Combination therapy with rituximab, low-dose cyclophosphamide, and prednisone for idiopathic membranous nephropathy: a case series

BACKGROUND: Membranous nephropathy is a common cause of the nephrotic syndrome. Treatment with standard regimens fails to induce complete remission in most patients. We evaluated the efficacy of combination therapy with rituximab, low-dose, oral cyclophosphamide, and an accelerated prednisone taper (RCP) for the treatment of idiopathic membranous nephropathy. METHODS: We analyzed 15 consecutive patients with idiopathic membranous nephropathy treated with RCP at Massachusetts General Hospital. Seven patients (47%) received RCP as initial therapy, and the other eight patients (53%) received RCP for relapsing or refractory disease. All patients had at least 1 year of follow-up. The co-primary outcomes were attainment of partial and complete remission. Partial remission was defined as a urinary protein to creatinine ratio (UPCR) < 3 g/g and a 50% reduction from baseline. Complete remission was defined as a UPCR < 0.3 g/g. Secondary outcomes were serious adverse events and the change in proteinuria, serum creatinine, serum albumin, cholesterol, triglycerides, and immunoglobulin G levels after 1 year of treatment. RESULTS: Over a median follow-up time of 37 (IQR, 34-44) months, 100% of patients achieved partial remission and 93% of patients achieved complete remission at a median time of 2 and 13 months, respectively. After 1 year of treatment, median (IQR) UPCR declined from 8.2 (6.6-11.1) to 0.3 (0.2-0.7) g/g (P < 0.001). Three serious adverse events occurred over 51 patient years. No patients died or progressed to ESKD. CONCLUSIONS: Treatment of idiopathic membranous nephropathy with RCP resulted in high rates of complete remission. Larger studies evaluating this regimen are warranted

Modulation of the Association Between Age and Death by Risk Factor Burden in Critically Ill Patients With COVID-19.

UNLABELLED: Older age is a key risk factor for adverse outcomes in critically ill patients with COVID-19. However, few studies have investigated whether preexisting comorbidities and acute physiologic ICU factors modify the association between age and death. DESIGN: Multicenter cohort study. SETTING: ICUs at 68 hospitals across the United States. PATIENTS: A total of 5,037 critically ill adults with COVID-19 admitted to ICUs between March 1, 2020, and July 1, 2020. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The primary exposure was age, modeled as a continuous variable. The primary outcome was 28-day inhospital mortality. Multivariable logistic regression tested the association between age and death. Effect modification by the number of risk factors was assessed through a multiplicative interaction term in the logistic regression model. Among the 5,037 patients included (mean age, 60.9 yr [± 14.7], 3,179 [63.1%] male), 1,786 (35.4%) died within 28 days. Age had a nonlinear association with 28-day mortality ( CONCLUSIONS: In a large population of critically ill patients with COVID-19, age had an independent exponential association with death. The number of preexisting comorbidities and acute physiologic ICU factors modified the association between age and death, but age still had an exponential association with death in subgroups according to the number of risk factors present. Additional studies are needed to identify the mechanisms underpinning why older age confers an increased risk of death in critically ill patients with COVID-19

Hispanic Ethnicity and Mortality Among Critically Ill Patients With Covid-19

BACKGROUND: Hispanic persons living in the United States (U.S.) are at higher risk of infection and death from coronavirus disease 2019 (COVID-19) compared with non-Hispanic persons. Whether this disparity exists among critically ill patients with COVID-19 is unknown. OBJECTIVE: To evaluate ethnic disparities in mortality among critically ill adults with COVID-19 enrolled in the Study of the Treatment and Outcomes in Critically Ill Patients with COVID-19 (STOP-COVID). METHODS: Multicenter cohort study of adults with laboratory-confirmed COVID-19 admitted to intensive care units (ICU) at 67 U.S. hospitals from March 4 to May 9, 2020. Multilevel logistic regression was used to evaluate 28-day mortality across racial/ethnic groups. RESULTS: A total of 2153 patients were included (994 [46.2%] Hispanic and 1159 [53.8%] non-Hispanic White). The median (IQR) age was 62 (51-71) years (non-Hispanic White, 66 [57-74] years; Hispanic, 56 [46-67] years), and 1462 (67.9%) were men. Compared with non-Hispanic White patients, Hispanic patients were younger; were less likely to have hypertension, chronic obstructive pulmonary disease, coronary artery disease, or heart failure; and had longer duration of symptoms prior to ICU admission. During median (IQR) follow-up of 14 (7-24) days, 785 patients (36.5%) died. In analyses adjusted for age, sex, clinical characteristics, and hospital size, Hispanic patients had higher odds of death compared with non-Hispanic White patients (OR, 1.44; 95% CI, 1.12-1.84). CONCLUSIONS: Among critically ill adults with COVID-19, Hispanic patients were more likely to die than non-Hispanic White patients, even though they were younger and had lower comorbidity burden. This finding highlights the need to provide earlier access to care to Hispanic individuals with COVID-19, especially given our finding of longer duration of symptoms prior to ICU admission among Hispanic patients. In addition, there is a critical need to address ongoing disparities in post hospital discharge care for patients with COVID-19

