Background: This is a Phase I trial demonstrating safety and tolerability of intravaginal curcumin for future use in women with cervical neoplasia. Objective: The objective of this study was to assess the safety, tolerability, and pharmacokinetics of intravaginal curcumin in healthy women. Study design: We conducted a 3+3 dose-escalation Phase I trial in a group of women aged 18–45 years. Thirteen subjects were given one of four doses of curcumin powder (500 mg, 1,000 mg, 1,500 mg, and 2,000 mg) packed in gelatin capsules, which was administered intravaginally daily for 14 days. The primary end point for this study was safety based on severe adverse events regarding laboratory toxicity, clinical findings, and colposcopic abnormalities. We administered an acceptability questionnaire to assess product experience and attributes. Results: No dose-limiting toxicities (0/13) were experienced (95% confidence interval: 0.0%– 22.8%) in this study. The pharmacokinetics data demonstrated that curcumin and curcumin conjugates were not measurable in the serum and negligible in the urine of the study participants. Although 23 adverse events occurred during the course of the trial, all events were grade I based on the National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.0 and were resolved by the end of the study in an average of 9 days. Fifty-six percent of the adverse events were related to the study drug, which included genital pruritus (23% of subjects), vaginal discharge (100%), vaginal dryness (15%), abnormal prothrombin (23%), and hypokalemia (8%). Conclusion: Intravaginal curcumin was well tolerated by all subjects and safe. In this Phase I trial, there were no severe adverse events observed at any of the administered dose levels. All adverse events were grade I and did not result in early termination of the study. There was no evidence of systemic absorption or significant local absorption of intravaginally administered curcumin.
Background: Resistance to malaria infection may be conferred by erythrocyte genetic variations including glucose-6-phosphate dehydrogenase (G6PD) deficiency and lack of Duffy antigens. In red blood cell (RBC) transfusion, G6PD deficiency may shorten transfusion survival. Because Duffy-null units are commonly transfused in sickle cell disease (SCD) due to antigen matching protocols, we examined whether Duffy-null donor RBC units have a higher prevalence of G6PD deficiency. Materials and methods: Pediatric patients with SCD on chronic transfusion therapy were followed prospectively for multiple transfusions. RBC unit segments were collected to measure G6PD activity and RBC genotyping. The decline in donor hemoglobin (ΔHbA) following transfusion was assessed from immediate posttransfusion estimates and HbA measurements approximately 1 month later. Results: Of 564 evaluable RBC units, 59 (10.5%) were G6PD deficient (23 severe, 36 moderate deficiency); 202 (37.6%) units were Duffy-null. G6PD deficiency occurred in 40 (19.8%) Duffy-null units versus 15 (4.5%) Duffy-positive units (p <.0001). In univariate analysis, the fraction of Duffy-null RBC units per transfusion was associated with greater decline in HbA (p =.038); however, in multivariate analysis, severe G6PD deficiency (p =.0238) but not Duffy-null RBC (p =.0139) were associated with ΔHbA. Conclusion: Selection of Duffy-null RBC units may result in shorter in vivo survival of transfused RBCs due to a higher likelihood of transfusing units from G6PD deficient donors.
BACKGROUND:
Enteral iron supplementation and RBC transfusions are routinely administered to very-low-birth-weight (VLBW) infants, although the potential risks of these exposures have not been adequately quantified. This study evaluated the association between the cumulative dose of enteral iron supplementation, total volume of RBCs transfused, and risk of bronchopulmonary dysplasia (BPD) in VLBW infants.
STUDY DESIGN AND METHODS:
Retrospective, multicenter observational cohort study in Atlanta, Georgia. Cumulative supplemental enteral iron exposure and total volume of RBCs transfused were measured until the age at assessment of BPD. Multivariable generalized linear models were used to control for confounding, and the reliability of the factors was assessed in 1000 bootstrap models.
