Add-on Eslicarbazepine Reduces Partial-Onset Seizures.


Once-daily adjunctive therapy with eslicarbazepine significantly reduced the frequency of partial-onset seizures in adult patients compared with adding a placebo, and the effect was sustained out to 1 year. In an analysis of pooled data from 3 phase-3 pivotal trials, doses of 800 mg and 1200 mg were well tolerated.

Eslicarbazepine is an oral drug that stabilizes the inactive state of voltage-gated sodium channels and blocks T-type voltage-gated calcium channels.

Patrício Soares-da-Silva, MD, PhD, head of research and development at BIAL in S. Mamede do Coronado, Portugal, the developer of the drug, presented trial results here at the XXI World Congress of Neurology (WCN).

The 3 trials had slight variations in protocols, but in general involved an 8-week observation or single-blind drug period, 2 weeks of drug titration depending on dose, a 12-week double-blind maintenance period, 4 weeks of tapering of the drug or not, and an open-label extension period. Two trials (BIA-2093-301 and 302) tested the drug at 400 mg, 800 mg, or 1200 mg daily or placebo for the maintenance period, with about 100 patients in each group. Trial BIA-2093-303 dropped the 400-mg dose (about 84 patients per group).

The pooled groups were well matched for mean age (about 37 years), sex (half were men), seizure types, duration of epilepsy (22 years), and the number of concomitant antiepileptic drugs (AEDs) they were taking. About 70% of patients in each group were receiving 2 other AEDs besides the trial drug.

Dr. Soares-da-Silva said that eslicarbazepine significantly reduced the seizure frequency in each 4-week period of the 12-week double-blind maintenance phase from 8.17 ± 0.034 with placebo (n = 279) to 6.24 ± 0.034 with 800 mg (n = 262) and to 5.95 ± 0.035 with 1200 mg (n = 253) (both P < .001 vs placebo), the primary endpoint of the trials.

The responder rate, defined as a 50% or greater reduction in seizure frequency over the 12-week period, rose from 21.5% with placebo to 36.3% with 800 mg of eslicarbazepine and 43.5% with 1200 mg.

Positive Results Continue to 1 Year

Of 857 patients completing the double-blind period, 833 entered the open-label extension phase, and 612 (73.5%) completed the full year, with a median daily dose of 800 mg. The maximum allowed dose was 1200 mg.

The drug maintained its efficacy during the open-label extension period and showed a slight rise in both the responder rate and the proportion of patients free of seizures.

Table. Eslicarbazepine Efficacy During 1-year Extension Period*

Time Period

Responder Rate (%)

Proportion of Seizure-Free Patients (%)

Weeks 5 to 16

46.1

6.3

Weeks 17 to 28

47.0

9.4

Weeks 29 to 40

48.2

10.1

Weeks 41 to 52

50.1

13.6

*Median eslicarbazepine dose was 800 mg.

 

Treatment with adjunctive eslicarbazepine was associated with improvements in mood and quality of life, as assessed by QOLIE-31 and Montgomery-Åsberg Depression Rating Scale (MADRS) scores. Whether patients had mild, moderate, or severe symptoms, all those who improved had improved significantly at the final assessment compared with baseline (all P < .001).

On the basis of the results of the pivotal trials, Dr. Soares-da-Silva said the European Medicines Agency approved eslicarbazepine for use in Europe as adjunctive therapy for adults with partial-onset seizures. It has not been approved in the United States, but he noted it is now undergoing trials in the United States as monotherapy.

Monotherapy Trials

Topline results of 2 phase 3 monotherapy trials of eslicarbazepine were just reported by Sunovion Pharmaceuticals. In both trials the drug met the primary endpoints.

Treatment was well tolerated and demonstrated seizure control rates superior to those among historical controls in adult patients with partial-onset seizures with or without secondary generalization who were not well controlled with current antiepileptic drugs, a statement from Sunovion released September 17 notes.

