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Longitudinal analysis of #impulse control disorders in #Parkinson disease

http://n.neurology.org/content/early/2018/06/20/WNL.0000000000005816


Among 411 patients (40.6% women, mean age 62.3 years, average follow-up 3.3 years, SD 1.7 years), 356 (86.6%) took a DA at least once since disease onset. In 306 patients without ICDs at baseline, the 5-year cumulative incidence of ICDs was 46.1% (95% confidence interval CI 37.4–55.7, DA ever users 51.5% 95% CI 41.8–62.1, DA never users 12.4% 95% CI 4.8–30.0). ICD prevalence increased from 19.7% at baseline to 32.8% after 5 years. ICDs were associated with ever DA use (prevalence ratio 4.23, 95% CI 1.78–10.09). Lifetime average daily dose and duration of treatment were independently associated with ICDs with significant dose-effect relationships. Similar analyses for levodopa were not in favor of a strong association. ICDs progressively resolved after DA discontinuation.

Conclusion In this longitudinal study of patients with PD characterized by a high prevalence of DA treatment, the 5-year cumulative incidence of ICDs was ≈46%. ICDs were strongly associated with DA use with a dose-effect relationship; both increasing duration and dose were associated with ICDs. ICDs progressively resolved after DA discontinuation.

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Multiscale Analysis of Independent #Alzheimer’s Cohorts Finds Disruption of Molecular, Genetic, and Clinical Networks by Human #Herpesvirus

https://www.cell.com/neuron/fulltext/S0896-6273(18)30421-5


Investigators have long suspected that pathogenic microbes might contribute to the onset and progression of Alzheimer’s disease (AD) although definitive evidence has not been presented Whether such findings represent a causal contribution, or reflect opportunistic passengers of neurodegeneration, is also difficult to resolve. We constructed multiscale networks of the late-onset AD-associated virome, integrating genomic, transcriptomic, proteomic, and histopathological data across four brain regions from human post-mortem tissue. We observed increased human herpesvirus 6A (HHV-6A) and human herpesvirus 7 (HHV-7) from subjects with AD compared with controls. These results were replicated in two additional, independent and geographically dispersed cohorts. We observed regulatory relationships linking viral abundance and modulators of APP metabolism, including induction of APBB2, APPBP2, BIN1, BACE1, CLU, PICALM, and PSEN1 by HHV-6A. This study elucidates networks linking molecular, clinical, and neuropathological features with viral activity and is consistent with viral activity constituting a general feature of AD

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Bioimpedance and New‐Onset Heart Failure: A Longitudinal Study of >500 000 Individuals From the General Population

http://jaha.ahajournals.org/content/7/13/e008970


... Mean reticulocyte volume appeared as one novel factor and leg bioimpedance another, the latter appearing as the most important new marker. Leg bioimpedance was lower in those who developed heart failure during an up to 9.8‐year follow‐up. When adjusting for known heart failure risk factors, leg bioimpedance was inversely related to heart failure (hazard ratio [95% confidence interval], 0.60 [0.48–0.73] and 0.75 [0.59–0.94], in age‐ and sex‐adjusted and fully adjusted models, respectively, comparing the upper versus lower quartile). A model including leg bioimpedance, age, sex, and self‐reported history of myocardial infarction showed good discrimination for future heart failure hospitalization (Concordance index [C‐index]=0.82) and good calibration.

Conclusions Leg bioimpedance is inversely associated with heart failure incidence in the general population. A simple model of exclusively noninvasive measures, combining leg bioimpedance with history of myocardial infarction, age, and sex provides accurate predictive capacity

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CDKN1B/p27 is localized in #mitochondria and improves respiration-dependent processes in the cardiovascular system—New mode of action for #caffeine

http://journals.plos.org/plosbiology/article?id=10.1371/journal.pbio.2004408


...In addition, mitochondrial p27 protects cardiomyocytes against apoptosis. Moreover, mitochondrial p27 is necessary and sufficient for cardiac myofibroblast differentiation. In addition, p27 deficiency and aging decrease respiration in heart mitochondria. Caffeine does not increase respiration in p27-deficient animals, whereas aged mice display improvement after 10 days of caffeine in drinking water. Moreover, caffeine induces transcriptome changes in a p27-dependent manner, affecting mostly genes relevant for mitochondrial processes. Caffeine also reduces infarct size after myocardial infarction in prediabetic mice and increases mitochondrial p27. Our data characterize mitochondrial p27 as a common denominator that improves mitochondria-dependent processes and define an increase in mitochondrial p27 as a new mode of action of caffeine

