IMPORTANCE: Macrovascular disease is a leading cause of morbidity and mortality for patients with type 2 diabetes, and medical management, including lifestyle changes, may not be successful at ...lowering risk. OBJECTIVE: To investigate the relationship between bariatric surgery and incident macrovascular (coronary artery disease and cerebrovascular diseases) events in patients with severe obesity and type 2 diabetes. DESIGN, SETTING, AND PARTICIPANTS: In this retrospective, matched cohort study, patients with severe obesity (body mass index ≥35) aged 19 to 79 years with diabetes who underwent bariatric surgery from 2005 to 2011 in 4 integrated health systems in the United States (n = 5301) were matched to 14 934 control patients on site, age, sex, body mass index, hemoglobin A1c, insulin use, observed diabetes duration, and prior health care utilization, with follow-up through September 2015. EXPOSURES: Bariatric procedures (76% Roux-en-Y gastric bypass, 17% sleeve gastrectomy, and 7% adjustable gastric banding) were compared with usual care for diabetes. MAIN OUTCOMES AND MEASURES: Multivariable-adjusted Cox regression analysis investigated time to incident macrovascular disease (defined as first occurrence of coronary artery disease acute myocardial infarction, unstable angina, percutaneous coronary intervention, or coronary artery bypass grafting or cerebrovascular events ischemic stroke, hemorrhagic stroke, carotid stenting, or carotid endarterectomy). Secondary outcomes included coronary artery disease and cerebrovascular outcomes separately. RESULTS: Among a combined 20 235 surgical and nonsurgical patients, the mean (SD) age was 50 (10) years; 76% of the surgical and 75% of the nonsurgical patients were female; and the baseline mean (SD) body mass index was 44.7 (6.9) and 43.8 (6.7) in the surgical and nonsurgical groups, respectively. At the end of the study period, there were 106 macrovascular events in surgical patients (including 37 cerebrovascular and 78 coronary artery events over a median of 4.7 years; interquartile range, 3.2-6.2 years) and 596 events in the matched control patients (including 227 cerebrovascular and 398 coronary artery events over a median of 4.6 years; interquartile range, 3.1-6.1 years). Bariatric surgery was associated with a lower composite incidence of macrovascular events at 5 years (2.1% in the surgical group vs 4.3% in the nonsurgical group; hazard ratio, 0.60 95% CI, 0.42-0.86), as well as a lower incidence of coronary artery disease (1.6% in the surgical group vs 2.8% in the nonsurgical group; hazard ratio, 0.64 95% CI, 0.42-0.99). The incidence of cerebrovascular disease was not significantly different between groups at 5 years (0.7% in the surgical group vs 1.7% in the nonsurgical group; hazard ratio, 0.69 95% CI, 0.38-1.25). CONCLUSIONS AND RELEVANCE: In this observational study of patients with type 2 diabetes and severe obesity who underwent surgery, compared with those who did not undergo surgery, bariatric surgery was associated with a lower risk of macrovascular outcomes. The findings require confirmation in randomized clinical trials. Health care professionals should engage patients with severe obesity and type 2 diabetes in a shared decision making conversation about the potential role of bariatric surgery in the prevention of macrovascular events.
The purpose of this study was to evaluate the impact of carboplatin and paclitaxel in patients with advanced previously untreated thymoma and thymic carcinoma.
We conducted a prospective multicenter ...study in patients with unresectable thymoma (n = 21) or thymic carcinoma (n = 23). Patients were treated with carboplatin (area under the curve, 6) plus paclitaxel (225 mg/m(2)) every 3 weeks for a maximum of six cycles. The primary end point of this trial was to evaluate the objective response rate.
From February 2001 through January 2008, 46 patients were enrolled. Thirteen patients had grade 4 or greater toxicity, mostly neutropenia. Using RECIST (Response Evaluation Criteria in Solid Tumors) 1.0 criteria, three complete responses (CRs) and six partial responses (PRs; objective response rate ORR, 42.9%; 90% CI, 24.5% to 62.8%) were observed in the thymoma cohort; 10 patients had stable disease. For patients with thymic carcinoma, no CRs and five PRs (ORR, 21.7%; 90% CI, 9.0% to 40.4%) were observed; 12 patients had stable disease. Progression-free survival (PFS) was 16.7 (95% CI, 7.2 to 19.8) and 5.0 (95% CI, 3.0 to 8.3) months for thymoma and thymic carcinoma cohorts, respectively. To date, only seven patients (33.3%) with thymoma have died, compared with 16 patients (69.6%) with thymic carcinoma. Median survival time was 20.0 months (95% CI, 5.0 to 43.6 months) for patients with thymic carcinoma, but it has not been reached for patients with thymoma.
