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Evaluation of the #diet wide contribution to serum #urate levels: meta-analysis of population based cohorts

https://www.bmj.com/content/363/bmj.k3951

Seven foods were associated with raised serum urate levels (beer, liquor, wine, potato, poultry, soft drinks, and meat (beef, pork, or lamb)) and eight foods were associated with reduced serum urate levels (eggs, peanuts, cold cereal, skim milk, cheese, brown bread, margarine, and non-citrus fruits) in the male, female, or full cohorts. Three diet scores, constructed on the basis of healthy diet guidelines, were inversely associated with serum urate levels and a fourth, data driven diet pattern positively associated with raised serum urate levels, but each explained ≤0.3% of variance in serum urate. In comparison, 23.9% of variance in serum urate levels was explained by common, genome wide single nucleotide variation.

Conclusion In contrast with genetic contributions, diet explains very little variation in serum urate levels in the general population

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Association of #Obesity With Risk of Early-Onset #Colorectal Cancer Among Women

https://jamanetwork.com/journals/jamaoncology/article-abstract/2705608

Compared with women with a BMI of 18.5 to 22.9, the multivariable RR was 1.37 (95% CI, 0.81-2.30) for overweight women (BMI, 25.0-29.9) and 1.93 (95% CI, 1.15-3.25) for obese women (BMI, ≥30.0). The RR for each 5-unit increment in BMI was 1.20 (95% CI, 1.05-1.38; P = .01 for trend). Similar associations were observed among women without a family history of CRC and without lower endoscopy within the past 10 years. Both BMI at 18 years of age and weight gain since 18 years of age contributed to this observation. Compared with women with a BMI of 18.5 to 20.9 at 18 years of age, the RR of early-onset CRC was 1.32 (95% CI, 0.80-2.16) for women with a BMI of 21.0 to 22.9 and 1.63 (95% CI, 1.01-2.61) for women with a BMI of 23.0 or greater at 18 years of age (P = .66 for trend). Compared with women who had gained less than 5.0 kg or had lost weight, the RR of early-onset CRC was 1.65 (95% CI, 0.96-2.81) for women gaining 20.0 to 39.9 kg and 2.15 (95% CI, 1.01-4.55) for women gaining 40.0 kg or more (P = .007 for trend).

Conclusions and Relevance Obesity was associated with an increased risk of early-onset CRC among women. Further investigations among men and to elucidate the underlying biological mechanisms are warranted.

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Concurrent change in #quadriceps strength and physical function over 5 years in The Multicenter #Osteoarthritis Study

https://onlinelibrary.wiley.com/doi/10.1002/acr.23754

Among 1534 participants (60.6% women), 22% of men and 30% of women increased strength by at least 15% at 5 years. Compared with women whose strength did not change, women whose strength increased had improved chair stand performance (OR=2.27, 95% CI 1.56, 3.30) but no improvements in other functions. In men, increase in strength was not associated with significant improvement in physical function. 20% or 30% change showed similar results.

Conclusion
Modest improvement in quadriceps strength was associated with improved chair stand performance in women, but not in men. Most functions did not improve with an increase in strength, and may require targeted interventions to improve functional status.

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Left #Ventricular Systolic Myocardial Function in Ankylosing #Spondylitis

https://onlinelibrary.wiley.com/doi/abs/10.1002/acr.23765

CVD risk factors were similarly distributed among AS patients and controls, but more controls used statin therapy (p=0.05). GLS was significantly lower in AS patients vs. controls (‐17.7±2.5% vs.‐18.4±2.3%, p=0.03). In univariable linear regression analyses in the total study population, lower GLS was associated with having AS, male sex, higher body mass index, LV mass index and lower LV ejection fraction (all p<0.05). Having AS retained an independent association with lower GLS when adjusted for these factors in multivariable analyses (β 0.16, p=0.02). In AS patients, lower GLS was independently associated with larger aortic root diameter in multivariable analyses (β 0.24, p=0.02), while no association with AS disease activity, disease duration or use of anti‐rheumatic medication was found.