The agent is under review by the US Food and Drug Administration (FDA) as a once-daily adjunctive therapy for partial-onset seizures in patients aged 18 years or older with epilepsy.

“Pending the outcome of FDA review of the current New Drug Application (NDA) resubmission for eslicarbazepine acetate as an adjunctive treatment, Sunovion plans to submit these data as part of a supplemental NDA in support of a monotherapy indication,” Fred Grossman, DO, senior vice president, clinical development and medical affairs at Sunovion, said in the company’s statement.

The phase 3 studies, dubbed 093-045 and 093-046, were double-blind, historical-controlled, randomized trials with identical designs. Study 093-045 included 193 patients from 67 study centers in North America, and study 093-046 included 172 patients from 41 centers in 5 countries.

The primary endpoint of both studies was the proportion of patients meeting predefined exit criteria, “signifying worsening seizure control,” the statement notes, 16 weeks after titration compared with historical controls.

In both studies, adults with partial-onset seizures that were not well controlled, defined as 4 or more partial-onset seizures in the 8 weeks before screening and no 4-week seizure-free period, with 1 to 2 AEDs, were gradually converted to monotherapy treatment with eslicarbazepine. They were then randomly assigned in a 1:2 ratio to receive 1200 or 1600 mg of eslicarbazepine daily.

Detailed results from the 2 monotherapy studies will be presented at upcoming scientific meetings, the company notes.

Difference Debated?

Asked to comment about what eslicarbazepine may add to the AED armamentarium as adjunctive therapy, session chair Reeta Kälviäinen, MD, from the Kuopio Epilepsy Center, and professor of clinical epileptology at the University of Eastern Finland in Kupio, told Medscape Medical News that it is something of a debate at the moment whether eslicarbazepine differs significantly from oxcarbazepine.

“It’s a metabolite of oxcarbazepine, and we think at the moment that it might have a little bit less adverse effects than oxcarbazepine, less hyponatremia and less idiosynchrous reactions,” she said. “And we hope that therefore it would be better tolerated, perhaps as carbamazepine, as effective as oxcarbazepine, and then you can dose it once daily, which is a benefit.”

She said that she was “a little bit disappointed” that the study did not show which AEDs eslicarbazepine might be best used with but that current studies and clinical practice may reveal the better combinations. But for now, “definitely you shouldn’t add it on top of other sodium channel blockers. That’s not the way to use it,” because of additive adverse effects.

Similarly, if a patient has problems while receiving carbamazepine or oxcarbazepine, switching to eslicarbazepine would be a bad idea. “It’s nearly the same drug, so that’s a dangerous situation. So that’s a contraindication,” Dr. Kälviäinen noted. She said clinicians are now “a little bit mixed up” in choosing among these similar drugs, and clearer studies on the differences among them are needed.

Otto Muzik, PhD, a professor of radiology and pediatrics at Wayne State Medical School in Detroit, Michigan, questioned the value of adding another drug in this same class.

“It’s still not approved in the States, and it appears to me that the FDA does not believe that there is added value,” he mentioned to Medscape Medical News. “So that means that…it’s probably going to do better than a placebo, but if you now say, ‘Give me the best combined therapy of drugs,’ and now we throw in this new drug, is it more efficacious or not, and the jury seems to be still out on that.”

Diagnostic Accuracy of Quantitative PCR (Xpert MTB/RIF) for Tuberculous Meningitis in a High Burden Setting: A Prospective Study.


Background

Tuberculous meningitis (TBM) is difficult to diagnose promptly. The utility of the Xpert MTB/RIF test for the diagnosis of TBM remains unclear, and the effect of host- and sample-related factors on test performance is unknown. This study sought to evaluate the sensitivity and specificity of Xpert MTB/RIF for the diagnosis of TBM.

Methods and Findings

235 South-African patients with a meningeal-like illness were categorised as having definite (culture or Amplicor PCR positive), probable (anti-TBM treatment initiated but microbiological confirmation lacking), or non-TBM. Xpert MTB/RIF accuracy was evaluated using 1 ml of uncentrifuged and, when available, 3 ml of centrifuged cerebrospinal fluid (CSF). To evaluate the incremental value of MTB/RIF over a clinically based diagnosis, test accuracy was compared to a clinical score (CS) derived using basic clinical and laboratory information.

