Chronic #Cigarette Smoke-Induced #Epigenomic Changes Precede Sensitization of Bronchial Epithelial Cells to Single-Step Transformation by KRAS Mutations
http://www.cell.com/cancer-cell/fulltext/S1535-6108(17)30349-5

Highlights
•Chronic smoke exposure causes sequential chromatin changes leading to gene silencing
•Silenced genes are normally polycomb controlled but adopt abnormal DNA methylation
•Gene methylation causes sequential upregulation of key signal transduction pathways
•Epigenetic alterations sensitize cells to transformation by a single oncogenic event

We define how chronic cigarette smoke-induced time-dependent epigenetic alterations can sensitize human bronchial epithelial cells for transformation by a single oncogene. The smoke-induced chromatin changes include initial repressive polycomb marking of genes, later manifesting abnormal DNA methylation by 10 months. At this time, cells exhibit epithelial-to-mesenchymal changes, anchorage-independent growth, and upregulated RAS/MAPK signaling with silencing of hypermethylated genes, which normally inhibit these pathways and are associated with smoking-related non-small cell lung cancer. These cells, in the absence of any driver gene mutations, now transform by introducing a single KRAS mutation and form adenosquamous lung carcinomas in mice. Thus, epigenetic abnormalities may prime for changing oncogene senescence to addiction for a single key oncogene involved in lung cancer initiation

Effectiveness of Psychological and/or Educational #Interventions in the Prevention of #Anxiety
A Systematic Review, Meta-analysis, and Meta-regression
http://jamanetwork.com/journals/jamapsychiatry/fullarticle/2652827

To our knowledge, no systematic reviews or meta-analyses have been conducted to assess the effectiveness of preventive psychological and/or educational interventions for anxiety in varied populations There was evidence of publication bias, but the effect size barely varied after adjustment (SMD, −0.27; 95% CI, −0.37 to −0.17; P < .001). Sensitivity analyses confirmed the robustness of effect size results. A meta-regression including 5 variables explained 99.6% of between-study variability, revealing an association between higher SMD, waiting list (comparator) (β = −0.33 95% CI, −0.55 to −0.11; P = .005) and a lower sample size (lg) (β = 0.15 95% CI, 0.06 to 0.23; P = .001). No association was observed with risk of bias, family physician providing intervention, and use of standardized interviews as outcomes.

Conclusions and Relevance Psychological and/or educational interventions had a small but statistically significant benefit for anxiety prevention in all populations evaluated. Although more studies with larger samples and active comparators are needed, these findings suggest that anxiety prevention programs should be further developed and implemented

Draft Recommendation Statement
#Cervical Cancer: #Screening
https://www.uspreventiveservicestaskforce.org/Page/Document/draft-recommendation-statement/cervical-cancer-screening2

-The USPSTF recommends screening for cervical cancer every 3 years with cervical cytology alone in women ages 21 to 29 years. The USPSTF recommends either screening every 3 years with cervical cytology alone or every 5 years with high-risk human papillomavirus (hrHPV) testing alone in women ages 30 to 65 years.
See the Clinical Considerations section for the relative benefits and harms of alternative screening strategies for women age 30 years or older

- The USPSTF recommends against screening for cervical cancer in women older than age 65 years who have had adequate prior screening and are not otherwise at high risk for cervical cancer.
See the Clinical Considerations section for a discussion of adequate prior screening and risk factors that support screening after age 65 years

- The USPSTF recommends against screening for cervical cancer in women younger than age 21 years

- The USPSTF recommends against screening for cervical cancer in women who have had a hysterectomy with removal of the cervix and do not have a history of a high-grade precancerous lesion (i.e., cervical intraepithelial neoplasia CIN grade 2 or 3) or cervical cancer

Low-dose #CT for the diagnosis of #appendicitis in adolescents and young adults (LOCAT): a pragmatic, multicentre, randomised controlled non-inferiority trial

http://www.thelancet.com/journals/langas/article/PIIS2468-1253(17)30247-9/fulltext

CT radiation is arguably carcinogenic. Results from single-centre studies, mostly retrospective, have advocated lowering the CT radiation dose for the diagnosis of appendicitis. However, adoption of low-dose CT has been slow. We aimed to assess the effectiveness of low-dose CT compared with standard-dose CT in the diagnosis of appendicitis in adolescents and young adults