Conclusion
Patients with AS had lower GLS than controls independent of confounders. In AS patients, lower GLS was associated with larger aortic root diameter. Whether lower GLS contributes to the observed higher CVD risk in AS patients should be tested in prospective studies.

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#Fatty acid biomarkers of dairy fat consumption and incidence of type 2 #diabetes: A pooled analysis of prospective cohort studies

https://journals.plos.org/plosmedicine/article?id=10.1371/journal.pmed.1002670

We aimed to investigate prospective associations of circulating or adipose tissue odd-chain fatty acids 15:0 and 17:0 and trans-palmitoleic acid, t16:1n-7, as potential biomarkers of dairy fat intake, with incident type 2 diabetes (T2D)

After adjustment for potential confounders, including measures of adiposity (BMI, waist circumference) and lipogenesis (levels of palmitate, triglycerides), higher levels of 15:0, 17:0, and t16:1n-7 were associated with lower incidence of T2D. In the most adjusted model, the hazard ratio (95% CI) for incident T2D per cohort-specific 10th to 90th percentile range of 15:0 was 0.80 (0.73–0.87); of 17:0, 0.65 (0.59–0.72); of t16:1n7, 0.82 (0.70–0.96); and of their sum, 0.71 (0.63–0.79). In exploratory analyses, similar associations for 15:0, 17:0, and the sum of all three fatty acids were present in both genders but stronger in women than in men (pinteraction < 0.001). Whereas studying associations with biomarkers has several advantages, as limitations, the biomarkers do not distinguish between different food sources of dairy fat (e.g., cheese, yogurt, milk), and residual confounding by unmeasured or imprecisely measured confounders may exist.

Conclusions
In a large meta-analysis that pooled the findings from 16 prospective cohort studies, higher levels of 15:0, 17:0, and t16:1n-7 were associated with a lower risk of T2D

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Eradicating the Burden of #Atherosclerotic Cardiovascular Disease by Lowering Apolipoprotein B #Lipoproteins Earlier in Life

https://www.ahajournals.org/doi/full/10.1161/JAHA.118.009778

A new paradigm for preventing atherosclerotic cardiovascular disease (ASCVD) is needed. The most recent US data show the long‐term decline in cardiovascular deaths has stopped, and has started to increase in the most at‐risk populations.1 Indeed, rising rates of obesity and diabetes mellitus in the setting of suboptimal risk factor control have resulted in a similar number of cardiovascular events occurring in those aged <65 years as ≥65 years.2 Although preventive drug therapies reduce the relative risk of cardiovascular events in primary and secondary prevention patients, the absolute risk of subsequent ASCVD events remains high.3 If nothing changes, it is projected that by 2035 nearly half the US population will have some form of cardiovascular disease and costs will double to $1.1 trillion annually..

As a next step, we describe a proposed clinical trial to test early intervention to profoundly lower the concentration of low‐density lipoprotein (assessed by its cholesterol component, LDL‐C) and other apo B‐containing lipoprotein in individuals aged 25 to 55 years who have image‐documented preclinical atherosclerosis. Such a trial may provide the first direct evidence to support marked or even complete regression of early atherosclerosis in humans, and lay the ground work for definitive trials to support a new prevention paradigm of intensive regression therapy followed by intermittent retreatment for eradication of the clinical burden of ASCVD

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#diabetic patients are more at risk of death from alcohol, accidents and #suicide

https://www.eurekalert.org/pub_releases/2018-10/esoe-dpa100918.php

Diabetic patients are more likely to die from alcohol-related factors, accidents or suicide, according to a study published in the European Journal of Endocrinology. The study findings suggest that the increased risk of death from these causes may be related to the mental health of patients, which may be adversely affected by the psychological burden of living with and self-treating this debilitating disease, with potentially serious complications.

Type-1 and type-2 diabetes are highly prevalent global diseases, causing millions of deaths every year. It is well known that diabetic patients have a higher risk of developing cardiovascular disease, cancer and kidney disorders, which can lead to earlier death. However, more recently diabetes has been linked to an increased risk of depression but how poor mental health may affect patients with diabetes has not been fully investigated.