RESULTS:
A total of 598 VLBW infants were studied. In multivariable analyses, a greater cumulative dose of supplemental enteral iron exposure was associated with an increased risk of BPD (adjusted relative risk per 50-mg increase, 1.07; 95% confidence interval [CI], 1.02–1.11; p = 0.002). Similarly, a greater volume of RBCs transfused was associated with a higher risk of BPD (adjusted relative risk per 20-mL increase, 1.05; 95% CI, 1.02–1.07; p < 0.001). Both factors were reliably associated with BPD (>50%). Volume of RBCs transfused was similar to gestational age in reliability as a risk factor for BPD (present in 100% of models) and was more reliable than mechanical ventilation at 1 week of age.
CONCLUSION:
The cumulative dose of supplemental enteral iron exposure and total volume of RBC transfusion are both independently associated with an increased risk of BPD in VLBW infants.
BACKGROUND:
Prior studies have suggested an association between platelet transfusions (PTXs) and worse outcomes among infants with necrotizing enterocolitis (NEC), potentially mediated by proinflammatory factors released by platelets. However, the effects of storage on platelet proinflammatory factor release and the confounding role of illness severity on NEC outcomes have not been determined.
STUDY DESIGN AND METHODS:
First, neuropeptide Y (a potent splanchnic vasoconstrictor released by platelets) was measured by enzyme-linked immunosorbent assay in fresh frozen plasma and in the supernatant of leukoreduced apheresis-derived platelets at different times during storage. Next, we evaluated the relationship between PTX rates and death in a multicenter cohort of very-low-birth-weight infants with NEC, adjusting for illness severity.
RESULTS:
Neuropeptide Y levels increased over time in the supernatant of leukoreduced apheresis-derived platelets and were 4.4-fold and 8.9-fold higher than in fresh frozen plasma on Days 2 and 3 of storage, respectively (p < 0.001). Among 598 very-low-birth-weight infants, 44 developed NEC. In unadjusted analysis, PTX rate was 30.3 (95% confidence interval [CI], 11.5–80.1) per 100 infant-days among infants who died, compared to 6.0 (95% CI, 3.2–11.2) among survivors (incidence rate ratio, 5.1; 95% CI, 1.6–16.2; p = 0.006). In multivariable analysis, there was no association between PTX rate and mortality (incidence rate ratio, 3.0; 95% CI, 0.6–15.0; p = 0.18), although estimation was imprecise.
CONCLUSION:
Proinflammatory mediators accumulate in platelet suspensions during storage. Although PTX rates were not associated with increased mortality among infants with NEC in our study, our estimates suggest the potential for such an association that needs evaluation in larger studies.
In HIV/SIV-infected humans and rhesus macaques (RMs), a severe depletion of intestinal CD4+ T-cells producing interleukin IL-17 and IL-22 associates with loss of mucosal integrity and chronic immune activation. However, little is known about the function of IL-17 and IL-22 producing cells during lentiviral infections. Here, we longitudinally determined the levels and functions of IL-17, IL-22 and IL-17/IL-22 producing CD4+ T-cells in blood, lymph node and colorectum of SIV-infected RMs, as well as how they recover during effective ART and are affected by ART interruption. Intestinal IL-17 and IL-22 producing CD4+ T-cells are polyfunctional in SIV-uninfected RMs, with the large majority of cells producing four or five cytokines. SIV infection induced a severe dysfunction of colorectal IL-17, IL-22 and IL-17/IL-22 producing CD4+ T-cells, the extent of which associated with the levels of immune activation (HLA-DR+CD38+), proliferation (Ki-67+) and CD4+ T-cell counts before and during ART. Additionally, Th17 cell function during ART negatively correlated with residual plasma viremia and levels of sCD163, a soluble marker of inflammation and disease progression. Furthermore, IL-17 and IL-22 producing cell frequency and function at various pre, on, and off-ART experimental points associated with and predicted total SIV-DNA content in the colorectum and blood. While ART restored Th22 cell function to levels similar to pre-infection, it did not fully restore Th17 cell function, and all cell types were rapidly and severely affected—both quantitatively and qualitatively—after ART interruption. In conclusion, intestinal IL-17 producing cell function is severely impaired by SIV infection, not fully normalized despite effective ART, and strongly associates with inflammation as well as SIV persistence off and on ART. As such, strategies able to preserve and/or regenerate the functions of these CD4+ T-cells central for mucosal immunity are critically needed in future HIV cure research.