Between Dec 4, 2013, and Aug 18, 2016, we assigned 1535 patients to the low-dose CT group and 1539 patients to the standard-dose CT group. 22 (3·9%) of 559 patients had a negative appendectomy in the low-dose group versus 16 (2·7%) of 601 patients in the standard-dose group (difference 1·3%, 95% CI −0·8 to 3·3; p=0·0022 for the non-inferiority test). We recorded 43 adverse events in 43 (2·8%) of 1535 patients in the low-dose group and 41 adverse events in 40 (2·6%) of 1539 patients in the standard-dose group. One life-threatening adverse event of anaphylaxis caused by an iodinated contrast material occurred in the low-dose group

Radiation dose of appendiceal CT for adolescents and young adults can be reduced to 2 mSv without impairing clinical outcomes. In view of the vast number of appendiceal CT examinations done worldwide, use of low-dose CT could prevent a sizeable number of radiation-associated cancers in the future

Association Between #Laparoscopic Antireflux Surgery and Recurrence of Gastroesophageal #Reflux
http://jamanetwork.com/journals/jama/article-abstract/2653734

.. 470 patients (17.7%) had reflux recurrence; 393 (83.6%) received long-term antireflux medication and 77 (16.4%) underwent secondary antireflux surgery. Risk factors for reflux recurrence included female sex (hazard ratio HR, 1.57 95% CI, 1.29-1.90; 286 of 1301 women 22.0% and 184 of 1354 men 13.6% had recurrence of reflux), older age (HR, 1.41 95% CI, 1.10-1.81 for age ≥61 years compared with ≤45 years; recurrence among 156 of 715 patients and 133 of 989 patients, respectively), and comorbidity (HR, 1.36 95% CI, 1.13-1.65 for Charlson comorbidity index score ≥1 compared with 0; recurrence among 180 of 804 patients and 290 of 1851 patients, respectively). Hospital volume of antireflux surgery was not associated with risk of reflux recurrence (HR, 1.09 95% CI, 0.77-1.53 for hospital volume ≤24 surgeries compared with ≥76 surgeries; recurrence among 38 of 266 patients 14.3% and 271 of 1526 patients 17.8%, respectively).

Conclusions and Relevance Among patients who underwent primary laparoscopic antireflux surgery, 17.7% experienced recurrent gastroesophageal reflux requiring long-term medication use or secondary antireflux surgery. Risk factors for recurrence were older age, female sex, and comorbidity. Laparoscopic antireflux surgery was associated with a relatively high rate of recurrent gastroesophageal reflux disease requiring treatment, diminishing some of the benefits of the operation. Cohort studies, mainly based on questionnaires and interviews, have reported high rates of reflux recurrence after antireflux surgery, which may have contributed to a decline in its use. Reflux recurrence after laparoscopic antireflux surgery has not been assessed in a long-term population-based study of unselected patients

25-Hydroxyvitamin #D deficiency and risk of #MS among women in the Finnish Maternity Cohort
http://m.neurology.org/content/early/2017/09/13/WNL.0000000000004489

To determine whether and to what extent vitamin D deficiency is associated with multiple sclerosis (MS) risk. A 50 nmol/L increase in 25(OH)D was associated with a 39% reduced risk of MS (RR 0.61, 95% CI 0.44–0.85), p = 0.003. Women with 25(OH)D levels <30 nmol/L had a 43% higher MS risk (RR 1.43, 95% CI 1.02–1.99, p = 0.04) as compared to women with levels ≥50 nmol/L. In women with ≥2 samples, MS risk was 2-fold higher in women with 25(OH)D <30 nmol/L as compared to women with 25(OH)D ≥50 nmol/L (RR 2.02, 95% CI 1.18–3.45, p = 0.01).