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Maternal Type 1 #Diabetes and Risk of #Autism in Offspring

https://jamanetwork.com/journals/jama/fullarticle/2685775


Unadjusted average annual ASD incidence rates per 1000 children were 4.4 for exposure to T1D; 3.6 for T2D; 2.9 for GDM by 26 weeks; 2.1 for GDM after 26 weeks; and 1.8 for no diabetes. The Figure depicts the cumulative incidence rates by maternal diabetes exposure groups. Relative to no diabetes exposure, the adjusted HRs for exposure to maternal diabetes were 2.36 (95% CI, 1.36-4.12) for T1D, 1.45 (95% CI, 1.24-1.70) for T2D, 1.30 (95% CI, 1.12-1.51) for GDM by 26 weeks’ gestation, and 0.99 (95% CI, 0.88-1.12) for GDM after 26 weeks. Additional adjustment for maternal smoking during pregnancy and prepregnancy BMI changed results only slightly (Table). Risks were not statistically significantly different between those with vs without antidiabetic medication exposure during pregnancy within the GDM group (adjusted HR, 1.18 95% CI, 0.97-1.43; P = .10).

Discussion
Among the 3 main types of diabetes complicating pregnancy, the risk of ASD in offspring was elevated in mothers with T1D, T2D, and GDM diagnosed by 26 weeks’ gestation compared with no diabetes. These results add new information on T1D and extend previous findings1 for preexisting T2D and GDM. GDM diagnosed after 26 weeks’ gestation was not associated with excess risk compared with no diabetes.

These results suggest that the severity of maternal diabetes and the timing of exposure (early vs late in pregnancy) may be associated with the risk of ASD in offspring of diabetic mothers. The potential role of maternal glycemia; other features of T1D such as autoimmunity and genetic factors3,4; prematurity; and neonatal hypoglycemia5 remains to be explored. Confounding due to paternal risk factors and other intrauterine and postnatal exposures could not be assessed

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Impact of novel #therapies for mantle cell lymphoma in the real world setting: a report from the UK's #Haematological Malignancy Research Network (HMRN)

https://onlinelibrary.wiley.com/doi/abs/10.1111/bjh.15170


The treatment landscape for mantle cell lymphoma (MCL) has changed dramatically in recent years, with findings from clinical trials reporting improvements in survival. Data on the general patient population are, however, sparse; and it is unclear whether the effects observed in clinical trials have translated into the real‐world setting. To investigate this, we examined first‐line and relapsed/refractory (RR) disease management in 335 MCL patients diagnosed between 2004 and 2015 in an established population‐based patient cohort, along with data on demographic, diagnostic and prognostic factors. Marked treatment and survival changes were observed; first‐line rituximab immunotherapy, for example, increased from 32% to 86% over the 11‐year period, and median survival increased from 2·0 years among those first treated in 2004–2011 to 3·5 years among those treated in 2012–2015. Outcomes for RR disease also improved, from 8 months in 2004–2011 to 16·8 months in 2012–2015, coinciding with the introduction of agents, such as bendamustine and ibrutinib. Encouragingly, improvements were seen across all ages; 1‐year overall survival among patients over 70 years treated for RR disease almost doubled. Our analyses underscore the importance of monitoring the impact of treatment changes in the real‐world setting.

