Citations

Gut microbiota may modulate the efficacy and/or toxicity of immune checkpoint blockade therapy in cancer.

ABSTRACT CONTEXT AND OBJECTIVE: To evaluate predictors of changes in lipid parameters consisting of LDL-C (low-density lipoprotein cholesterol), TC (total cholesterol) and non-HDL-C (non-high density lipoprotein cholesterol) among primary care patients. DESIGN AND SETTING: Retrospective study conducted on family medicine patients. METHODS: Demographic features and other clinically relevant information were abstracted from medical records. The primary outcome was the difference in LDL-C level from initial testing to the index test. Secondary outcomes were the changes in TC and non-HDL-C levels between two measurements. RESULTS: Three hundred and eleven participants were included in the final secondary analysis. Multiple linear regression revealed that male patients (β = 4.97, P = 0.040), diabetes (β = 9.75, P = 0.003) and higher LDL-C levels at baseline (β = 0.35, P < 0.001) were positively associated with LDL variance, whereas longer time period (β = -0.15, P = 0.045) and familial hypercholesterolemia history (β = -7.56, P = 0.033) were negatively associated. Male patients (β = 8.45, P = 0.002), DM (β = 9.26, P = 0.011), higher TC levels at baseline (β = 0.35, P < 0.001) and taking statins (β = 7.31, P = 0.023) were positively associated with TC variance, whilst longer time period (β = -0.183, P = 0.031) and familial hypercholesterolemia (β = -10.70, P = 0.008) were negatively associated. CONCLUSION: In the present study, patients who were male, on statin treatment, diagnosed with diabetes and had higher baseline lipid values were more likely associated with better lipid outcomes at future testing.

Human studies use varying levels of low-dose (1-4 μg·kg −1 ·min −1 ) dopamine to examine peripheral chemosensitivity, based on its known ability to blunt carotid body responsiveness to hypoxia. However, the effect of dopamine on the ventilatory responses to hypoxia is highly variable between individuals. Thus we sought to determine 1) the dose response relationship between dopamine and peripheral chemosensitivity as assessed by the ventilatory response to hypoxia in a cohort of healthy adults, and 2) potential confounding cardiovascular responses at variable low doses of dopamine. Young, healthy adults ( n = 30, age = 32 ± 1, 24 male/6 female) were given intravenous (iv) saline and a range of iv dopamine doses (1–4 μg·kg −1 ·min −1 ) prior to and throughout five hypoxic ventilatory response (HVR) tests. Subjects initially received iv saline, and after each HVR the dopamine infusion rate was increased by 1 μg·kg −1 ·min −1 . Tidal volume, respiratory rate, heart rate, blood pressure, and oxygen saturation were continuously measured. Dopamine significantly reduced HVR at all doses ( P < 0.05). When subjects were divided into high ( n = 13) and low ( n = 17) baseline chemosensitivity, dopamine infusion (when assessed by dose) reduced HVR in the high group only ( P < 0.01), with no effect of dopamine on HVR in the low group ( P > 0.05). Dopamine infusion also resulted in a reduction in blood pressure (3 μg·kg −1 ·min −1 ) and total peripheral resistance (1–4 μg·kg −1 ·min −1 ), driven primarily by subjects with low baseline chemosensitivity. In conclusion, we did not find a single dose of dopamine that elicited a nadir HVR in all subjects. Additionally, potential confounding cardiovascular responses occur with dopamine infusion, which may limit its usage.

PurposeTo characterize peripheral nerve stimulation (PNS) of an asymmetric head‐only gradient coil that is compatible with a commercial high–channel‐count receive‐only array.MethodsTwo prototypes of an asymmetric head‐only gradient coil set with a 42‐cm inner diameter were constructed for brain imaging at 3T with maximum performance specifications of up to 85 mT/m and 708 T/m/s. Tests were performed in 24 volunteers to measure PNS thresholds with the transverse (x = left–right; y = anterior–posterior [A/P]) gradient coils of both prototypes. Fourteen of these 24 volunteers were also tested for the z‐gradient PNS in the second prototype and were scanned with high–slew‐rate echo planar imaging (EPI) immediately after the PNS tests.ResultsFor both prototypes, the y‐gradient PNS threshold was markedly higher than the x‐gradient threshold. The z‐gradient threshold was intermediate between those for the x‐ and y‐coils. Of the 24 volunteers, only two experienced y‐gradient PNS at 80 mT/m and 500 T/m/s. All volunteers underwent the EPI scan without PNS when the readout direction was set to A/P.ConclusionMeasured PNS characteristics of asymmetric head‐only gradient coil prototypes indicate that such coils, especially in the A/P direction, can be used for fast EPI readout in high‐performance neuroimaging scans with substantially reduced PNS concerns compared with conventional whole body gradient coils. Magn Reson Med 76:1939–1950, 2016. © 2015 International Society for Magnetic Resonance in Medicine

