More than 50 years ago, John Bell proved that no theory of nature that obeys locality and realism can reproduce all the predictions of quantum theory: in any local-realist theory, the correlations ...between outcomes of measurements on distant particles satisfy an inequality that can be violated if the particles are entangled. Numerous Bell inequality tests have been reported; however, all experiments reported so far required additional assumptions to obtain a contradiction with local realism, resulting in 'loopholes'. Here we report a Bell experiment that is free of any such additional assumption and thus directly tests the principles underlying Bell's inequality. We use an event-ready scheme that enables the generation of robust entanglement between distant electron spins (estimated state fidelity of 0.92 ± 0.03). Efficient spin read-out avoids the fair-sampling assumption (detection loophole), while the use of fast random-basis selection and spin read-out combined with a spatial separation of 1.3 kilometres ensure the required locality conditions. We performed 245 trials that tested the CHSH-Bell inequality S ≤ 2 and found S = 2.42 ± 0.20 (where S quantifies the correlation between measurement outcomes). A null-hypothesis test yields a probability of at most P = 0.039 that a local-realist model for space-like separated sites could produce data with a violation at least as large as we observe, even when allowing for memory in the devices. Our data hence imply statistically significant rejection of the local-realist null hypothesis. This conclusion may be further consolidated in future experiments; for instance, reaching a value of P = 0.001 would require approximately 700 trials for an observed S = 2.4. With improvements, our experiment could be used for testing less-conventional theories, and for implementing device-independent quantum-secure communication and randomness certification.
The gut microbiome is associated with diverse diseases
, but a universal signature of a healthy or unhealthy microbiome has not been identified, and there is a need to understand how genetics, ...exposome, lifestyle and diet shape the microbiome in health and disease. Here we profiled bacterial composition, function, antibiotic resistance and virulence factors in the gut microbiomes of 8,208 Dutch individuals from a three-generational cohort comprising 2,756 families. We correlated these to 241 host and environmental factors, including physical and mental health, use of medication, diet, socioeconomic factors and childhood and current exposome. We identify that the microbiome is shaped primarily by the environment and cohabitation. Only around 6.6% of taxa are heritable, whereas the variance of around 48.6% of taxa is significantly explained by cohabitation. By identifying 2,856 associations between the microbiome and health, we find that seemingly unrelated diseases share a common microbiome signature that is independent of comorbidities. Furthermore, we identify 7,519 associations between microbiome features and diet, socioeconomics and early life and current exposome, with numerous early-life and current factors being significantly associated with microbiome function and composition. Overall, this study provides a comprehensive overview of gut microbiome and the underlying impact of heritability and exposures that will facilitate future development of microbiome-targeted therapies.
To investigate the construct validity of a bathroom scale measuring balance in elderly people.
Cross-sectional study.
Participants were recruited via nursing homes and an organization that provides ...exercise classes for community-dwelling elderly people.
Nursing home patients were compared with active community-dwelling elderly people. Eligibility criteria for both groups were: aged 65 years or older and being able to step onto a bathroom scale independently.
The balance measurement of the bathroom scale was compared with the following three clinical balance measurements: Performance Oriented Mobility Assessment (POMA), Timed Up and Go (TUG), and Four Test Balance Scale (FTBS). An independent samples t-test was performed to determine whether nursing home patients scored lower on these four balance tests compared with community-dwelling elderly people. Correlations were calculated between the bathroom scale balance scores and those of the clinical balance tests for nursing home patients and community-dwelling elderly people separately.
Forty-seven nursing home patients with a mean age of 81 years (SD 6.40) and 54 community-dwelling elderly people with a mean age of 76 years (SD 5.06) participated in the study. The results showed that nursing home patients had significantly lower scores on all four balance tests compared with community-dwelling elderly people. Correlations between the bathroom scale scores and the POMA, TUG, and FTBS in nursing home patients were all significant: .49, -.60, and .63, respectively. These correlations were not significant in active community-dwelling elderly people, -.04, -.42, and .33, respectively. Linear regression analyses showed that the correlations for the bathroom scale and POMA, bathroom scale and TUG, and bathroom scale and FTBS did not differ statistically between nursing home patients and community-dwelling elderly people.
These results suggest that the modified bathroom scale is useful for measuring balance in elderly people. However, the added value of this assessment method for clinical practice remains to be demonstrated.