Prof Leo Niskanen states, "This study has highlighted that there is a need for effective psychological support for people with diabetes. If they feel like they are under a heavy mental burden or consider that their use of alcohol is excessive, they should not hesitate to discuss these issues with their primary care physician. There are many ways that these problems can be managed, provided they are communicated."

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Assessment of Efficacy and Tolerability of Medicinal #Cannabinoids in Patients With Multiple #Sclerosis

https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2706499

Seventeen selected trials including 3161 patients were analyzed. Significant findings for the efficacy of cannabinoids vs placebo were SMD = −0.25 SD (95% CI, −0.38 to −0.13 SD) for spasticity (subjective patient assessment data), −0.17 SD (95% CI, −0.31 to −0.03 SD) for pain, and −0.11 SD (95% CI, −0.22 to −0.0008 SD) for bladder dysfunction. Results favored cannabinoids. Findings for tolerability were RR = 1.72 patient-years (95% CI, 1.46-2.02 patient-years) in the total adverse events analysis and 2.95 patient-years (95% CI, 2.14-4.07 patient-years) in withdrawals due to adverse events. Results described a higher risk for cannabinoids. The serious adverse events meta-analysis showed no statistical significance.

Conclusions and Relevance The results suggest a limited efficacy of cannabinoids for the treatment of spasticity, pain, and bladder dysfunction in patients with MS. Therapy using these drugs can be considered as safe

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#β-Blocker Use in Pregnancy and the Risk for Congenital #Malformations: An International Cohort Study

http://annals.org/aim/article-abstract/2707333/blocker-use-pregnancy-risk-congenital-malformations-international-cohort-study

Of 3577 women with hypertensive pregnancies in the Nordic cohort and 14 900 in the U.S. cohort, 682 (19.1%) and 1668 (11.2%), respectively, were exposed to β-blockers in the first trimester. The pooled adjusted relative risk (RR) and risk difference per 1000 persons exposed (RD1000) associated with β-blockers were 1.07 (95% CI, 0.89 to 1.30) and 3.0 (CI, −6.6 to 12.6), respectively, for any major malformation; 1.12 (CI, 0.83 to 1.51) and 2.1 (CI, −4.3 to 8.4) for any cardiac malformation; and 1.97 (CI, 0.74 to 5.25) and 1.0 (CI, −0.9 to 3.0) for cleft lip or palate. For CNS malformations, the adjusted RR was 1.37 (CI, 0.58 to 3.25) and the RD1000 was 1.0 (CI, −2.0 to 4.0) (based on U.S. cohort data only).

Limitation:
Analysis was restricted to live births, exposure was based on dispensed medication, and cleft lip or palate and CNS malformations had few outcomes.

Conclusion:
The results suggest that maternal use of β-blockers in the first trimester is not associated with a large increase in the risk for overall malformations or cardiac malformations, independent of measured confounders.

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Personalized #Gut Mucosal Colonization Resistance to Empiric #Probiotics Is Associated with Unique Host and Microbiome Features

https://www.cell.com/cell/fulltext/S0092-8674(18)31102-4

Empiric probiotics are commonly consumed by healthy individuals as means of life quality improvement and disease prevention. However, evidence of probiotic gut mucosal colonization efficacy remains sparse and controversial. We metagenomically characterized the murine and human mucosal-associated gastrointestinal microbiome and found it to only partially correlate with stool microbiome.

A sequential invasive multi-omics measurement at baseline and during consumption of an 11-strain probiotic combination or placebo demonstrated that probiotics remain viable upon gastrointestinal passage. In colonized, but not germ-free mice, probiotics encountered a marked mucosal colonization resistance.
In contrast, humans featured person-, region- and strain-specific mucosal colonization patterns, hallmarked by predictive baseline host and microbiome features, but indistinguishable by probiotics presence in stool.

Consequently, probiotics induced a transient, individualized impact on mucosal community structure and gut transcriptome. Collectively, empiric probiotics supplementation may be limited in universally and persistently impacting the gut mucosa, meriting development of new personalized probiotic approaches.