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Impact of #DAAs on liver #transplantation: major effects on the evolution of indications and results. An ELITA study based on the ELTR registry

https://www.journal-of-hepatology.eu/article/S0168-8278(18)32163-9/fulltext


Out of a total number of 60,527 LTs, 36,382 were performed in patients with HCV, HBV, ETOH and NASH. The percentage of LTs due to HCV-related liver disease varied significantly over time (p<0.0001), decreasing from 22.8% in IFN/RBV era to 17.4% in the DAA era, while those performed for NASH increased significantly (p<0.0001). In the DAA era, the percentage of LTs for HCV decreased significantly (p<0.0001) from 21.1% (first semester 2014) to 10.6% (first semester 2017). This decline was more evident in patients with DC (HCV-DC, -58.0%) than in those with HCC associated to HCV (HCV-HCC, -41.2%). Conversely, three-year survival of LT recipients with HCV related liver disease improved from 65.1% in the IFN/RBV era to 76.9% in the DAA era, being currently comparable to the survival of recipients with HBV infection (p=0.3807).

Conclusions
In Europe, the number of LTs due to HCV infection is rapidly declining for both HCV-DC and HCV-HCC indications and post-LT survival has dramatically improved over the last three years. This is the first comprehensive study of the overall impact of DAA treatment for HCV on liver transplantation in Europe.

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#Cancer prevalence among flight #attendants compared to the general population

https://ehjournal.biomedcentral.com/articles/10.1186/s12940-018-0396-8


Compared to NHANES participants with a similar socioeconomic status (n = 2729), flight attendants (n = 5366) had a higher prevalence of every cancer we examined, especially breast cancer, melanoma, and non-melanoma skin cancer among females. SPR for these conditions were 1.51 (95% CI: 1.02, 2.24), 2.27 (95% CI: 1.27, 4.06), and 4.09 (95% CI: 2.70, 6.20), respectively. Job tenure was positively related to non-melanoma skin cancer among females, with borderline associations for melanoma and non-melanoma skin cancers among males. Consistent with previous studies, we observed associations between job tenure and breast cancer among women who had three or more children.

Conclusions
We observed higher rates of specific cancers in flight attendants compared the general population, some of which were related to job tenure. Our results should be interpreted in light of self-reported health information and a cross-sectional study design. Future longitudinal studies should evaluate associations between specific exposures and cancers among cabin crew.

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#Screening for #Osteoporosis to Prevent Fractures
US Preventive Services Task Force Recommendation Statement

https://jamanetwork.com/journals/jama/fullarticle/2685995


The USPSTF found convincing evidence that bone measurement tests are accurate for detecting osteoporosis and predicting osteoporotic fractures in women and men. The USPSTF found adequate evidence that clinical risk assessment tools are moderately accurate in identifying risk of osteoporosis and osteoporotic fractures. The USPSTF found convincing evidence that drug therapies reduce subsequent fracture rates in postmenopausal women. The USPSTF found that the evidence is inadequate to assess the effectiveness of drug therapies in reducing subsequent fracture rates in men without previous fractures.

Conclusions and Recommendation The USPSTF recommends screening for osteoporosis with bone measurement testing to prevent osteoporotic fractures in women 65 years and older. (B recommendation) The USPSTF recommends screening for osteoporosis with bone measurement testing to prevent osteoporotic fractures in postmenopausal women younger than 65 years at increased risk of osteoporosis, as determined by a formal clinical risk assessment tool. (B recommendation) The USPSTF concludes that the current evidence is insufficient to assess the balance of benefits and harms of screening for osteoporosis to prevent osteoporotic fractures in men. (I statement)

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A Validated Clinical Risk Prediction Model for #Lung Cancer in #Smokers of All Ages and Exposure Types: A HUNT Study

https://www.sciencedirect.com/science/article/pii/S2352396418301142?via%3Dihub


Highlights
•
Applying this risk model in adults, screening 22% of ever-smokers would identify 81·85% of all lung cancers within 6 years.

•
Two novel highly significant factors were identified, periodical daily cough, and hours of daily indoors exposure to smoke.

•
The HUNT Lung Cancer Model is an accurate risk predictor useful in prospective screening studies for lung cancer.

Our final HUNT Lung Cancer Model included age, pack-years, smoking intensity, years since smoking cessation, body mass index, daily cough, and hours of daily indoors exposure to smoke. External validation showed a 0·879 concordance index (95% CI 0·866–0·891) with an area under the curve of 0·87 (95% CI 0·85–0·89) within 6 years. Only 22% of ever-smokers would need screening to identify 81·85% of all lung cancers within 6 years.