Medication-related problems can cause serious adverse drug events (ADEs) that may lead to hospitalization of the patient. There are multiple screening methods to detect and reduce potentially ...inappropriate medications (PIMs) and potential prescribing omissions (PPOs). Whether this will result in less medication-related hospitalizations is unknown. The study objective was to assess the risk of preventable medication-related hospital admissions associated with potentially inappropriate prescribing, using the Beers 2012 and the Screening Tool of Older Person's Prescriptions and the Screening Tool to Alert doctors to Right Treatment (STOPP & START) 2008 criteria.
A nested case-control study was conducted with a subset of Dutch participants from the Hospital Admissions Related to Medication (HARM) study. Cases were defined as patients aged ≥65 years with a potentially preventable medication-related hospital admission. For each case, one control was selected, matched for age and sex. The primary determinant was the presence of one or more PIMs according to the Beers 2012 and STOPP 2008 criteria. The secondary determinant was the presence of one or more PIMs and PPOs according to the STOPP & START 2008 criteria. The strength of the association between inappropriate prescribing and medication-related hospital admission was evaluated with multivariate logistic regression and expressed as odds ratios (ORs) with 95 % confidence intervals (CIs).
The prevalence of Beers 2012 criteria PIMs in the total cohort was 44.4 %. The prevalence of STOPP & START 2008 criteria PIMs and PPOs were, respectively, 34.1 and 57.7 %. STOPP 2008 criteria PIMs were associated with preventable medication-related hospital admissions OR adjusted for number of drugs and comorbidities (ORadj) 2.30, 95 % CI 1.30-4.07, whereas there was no association with Beers 2012 criteria PIMs (ORadj 1.49, 95 % CI 0.90-2.47). STOPP PIMs and START PPOs together were also associated with preventable medication-related hospital admissions (ORadj 3.47, 95 % CI 1.70-7.09).
Our study shows that patients with potentially inappropriate prescribing detected with the STOPP & START 2008 criteria are at risk of preventable medication-related hospital admissions. The STOPP & START 2008 criteria can be used to identify older people at risk of medication-related problems.
PURPOSEAn analysis of trends in U.S. pharmaceutical spending is presented, including projections for drug expenditures in nonfederal hospital and clinic settings in 2014.
METHODSTrends in ...pharmaceutical expenditures and developments likely to influence future spending, including new drug approvals and patent expirations, were analyzed using data from the IMS Health National Sales Perspectives database. Projections were based on a combination of quantitative and qualitative analyses and expert opinion.
RESULTSTotal prescription sales for the 12 months ending September 2013 were approximately $326 billion, 0.7% lower than sales during the previous 12 months; pharmaceutical spending by clinics and nonfederal hospitals grew by 4.5% and 1.8%, respectively. Vaccines were among the products driving large sales increases in clinic settings, with alteplase and pegfilgrastim topping the list of fast-growing drugs by hospital expenditures. Few new drug approvals anticipated in 2014 are expected to result in major expenditures by hospitals and clinics. Expansion of access to health care and other changes related to the Patient Protection and Affordable Care Act, as well as continued improvement in the U.S. economy, may drive growth in pharmaceutical spending over the next 12–24 months.
CONCLUSIONGrowth in U.S. prescription drug expenditures is expected to rebound in 2014, with a projected 3–5% increase in total drug expenditures across all settings this year, including a 5–7% increase in clinic spending and a 1–3% increase in hospital spending. Health-system pharmacy leaders should carefully examine local drug-utilization patterns to determine their respective organizationʼs anticipated spending in 2014.
Background and Purpose- It is unclear whether endovascular treatment (EVT) is beneficial for patients with acute ischemic stroke with occlusion of the M2 segment of the middle cerebral artery. We ...aimed to compare functional outcomes, technical aspects, and complications of EVT between patients with acute ischemic stroke because of M2 and M1 occlusions in clinical practice. Furthermore, outcome and complications after EVT in dominant and nondominant caliber M2 division occlusions were studied. Methods- Data were obtained from the MR CLEAN Registry (Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands) which is an ongoing observational study in 16 Dutch centers performing EVT in the Netherlands. Functional outcome was measured with the modified Rankin Scale score at 90 days. Neurological recovery (delta National Institutes of Health Stroke Scale), successful reperfusion rates (extended Thrombolysis in Cerebral Infarction ≥2B), and safety outcomes were also investigated. Associations between occlusion location and outcome were analyzed with ordinal logistic regression models, with adjustment for other prognostic factors. Results- In total, 244 (24%) patients with an M2 and 759 (76%) patients with an M1 occlusion who underwent EVT were analyzed. Functional outcomes were not significantly different between patients with M2 versus M1 occlusions (adjusted common odds ratio, 1.24; 95% CI, 0.87-1.73). Occurrence of symptomatic intracerebral hemorrhage was also similar for M2 and M1 occlusions (6.6% versus 5.9%; P=0.84). Further analysis about dominance of an M2 branch was performed in 175 (72%) patients. Neurological recovery was comparable (mean delta National Institutes of Health Stroke Scale, -2±10 for dominant M2, -5±5 for nondominant M2, and -4±9 P=0.24 for M1 occlusions). Furthermore, the effect of reperfusion status on functional outcome was comparable between occlusion divisions (common odds ratio, 1.27; 95% CI, 1.06-1.53 for dominant M2; common odds ratio, 1.32; 95% CI, 0.93-1.87 for nondominant M2; and common odds ratio, 1.35; 95% CI, 1.24-1.46 for M1 occlusions). Conclusions- Outcomes and complication rates after EVT were similar in patients with M2 and M1 occlusions. Although based on observational data and a limited sample size, a similar association of reperfusion status with functional outcome for all subgroups provides no evidence that patients with either a dominant or a nondominant M2 occlusion should be routinely excluded from EVT.