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Post- #Antibiotic Gut Mucosal Microbiome Reconstitution Is Impaired by Probiotics and Improved by Autologous #FMT

https://www.cell.com/cell/fulltext/S0092-8674(18)31108-5?_returnURL=https%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS0092867418311085%3Fshowall%3Dtrue

Probiotics are widely prescribed for prevention of antibiotics-associated dysbiosis and related adverse effects. However, probiotic impact on post-antibiotic reconstitution of the gut mucosal host-microbiome niche remains elusive. We invasively examined the effects of multi-strain probiotics or autologous fecal microbiome transplantation (aFMT) on post-antibiotic reconstitution of the murine and human mucosal microbiome niche.

Contrary to homeostasis, antibiotic perturbation enhanced probiotics colonization in the human mucosa but only mildly improved colonization in mice. Compared to spontaneous post-antibiotic recovery, probiotics induced a markedly delayed and persistently incomplete indigenous stool/mucosal microbiome reconstitution and host transcriptome recovery toward homeostatic configuration, while aFMT induced a rapid and near-complete recovery within days of administration.

In vitro, Lactobacillus-secreted soluble factors contributed to probiotics-induced microbiome inhibition. Collectively, potential post-antibiotic probiotic benefits may be offset by a compromised gut mucosal recovery, highlighting a need of developing a FMT or personalized probiotic approaches achieving mucosal protection without compromising microbiome recolonization in the antibiotics-perturbed host.

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Association Between #Bariatric Surgery and Macrovascular Disease Outcomes in Patients With Type 2 #Diabetes and Severe Obesity

https://jamanetwork.com/journals/jama/article-abstract/2707461

.. 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 outcome

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#Sleep duration and risk of incident #stroke by age, sex, and race
The REGARDS study

http://n.neurology.org/content/early/2018/10/03/WNL.0000000000006424

The sample comprised 10.4% (n = 1,747) short sleepers (<6 hours) and 6.8% (n = 1,134) long sleepers (≥9 hours). Over an average 6.1 years follow-up, 460 strokes occurred. There were significant interactions between sleep duration and race (p = 0.018) and sleep duration and race–sex groups (p = 0.0023) in association with incident stroke. Short sleep duration was significantly associated with decreased risk for stroke among black participants (hazard ratio HR 0.49 95% confidence interval (CI) 0.28–0.85), particularly black men (HR 0.21 95% CI 0.07–0.69), whereas long sleep duration was significantly associated with increased risk for stroke among white men (HR 1.71 95% CI 1.06–2.76).

Conclusions The association of sleep duration with incident stroke differs by race and sex, with short sleep duration among black men associated with decreased risk, whereas long sleep duration among white men associated with increased risk for stroke

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Association of #Aspirin With Prevention of Venous Thromboembolism in Patients After Total Knee #Arthroplasty Compared With Other Anticoagulants
A Noninferiority Analysis

https://jamanetwork.com/journals/jamasurgery/article-abstract/2708020

Of the 41 537 patients, 14 966 were men (36%), and the mean age was 65.8 years. A VTE event occurred in 573 of 41 537 patients (1.38%); 32 of 668 (4.79%) who received no pharmacologic prophylaxis, 149 of 12 831 (1.16%) treated with aspirin alone, 321 of 22 620 (1.42%) with anticoagulation alone, and 71 of 5418 (1.31%) prescribed both aspirin and anticoagulation. Aspirin only was noninferior for the composite VTE outcome compared with those receiving other chemoprophylaxis (adjusted odds ratio, 0.85; 95% CI, 0.68-1.07, P for inferiority = .007). Bleeding occurred in 457 of 41 537 patients (1.10%), 10 of 668 (1.50%) without prophylaxis, 116 of 12 831 (0.90%) in the aspirin group, 258 of 22 620 (1.14%) with anticoagulation, and 73 of 5418 (1.35%) of those receiving both. Aspirin alone was also noninferior for bleeding complications (adjusted odds ratio, 0.80; 95% CI, 0.63-1.00, P for inferiority <.001).