Of 204 evaluable patients (of whom 87% were HIV-infected), 59 had definite TBM, 64 probable TBM, and 81 non-TBM. Overall sensitivity and specificity (95% CI) were 62% (48%–75%) and 95% (87%–99%), respectively. The sensitivity of Xpert MTB/RIF was significantly better than that of smear microscopy (62% versus 12%; p = 0.001) and significantly better than that of the CS (62% versus 30%; p = 0.001; C statistic 85% [79%–92%]). Xpert MTB/RIF sensitivity was higher when centrifuged versus uncentrifuged samples were used (82% [62%–94%] versus 47% [31%–61%]; p = 0.004). The combination of CS and Xpert MTB/RIF (Xpert MTB/RIF performed if CS<8) performed as well as Xpert MTB/RIF alone but with a ~10% reduction in test usage. This overall pattern of results remained unchanged when the definite and probable TBM groups were combined. Xpert MTB/RIF was not useful in identifying TBM among HIV-uninfected individuals, although the sample was small. There was no evidence of PCR inhibition, and the limit of detection was ~80 colony forming units per millilitre. Study limitations included a predominantly HIV-infected cohort and the limited number of culture-positive CSF samples.

Conclusions

Xpert MTB/RIF may be a good rule-in test for the diagnosis of TBM in HIV-infected individuals from a tuberculosis-endemic setting, particularly when a centrifuged CSF pellet is used. Further studies are required to confirm these findings in different settings.

Discussion

Although the utility profile and accuracy of Xpert MTB/RIF has been well characterised in sputum samples, there are hardly any data to guide its utility and implementation for TBM. This is critical as the rollout of Xpert MTB/RIF means that quantitative PCR is now available in many high burden settings, and data are urgently required to guide appropriate and relevant usage of this technology in biological fluids other than sputum. That Xpert MTB/RIF performs poorly in fluids from some compartments, e.g., the pleural space, highlights the need for such data [27]. The key findings of this study were as follows: (1) Xpert MTB/RIF is likely a good rule-in test for the diagnosis of TBM in HIV-infected patients; (2) centrifugation of the sample improved sensitivity in this context to almost 80%; (3) among HIV-infected patients, Xpert MTB/RIF performed significantly better than the widely available same-day alternative tests, i.e., smear microscopy, which suggests that prompt diagnosis of TBM is potentially achievable in the majority of patients in this setting; (4) the diagnostic value of Xpert MTB/RIF for HIV-infected patients is clinically meaningful given that it performed significantly better than hypothetical decision-making based on clinical characteristics and basic laboratory data (the CS); and (5) when combined with the CS, Xpert MTB/RIF test usage could be reduced by only a modest ~10% whilst retaining similar sensitivity and specificity compared to using Xpert MTB/RIF alone. This last finding informs clinical practice in resource-poor settings. Finally, we quantified the limit of detection of the assay, its relationship to bacterial load, and the impact of PCR inhibition. These data require reproduction in HIV-uninfected and non-TB-endemic populations.

There are limited data about Xpert MTB/RIF performance in TBM [28]. Published data include only small numbers of microbiologically proven TBM cases (range of 0 to 23) [29][32], often in a case-control design with a non-uniform reference standard, and often CSF-associated data were published as part of a laboratory-based evaluation of extrapulmonary TB samples, usually including samples from countries with low TB prevalence. Furthermore, there are no studies from high burden settings, and technical performance evaluations, including bacterial load studies, threshold level of detection, and impact of PCR inhibition, have hitherto not been undertaken.