Our model of seven variables is simple, accurate, and useful for screening selection

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Combined Analysis of #Asthma Safety Trials of Long-Acting #β2-Agonists

https://www.nejm.org/doi/full/10.1056/NEJMoa1716868


Among the 36,010 patients in the intention-to-treat study, there were three asthma-related intubations (two in the inhaled-glucocorticoid group and one in the combination-therapy group) and two asthma-related deaths (both in the combination-therapy group) in 4 patients. In the secondary analysis of serious asthma-related events (a composite of hospitalization, intubation, or death), 108 of 18,006 patients (0.60%) in the inhaled-glucocorticoid group and 119 of 18,004 patients (0.66%) in the combination-therapy group had at least one composite event (relative risk in the combination-therapy group, 1.09; 95% confidence interval CI, 0.83 to 1.43; P=0.55); 2100 patients in the inhaled-glucocorticoid group (11.7%) and 1768 in the combination-therapy group (9.8%) had at least one asthma exacerbation (relative risk, 0.83; 95% CI, 0.78 to 0.89; P<0.001).

CONCLUSIONS
Combination therapy with a LABA plus an inhaled glucocorticoid did not result in a significantly higher risk of serious asthma-related events than treatment with an inhaled glucocorticoid alone but resulted in significantly fewer asthma exacerbations

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Risk of meticillin resistant #Staphylococcus aureus and #Clostridium difficile in patients with a documented #penicillin allergy: population based matched cohort study

https://www.bmj.com/content/361/bmj.k2400


The primary outcome was risk of incident MRSA and C difficile. Secondary outcomes were use of β lactam antibiotics and β lactam alternative antibiotics.

Results Among 64 141 adults with penicillin allergy and 237 258 matched comparators, 1365 developed MRSA (442 participants with penicillin allergy and 923 comparators) and 1688 developed C difficile (442 participants with penicillin allergy and 1246 comparators) during a mean 6.0 years of follow-up. Among patients with penicillin allergy the adjusted hazard ratio for MRSA was 1.69 (95% confidence interval 1.51 to 1.90) and for C difficile was 1.26 (1.12 to 1.40). The adjusted incidence rate ratios for antibiotic use among patients with penicillin allergy were 4.15 (95% confidence interval 4.12 to 4.17) for macrolides, 3.89 (3.66 to 4.12) for clindamycin, and 2.10 (2.08 to 2.13) for fluoroquinolones. Increased use of β lactam alternative antibiotics accounted for 55% of the increased risk of MRSA and 35% of the increased risk of C difficile.

Conclusions Documented penicillin allergy was associated with an increased risk of MRSA and C difficile that was mediated by the increased use of β lactam alternative antibiotics. Systematically addressing penicillin allergies may be an important public health strategy to reduce the incidence of MRSA and C difficile among patients with a penicillin allergy label.

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Systemic #isradipine treatment diminishes calcium-dependent mitochondrial oxidant stress

https://www.jci.org/articles/view/95898


The ability of the Cav1 channel inhibitor isradipine to slow the loss of substantia nigra pars compacta (SNc) dopaminergic (DA) neurons and the progression of #Parkinson’s disease (PD) is being tested in a phase 3 human clinical trial. But it is unclear whether and how chronic isradipine treatment will benefit SNc DA neurons in vivo. To pursue this question, isradipine was given systemically to mice at doses that achieved low nanomolar concentrations in plasma, near those achieved in patients. This treatment diminished cytosolic Ca2+ oscillations in SNc DA neurons without altering autonomous spiking or expression of Ca2+ channels, an effect mimicked by selectively knocking down expression of Cav1.3 channel subunits. Treatment also lowered mitochondrial oxidant stress, reduced a high basal rate of mitophagy, and normalized mitochondrial mass — demonstrating that Cav1 channels drive mitochondrial oxidant stress and turnover in vivo. Thus, chronic isradipine treatment remodeled SNc DA neurons in a way that should not only diminish their vulnerability to mitochondrial challenges, but to autophagic stress as well.