Conclusions: These results directly support vitamin D deficiency as a risk factor for MS and strengthen the rationale for broad public health interventions to improve vitamin D levels

Effects on the incidence of cardiovascular events of the addition of #pioglitazone versus #sulfonylureas in patients with type 2 #diabetes inadequately controlled with metformin (TOSCA.IT): a randomised, multicentre trial
http://thelancet.com/journals/landia/article/PIIS2213-8587(17)30317-0/fulltext

The best treatment option for patients with type 2 diabetes in whom treatment with metformin alone fails to achieve adequate glycaemic control is debated. We aimed to compare the long-term effects of pioglitazone versus sulfonylureas, given in addition to metformin, on cardiovascular events in patients with type 2 diabetes

Between Sept 18, 2008, and Jan 15, 2014, 3028 patients were randomly assigned and included in the analyses. 1535 were assigned to pioglitazone and 1493 to sulfonylureas (glibenclamide 24 2%, glimepiride 723 48%, gliclazide 745 50%). At baseline, 335 (11%) participants had a previous cardiovascular event. The study was stopped early on the basis of a futility analysis after a median follow-up of 57·3 months. The primary outcome occurred in 105 patients (1·5 per 100 person-years) who were given pioglitazone and 108 (1·5 per 100 person-years) who were given sulfonylureas (hazard ratio 0·96, 95% CI 0·74–1·26, p=0·79). Fewer patients had hypoglycaemias in the pioglitazone group than in the sulfonylureas group (148 10% vs 508 34%, p<0·0001). Moderate weight gain (less than 2 kg, on average) occurred in both groups. Rates of heart failure, bladder cancer, and fractures were not significantly different between treatment groups.

Interpretation
In this long-term, pragmatic trial, incidence of cardiovascular events was similar with sulfonylureas (mostly glimepiride and gliclazide) and pioglitazone as add-on treatments to metformin. Both of these widely available and affordable treatments are suitable options with respect to efficacy and adverse events, although pioglitazone was associated with fewer hypoglycaemia events

Risk of relapse after #antidepressant discontinuation in #anxiety disorders, obsessive-compulsive disorder, and post-traumatic stress disorder: systematic review and meta-analysis of relapse prevention trials
http://www.bmj.com/content/358/bmj.j3927

To examine the risk of relapse and time to relapse after discontinuation of antidepressants in patients with anxiety disorder who responded to antidepressants, and to explore whether relapse risk is related to type of anxiety disorder, type of antidepressant, mode of discontinuation, duration of treatment and follow-up, comorbidity, and allowance of psychotherapy relapse compared with continuing antidepressants (summary odds ratio 3.11, 95% confidence interval 2.48 to 3.89).

Subgroup analyses and meta-regression analyses showed no statistical significance. Time to relapse (n=3002) was shorter when antidepressants were discontinued (summary hazard ratio 3.63, 2.58 to 5.10; n=11 studies). Summary relapse prevalences were 36.4% (30.8% to 42.1%; n=28 studies) for the placebo group and 16.4% (12.6% to 20.1%; n=28 studies) for the antidepressant group, but prevalence varied considerably across studies, most likely owing to differences in the length of follow-up. Dropout was higher in the placebo group (summary odds ratio 1.31, 1.06 to 1.63; n=27 studies).

Conclusions Up to one year of follow-up, discontinuation of antidepressant treatment results in higher relapse rates among responders compared with treatment continuation. The lack of evidence after a one year period should not be interpreted as explicit advice to discontinue antidepressants after one year. Given the chronicity of anxiety disorders, treatment should be directed by long term considerations, including relapse prevalence, side effects, and patients’ preferences

Effect of #Sofosbuvir-Based Hepatitis C Virus Therapy on #Kidney Function in Patients with CKD
http://m.cjasn.asnjournals.org/content/early/2017/09/07/CJN.02510317.abstract

Hepatitis C virus infection is common in patients with CKD and leads to accelerated progression to ESRD. Sofosbuvir is a potent direct-acting antiviral therapy against hepatitis C virus; however, there are concerns about its safety in patients with CKD. The objective of our study was to determine the safety and efficacy of sofosbuvir in patients with CKD Ninety-eight patients with CKD (42% stage 1 or 2 CKD and 58% stage 3 CKD) were included. Mean age was 62 years old, 78% were men, and 65% were white. Additionally, 49% of patients had diabetes, 38% of patients had cirrhosis, and 33% of patients had prior solid organ transplant. Overall sustained virologic response was 81% and varied by regimen used and viral genotype. Average baseline eGFR was equivalent to average on-treatment eGFR, but seven patients experienced a rise in creatinine ≥1.5 times baseline while taking sofosbuvir; all but one recovered. In patients with eGFR<60 ml/min per 1.73 m2 at baseline (stage 3 CKD), regression models showed that hepatitis C cure was associated with a 9.3 (95% confidence interval, 0.44 to 18) ml/min per 1.73 m2 improvement in eGFR during the 6-month post-treatment follow-up period. Adverse events were common (81%), but serious adverse events (17%) and treatment discontinuations (8%) were uncommon.

