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BACKGROUNDLong-term prognosis of WHO grade II low-grade gliomas (LGGs) is poor, with a high risk of recurrence and malignant transformation into high-grade gliomas. Given the relatively intact immune system of patients with LGGs and the slow tumor growth rate, vaccines are an attractive treatment strategy.METHODSWe conducted a pilot study to evaluate the safety and immunological effects of vaccination with GBM6-AD, lysate of an allogeneic glioblastoma stem cell line, with poly-ICLC in patients with LGGs. Patients were randomized to receive the vaccines before surgery (arm 1) or not (arm 2) and all patients received adjuvant vaccines. Coprimary outcomes were to evaluate safety and immune response in the tumor.RESULTSA total of 17 eligible patients were enrolled - 9 in arm 1 and 8 in arm 2. This regimen was well tolerated with no regimen-limiting toxicity. Neoadjuvant vaccination induced upregulation of type-1 cytokines and chemokines and increased activated CD8+ T cells in peripheral blood. Single-cell RNA/T cell receptor sequencing detected CD8+ T cell clones that expanded with effector phenotype and migrated into the tumor microenvironment (TME) in response to neoadjuvant vaccination. Mass cytometric analyses detected increased tissue resident-like CD8+ T cells with effector memory phenotype in the TME after the neoadjuvant vaccination.CONCLUSIONThe regimen induced effector CD8+ T cell response in peripheral blood and enabled vaccine-reactive CD8+ T cells to migrate into the TME. Further refinements of the regimen may have to be integrated into future strategies.TRIAL REGISTRATIONClinicalTrials.gov NCT02549833.FUNDINGNIH (1R35NS105068, 1R21CA233856), Dabbiere Foundation, Parker Institute for Cancer Immunotherapy, and Daiichi Sankyo Foundation of Life Science.

Objectives Headaches are a common medical problem, yet few studies, particularly trials, have evaluated therapies that might prevent or control headaches. We, thus, investigated the effects on the occurrence of headaches of three levels of dietary sodium intake and two diet patterns (the Dietary Approaches to Stop Hypertension (DASH) diet (rich in fruits, vegetables and low-fat dairy products with reduced saturated and total fat) and a control diet (typical of Western consumption patterns)). Design Randomised multicentre clinical trial. Setting Post hoc analyses of the DASH-Sodium trial in the USA. Participants In a multicentre feeding study with three 30 day periods, 390 participants were randomised to the DASH or control diet. On their assigned diet, participants ate food with high sodium during one period, intermediate sodium during another period and low sodium during another period, in random order. Outcome measures Occurrence and severity of headache were ascertained from self-administered questionnaires, completed at the end of each feeding period. Results The occurrence of headaches was similar in DASH versus control, at high (OR (95% CI)=0.65 (0.37 to 1.12); p=0.12), intermediate (0.57 (0.29 to 1.12); p=0.10) and low (0.64 (0.36 to 1.13); p=0.12) sodium levels. By contrast, there was a lower risk of headache on the low, compared with high, sodium level, both on the control (0.69 (0.49 to 0.99); p=0.05) and DASH (0.69 (0.49 to 0.98); p=0.04) diets. Conclusions A reduced sodium intake was associated with a significantly lower risk of headache, while dietary patterns had no effect on the risk of headaches in adults. Reduced dietary sodium intake offers a novel approach to prevent headaches. Trial registration number NCT00000608.