Conclusions and Relevance In this study of patients undergoing TKA, aspirin was not inferior to other anticoagulants in the postoperative rate of VTE or death. Aspirin alone may provide similar protection from postoperative VTE compared with other anticoagulation treatments

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Pre-#eclampsia and risk of #dementia later in life: nationwide cohort study

https://www.bmj.com/content/363/bmj.k4109

The cohort consisted of 1 178 005 women with 20 352 695 person years of follow-up. Women with a history of pre-eclampsia had more than three times the risk of vascular dementia (hazard ratio 3.46, 95% confidence interval 1.97 to 6.10) later in life, compared with women with no history of pre-eclampsia. The association with vascular dementia seemed to be stronger for late onset disease (hazard ratio 6.53, 2.82 to 15.1) than for early onset disease (2.32, 1.06 to 5.06) (P=0.08). Adjustment for diabetes, hypertension, and cardiovascular disease attenuated the hazard ratios only moderately; sensitivity analyses suggested that body mass index was unlikely to explain the association with vascular dementia. In contrast, only modest associations were observed for Alzheimer’s disease (hazard ratio 1.45, 1.05 to 1.99) and other/unspecified dementia (1.40, 1.08 to 1.83).

Conclusions Pre-eclampsia was associated with an increased risk of dementia, particularly vascular dementia. Cardiovascular disease, hypertension, and diabetes were unlikely to mediate the associations substantially, suggesting that pre-eclampsia and vascular dementia may share underlying mechanisms or susceptibility pathways. Asking about a history of pre-eclampsia could help physicians to identify women who might benefit from screening for early signs of disease, allowing for early clinical intervention.

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Association of #Caffeine Intake and Caffeinated Coffee Consumption With Risk of Incident #Rosacea In Women

https://jamanetwork.com/journals/jamadermatology/fullarticle/2707780

... After adjustment for other risk factors, we found an inverse association between increased caffeine intake and risk of rosacea (hazard ratio for the highest quintile of caffeine intake vs the lowest, 0.76; 95% CI, 0.69-0.84; P < .001 for trend). A significant inverse association with risk of rosacea was also observed for caffeinated coffee consumption (HR, 0.77 for those who consumed ≥4 servings/d vs those who consumed <1/mo; 95% CI, 0.69-0.87; P < .001 for trend), but not for decaffeinated coffee (HR, 0.80; 95% CI, 0.56-1.14; P = .39 for trend). Further analyses found that increased caffeine intake from foods other than coffee (tea, soda, and chocolate) was not significantly associated with decreased risk of rosacea.

Conclusions and Relevance Increased caffeine intake from coffee was inversely associated with the risk of incident rosacea. Our findings do not support limiting caffeine intake as a means to prevent rosacea. Further studies are required to explain the mechanisms of action of these associations, to replicate our findings in other populations, and to explore the relationship of caffeine with different rosacea subtypes.

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Triple #CFTR Modulator Therapy for #Cystic Fibrosis

https://www.nejm.org/doi/full/10.1056/NEJMe1811996

In addition to the standard symptomatic treatments for cystic fibrosis, two types of CFTR modulator have been approved for treatment. These include a potentiator (ivacaftor), which increases CFTR channel opening at the cell surface, and correctors (lumacaftor and tezacaftor), which increase the amount of CFTR protein at the cell surface.3 Individually, these therapies have not been proved effective in patients with a Phe508del CFTR mutation, which occurs in approximately two thirds of patients with cystic fibrosis and is characterized by a reduction in CFTR trafficking and processing as a result of impaired function.4

Combination therapy, with a potentiator and a corrector, on the other hand, improved clinical outcomes in two phase 3 clinical trials. In patients homozygous for the CFTR mutation (Phe508del–Phe508del), 24 weeks of treatment with lumacaftor–ivacaftor resulted in an absolute improvement in the percentage of predicted forced expiratory volume in 1 second (FEV1) of 2.6 to 4.0 points as compared with placebo, whereas 24 weeks of treatment with tezacaftor–ivacaftor increased FEV1 by 4 points..