Objective: To determine whether glutamine (GLN)-supplemented parenteral nutrition (PN) improves clinical outcomes in surgical ICU (SICU) patients.
Summary Background Data: GLN requirements may increase with critical illness. GLN-supplemented PN may improve clinical outcomes in SICU patients, but data in patient subgroups are limited.
Methods: A parallel-group, multicenter, double blind, randomized, controlled clinical trial in adults after gastrointestinal, vascular, or cardiac surgery who required PN and SICU care. Subjects were without significant renal or hepatic failure or shock at entry. All received isonitrogenous, isocaloric PN [1.5 g/kg/d amino acids (AA) and energy at 1.3 × estimated basal energy expenditure]. Controls (n = 75) received standard GLN-free PN (STD-PN); the GLN group (n = 75) received PN containing alanyl-GLN dipeptide (0.5 g/kg/d), proportionally replacing AA in control PN (GLN-PN). Enteral nutrition (EN) was advanced and PN weaned as indicated. Hospital mortality and infections were primary endpoints.
Results: Baseline characteristics, days on study PN and daily energy and amino acid/protein intakes via PN and EN were similar between groups. There were 11 hospital deaths (14.7%) in the GLN-PN group and 13 deaths in the STD-PN group and (17.3%; difference, −2.6%; 95% confidence interval −14.6 to 9.3%; P = 0.66). The 6-month cumulative all-cause mortality was 31.4% in the GLN-PN group and 29.7% in the STD-PN group (P = 0.88). Incident bloodstream infection rate was 9.6 and 8.4 per 1000 hospital days in the GLN-PN and STD-PN groups, respectively (P= 0.73). Other clinical outcomes and adverse events were similar.
Conclusions: PN supplemented with GLN dipeptide was safe but did not alter clinical outcomes among SICU patients.
More than 90% of allogeneic hematopoietic stem cell transplantation (allo-HSCT) recipients receive red blood cell (RBC) or platelet transfusions in the peritransplantation period. We tested the hypothesis that transfusions are associated with the development of severe (grade III-IV) acute graft-versus-host disease (aGVHD) or mortality after allo-HSCT in a retrospective study of 322 consecutive patients receiving an allogeneic bone marrow or granulocyte colony-stimulating factor-mobilized blood stem cell graft for a hematologic malignancy. Counting transfused RBC and platelet units between day −7 pretransplantation and day +27 post-transplantation, but excluding transfusions administered after a diagnosis of aGVHD, yielded medians of 5 RBC units and 2 platelet units transfused. Sixty-three patients (20%) developed a maximal grade III-IV aGVHD with onset up to day +150 post-transplantation (median aGVHD onset of 28 days). HLA mismatch (hazard ratio [HR], 2.4; 95% confidence interval [CI], 1.2 to 4.7; P =.01), and transfusion of more than the median number of RBC units (HR, 2.1; 95% CI, 1.1 to 3.7; P =.02) were independently associated with greater risk of grade III-IV aGVHD in a multivariable analysis model. Disease risk strata (HR, 1.7; 95% CI, 1.2 to 2.4 for high risk versus low risk; P =.005) and transfusion of more than the median number of RBC units (HR, 1.4; 95% CI, 1.0 to 2.0; P =.054) were independently associated with inferior overall survival. These data support our hypothesis that peritransplantation RBC transfusions are associated with the risk of developing severe aGVHD and worse overall survival following allo-HSCT, and suggest that strategies to reduce routine RBC transfusion may favorably reduce the incidence and severity of GVHD.
Objective: Higher incidence of osteopenia and osteoporosis underlie increased rates of fragility fracture in HIV infection. B cells are a major source of osteoprotegerin (OPG), an inhibitor of the key osteoclastogenic cytokine receptor activator of nuclear factor-κB ligand (RANKL). We previously showed that higher B-cell RANKL/OPG ratio contributes to HIV-induced bone loss. T-cell OPG production in humans, however, remains undefined and the contribution of T-cell OPG and RANKL to HIV-induced bone loss has not been explored. Design: We investigated T-cell OPG and RANKL production in ART-naive HIV-infected and uninfected individuals in relation to indices of bone loss in a cross-sectional study.
