Statin treatment and variants in the gene encoding HMG-CoA reductase are associated with reductions in both the concentration of LDL cholesterol and the risk of coronary heart disease, but also with ...modest hyperglycaemia, increased bodyweight, and modestly increased risk of type 2 diabetes, which in no way offsets their substantial benefits. We sought to investigate the associations of LDL cholesterol-lowering PCSK9 variants with type 2 diabetes and related biomarkers to gauge the likely effects of PCSK9 inhibitors on diabetes risk.
In this mendelian randomisation study, we used data from cohort studies, randomised controlled trials, case control studies, and genetic consortia to estimate associations of PCSK9 genetic variants with LDL cholesterol, fasting blood glucose, HbA1c, fasting insulin, bodyweight, waist-to-hip ratio, BMI, and risk of type 2 diabetes, using a standardised analysis plan, meta-analyses, and weighted gene-centric scores.
Data were available for more than 550 000 individuals and 51 623 cases of type 2 diabetes. Combined analyses of four independent PCSK9 variants (rs11583680, rs11591147, rs2479409, and rs11206510) scaled to 1 mmol/L lower LDL cholesterol showed associations with increased fasting glucose (0·09 mmol/L, 95% CI 0·02 to 0·15), bodyweight (1·03 kg, 0·24 to 1·82), waist-to-hip ratio (0·006, 0·003 to 0·010), and an odds ratio for type diabetes of 1·29 (1·11 to 1·50). Based on the collected data, we did not identify associations with HbA1c (0·03%, −0·01 to 0·08), fasting insulin (0·00%, −0·06 to 0·07), and BMI (0·11 kg/m2, −0·09 to 0·30).
PCSK9 variants associated with lower LDL cholesterol were also associated with circulating higher fasting glucose concentration, bodyweight, and waist-to-hip ratio, and an increased risk of type 2 diabetes. In trials of PCSK9 inhibitor drugs, investigators should carefully assess these safety outcomes and quantify the risks and benefits of PCSK9 inhibitor treatment, as was previously done for statins.
British Heart Foundation, and University College London Hospitals NHS Foundation Trust (UCLH) National Institute for Health Research (NIHR) Biomedical Research Centre.
Premenstrual syndrome is defined as recurrent moderate psychological and physical symptoms that occur during the luteal phase of menses and resolve with menstruation. It affects 20 to 32 percent of ...premenopausal women. Women with premenstrual dysphoric disorder experience affective or somatic symptoms that cause severe dysfunction in social or occupational realms. The disorder affects 3 to 8 percent of premenopausal women. Proposed etiologies include increased sensitivity to normal cycling levels of estrogen and progesterone, increased aldosterone and plasma renin activity, and neurotransmitter abnormalities, particularly serotonin. The Daily Record of Severity of Problems is one tool with which women may self-report the presence and severity of premenstrual symptoms that correlate with the criteria for premenstrual dysphoric disorder in the Diagnostic and Statistical Manual of Mental Disorders, 4th ed., text revision. Symptom relief is the goal for treatment of premenstrual syndrome and premenstrual dysphoric disorder. There is limited evidence to support the use of calcium, vitamin D, and vitamin B6 supplementation, and insufficient evidence to support cognitive behavior therapy. Serotonergic antidepressants (citalopram, escitalopram, fluoxetine, sertraline, venlafaxine) are first-line pharmacologic therapy.