Xpert MTB/RIF sensitivity was as high as 80% when a centrifuged CSF sample from an HIV-infected patient was used. This suggests that Xpert MTB/RIF, at least in an HIV-endemic environment, represents a possible new standard of care for the diagnosis of TBM. Sensitivity was considerably better than in previous studies using commercially available or non-standardised PCR tools [9],[32][34]. The ostensibly better performance is likely related to a combination of centrifugation (and hence concentration of bacilli) and technical aspects, including a more efficient standardised extraction protocol, fractionation of mycobacteria by a pre-sonication step, and a nested PCR protocol, thus maximising amplification. However, possibly higher bacterial loads in HIV-infected patients may have also played a role. Our findings have practical relevance because they imply that at least 3 ml of CSF should be set aside and centrifuged, and re-suspended in phosphate-buffered saline, before being run on the Xpert MTB/RIF. This high-sensitivity and potentially rapid diagnosis in most cases is likely to benefit HIV-infected patients suspected of having M.tb., as diagnostic and treatment delay is associated with higher mortality [35][37]. Impact-related studies are now required to verify this hypothesis. It is noteworthy that a second sample improved sensitivity minimally. These data suggest that, at least in an HIV-endemic setting, using a second cartridge is unlikely to give further benefit. However, larger studies are required to confirm this possibility.

Similar to the findings when using sputum, the level of detection of Xpert MTB/RIF was between 80 and 100 colony forming units per millilitre. This explains the sub-optimal sensitivity of Xpert MTB/RIF compared to culture, where the detection threshold is as low as 1–10 organisms per millilitre [38]. We did not find a correlation between TTP and Xpert MTB/RIF CT values, as has been shown in sputum [39]. In contrast to previous PCR-based studies [40],[41], we found that CSF had a minimal inhibitory effect on the PCR reaction when compared to sputum. This may be due to the wash step incorporated into the assay that removes extracellular debris. We did not find a difference in TTP between the Xpert MTB/RIF–positive samples from centrifuged versus uncentrifuged CSF. This may be due to a type two statistical error, as the sample numbers were small.

There were three patients who were culture negative but Xpert MTB/RIF positive, i.e., Xpert MTB/RIF positive in the non-TB group. Our previous work has shown that such cases (Xpert MTB/RIF positive but culture negative) are likely to be true TB positives, and this is corroborated by high specificity obtained in large sputum-based studies where a significant minority of the patients had had previous TB [11]. If these culture-negative Xpert MTB/RIF–positive individuals are hypothetically designated definite-TB cases, then the overall case detection rate improves by a further ~10%.

The proper and meaningful value of a test lies in its ability to influence patient management through its incremental value over pre-test probability, or to have an impact on decision-making based on logical clinical judgement (based upon clinical features and basic laboratory parameters). We therefore derived a CS, hitherto unavailable for HIV-endemic settings, to evaluate Xpert MTB/RIF utility in clinical practice. Xpert MTB/RIF had significantly better performance outcomes than the clinical prediction rule (using a rule-in cut point, so appropriate comparisons could be made). Furthermore, hypothetically combining the CS with Xpert MTB/RIF resulted only in a modest ~10% reduction in test usage, but still maintained high sensitivity and specificity. These data suggest that clinical algorithms or scoring systems to limit test usage are unlikely to be significantly useful in resource-poor settings.

There are several limitations of our study. We could not determine the impact of Xpert MTB/RIF (time and proportion of patients initiated on treatment) compared to a smear microscopy/empiric treatment-based strategy given our study design and the fact that management decisions were not based on Xpert MTB/RIF results. However, this was because Xpert MTB/RIF had not yet been endorsed by the World Health Organization when the study commenced, had not been validated for use in CSF, and had been used as a research tool only (thus, for ethical reasons, study samples were evaluated only several weeks later). Although the confidence intervals of some of our estimates are wide (because of limited sample numbers), this is to our knowledge the largest diagnostic study undertaken in TBM (based on the number of microbiologically proven TBM cases; n = 59). This reflects the challenge and difficulty in performing such studies in resource-poor settings. It is possible that the Xpert MTB/RIF performs much better in HIV-infected individuals because of a possibly higher bacterial load, and thus our findings need to be confirmed in other settings. Given the small number of HIV-uninfected patients, we were unable to meaningfully compare this sub-group. The CS was developed to assess only incremental value above basic clinical and CSF parameters. The CS and the combination of CS plus Xpert MTB/RIF need prospective and independent validation. The non-significant difference in sensitivity between the paired centrifuged and non-centrifuged samples may reflect a type two statistical error, as the number of culture-positive paired samples was limited. Lastly, there were nine patients who could not be categorised within our defined groups and were excluded from the analysis.