Background Cancer vaccines require adjuvants to induce effective immune responses; however, there is no consensus on optimal adjuvants. We hypothesized that toll-like receptor (TLR)3 agonist polyICLC or TLR4 agonist lipopolysaccharide (LPS), combined with CD4 T cell activation, would support strong and durable CD8 + T cell responses, whereas addition of an incomplete Freund’s adjuvant (IFA) would reduce magnitude and persistence of immune responses. Patients and methods Participants with resected stage IIB-IV melanoma received a vaccine comprised of 12 melanoma peptides restricted by Class I MHC (12MP), plus a tetanus helper peptide (Tet). Participants were randomly assigned 2:1 to cohort 1 (LPS dose-escalation) or cohort 2 (polyICLC). Each cohort included 3 subgroups (a-c), receiving 12MP + Tet + TLR agonist without IFA (0), or with IFA in vaccine one (V1), or all six vaccines (V6). Toxicities were recorded (CTCAE v4). T cell responses were measured with IFNγ ELIspot assay ex vivo or after one in vitro stimulation (IVS). Results Fifty-three eligible patients were enrolled, of which fifty-one were treated. Treatment-related dose-limiting toxicities (DLTs) were observed in 0/33 patients in cohort 1 and in 2/18 patients in cohort 2 (11%). CD8 T cell responses to 12MP were detected ex vivo in cohort 1 (42%) and in cohort 2 (56%) and in 18, 50, and 72% for subgroups V0, V1, and V6, respectively. T cell responses to melanoma peptides were more durable and of highest magnitude for IFA V6. Conclusions LPS and polyICLC are safe and effective vaccine adjuvants when combined with IFA. Contrary to the central hypothesis, IFA enhanced T cell responses to peptide vaccines when added to TLR agonists. Future studies will aim to understand mechanisms underlying the favorable effects with IFA. Trial registration The clinical trial Mel58 was performed with IRB (#15781) and FDA approval and is registered with Clinicaltrials.gov on April 25, 2012 (NCT01585350). Patients provided written informed consent to participate. Enrollment started on June 24, 2012.

Increased dietary sodium is linked to hypertension, but most young adults display “sodium‐resistant” blood pressure (BP), meaning BP is not elevated with sodium loading. In sodium‐resistant rodents, fructose induces salt‐sensitive BP via increased renal sodium reabsorption. Therefore, we tested the impact of fructose and sodium on renal sodium handling and BP in healthy adults, hypothesizing that their combination would impair sodium excretion and increase BP. Thirty‐six participants enrolled in a randomized, double‐blind, crossover trial involving three diets varying in fructose and sodium. On day 7, participants wore ambulatory BP monitors and collected 24‐h urine. Although high sodium increased urinary sodium excretion, excretion was 15% lower with high fructose plus high salt versus high salt alone (235.1 ± 85.0 vs. 277.9 ± 121.2 mmol/24 h, p = 0.05). Compared to the recommended diet, high salt alone did not significantly change 24 h. MAP; however, high fructose plus high salt modestly raised 24 h MAP (81 ± 6 vs. 84 ± 7 mmHg, p = 0.03). High fructose and high salt increased serum interleukin‐6 concentrations compared to the recommended diet (0.31 ± 0.2 vs. 0.24 ± 0.19 pg/mL, p = 0.04). These findings suggest that increased sodium and fructose alter renal sodium handling and BP in young adults.

PurposeTo determine the effects of the sodium content of maintenance fluid therapy on cumulative fluid balance and electrolyte disorders.MethodsWe performed a randomized controlled trial of adults undergoing major thoracic surgery, randomly assigned (1:1) to receive maintenance fluids containing 154 mmol/L (Na154) or 54 mmol/L (Na54) of sodium from the start of surgery until their discharge from the ICU, the occurrence of a serious adverse event or the third postoperative day at the latest. Investigators, caregivers and patients were blinded to the treatment. Primary outcome was cumulative fluid balance. Electrolyte disturbances were assessed as secondary endpoints, different adverse events and physiological markers as safety and exploratory endpoints.FindingsWe randomly assigned 70 patients; primary outcome data were available for 33 and 34 patients in the Na54 and Na154 treatment arms, respectively. Estimated cumulative fluid balance at 72 h was 1369 mL (95% CI 601–2137) more positive in the Na154 arm (p < 0.001), despite comparable non-study fluid sources. Hyponatremia < 135 mmol/L was encountered in four patients (11.8%) under Na54 compared to none under Na154 (p = 0.04), but there was no significantly more hyponatremia < 130 mmol/L (1 versus 0; p = 0.31). There was more hyperchloremia > 109 mmol/L under Na154 (24/35 patients, 68.6%) than under Na54 (4/34 patients, 11.8%) (p < 0.001). The treating clinicians discontinued the study due to clinical or radiographic fluid overload in six patients receiving Na154 compared to one patient under Na54 (excess risk 14.2%; 95% CI − 0.2–30.4%, p = 0.05).ConclusionsIn adult surgical patients, sodium-rich maintenance solutions were associated with a more positive cumulative fluid balance and hyperchloremia; hypotonic fluids were associated with mild and asymptomatic hyponatremia.