Summary
Aggregatibacter actinomycetemcomitans QseBC regulates its own expression and is essential for biofilm growth and virulence. However, the signal that activates the QseC sensor has not been ...identified and the qseBC regulon has not been defined. In this study, we show that QseC is activated by catecholamine hormones and iron but not by either component alone. Activation of QseC requires an EYRDD motif in the periplasmic domain of the sensor and site‐specific mutations in EYRDD or the deletion of the periplasmic domain inhibits catecholamine/iron‐dependent induction of the ygiW‐qseBC operon. Catecholamine/iron‐dependent induction of transcription also requires interaction of the QseB response regulator with its binding site in the ygiW‐qseBC promoter. Whole genome microarrays were used to compare gene expression profiles of A. actinomycetemcomitans grown in a chemically defined medium with and without catecholamine and iron supplementation. Approximately 11.5% of the A. actinomycetemcomitans genome was differentially expressed by at least two‐fold upon exposure to catecholamines and iron. The expression of ferritin was strongly induced, suggesting that intracellular iron storage capacity is increased upon QseBC activation. Consistent with this, genes encoding iron binding and transport proteins were down‐regulated by QseBC. Strikingly, 57% of the QseBC up‐regulated genes (56/99) encode proteins associated with anaerobic metabolism and respiration. Most of these up‐regulated genes were recently reported to be induced during in vivo growth of A. actinomycetemcomitans. These results suggest that detection of catecholamines and iron by QseBC may alter the cellular metabolism of A. actinomycetemcomitans for increased fitness and growth in an anaerobic host environment.
Abstract In acute periprosthetic infection, irrigation and debridement with component retention has a high failure rate in some studies. We hypothesize that pulse lavage irrigation is ineffective at ...removing biofilm from total knee arthroplasty (TKA) components. Staphylococcus aureus biofilm mass and location was directly visualized on arthroplasty materials with a photon collection camera and laser scanning confocal microscopy. There was a substantial reduction in biofilm signal intensity, but the reduction was less than a ten-fold decrease. This suggests that irrigation needs to be further improved for the removal of biofilm mass below the necessary bioburden level to prevent recurrence of acute infection in total knee arthroplasty.
Objective May-Thurner syndrome is characterized by left common iliac obstruction secondary to compression of the left iliac vein by the right common iliac artery against the fifth-lumbar vertebra. ...This anatomic variant results in an increased incidence of left-sided deep venous thrombosis (DVT). Furthermore, while a preponderance of left-sided DVT has been demonstrated in women during pregnancy and oral contraceptive use, patients are not typically screened for this condition after developing a left-sided DVT. As anticoagulation alone is ineffective for DVT treatment in the setting of May-Thurner anatomy, more aggressive treatment is warranted. Failure to diagnosis this condition predisposes these women to the unnecessary risks of recurrent DVT and post-thrombotic syndrome. Methods We present the occurrence of 7 adolescent patients with previously undiagnosed May-Thurner syndrome who presented with DVT after the initiation of oral contraceptive steroids (OCP) use. All 7 patients elected to proceed with mechanical thrombolysis/catheter based thrombolysis followed by endovascular stenting and were postoperatively treated with 6 months of warfarin. Results Mean patient age was 18.3 ± 3.3 years (range, 16-24 years). Mean time to presentation after initiation of OCP was 5 weeks (range, 2-10 weeks). Mean time to intervention was 16.8 days (range, 10-24 days). All patients were treated with mechanical thrombectomy. Our rate of intraoperative clot resolution was 100%. All 7 patients were treated with self expanding nitinol stents after angioplasty of the iliac vein stenosis with resolution of the stenotic segment. Primary stent patency is 100% (7/7). Mean follow-up time is 13 ± 13.84 months (range, 6-42 months). There have been no long-term complications related to surgical treatment or anticoagulation. All 7 patients have experienced resolution of left leg swelling and pain and have no evidence of post-thrombotic syndrome or DVT recurrence to date. Conclusions Women on OCPs presenting with left-sided iliofemoral DVT should be screened for hypercoagulable disorders and underlying May-Thurner anatomy. Treatment of May-Thurner syndrome should include thrombolysis/thrombectomy and anticoagulation for current DVT in addition to angioplasty and stenting of the underlying obstruction.