In conclusion, Xpert MTB/RIF may be a good rule-in test for the diagnosis of TBM in HIV-infected individuals in a TB-endemic setting, particularly when a centrifuged CSF pellet is used. A second Xpert MTB/RIF test had minimal incremental benefit. Smear microscopy and the CS, when combined with Xpert MTB/RIF, only modestly minimised test usage in a resource-poor setting. Further studies are now required in non-HIV-endemic settings, and using validated scoring systems, to evaluate the impact of Xpert MTB/RIF on diagnostic accuracy, and morbidity and mortality in patients with TBM.

Source:PLOS

Lymph node micrometastasis in gastrointestinal tract cancer—a clinical aspect.


Abstract

Lymph node micrometastasis (LNM) can now be detected thanks to the development of various biological methods such as immunohistochemistry (IHC) and reverse transcription-polymerase chain reaction (RT-PCR). Although several reports have examined LNM in various carcinomas, including gastrointestinal (GI) cancer, the clinical significance of LNM remains controversial. Clinically, the presence of LNM is particularly important in patients without nodal metastasis on routine histological examination (pN0), because patients with pN0 but with LNM already in fact have metastatic potential. However, at present, several technical obstacles are impeding the detection of LNM using methods such as IHC or RT-PCR. Accurate evaluation should be carried out using the same antibody or primer and the same technique in a large number of patients. The clinical importance of the difference between LNM and isolated tumor cells (≤0.2 mm in diameter) will also be gradually clarified. It is important that the results of basic studies on LNM are prospectively introduced into the clinical field. Rapid diagnosis of LNM using IHC and RT-PCR during surgery would be clinically useful. Currently, minimally invasive treatments such as endoscopic submucosal dissection and laparoscopic surgery with individualized lymphadenectomy are increasingly being performed. Accurate diagnosis of LNM would clarify issues of curability and safety when performing such treatments. In the near future, individualized lymphadenectomy will develop based on the establishment of rapid, accurate diagnosis of LNM.

Source: International Journal of Clinical Oncology

Study Shows Higher Rate of Unruptured Cerebral Aneurysm.


A large survey of adult residents of China has determined that the prevalence of unruptured cerebral aneurysms (UCAs) is 7%, that UCAs increase with age, and that they seem to be more common in women.

This prevalence rate is higher than in previous research, in some cases more than twice as high, probably at least in part because researchers used high-resolution magnetic resonance angiography (MRA) to detect UCAs, said lead author Ming-Hua Li, MD, PhD, professor and chairman of Neuro-radiology, Shanghai Jiao Tong University, China.

Of these, though, only about 8.7% were judged to be at any imminent risk for rupture, they note.

The study was published in the October 15 issue of the Annals of Internal Medicine.

High Diagnostic Accuracy

This new analysis included 4813 residents aged 35 to 75 years from 2 Shanghai districts: Changning, an economically well-developed urban area, and Zhabei, a less developed suburban area. This age group represents the range that is most clinically significant in terms of screening, said Dr. Li. Those younger than 35 years are less likely to have UCAs and those older than 75 have a shorter life expectancy, he said.

Participants completed a standard questionnaire to provide demographic information, personal and family medical history, and lifestyle risk factors, and they underwent a physical examination.