STUDY QUESTION
What is the optimal management of women with endometriosis based on the best available evidence in the literature?
SUMMARY ANSWER
Using the structured methodology of the Manual for ...ESHRE Guideline Development, 83 recommendations were formulated that answered the 22 key questions on optimal management of women with endometriosis.
WHAT IS KNOWN ALREADY
The European Society of Human Reproduction and Embryology (ESHRE) guideline for the diagnosis and treatment of endometriosis (2005) has been a reference point for best clinical care in endometriosis for years, but this guideline was in need of updating.
STUDY DESIGN, SIZE, DURATION
This guideline was produced by a group of experts in the field using the methodology of the Manual for ESHRE Guideline Development, including a thorough systematic search of the literature, quality assessment of the included papers up to January 2012 and consensus within the guideline group on all recommendations. To ensure input from women with endometriosis, a patient representative was part of the guideline development group. In addition, patient and additional clinical input was collected during the scoping and review phase of the guideline.
PARTICIPANTS/MATERIALS, SETTING, METHODS
NA.
MAIN RESULTS AND THE ROLE OF CHANCE
The guideline provides 83 recommendations on diagnosis of endometriosis and on the treatment of endometriosis-associated pain and infertility, on the management of women in whom the disease is found incidentally (without pain or infertility), on prevention of recurrence of disease and/or painful symptoms, on treatment of menopausal symptoms in patients with a history of endometriosis and on the possible association of endometriosis and malignancy.
LIMITATIONS, REASONS FOR CAUTION
We identified several areas in care of women with endometriosis for which robust evidence is lacking. These areas were addressed by formulating good practice points (GPP), based on the expert opinion of the guideline group members.
WIDER IMPLICATIONS OF THE FINDINGS
Since 32 out of the 83 recommendations for the management of women with endometriosis could not be based on high level evidence and therefore were GPP, the guideline group formulated research recommendations to guide future research with the aim of increasing the body of evidence.
STUDY FUNDING/COMPETING INTEREST(S)
The guideline was developed and funded by ESHRE, covering expenses associated with the guideline meetings, with the literature searches and with the implementation of the guideline. The guideline group members did not receive payment. All guideline group members disclosed any relevant conflicts of interest (see Conflicts of interest).
TRIAL REGISTRATION NUMBER
NA.
Tapentadol is a centrally acting analgesic with two mechanisms of action, µ-opioid receptor agonism and noradrenaline reuptake inhibition. The objectives were to describe the pharmacokinetic behavior ...of tapentadol after oral administration of an extended-release (ER) formulation in healthy subjects and patients with chronic pain and to evaluate covariate effects.
Data were obtained from 2276 subjects enrolled in five phase I and nine phase II and III studies. Nonlinear mixed-effects modeling was conducted using NONMEM.
The population estimates of apparent oral clearance and apparent central volume of distribution were 257 L/h and 1870 L, respectively. The complex absorption was described with a transit compartment for the first input. The second input function embraces saturable "binding" in the "absorption compartment", and a time-varying rate constant. Covariate evaluation demonstrated that age, aspartate aminotransferase, and health (painful diabetic neuropathy or not) had a statistically significant effect on apparent clearance, and bioavailability appeared to be dependent on body weight. The pcVPC indicted that the model provided a robust and unbiased fit to the data.
A one-compartment disposition model with two input functions and first-order elimination adequately described the pharmacokinetics of tapentadol ER. The dose-dependency in the pharmacokinetics of tapentadol ER is adequately described by the absorption model. None of the covariates were considered as clinically relevant factors that warrant dose adjustments.
PDF