Background/objectivesObjective methods such as the monitoring of salt concentrations in home-prepared dishes may be effective in reducing salt intake. We investigated the effect of monitoring the salt concentration of home-prepared dishes (Monitoring) on salt reduction and change in taste threshold, and the effect of the simultaneous use of low-sodium seasonings (Seasoning) to compare the effect of Monitoring with the conventional method.Subjects/methodsWe conducted a double-blind randomized controlled study using a 2 × 2 factorial design with two interventions. A total of 50 participants (40–75 years-old) were recruited among residents of Niigata Prefecture, a high sodium-consuming population in Japan, then randomly allocated to four groups. After excluding participants with incomplete urine collection, change in salt intake was evaluated using 24-hour urinary excretion as a surrogate of intake for 43 participants. Change in taste threshold was evaluated in 48 participants after excluding those with incomplete threshold measurement.ResultsThe Monitoring intervention group showed a significant decrease in sodium intake (−777 mg/24 h), whereas the decrease in the Seasoning intervention group was not significant (−413 mg/24 h). Sodium intake did not statistically differ between the intervention and control groups (−1011 mg/24 h and −283 mg/24 h for Monitoring and Seasoning, respectively). The changes in taste threshold measurement were very small and did not markedly differ between groups.ConclusionsMonitoring the salt concentration of dishes had a potentially stronger salt-reducing effect than the use of low-sodium seasonings, a conventional method. Confirmation requires additional study with a larger sample size.

In a large study in 17 countries, an estimated sodium intake that was either higher or lower than the average estimated sodium intake was associated with an increased risk of cardiovascular events. A higher-than-average potassium intake was associated with reduced risk. Most of the global population consumes between 3.0 and 6.0 g of sodium per day (7.5 to 15.0 g of salt per day). 1 , 2 Guidelines on cardiovascular disease prevention recommend a maximum sodium intake of 1.5 to 2.4 g per day, but achieving this target will require a substantial change in diet for most people. 3 – 5 Although clinical trials have shown a reduction in blood pressure with a reduced sodium intake, to our knowledge, no large randomized trial has been conducted to document reductions in the risk of cardiovascular disease with low sodium intake. 6 Prospective cohort studies have shown inconsistent . . .