The researchers used 3-dimensional (3D) time-of-flight MRA with a voxel size of less than 0.7 mm. To evaluate UCAs, they applied 3D volume rendering and single artery highlighting. This imaging modality was proven in a previous study by the same research group to have very high diagnostic accuracy for detecting intracranial aneurysms compared with 3D digital subtraction angiography (DSA), said Dr. Li.

In the current study, 3 radiologists who were blinded to participants’ information determined the location and size of the UCAs.

UCAs were defined as abnormal focal dilatations of a cerebral artery with attenuation of the vessel wall or an infundibulum in patients without a history of subarachnoid hemorrhage (SAH). Aneurysms were categorized as less than 3 mm, 3 mm to less than 5 mm, 5 mm to less than 10 mm, or 10 mm or more.

The survey excluded UCAs with a diameter of less than 2 mm because, as Dr. Li explained, aneurysms with such a small diameter are difficult to diagnose with the spatial resolution of the imaging modality used.

Aneurysm Sites

Aneurysms were morphologically classified as regular (saccular), irregular (lobular), or fusiform. Sites were classified as internal carotid artery (including the posterior communicating artery), anterior cerebral artery (including the anterior communicating artery), middle cerebral artery (including the MI-2 bifurcation), and vertebrobasilar artery.

The researchers found that 130 men and 206 women had UCAs, with excellent interobserver agreement. The prevalence of UCAs was 7.0% (95% confidence interval, 6.3% to 7.7%).

This is a higher prevalence than in other studies, probably because the researchers used 3D high-resolution MRA, which enabled them to detect small UCAs, Dr. Li speculated. “Those small UCAs could possibly be missed on 2D invasive angiography due to overlapping,” he said. “In addition, we excluded volunteers younger than 35, who are less likely to have UCAs. This could potentially lead to higher prevalence in our survey compared to studies with a wider age range.”

The prevalence of unruptured UCAs in North America is still unknown, said Dr. Li.

The prevalence was higher in women (8.6%) than in men (5.5%) (P < .001). “We hypothesized that decreases in estrogen concentration and estrogen-receptor density may contribute to an increased risk of cerebral aneurysm development in women,” said Dr. Li.

The prevalence of UCAs increased with age and peaked at ages 55 to 64 years in both men and women. This, said Dr. Li, is in line with a meta-analysis published in Lancet Neurology in 2011.

The majority (90.2%) of the UCAs were less than 5 mm in diameter. The mean maximum diameter of the aneurysm sac was 3.5 mm, and the diameter was larger in women.

Most aneurysms (81%) were located in the internal carotid artery (ICA), with more than half (53.9%) in the C5–C6 segments of the ICA. A possible explanation for this, said the authors, is that the study excluded ruptured aneurysms, which are most often located in the anterior or posterior communicating arteries. In addition, the MRA technology allowed for visualization of more UCAs in the siphon segment of the internal carotid artery.

The researchers found that 8.7% of the detected lesions were potentially risky in that they were large, lobulated aneurysms or grew during follow-up and so may have been prone to rupture.

The patients with these aneurysms potentially in danger of rupture are being followed closely, said Dr. Li. “We currently follow up those patients annually by 3D MRA if the lesions remain stable — so no growth or daughter-sac formation. If lesion growth is detected at follow-up, we suggest further treatment accordingly.”

The study did not show an association between the prevalence of aneurysms and hypertension or cardiovascular disease. This was a cross-sectional study that mainly focused on the prevalence of UCAs, explained Dr. Li, adding that the association between risk factors such as hypertension and cardiovascular disease and development of UCAs in Chinese adults needs to be explored in other longitudinal studies.

The findings may not apply to the general population or to populations outside of China, said the authors.

No Higher

R. Loch Macdonald, MD, PhD, Keenan Endowed Chair in Surgery and head, Division of Neurosurgery, St. Michael’s Hospital, and professor of surgery, University of Toronto, Ontario, Canada, who has a special research interest in cerebral aneurysms, doesn’t believe that the prevalence of aneurysms is any higher in China than elsewhere in the world.