Carboplatin plus paclitaxel has moderate clinical activity for patients with thymic malignancies, but this seems less than expected with anthracycline-based therapy. Patients with thymic carcinoma have poorer PFS and overall survival than patients with thymoma.
The role of inflammation in obesity-related pathologies is well established. We investigated the therapeutic potential of LipoxinA4 (LXA4:5(S),6(R),15(S)-trihydroxy-7E,9E,11Z,13E,-eicosatetraenoic ...acid) and a synthetic 15(R)-Benzo-LXA4-analog as interventions in a 3-month high-fat diet (HFD; 60% fat)-induced obesity model. Obesity caused distinct pathologies, including impaired glucose tolerance, adipose inflammation, fatty liver, and chronic kidney disease (CKD). Lipoxins (LXs) attenuated obesity-induced CKD, reducing glomerular expansion, mesangial matrix, and urinary H2O2. Furthermore, LXA4 reduced liver weight, serum alanine-aminotransferase, and hepatic triglycerides. LXA4 decreased obesity-induced adipose inflammation, attenuating TNF-α and CD11c+ M1-macrophages (MΦs), while restoring CD206+ M2-MΦs and increasing Annexin-A1. LXs did not affect renal or hepatic MΦs, suggesting protection occurred via attenuation of adipose inflammation. LXs restored adipose expression of autophagy markers LC3-II and p62. LX-mediated protection was demonstrable in adiponectin−/− mice, suggesting that the mechanism was adiponectin independent. In conclusion, LXs protect against obesity-induced systemic disease, and these data support a novel therapeutic paradigm for treating obesity and associated pathologies.
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•Lipoxins attenuated high-fat diet-induced liver and kidney disease•LXA4 attenuated adipose inflammation, promoting a macrophage M1-to-M2 switch•LXA4 restored obesity-induced attenuation of autophagy markers LC3-II and p62•LXA4-mediated protection was adiponectin independent, but restored Annexin-A1
Börgeson et al. investigated the role of anti-inflammatory lipid mediators in obesity. LipoxinA4 and a synthetic lipoxin analog protected against obesity-induced kidney and liver disease. Lipoxins mediated protection by decreasing adipose inflammation and promoting a macrophage M1-to-M2 switch. Lipoxin-mediated protection was adiponectin independent, but correlated with restored adipose Annexin-A1 levels.
Tuberculosis kills more people than any other infectious disease. Three pivotal trials testing 4-month regimens failed to meet non-inferiority margins; however, approximately four-fifths of ...participants were cured. Through a pooled analysis of patient-level data with external validation, we identify populations eligible for 4-month treatment, define phenotypes that are hard to treat and evaluate the impact of adherence and dosing strategy on outcomes. In 3,405 participants included in analyses, baseline smear grade of 3+ relative to <2+, HIV seropositivity and adherence of ≤90% were significant risk factors for unfavorable outcome. Four-month regimens were non-inferior in participants with minimal disease defined by <2+ sputum smear grade or non-cavitary disease. A hard-to-treat phenotype, defined by high smear grades and cavitation, may require durations >6 months to cure all. Regimen duration can be selected in order to improve outcomes, providing a stratified medicine approach as an alternative to the 'one-size-fits-all' treatment currently used worldwide.
Janus kinases (JAKs) are receptor-associated multidomain tyrosine kinases that act downstream of many cytokines and interferons. JAK kinase activity is regulated by the adjacent pseudokinase domain ...via an unknown mechanism. Here, we report the 2.8-Å structure of the two-domain pseudokinase–kinase module from the JAK family member TYK2 in its autoinhibited form. We find that the pseudokinase and kinase interact near the kinase active site and that most reported mutations in cancer-associated JAK alleles cluster in or near this interface. Mutation of residues near the TYK2 interface that are analogous to those in cancer-associated JAK alleles, including the V617F and “exon 12” JAK2 mutations, results in increased kinase activity in vitro. These data indicate that JAK pseudokinases are autoinhibitory domains that hold the kinase domain inactive until receptor dimerization stimulates transition to an active state.