Safety and Toxicity of Catheter Gene Delivery to the Pulmonary Vasculature in a Patient with Metastatic Melanoma

Overview summary Transcatheter delivery of HLA-B7 DNA and cationic liposomes into a segment of a pulmonary artery was safely performed in 1 patient with tumor nodules in the lung. No immunologic or organ toxicities were observed. Percutaneous catheter gene delivery has been performed in humans. Further refinements of this approach may lead to useful treatments for a variety of human diseases.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/63196/1/hum.1994.5.9-1089.pd

Timing of Invasive Mechanical Ventilation and Death in Critically Ill Adults With Covid-19: A Multicenter Cohort Study

PURPOSE: To investigate if the timing of initiation of invasive mechanical ventilation (IMV) for critically ill patients with COVID-19 is associated with mortality. MATERIALS AND METHODS: The data for this study were derived from a multicenter cohort study of critically ill adults with COVID-19 admitted to ICUs at 68 hospitals across the US from March 1 to July 1, 2020. We examined the association between early (ICU days 1-2) versus late (ICU days 3-7) initiation of IMV and time-to-death. Patients were followed until the first of hospital discharge, death, or 90 days. We adjusted for confounding using a multivariable Cox model. RESULTS: Among the 1879 patients included in this analysis (1199 male [63.8%]; median age, 63 [IQR, 53-72] years), 1526 (81.2%) initiated IMV early and 353 (18.8%) initiated IMV late. A total of 644 of the 1526 patients (42.2%) in the early IMV group died, and 180 of the 353 (51.0%) in the late IMV group died (adjusted HR 0.77 [95% CI, 0.65-0.93]). CONCLUSIONS: In critically ill adults with respiratory failure from COVID-19, early compared to late initiation of IMV is associated with reduced mortality

Erythropoietin, Fibroblast Growth Factor 23, and Death After Kidney Transplantation

Elevated levels of erythropoietin (EPO) are associated with an increased risk of death in renal transplant recipients (RTRs), but the underlying mechanisms remain unclear. Emerging data suggest that EPO stimulates production of the phosphaturic hormone fibroblast growth factor 23 (FGF23), another strong risk factor for death in RTRs. We hypothesized that the hitherto unexplained association between EPO levels and adverse outcomes may be attributable to increased levels of FGF23. We included 579 RTRs (age 51 ± 12 years, 55% males) from the TransplantLines Insulin Resistance and Inflammation Cohort study (NCT03272854). During a follow-up of 7.0 years, 121 RTRs died, of which 62 were due to cardiovascular cause. In multivariable Cox regression analysis, EPO was independently associated with all-cause (HR, 1.66; 95% CI 1.16-2.36; P = 0.005) and cardiovascular death (HR, 1.87; 95% CI 1.14-3.06; P = 0.01). However, the associations were abrogated following adjustment for FGF23 (HR, 1.28; 95% CI 0.87-1.88; P = 0.20, and HR, 1.45; 95% CI 0.84-2.48; P = 0.18, respectively). In subsequent mediation analysis, FGF23 mediated 72% and 50% of the association between EPO and all-cause and cardiovascular death, respectively. Our results underline the strong relationship between EPO and FGF23 physiology, and provide a potential mechanism underlying the relationship between increased EPO levels and adverse outcomes in RTRs

Obesity, inflammatory and thrombotic markers, and major clinical outcomes in critically ill patients with COVID‐19 in the US

OBJECTIVE: This study aimed to determine whether obesity is independently associated with major adverse clinical outcomes and inflammatory and thrombotic markers in critically ill patients with COVID-19. METHODS: The primary outcome was in-hospital mortality in adults with COVID-19 admitted to intensive care units across the US. Secondary outcomes were acute respiratory distress syndrome (ARDS), acute kidney injury requiring renal replacement therapy (AKI-RRT), thrombotic events, and seven blood markers of inflammation and thrombosis. Unadjusted and multivariable-adjusted models were used. RESULTS: Among the 4,908 study patients, mean (SD) age was 60.9 (14.7) years, 3,095 (62.8%) were male, and 2,552 (52.0%) had obesity. In multivariable models, BMI was not associated with mortality. Higher BMI beginning at 25 kg/m2 was associated with a greater risk of ARDS and AKI-RRT but not thrombosis. There was no clinically significant association between BMI and inflammatory or thrombotic markers. CONCLUSIONS: In critically ill patients with COVID-19, higher BMI was not associated with death or thrombotic events but was associated with a greater risk of ARDS and AKI-RRT. The lack of an association between BMI and circulating biomarkers calls into question the paradigm that obesity contributes to poor outcomes in critically ill patients with COVID-19 by upregulating systemic inflammatory and prothrombotic pathways