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Continuity of care with doctors—a matter of life and death? A systematic review of continuity of care and mortality

https://bmjopen.bmj.com/content/8/6/e021161


.. These studies came from nine countries with very different cultures and health systems. We found such heterogeneity of continuity and mortality measurement methods and time frames that it was not possible to combine the results of studies. However, 18 (81.8%) high-quality studies reported statistically significant reductions in mortality, with increased continuity of care. 16 of these were with all-cause mortality. Three others showed no association and one demonstrated mixed results. These significant protective effects occurred with both generalist and specialist doctors.

Conclusions This first systematic review reveals that increased continuity of care by doctors is associated with lower mortality rates. Although all the evidence is observational, patients across cultural boundaries appear to benefit from continuity of care with both generalist and specialist doctors. Many of these articles called for continuity to be given a higher priority in healthcare planning. Despite substantial, successive, technical advances in medicine, interpersonal factors remain important.

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CAABL-AF (California Study of #Ablation for Atrial #Fibrillation)
Mortality and Stroke, 2005 to 2013

http://circep.ahajournals.org/content/11/6/e005739


Ablation for atrial fibrillation (AF) is superior to medical therapy for rhythm control. We compared stroke and mortality among patients undergoing ablation for AF to matched controls in a large multiethnic population

There were 4169 ablation cases and 4169 weighted-matched controls; 39% percent of the ablation group was >65 years, 72% men, 84% white; mean follow-up was up to 3.6±0.9 years. In adjusted models, ablation was associated with significantly lower mortality (per patient-years) 0.9% versus 1.9%, hazard ratio=0.59 (P<0.0001; confidence interval: 0.45–0.77); ischemic stroke (>30 days post-ablation ≤5 years), 0.37% versus 0.59%, hazard ratio=0.68 (P=0.04; confidence interval: 0.47–0.97); hemorrhagic stroke 0.11% versus 0.35%, hazard ratio=0.36 (P=0.001; confidence interval: 0.20–0.64) compared with controls.

Conclusions: In this large population-based study of hospitalized patients with nonvalvular AF, ablation was associated with lower mortality, ischemic stroke, and hemorrhagic stroke compared with controls

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#Marijuana Use, Respiratory Symptoms, and #Pulmonary Function: A Systematic Review and Meta-analysis

http://annals.org/aim/article-abstract/2686986/marijuana-use-respiratory-symptoms-pulmonary-function-systematic-review-meta-analysis


Twenty-two studies were included. A pooled analysis of 2 prospective studies showed that marijuana use was associated with an increased risk for cough (risk ratio RR, 2.04 95% CI, 1.02 to 4.06) and sputum production (RR, 3.84 CI, 1.62 to 9.07). Pooled analysis of cross-sectional studies (1 low and 3 moderate risk of bias) showed that marijuana use was associated with cough (RR, 4.37 CI, 1.71 to 11.19), sputum production (RR, 3.40 CI, 1.99 to 5.79), wheezing (RR, 2.83 CI, 1.89 to 4.23), and dyspnea (RR, 1.56 CI, 1.33 to 1.83). Data on pulmonary function and obstructive lung disease were insufficient

Low-strength evidence suggests that smoking marijuana is associated with cough, sputum production, and wheezing. Evidence on the association between marijuana use and obstructive lung disease and pulmonary function is insufficient

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#Anticonvulsants in the treatment of low #back pain and lumbar radicular pain: a systematic review and meta-analysis

http://www.cmaj.ca/content/190/26/E786

Nine trials compared topiramate, gabapentin or pregabalin to placebo in 859 unique participants. Fourteen of 15 comparisons found anticonvulsants were not effective to reduce pain or disability in low back pain or lumbar radicular pain; for example, there was high-quality evidence of no effect of gabapentinoids versus placebo on chronic low back pain in the short term (pooled mean difference MD −0.0, 95% confidence interval CI −0.8 to 0.7) or for lumbar radicular pain in the immediate term (pooled MD −0.1, 95% CI −0.7 to 0.5). The lack of efficacy is accompanied by increased risk of adverse events from use of gabapentinoids, for which the level of evidence is high.