Summary Peripheral T‐cell lymphomas ( PTCL ) have suboptimal outcomes using conventional CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) chemotherapy. The anti‐folate pralatrexate, the first drug approved for patients with relapsed/refractory PTCL , provided a rationale to incorporate it into the front‐line setting. This phase 2 study evaluated a novel front‐line combination whereby cyclophosphamide, etoposide, vincristine and prednisone ( CEOP ) alternated with pralatrexate ( CEOP ‐P) in PTCL . Patients achieving a complete or partial remission ( CR / PR ) were eligible for consolidative stem cell transplantation ( SCT ) after 4 cycles. Thirty‐three stage II ‐ IV PTCL patients were treated: 21 PTCL ‐not otherwise specified (64%), 8 angioimmunoblastic T cell lymphoma (24%) and 4 anaplastic large cell lymphoma (12%). The majority (61%) had stage IV disease and 46% were International Prognostic Index high/intermediate or high risk. Grade 3–4 toxicities included anaemia (27%), thrombocytopenia (12%), febrile neutropenia (18%), mucositis (18%), sepsis (15%), increased creatinine (12%) and liver transaminases (12%). Seventeen patients (52%) achieved a CR . The 2‐year progression‐free survival and overall survial, were 39% (95% confidence interval 21–57) and 60% (95% confidence interval 39–76), respectively. Fifteen patients (45%) (12 CR ) received SCT and all remained in CR at a median follow‐up of 21·5 months. CEOP ‐P did not improve outcomes compared to historical data using CHOP . Defining optimal front line therapy in PTCL continues to be a challenge and an unmet need.

Background: The principle aim of this study was to investigate the associations between heat pain (HP) perception, pain catastrophizing, and pain-related anxiety in a heterogenous cohort of community-dwelling adults with chronic pain admitted to a 3-week outpatient pain rehabilitation program. Methods: All adults consecutively admitted to an outpatient pain rehabilitation program from July 2009 through January 2011 were eligible for study recruitment (n=574). Upon admission, patients completed the Pain Catastrophizing Scale (PCS), the short version of the Pain Anxiety Symptoms Scale (PASS-20), and HP perception was assessed using a standardized quantitative sensory testing (QST) method of levels. Results: Greater PCS scores were significantly correlated with lower standardized values of HP threshold (HP 0.5) (P=0.006) and tolerance (HP 5) (P=0.003). In a multiple variable model adjusted for demographic and clinical factors known to influence HP perception, every 10-point increase in the PCS was associated with a −0.124 point change in HP 0.5 (P=0.014) and a −0.142 change in HP 5 (P=0.014) indicating that participants with higher PCS scores had lower HP thresholds and tolerances, respectively. Similarly, greater PASS-20 scores significantly correlated with lower standardized values of HP 0.5 and HP 5. In a multiple variable model, every 10-point increase in the PASS-20 was associated with a −0.084 point change in HP 0.5 (P=0.005) and a −0.116 point change in HP 5 (P=0.001) indicating that participants with higher PASS-20 scores had lower HP thresholds and tolerances, respectively. Conclusions: The findings of this study extend the use of a standardized method for assessing HP in a heterogenous sample of adults with chronic pain. Although pain catastrophizing shares significant variance with pain-related anxiety, our findings suggest that either measure would be appropriate for use in future studies that incorporate the QST method of levels.