Conclusions Sofosbuvir-based direct-acting antiviral therapy is safe and effective in a cohort of patients with CKD infected with hepatitis C

Continuous glucose #monitoring in pregnant women with type 1 #diabetes (CONCEPTT): a multicentre international randomised controlled trial
http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(17)32400-5/abstract

We found a small difference in HbA1c in pregnant women using CGM (mean difference −0·19%; 95% CI −0·34 to −0·03; p=0·0207). Pregnant CGM users spent more time in target (68% vs 61%; p=0·0034) and less time hyperglycaemic (27% vs 32%; p=0·0279) than did pregnant control participants, with comparable severe hypoglycaemia episodes (18 CGM and 21 control) and time spent hypoglycaemic (3% vs 4%; p=0·10). Neonatal health outcomes were significantly improved, with lower incidence of large for gestational age (odds ratio 0·51, 95% CI 0·28 to 0·90; p=0·0210), fewer neonatal intensive care admissions lasting more than 24 h (0·48; 0·26 to 0·86; p=0·0157), fewer incidences of neonatal hypoglycaemia (0·45; 0·22 to 0·89; p=0·0250), and 1-day shorter length of hospital stay (p=0·0091). We found no apparent benefit of CGM in women planning pregnancy. Adverse events occurred in 51 (48%) of CGM participants and 43 (40%) of control participants in the pregnancy trial, and in 12 (27%) of CGM participants and 21 (37%) of control participants in the planning pregnancy trial. Serious adverse events occurred in 13 (6%) participants in the pregnancy trial (eight 7% CGM, five 5% control) and in three (3%) participants in the planning pregnancy trial (two 4% CGM and one 2% control). The most common adverse events were skin reactions occurring in 49 (48%) of 103 CGM participants and eight (8%) of 104 control participants during pregnancy and in 23 (44%) of 52 CGM participants and five (9%) of 57 control participants in the planning pregnancy trial. The most common serious adverse events were gastrointestinal (nausea and vomiting in four participants during pregnancy and three participants planning pregnancy).

Interpretation
Use of CGM during pregnancy in patients with type 1 diabetes is associated with improved neonatal outcomes, which are likely to be attributed to reduced exposure to maternal hyperglycaemia. CGM should be offered to all pregnant women with type 1 diabetes using intensive insulin therapy. This study is the first to indicate potential for improvements in non-glycaemic health outcomes from CGM use

Multicenter prevalence of #anaphylaxis in clinic-based oral #food challenges
http://www.annallergy.org/article/S1081-1206(17)30595-1/fulltext

Although previous single-center studies report the rate of anaphylaxis for oral food challenges (OFCs) as 9% to 11%, little is known regarding the epidemiology of clinical OFCs across multiple centers in the United States A total of 6,377 OFCs were performed, and the pooled estimate of anaphylaxis was 2% (95% CI, 1%-3%). The rate of allergic reactions was 14% (95% CI, 13%-16%) and was consistent during the study period (P = .40). Reaction rates ranged from 13% to 33%. Males reacted 16% more frequently than females (95% CI, 4%-37.5%; P = .04). Foods challenged in 2013 varied geographically, with peanut as the most challenged food in the Northeast, Midwest, and West and egg as the most challenged in the South.

Conclusion

As the largest national survey of allergic reactions of clinical open OFCs in a nonresearch setting in the United States, this study found that performing clinical nonresearch open low-risk OFCs results in few allergic reactions, with 86% of challenges resulting in no reactions and 98% without anaphylaxis

#Sodium intake and the risk of type 2 #diabetes and Latent Autoimmune Diabetes in Adults (LADA)
http://www.abstractsonline.com/pp8/#!/4294/presentation/6091

It has been suggested that salt (sodium chloride) may increase the risk of T2D, hypothetically through an effect on insulin resistance and/or by way of promoting hypertension and weight gain. Whether sodium intake is related to onset of autoimmune diabetes has not been investigated. However, experimental studies have shown that excessive sodium intake may initiate an autoimmune reaction by enhancing the production of TH17 cells which are highly proinflammatory. We aimed to study, for the first time, whether sodium intake is associated with an increased risk of LADA