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Anti-herpetic Medications and Reduced Risk of #Dementia in Patients with #Herpes Simplex Virus Infections—a Nationwide, Population-Based Cohort Study in Taiwan

https://link.springer.com/article/10.1007/s13311-018-0611-x

This retrospective cohort study is to investigate the association between herpes simplex virus (HSV) infections and dementia, and the effects of anti-herpetic medications on the risk involved, using Taiwan’s National Health Insurance Research Database (NHIRD). We enrolled a total of 33,448 subjects, and identified 8362 with newly diagnosed HSV infections and 25,086 randomly selected sex- and age-matched controls without HSV infections in a ratio of 1:3, selected from January 1, to December 31, 2000.

A multivariable Cox proportional hazards regression model was used to evaluate the risk of developing dementia in the HSV cohort. This analysis revealed an adjusted hazard ratio of 2.564 (95% CI: 2.351-2.795, P < 0.001) for the development of dementia in the HSV-infected cohort relative to the non-HSV cohort. Thus, patients with HSV infections may have a 2.56-fold increased risk of developing dementia. A risk reduction of dementia development in patients affected by HSV infections was found upon treatment with anti-herpetic medications (adjusted HR = 0.092 [95% CI 0.079-0.108], P < 0.001).

The usage of anti-herpetic medications in the treatment of HSV infections was associated with a decreased risk of dementia. These findings could be a signal to clinicians caring for patients with HSV infections. Further research is, therefore, necessary to explore the underlying mechanism(s) of these associations.

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Small-molecule AgrA inhibitors F12 and F19 act as anti #virulence agents against #Gram-positive pathogens

https://www.nature.com/articles/s41598-018-32829-w

Small-molecule antivirulence agents represent a promising alternative or adjuvant to antibiotics. These compounds disarm pathogens of disease-causing toxins without killing them, thereby diminishing survival pressure to develop resistance.

Here we show that the small-molecule antivirulence agents F12 and F19 block staphylococcal transcription factor AgrA from binding to its promoter. Consequently, toxin expression is inhibited, thus preventing host cell damage by Gram-positive pathogens. Broad spectrum efficacy against Gram-positive pathogens is due to the existence of AgrA homologs in many Gram-positive bacteria.

F12 is more efficacious in vitro and F19 works better in vivo. In a murine MRSA bacteremia/sepsis model, F19 treatment alone resulted in 100% survival while untreated animals had 70% mortality. Furthermore, F19 enhances antibiotic efficacy in vivo. Notably, in a murine MRSA wound infection model, combination of F19 with antibiotics resulted in bacterial load reduction. Thus, F19 could be used alone or in combination with antibiotics to prevent and treat infections of Gram-positive pathogens.

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GDP-l-fucose synthase is a CD4+ T cell–specific autoantigen in DRB3*02:02 patients with multiple #sclerosis

http://stm.sciencemag.org/content/10/462/eaat4301

Multiple sclerosis is an immune-mediated autoimmune disease of the central nervous system that develops in genetically susceptible individuals and likely requires environmental triggers. The autoantigens and molecular mimics triggering the autoimmune response in multiple sclerosis remain incompletely understood.

By using a brain-infiltrating CD4+ T cell clone that is clonally expanded in multiple sclerosis brain lesions and a systematic approach for the identification of its target antigens, positional scanning peptide libraries in combination with biometrical analysis, we have identified guanosine diphosphate (GDP)–L-fucose synthase as an autoantigen that is recognized by cerebrospinal fluid–infiltrating CD4+ T cells from HLA-DRB3*–positive patients.

Significant associations were found between reactivity to GDP-L-fucose synthase peptides and DRB3*02:02 expression, along with reactivity against an immunodominant myelin basic protein peptide. These results, coupled with the cross-recognition of homologous peptides from gut #microbiota, suggest a possible role of this antigen as an inducer or driver of pathogenic autoimmune responses in multiple sclerosis