Background Patients with atrial fibrillation ( AF ) and hypertension are at high risk for stroke. Previous studies have shown elevated risk of stroke in patients with AF who have a history of hypertension (regardless of blood pressure [ BP ] control) and in patients with elevated BP . We assessed the association of hypertension and BP control on clinical outcomes. Methods and Results In ARISTOTLE (n=18 201), BP was evaluated as history of hypertension requiring treatment and elevated BP (systolic ≥140 and/or diastolic ≥90 mm Hg) at study entry and any point during the trial. Hazard ratios ( HR s) were derived from Cox proportional hazards models including BP as a time‐dependent covariate. A total of 15 916 (87.5%) patients had a history of hypertension requiring treatment. In patients with elevated BP measurement at any point during the trial, the rate of stroke or systemic embolism was significantly higher ( HR , 1.53; 95% confidence interval [ CI ], 1.25–1.86), as was hemorrhagic stroke ( HR 1.85; 95% CI , 1.26–2.72) and ischemic stroke ( HR , 1.50; 95% CI , 1.18–1.90). Rates of major bleeding were lower in patients with a history of hypertension ( HR , 0.80; 95% CI , 0.66–0.98) and nonsignificantly lower in patients with elevated BP at study entry ( HR , 0.89; 95% CI , 0.77–1.03). The benefit of apixaban versus warfarin on preventing stroke or systemic embolism was consistent among patients with and without a history of hypertension ( P interaction=0.27), BP control at baseline ( P interaction=0.43), and BP control during the trial ( P interaction=0.97). Conclusions High BP measurement at any point during the trial was independently associated with a substantially higher risk of stroke or systemic embolism. These results strongly support efforts to treat elevated BP as an important strategy to optimally lower risk of stroke in patients with AF . Clinical Trial Registration URL : https://ClinicalTrials.gov/ . Unique identifier: NCT 00412984.

Objectives: We aimed to construct a predictive model for one‐year mortality in patients undergoing invasive coronary evaluation and to examine the impact of bivalirudin on survival according to the level of baseline risk.Background: Compared to heparin plus GP IIb/IIIa inhibitors (HEP/GPI), bivalirudin decreases bleeding complications in a range of clinical presentations. The impact of preprocedural risk assessment on survival and whether this is modified by bivalirudin, has not been investigated in detail.Methods: We examined patient‐level data from the REPLACE‐2, ACUITY, and HORIZONS‐AMI trials (n = 18,819) to construct a risk‐adjusted mortality model using baseline clinical variables.Results: One‐year mortality occurred in 287 patients (3.1%) assigned to bivalirudin and 336 patients (3.6%) assigned to HEP/GPI (HR 0.85; 95% CI, 0.73–1.00; P = 0.048). Using 11 highly significant predictors of mortality, we developed an integer‐risk score to classify patients into risk tertiles. High‐risk patients had a rate of 1‐year mortality over 9‐fold greater than low‐risk patients. Consequently, the absolute mortality reduction attributed to bivalirudin was more marked in high‐risk patients: 3.1% (−0.8% to 7.0%) in the overall cohort, 4.8% (0.5% to 9.2%) in the PCI cohort (P‐interaction versus intermediate and low risk categories, 0.09 and P = 0.02, respectively).Conclusions: In patients undergoing invasive coronary evaluation, 1‐year mortality can be predicted using baseline variables. Bivalirudin treatment (versus HEP/GPI) conferred a survival benefit. © 2015 Wiley Periodicals, Inc.

Krüppel-like factor (KLF)-10 is an important transcriptional regulator of TGF-β1signaling in both CD8+and CD4+T lymphocytes. In the present study, we demonstrate a novel role for KLF10 in the regulation of TGFβRII expression with functional relevance in macrophage differentiation and activation. We first show that transfer of KLF10−/−bone marrow-derived macrophages into wild-type (WT) mice leads to exacerbation of experimental colitis. At the cell biological level, using two phenotypic strategies, we show that KLF10-deficient mice have an altered colonic macrophage phenotype with higher frequency of proinflammatory LyC6+MHCII+cells and a reciprocal decrease of the anti-inflammatory LyC6−MHCII+subset. Additionally, the anti-inflammatory CD11b+CX3CR1hisubset of colonic macrophages is significantly decreased in KLF10−/−compared with WT mice under inflammatory conditions. Molecularly, CD11b+colonic macrophages from KLF10−/−mice exhibit a proinflammatory cytokine profile with increased production of TNF-α and lower production of IL-10 in response to LPS stimulation. Because KLF10 is a transcription factor, we explored how this protein may regulate macrophage function. Consequently, we analyzed the expression of TGFβRII expression in colonic macrophages and found that, in the absence of KLF10, macrophages express lower levels of TGFβRII and display an attenuated Smad-2 phosphorylation following TGF-β1stimulation. We further show that KLF10 directly binds to the TGFβRII promoter in macrophages, leading to enhanced gene expression through histone H3 acetylation. Collectively, our data reveal a critical role for KLF10 in the epigenetic regulation of TGFβRII expression in macrophages and the acquisition of a “regulatory” phenotype that contributes to intestinal mucosal homeostasis.