%; P=0.0005). Fewer adverse events occurred with Thymoglobulin (P=0.013). Leukopenia was more common with Thymoglobulin than Atgam (56% vs. 4%; P<0.0001) during induction. The mean absolute lymphocyte count remained below baseline with Thymoglobulin throughout the study (P<0.007), but with Atgam, significant lymphocyte reductions occurred only at day 7. The incidence of cytomegalovirus disease was less with Thymoglobulin than Atgam at 6 months (10% vs. 33%; P=0.025)., Conclusions: Brief (7-day) induction with Thymoglobulin resulted in less frequent and less severe rejection, a better event-free survival, less cytomegalovirus disease, fewer serious adverse events, but more frequent early leukopenia than induction with Atgam. These results may in fact be explained by a more profound and durable beneficial lymphopenia.

Endometrial adenocarcinoma is commonly seen in the perimenopausal and postmenopausal age groups. Certain medical conditions (such as diabetes, hypertension, and obesity) are often associated with development of this disease. Consequently, when irregular bleeding develops, a decision to sample the endometrium is often predicated on the patient's age and the presence of these associated conditions. Often, healthy young women receive empirical hormonal therapy for irregular bleeding without prior endometrial sampling. An unusual case of endometrial adenocarcinoma arising during lactation in a young healthy woman is presented.