IMPORTANCE: The accumulation of aggregated β-amyloid and tau proteins into plaques and tangles is a central feature of Alzheimer disease (AD). While plaque and tangle accumulation likely contributes ...to neuron and synapse loss, disease-related changes to oligodendrocytes and myelin are also suspected of playing a role in development of AD dementia. Still, to our knowledge, little is known about AD-related myelin changes, and even when present, they are often regarded as secondary to concomitant arteriosclerosis or related to aging. OBJECTIVE: To assess associations between hallmark AD pathology and novel quantitative neuroimaging markers while being sensitive to white matter myelin content. DESIGN, SETTING, AND PARTICIPANTS: Magnetic resonance imaging was performed at an academic research neuroimaging center on a cohort of 71 cognitively asymptomatic adults enriched for AD risk. Lumbar punctures were performed and assayed for cerebrospinal fluid (CSF) biomarkers of AD pathology, including β-amyloid 42, total tau protein, phosphorylated tau 181, and soluble amyloid precursor protein. We measured whole-brain longitudinal and transverse relaxation rates as well as the myelin water fraction from each of these individuals. MAIN OUTCOMES AND MEASURES: Automated brain mapping algorithms and statistical models were used to evaluate the relationships between age, CSF biomarkers of AD pathology, and quantitative magnetic resonance imaging relaxometry measures, including the longitudinal and transverse relaxation rates and the myelin water fraction. RESULTS: The mean (SD) age for the 19 male participants and 52 female participants in the study was 61.6 (6.4) years. Widespread age-related changes to myelin were observed across the brain, particularly in late myelinating brain regions such as frontal white matter and the genu of the corpus callosum. Quantitative relaxometry measures were negatively associated with levels of CSF biomarkers across brain white matter and in areas preferentially affected in AD. Furthermore, significant age-by-biomarker interactions were observed between myelin water fraction and phosphorylated tau 181/β-amyloid 42, suggesting that phosphorylated tau 181/β-amyloid 42 levels modulate age-related changes in myelin water fraction. CONCLUSIONS AND RELEVANCE: These findings suggest amyloid pathologies significantly influence white matter and that these abnormalities may signify an early feature of the disease process. We expect that clarifying the nature of myelin damage in preclinical AD may be informative on the disease’s course and lead to new markers of efficacy for prevention and treatment trials.
Bariatric surgery improves glycemic control in patients with type 2 diabetes mellitus (T2DM), but less is known about microvascular outcomes.
To investigate the relationship between bariatric surgery ...and incident microvascular complications of T2DM.
Retrospective matched cohort study from 2005 to 2011 with follow-up through September 2015.
4 integrated health systems in the United States.
Patients aged 19 to 79 years with T2DM who had bariatric surgery (n = 4024) were matched on age, sex, body mass index, hemoglobin A1c level, insulin use, diabetes duration, and intensity of health care use up to 3 nonsurgical participants (n = 11 059).
Bariatric procedures (76% gastric bypass, 17% sleeve gastrectomy, and 7% adjustable gastric banding) compared with usual care.
Adjusted Cox regression analysis investigated time to incident microvascular disease, defined as first occurrence of diabetic retinopathy, neuropathy, or nephropathy.
Median follow-up was 4.3 years for both surgical and nonsurgical patients. Bariatric surgery was associated with significantly lower risk for incident microvascular disease at 5 years (16.9% for surgical vs. 34.7% for nonsurgical patients; adjusted hazard ratio HR, 0.41 95% CI, 0.34 to 0.48). Bariatric surgery was associated with lower cumulative incidence at 5 years of diabetic neuropathy (7.2% for surgical vs. 21.4% for nonsurgical patients; HR, 0.37 CI, 0.30 to 0.47), nephropathy (4.9% for surgical vs. 10.0% for nonsurgical patients; HR, 0.41 CI, 0.29 to 0.58), and retinopathy (7.2% for surgical vs. 11.2% for nonsurgical patients; HR, 0.55 CI, 0.42 to 0.73).
Electronic health record databases could misclassify microvascular disease status for some patients.
In this large, multicenter study of adults with T2DM, bariatric surgery was associated with lower overall incidence of microvascular disease (including lower risk for neuropathy, nephropathy, and retinopathy) than usual care.
National Institute of Diabetes and Digestive and Kidney Diseases.
Purpose
Medial meniscus posterior root tears (MMPRTs) are a significant source of pain and dysfunction, but little is known about the natural history and outcome and for non-operative management of ...these lesions. The purpose of this study was to evaluate (1) the mid-term clinical and radiographic outcomes of non-operative treatment of MMPRTs and (2) risk factors for worse outcomes.