Safety and Short-Term Toxicity of a Novel Cationic Lipid Formulation for Human Gene Therapy

Overview summary Although several viral vectors have been widely applied to the treatment of human disease, the development of nonviral vectors is still in their infancy. In this report, a novel cationic lipid, DMRIE/DOPE, has been incorporated into the DNA–liposome formulation that improves transfection efficiencies and allows up to 1,000-fold higher concentrations of DNA to be administered in vivo. In this paper, the safety and toxicity of this formulation is described in two species, mice and pigs, suggesting that it may prove useful for human gene therapy.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/63224/1/hum.1993.4.6-781.pd

Hospital-Level Variation in Death for Critically Ill Patients with COVID-19

Rationale: Variation in hospital mortality has been described for coronavirus disease 2019 (COVID-19), but the factors that explain these differences remain unclear. Objective: Our objective was to utilize a large, nationally representative dataset of critically ill adults with COVID-19 to determine which factors explain mortality variability. Methods: In this multicenter cohort study, we examined adults hospitalized in intensive care units with COVID-19 at 70 United States hospitals between March and June 2020. The primary outcome was 28-day mortality. We examined patient-level and hospital-level variables. Mixed-effects logistic regression was used to identify factors associated with interhospital variation. The median odds ratio (OR) was calculated to compare outcomes in higher- vs. lower-mortality hospitals. A gradient boosted machine algorithm was developed for individual-level mortality models. Measurements and Main Results: A total of 4,019 patients were included, 1537 (38%) of whom died by 28 days. Mortality varied considerably across hospitals (0-82%). After adjustment for patient- and hospital-level domains, interhospital variation was attenuated (OR decline from 2.06 [95% CI, 1.73-2.37] to 1.22 [95% CI, 1.00-1.38]), with the greatest changes occurring with adjustment for acute physiology, socioeconomic status, and strain. For individual patients, the relative contribution of each domain to mortality risk was: acute physiology (49%), demographics and comorbidities (20%), socioeconomic status (12%), strain (9%), hospital quality (8%), and treatments (3%). Conclusion: There is considerable interhospital variation in mortality for critically ill patients with COVID-19, which is mostly explained by hospital-level socioeconomic status, strain, and acute physiologic differences. Individual mortality is driven mostly by patient-level factors

Seasonal Phytoplankton Blooms in the North Atlantic Linked to the Overwintering Strategies of Copepods

The North Atlantic Ocean contains diverse patterns of seasonal phytoplankton blooms with distinct internal dynamics. We analyzed blooms using remotely-sensed chlorophyll a concentration data and change point statistics. The first bloom of the year began during spring at low latitudes and later in summer at higher latitudes. In regions where spring blooms occurred at high frequency (i. e., proportion of years that a bloom was detected), there was a negative correlation between bloom timing and duration, indicating that early blooms last longer. In much of the Northeast Atlantic, bloom development extended over multiple seasons resulting in peak chlorophyll concentrations in summer. Spring bloom start day was found to be positively correlated with a spring phenology index and showed both positive and negative correlations to sea surface temperature and the North Atlantic Oscillation in different regions. Based on the characteristics of spring and summer blooms, the North Atlantic can be classified into two regions: a seasonal bloom region, with a well-defined bloom limited to a single season; and a multi-seasonal bloom region, with blooms extending over multiple seasons. These regions differed in the correlation between bloom start and duration with only the seasonal bloom region showing a significant, negative correlation. We tested the hypothesis that the near-surface springtime distribution of copepods that undergo diapause (Calanus finmarchicus, C. helgolandicus, C. glacialis, and C. hyperboreus) may contribute to the contrast in bloom development between the two regions. Peak near-surface spring abundance of the late stages of these Calanoid copepods was generally associated with areas having a well-defined seasonal bloom, implying a link between bloom shape and their abundance. We suggest that either grazing is a factor in shaping the seasonal bloom or bloom shape determines whether a habitat is conducive to diapause, while recognizing that both factors can re-enforce each other