Methods: T-cell RANKL and OPG production was determined by intracellular staining and flow cytometry, and plasma levels of bone resorption markers were determined by ELISA.
Results: We demonstrate for the first time in-vivo human T-cell OPG production, which was significantly lower in HIV-infected individuals and was coupled with moderately higher T-cell RANKL production, resulting in a significantly higher T-cell RANKL/OPG ratio. T-cell RANKL/OPG ratio correlated significantly with BMD-derived z-scores at the hip, lumbar spine and femur neck in HIV-infected individuals with CD4+ T-cell counts at least 200 cells/μl but not in those with lower counts.
Conclusion: Our data suggest that T cells may be a physiologically relevant source of OPG and T-cell RANKL/OPG imbalance is associated with HIV-induced bone loss in CD4+ T-cell-sufficient patients. Both B and T lymphocytes may thus contribute to HIV-induced bone loss.
Background: Medicaid payer status has been shown to affect resource utilization across multiple medical specialties. There is no large database assessment of Medicaid and resource utilization in primary total knee arthroplasty (TKA), which this study sets out to achieve. Methods: The Nationwide Readmissions Database was used to identify patients who underwent TKA in 2013 and corresponding “Medicaid” or “non-Medicaid” payer statuses. Demographics, 15 individual comorbidities, readmission rates, length of stay, and direct cost were evaluated. A propensity score–based matching model was then used to control for baseline confounding variables between payer groups. A chi-square test for paired proportions was used to compare readmission rates between the 2 groups. Length of stay and direct cost comparisons were evaluated using the Wilcoxon signed-rank test. Results: A total of 8372 Medicaid and 268,261 non-Medicaid TKA patients were identified from the 2013 Nationwide Readmissions Database. A propensity score was estimated for each patient based on the baseline demographics, and 8372 non-Medicaid patients were propensity score matched to the 8372 Medicaid patients. Medicaid payer status yielded a statistically significant increase in overall readmission rates of 18.4% vs 14.0% (P <.0001, relative risk = 1.31, 95% confidence interval [1.23-1.41]) with non-Medicaid status and 90-day readmission rates of 10.0% vs 7.4%, respectively (P <.001, relative risk = 1.35, 95% confidence interval [1.22-1.48]). The mean length of stay was longer in the Medicaid group compared with the non-Medicaid group at 4.0 days vs 3.3 days (P <.0001) as well as the mean total cost of $64,487 vs $61,021 (P <.0001). Conclusions: This study demonstrates that Medicaid payer status is independently associated with increased resource utilization, including readmission rates, length of stay, and total cost after TKA.
Objective Uncertain biological consequences of titanium-magnet (Ti-mag) tongue implants constrain application of the Tongue Drive System (TDS), a brain-tongue-computer interface for individuals with severe physical impairment. Here we describe oromotor function and tongue tissue response following Ti-Mag implantation and explantation in the miniature pig, an animal model with a tongue similar in size to humans. Design A 1.8 × 6.2 mm Ti-mag tracer was implanted into the anterior tongue in five Yucatan minipigs. X-rays were taken immediately and >six days after implantation to evaluate tracer migration. In three minipigs, the tracer was explanted?>16 days after implantation. Twenty-five days post-explantation, tongue tissue was harvested and processed for histological and immunohistochemical (IHC) markers of healing. In two minipigs tissue markers of healing were evaluated post-mortem following >12 days implantation. Drink cycle rate (DCR) was characterized to determine the impact of procedures on oromotor function. Results Neither implantation (N = 5) nor explantation (N = 3) changed DCR. X-rays revealed minimal tracer migration (N = 4, 0–4 mm). By histology and IHC a robust capsule was present two weeks post-implantation with limited fibrosis. Explantation produced localized fibrosis and limited muscle remodeling. Conclusions These findings suggest the safety of Ti-mag anterior tongue implants for assistive technologies in humans.