Methods
A retrospective review was performed for patients with symptomatic, unrepaired MMPRTs and a minimum 2-year follow-up for IKDC and Tegner outcome scores. Baseline and final radiographs were reviewed and graded according to Kellgren–Lawrence scores. Baseline MRIs were reviewed for the presence of meniscal extrusion, subchondral oedema, and insufficiency fractures. Failure was defined as conversion to arthroplasty or severely abnormal patient subjective IKDC score.
Results
Fifty-two patients (21M:31F) with a mean age of 58 ± 10 years were diagnosed with symptomatic MMPRTs clinically and confirmed by MRI and followed for a mean of 62 ± 30 months. Sixteen patients (31 %) underwent total knee arthroplasty at a mean of 30 ± 32 months after diagnosis with higher Kellgren–Lawrence grades associated with increased rates of arthroplasty (
p
= 0.01). Mean IKDC scores for the remaining patients were 61.2 ± 21 with significantly lower scores in females compared to males (75 ± 12 vs. 49 ± 20;
p
= 0.03). Mean Kellgren–Lawrence grades and rates of arthritis progressed over time on radiographs (1.5 ± 0.7 vs. 2.4 ± 1.0;
p
< 0.001 and 78 % vs. 51 %;
p
= 0.01). Overall, 87 % of patients failed non-operative treatment.
Conclusions
Non-operative treatment of medial meniscus posterior horn root tears is associated with poor clinical outcome, worsening arthritis, and a relatively high rate of arthroplasty at 5-year follow-up. Female gender was associated with lower subjective scores and higher rate of arthroplasty. The current study provides a natural history benchmark for clinical outcomes that can be expected in patients with medial meniscus posterior horn root tears undergoing non-operative treatment and helps in counselling patients with these types of injuries.
Level of evidence
IV.
The extremely broad infrared spectrum of water in the OH stretching region is a manifestation of how profoundly a water molecule is distorted when embedded in its extended hydrogen-bonding network. ...Many effects contribute to this breadth in solution at room temperature, which raises the question as to what the spectrum of a single OH oscillator would be in the absence of thermal fluctuations and coupling to nearby OH groups. We report the intrinsic spectral responses of isolated OH oscillators embedded in two cold (~20 K), hydrogen-bonded water cages adopted by the Cs
·(HDO)(D
O)
and D
O
·(HDO)(D
O)
clusters. Most OH oscillators yield single, isolated features that occur with linewidths that increase approximately linearly with their redshifts. Oscillators near 3,400 cm
, however, occur with a second feature, which indicates that OH stretch excitation of these molecules drives low-frequency, phonon-type motions of the cage. The excited state lifetimes inferred from the broadening are considered in the context of fluctuations in the local electric fields that are available even at low temperature.
Anticancer drug development is inefficient, but genetically engineered murine models (GEMM) and orthotopic, syngeneic transplants (OST) of cancer may offer advantages to in vitro and xenograft ...systems.
We assessed the activity of 16 treatment regimens in a RAS-driven, Ink4a/Arf-deficient melanoma GEMM. In addition, we tested a subset of treatment regimens in three breast cancer models representing distinct breast cancer subtypes: claudin-low (T11 OST), basal-like (C3-TAg GEMM), and luminal B (MMTV-Neu GEMM).
Like human RAS-mutant melanoma, the melanoma GEMM was refractory to chemotherapy and single-agent small molecule therapies. Combined treatment with AZD6244 mitogen-activated protein-extracellular signal-regulated kinase kinase (MEK) inhibitor and BEZ235 dual phosphoinositide-3 kinase (PI3K)/mammalian target of rapamycin (mTOR) inhibitor was the only treatment regimen to exhibit significant antitumor activity, showed by marked tumor regression and improved survival. Given the surprising activity of the "AZD/BEZ" combination in the melanoma GEMM, we next tested this regimen in the "claudin-low" breast cancer model that shares gene expression features with melanoma. The AZD/BEZ regimen also exhibited significant activity in this model, leading us to testing in even more diverse GEMMs of basal-like and luminal breast cancer. The AZD/BEZ combination was highly active in these distinct breast cancer models, showing equal or greater efficacy compared with any other regimen tested in studies of over 700 tumor-bearing mice. This regimen even exhibited activity in lapatinib-resistant HER2(+) tumors.
These results show the use of credentialed murine models for large-scale efficacy testing of diverse anticancer regimens and predict that combinations of PI3K/mTOR and MEK inhibitors will show antitumor activity in a wide range of human malignancies.
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