Summary Background Concurrent testing for human papillomavirus (HPV) and cervical cytology (co-testing) is an approved alternative to cytology alone in women aged 30 years and older. We aimed to ...assess the safety in routine clinical practice of 3-year screening intervals for women testing negative for HPV with normal cytology and to assess if co-testing can identify women at high risk of cervical cancer or cervical intraepithelial neoplasia grade 3 (CIN3) or worse over 5 years. Methods We assessed the 5-year cumulative incidence, starting in 2003–05, of cervical cancer and CIN3 or worse for 331 818 women aged 30 years and older who enrolled in co-testing at Kaiser Permanente Northern California (Berkeley, CA, USA) and had adequate enrolment co-test results. Follow-up continued until Dec 31, 2009. We defined cumulative incidence to include prevalence at enrolment and incidence after enrolment. Prevalence at enrolment was defined as the ratio of women diagnosed with each outcome on the biopsy visit immediately after their enrolment screening visit to the total enrolled women. At screening visits only HPV test and Pap smear samples were collected, and at biopsy visits colposcopically directed biopsies were taken. To estimate post-enrolment incidence, we used Weibull survival models. Findings In 315 061 women negative by HPV testing, the 5-year cumulative incidence of cancer was 3·8 per 100 000 women per year, slightly higher than for the 306 969 who were both negative by HPV and Pap testing (3·2 per 100 000), and half the cancer risk of the 319 177 who were negative by Pap testing (7·5 per 100 000). 313 465 (99·5%) women negative by HPV testing had either normal cytology or equivocal abnormalities. Abnormal cytology greatly increased cumulative incidence of CIN3 or worse over 5 years for the 16 757 positive by HPV testing (12·1% vs 5·9%; p<0·0001). By contrast, although statistically significant, abnormal cytology did not increase 5-year risk of CIN3 or worse for women negative by HPV testing to a substantial level (0·86% vs 0·16%; p=0·004). 12 208 (73%) of the women positive by HPV testing had no cytological abnormality, and these women had 258 (35%) of 747 CIN3 or adenocarcinoma in situ, 25 (29%) of 87 cancers, and 17 (63%) of 27 adenocarcinomas. Interpretation For women aged 30 years and older in routine clinical practice who are negative by co-testing (both HPV and cytology), 3-year screening intervals were safe because a single negative test for HPV was sufficient to reassure against cervical cancer over 5 years. Incorporating HPV testing with cytology also resulted in earlier identification of women at high risk of cervical cancer, especially adenocarcinoma. Testing for HPV without adjunctive cytology might be sufficiently sensitive for primary screening for cervical cancer. Funding Intramural Research Program of the US National Cancer Institute/NIH/DHHS, and the American Cancer Society.
Although studies in adults have shown a non-TH2 obese asthma phenotype, whether a similar phenotype exists in children is unclear.
We hypothesized that asthmatic children with obesity, defined as a ...body mass index above the 95th percentile for age and sex, would have poorer asthma control as well as decreased quality of life, increased health care utilization, and decreased pulmonary function measures as a function of increased TH1 versus TH2 polarization.
This study involved a post hoc analysis of cross sectional data from 269 children 6 to 17 years of age enrolled in the National Heart, Lung, and Blood Institute Severe Asthma Research Program. Children answered questionnaires and underwent spirometry, plethysmography, exhaled nitric oxide determination, and venipuncture for TH1/TH2 cytokine determination. Asthma control was defined according to national asthma treatment guidelines that are based on prespecified thresholds for lung function and symptom frequency.
Fifty-eight children (22%) were overweight and 67(25%) were obese. Obese children did not have poorer asthma control but were more likely to report nonspecific symptoms such as dyspnea and nocturnal awakenings. Obese children did have decreased asthma-related quality of life and increased health care utilization, but this was not associated with airflow limitation. Instead, obese children had decreased functional residual capacity. A unique pattern of TH1 or TH2 polarization was not observed.
Poor asthma control in obese children with asthma may be overestimated because of enhanced perception of nonspecific symptoms such as dyspnea that results from altered mechanical properties of the chest wall. Careful assessment of physiologic as well as symptom-based measures is needed in the evaluation of obese children with respiratory symptoms.
Highlights • Serum concentration of sPD-1 increase during erlotinib treatment. • Increase in serum concentration of sPD-1 during erlotinib treatment is associated with improved survival. • Dynamics ...of sPD-1 are not associated with clinic-pathological parameters. • Dynamics of sPD-1 are not associated with the emergence of T790M in ctDNA.
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