Sodium intake was associated with an increased risk of LADA (OR per gr/day; 1.73, 95% CI; 1.23-2.43); comparing the highest to lowest tertile of sodium intake indicated an OR of 2.19 (95% CI; 1.33-3.61) (Table 1). The risk was even more pronounced for LADA patients with high risk HLA genotypes; an almost four-fold (OR 3.87, 95% CI 1.87-8.01) increased risk was seen in the high consumers. We could also confirm that sodium intake was associated with an increased risk of T2D (OR per gr/day; 1.43, 95% CI; 1.09-1.88).

Conclusion: Our findings suggest that high sodium intake may be a risk factor for LADA, especially in carriers of high risk HLA genotypes. We could also confirm an association between sodium intake and T2D. If confirmed in other populations, these findings may have important implications in the primary prevention of diabetes with adult onset

From Misperception to #Social Connection: Correlates and #Consequences of Overestimating Others’ Social Connectedness

http://journals.sagepub.com/doi/10.1177/0146167217727496

Two studies document the existence and correlates of a widespread social belief, wherein individuals who have recently moved to a new social environment see their peers as more socially connected than they themselves are. In Study 1, the prevalence of this belief was documented in a large sample of first-year students (N = 1,099). In Study 2, the prevalence of this social belief was replicated in a targeted sample of university students (N = 389). Study 2 also documented both positive and negative implications of this belief. Specifically, at any given time, students who believed that their peers were more socially connected reported lower well-being and belonging. Over time, however, the belief that one’s peers are moderately more socially connected than oneself was associated with more friendship formation

Misattribution of #musical #arousal increases sexual attraction towards opposite-sex faces in females
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0183531


Several theories about the origins of music have emphasized its biological and social functions, including in courtship. Music may act as a courtship display due to its capacity to vary in complexity and emotional content. Support for music’s reproductive function comes from the recent finding that only women in the fertile phase of the reproductive cycle prefer composers of complex melodies to composers of simple ones as short-term sexual partners, which is also in line with the ovulatory shift hypothesis. However, the precise mechanisms by which music may influence sexual attraction are unknown, specifically how music may interact with visual attractiveness cues and affect perception and behaviour in both genders. Using a crossmodal priming paradigm, we examined whether listening to music influences ratings of facial attractiveness and dating desirability of opposite-sex faces. We also tested whether misattribution of arousal or pleasantness underlies these effects, and explored whether sex differences and menstrual cycle phase may be moderators.

Our sample comprised 64 women in the fertile or infertile phase (no hormonal contraception use) and 32 men, carefully matched for mood, relationship status, and musical preferences. Musical primes (25 s) varied in arousal and pleasantness, and targets were photos of faces with neutral expressions (2 s). Group-wise analyses indicated that women, but not men, gave significantly higher ratings of facial attractiveness and dating desirability after having listened to music than in the silent control condition.

High-arousing, complex music yielded the largest effects, suggesting that music may affect human courtship behaviour through induced arousal, which calls for further studies on the mechanisms by which music affects sexual attraction in real-life social contexts

Effect of Gastric #Bypass on #Bone Mineral Density, Parathyroid Hormone and Vitamin D: 5 Years Follow-up
https://link.springer.com/article/10.1007/s11695-016-2114-3

The aim of the present study was to see if there are longitudinal changes in bone mineral density (BMD), vitamin D or parathyroid hormone (PTH) in females 5 years after Laparoscopic Roux-en-Y Gastric Bypass (LRYGB) The mean decrease in BMI between baseline and 5 years after surgery was 29.4 %. BMD of the spine and femur measured as z- and t-scores, showed a linear, statistically significant declining trend over the years. The fall in BMD of the spine and femoral neck between baseline and 5 years after surgery was 19 and 25 %, respectively. The mean fP-PTH showed a significant increase over the study period (20.2 μg/L increase, 95 % CI:−31.99 to −8.41). S-calcium, both free and corrected for albumin, showed a decrease between baseline and 5 years after surgery.

Eight patients developed osteopenia and one osteoporosis after a 5-year follow-up.

Conclusion

LRYGB is an efficient method for sustained long-term body weight loss. There is, however, a concomitant decrease in BMD and S-calcium, and an increase in fP-PTH