INTERPRETATION: There is moderate- to high-quality evidence that anticonvulsants are ineffective for treatment of low back pain or lumbar radicular pain. There is high-quality evidence that gabapentinoids have a higher risk for adverse events

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Is local #platelet-rich plasma injection clinically superior to hyaluronic acid for treatment of knee #osteoarthritis? A systematic review of randomized controlled trials

https://arthritis-research.biomedcentral.com/articles/10.1186/s13075-018-1621-0


Seven articles reporting 908 patients and 908 knees were analyzed, including 44% men and 56% women with a mean age of 59.8 years. All studies met the minimal clinically important difference criteria and showed statistically significant improvements in clinical outcomes, including pain, physical function, and stiffness, with PRP treatment. All except two studies showed significant differences between PRP and HA regarding clinical outcomes of pain and function.

Conclusions
PRP intra-articular injection of the knee may be an effective alternative treatment for knee OA, especially in patients with mild knee OA. Although some studies suggested that the effect of PRP was no better than HA, we found that it was no worse. A large, multicenter, randomized trial is needed to further assess the efficacy of PRP treatment for patients with knee OA.

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Organic #solvents and #MS susceptibility
Interaction with MS risk HLA genes

http://n.neurology.org/content/early/2018/07/03/WNL.0000000000005906


Overall, exposure to organic solvents increased the risk of MS (odds ratio 1.5, 95% confidence interval 1.2–1.8, p = 0.0004). Among both ever and never smokers, an interaction between organic solvents, carriage of HLA-DRB115, and absence of HLA-A02 was observed with regard to MS risk, similar to the previously reported gene-environment interaction involving the same MS risk HLA genes and smoke exposure.

Conclusion The mechanism linking both smoking and exposure to organic solvents to MS risk may involve lung inflammation with a proinflammatory profile. Their interaction with MS risk HLA genes argues for an action of these environmental factors on adaptive immunity, perhaps through activation of autoaggressive cells resident in the lungs subsequently attacking the CNS.

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Association of Midlife Cardiorespiratory #Fitness With Incident #Depression and #Cardiovascular Death After Depression in Later Life

https://jamanetwork.com/journals/jamapsychiatry/article-abstract/2686049


... After 117 218 person-years of Medicare follow-up, 2701 depression diagnoses, 610 deaths due to CVD without prior depression, and 231 deaths due to CVD after depression were observed. A high level of fitness in midlife was associated with a 16% lower risk of depression (hazard ratio HR, 0.84; 95% CI, 0.74-0.95) compared with a low level of fitness. A high fitness level was also associated with a 61% lower risk of death due to CVD without depression (HR, 0.39; 95% CI, 0.31-0.48) compared with a low level of fitness. After a diagnosis of depression, a high fitness level was associated with a 56% lower risk of death due to CVD (HR, 0.44; 95% CI, 0.31-0.64) compared with a low fitness level.

Conclusions and Relevance Midlife fitness is associated with a lower risk of later-life depression, CVD mortality, and CVD mortality after incident later-life depression. These findings suggest the importance of midlife fitness in primary prevention of depression and subsequent CVD mortality in older age and should encourage physicians to consider fitness and physical activity in promoting healthy aging.

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Changes in the serum metabolite profile correlate with decreased brain #grey matter volume in moderate-to-heavy-#drinking young adults

https://www.sciencedirect.com/science/article/pii/S0741832917309849


Alterations in amino acid and energy metabolism were observed in the moderate-to-heavy drinking young adults when compared to the controls. After correction for multiple testing, the group of moderate-to-heavy drinking young adults had increased serum concentrations of 1-methylhistamine (p = 0.001, d = 0.82) when compared to the controls. Furthermore, concentrations of 1-methylhistamine (r = -0.48, p = 0.004) and creatine (r = -0.52, p = 0.001) were negatively correlated with the brain grey matter volumes in the females. Overall, our results show association between moderate-to-heavy use of alcohol and altered metabolite profile in young adults as well as suggest that some of these changes could be associated with the reduced brain grey matter volume.