Background Isotonic saline (IS) is widely used to secure perioperative cardiovascular stability. However, the high amount of chloride in IS can induce hyperchloremic acidosis. Therefore, IS is suspected to increase the risk of acute kidney injury (AKI). Biomarkers may have potential as indicators. Methods In a double-blinded, placebo-controlled study, 38 patients undergoing primary uncemented hip replacement were randomized to IS or PlasmaLyte (PL). Infusion was given during surgery as 15 ml/kg the first hour and 5 ml/kg the following two hours. Urinary samples were collected upon admission and the day after surgery. As surgery was initiated, urine was collected over the course of 4 h. Hereafter, another urine collection proceeded until the morning. Urine was analyzed for markers of AKI neutrophil gelatinase-associated lipocalin (NGAL) and kidney injury molecule-1 (KIM-1). Arterious and venous blood samples for measurements of pH and plasma electrolytes including chloride (p-Cl) were collected as surgery was initiated, at the end of surgery and the following morning. Results IS induced an increase in p-Cl (111 ± 2 mmol/L after IS and 108 ± 3 after PL, p  = 0.004) and a decrease in pH (7.39 ± 0.02 after IS and 7.43 ± 0.03 after PL, p  = 0.001). Urinary NGAL excretion increased in both groups (ΔNGAL: 5.5 [4.1; 11.7] μg/mmol creatinine p  = 0.004 after IS vs. 5.5 [2.1;9.4] μg/mmol creatinine after PL, p  < 0.001). No difference was found between the groups ( p  = 0.839). Similarly, urinary KIM-1 excretion increased in both groups (ΔKIM-1: IS 115.8 [74.1; 156.2] ng/mmol creatinine, p  < 0.001 vs. PL 152.4 [120.1; 307.9] ng/mmol creatinine, p < 0.001). No difference between the groups ( p  = 0.064). FE Na increased (1.08 ± 0.52% after IS and 1.66 ± 1.15% after PL, p  = 0.032). ENaC excretion was different within groups ( p  = 0.019). Conclusion A significantly higher plasma chloride and a lower pH was present in the group receiving isotonic saline. However, u-NGAL and u-KIM-1 increased significantly in both groups after surgery despite absence of changes in creatinine. These results indicate that surgery induced subclinical kidney injury. Also, the IS group had a delayed sodium excretion as compared to the PL group which may indicate that IS affects renal sodium excretion differently from PL. Trial registration ClinicalTrials.gov Identifier:  NCT02528448 , 19/08/2015

Calcium hydroxyapatite (CaHA)-carboxymethylcellulose (CMC)+ has unique properties that make it optimal for lifting, contouring, and defining the jawline. This long-term follow-up of a randomized, multicenter, rater-blinded trial reports efficacy and safety of CaHA-CMC(+) through 48 and up to 60 weeks post-treatment. Eligible patients were randomized (2:1) to the treatment or the control/delayed treatment group to receive CaHA-CMC(+) injections in both jawlines. While touch-ups were permitted 4 weeks post-treatment for both groups, only the treatment group was eligible for optional retreatment after 48 weeks. The primary outcome was ≥1-point improvement on both jawlines on the Merz Jawline Assessment Scale (MJAS); secondary endpoints included the Subject Global Aesthetic Improvement Scale (SGAIS) among others. Post hoc analysis included pooling up to 48-week data from the combined treatment and control/delayed groups and 60-week data for the treatment group. Overall, 175 received treatment. MJAS responder rates were 77.9%, 78.7%, and 62.9% at 12, 24, and 48 weeks post-treatment, respectively. Responder rate on the MJAS at 60 weeks was 74.6% for those who received retreatment and 43.5% for those patients who received only the initial and touchup treatments. SGAIS scores demonstrated 93.4%, 85.6%, and 68.5% of patients rated themselves very much improved after 12, 24, and 48 weeks, respectively. Adverse events consisted of procedure or CaHA-CMC(+)-related events that were mostly resolved and overwhelmingly mild. CaHA-CMC(+) produced clinically meaningful and long-lasting improvements in jawline contour and was well tolerated in patients through 60 weeks. ClinicalTrials.gov Identifier: NCT03583359.

Reductions in salt intake have the potential to markedly improve population health at low cost. Real life interventions that explore the feasibility and health effects of a gradual salt reduction lasting at least four weeks are required. The randomized controlled SalT Reduction InterVEntion (STRIVE) trial was developed to investigate the metabolic, behavioral and health effects of four months of consuming gradually salt reduced bread alone or in combination with dietary counselling. This paper describes the rationale and methods of STRIVE. Aiming at 120 healthy families, participants were recruited in February 2018 from the Danish Capital Region and randomly allocated into: (A) Salt reduced bread; (B) Salt reduced bread and dietary counseling; (C) Standard bread. Participants were examined before the intervention and at four months follow-up. Primary outcome is change in salt intake measured by 24 h urine. Secondary outcomes are change in urine measures of potassium and sodium/ potassium ratio, blood pressure, plasma lipids, the renin-angiotensin system, the sympathetic nervous response, dietary intake as well as salt taste sensitivity and preferences. The results will qualify mechanisms affected during a gradual reduction in salt intake in compliance with the current public health recommendations.