“I suspect they are not more common compared to other geographic regions and ethnicities or races and that the difference is due to a selected older population and more sensitive screening test,” used in the current study, said Dr. Macdonald when approached by Medscape Medical News for a comment.

He pointed to a previously published meta-analysis that found 3% of the population harbored an aneurysm, adjusted to a population with a mean age of 50 years that was 50% male, and expanded on why the numbers in the current study might be much higher.

“They may have found a higher incidence due to inclusion of only patients aged 35 to 75 years,” he added. “Second, the distribution of aneurysms includes many more very small proximal carotid aneurysms. These may not have been diagnosed as frequently before by other methods, so this new screening study may have detected more due to increased sensitivity of the screening method.”

Source:Medscape.com

Choosing Wisely: ACEP Lists 5 Tests to Question


The American College of Emergency Physicians (ACEP) issued a list of 5 tests and procedures that may not be cost-effective in some situations. The ACEP announced this list, which reflects its participation in the ABIM Foundation‘s Choosing Wisely campaign, at the opening session of their annual meeting in Seattle, Washington.

To lower healthcare costs and improve patient care, ACEP recommends that clinicians avoid these interventions when appropriate, after discussing that decision with patients and educating them regarding the rationale.

“ACEP needed a strategy to determine what emergency physicians could do to improve efficiency and reduce cost without affecting the quality of care we deliver,” ACEP Cost Effectiveness Task Force Chair David Ross, MD, an emergency physician in Colorado and medical director for more than 50 emergency medical services agencies in Colorado Springs, said in a news release. “The challenge also was to identify real cost savings, but also to develop consensus among emergency physicians.”

The ACEP board of directors approved the following 5 Choosing Wisely recommendations for patients seen in the emergency department:

1.      For patients with minor head injury who are deemed to be at low risk for skull fractures or hemorrhage, based on validated decision rules, clinicians should avoid head computed tomography scans. The majority of minor head injuries do not result in brain hemorrhage.

2.      For stable patients who can urinate on their own, clinicians should avoid placing indwelling urinary catheters for either urine output monitoring or patient or staff convenience.

3.      For patients likely to benefit from palliative and hospice care services, clinicians should not delay in engaging such services when available. Early referral from the emergency department can improve quality, as well as quantity, of life.

4.      For patients with uncomplicated skin and soft tissue abscesses successfully treated with incision and drainage, clinicians should provide adequate medical follow-up but avoid antibiotics and wound cultures.

5.      For children with mild to moderate, uncomplicated dehydration, clinicians should avoid giving intravenous fluids before a trial of oral rehydration therapy.

“Emergency physicians are dedicated to improving emergency care and to reducing health care costs,” ACEP President Alex Rosenau, DO, said in a news release. “These recommendations are evidence-based and developed with significant input from experts.”

An expert panel of emergency physicians and the ACEP board of directors reviewed pertinent research and input, including a survey of all ACEP members, before developing the recommendations.

In its Choosing Wisely campaign, the ABIM Foundation aims to facilitate discussion among physicians and patients about appropriate use of tests and treatments and avoidance of these interventions when the harms may outweigh the benefits.

More than 80 national, regional, and state medical specialty societies and consumer groups have joined Choosing Wisely since the campaign began in April 2012, but ACEP held off until February 2013. The delay resulted from potential conflicts of the Choosing Wisely strategy with the unique goals of emergency medicine and from concerns that the campaign does not advocate for medical liability reform.

“Overuse of medical tests is a serious problem, and health care reform is incomplete without medical liability reform,” said Dr. Rosenau. “Millions of dollars in defensive medicine are driving up the costs of health care for everyone. We will continue to encourage the ABIM Foundation and its many partners in this campaign to lend their influential voices to the need for medical liability reform.”

Source: American College of Emergency Physicians.

Increased inflammatory markers point toward higher risk for hip fracture.


Higher concentrations of inflammatory factors were associated with higher risk for hip fracture, according to study results presented here.

 “Inflammatory burden may be an important biological factor in fracture etiology, particularly for hip fractures, and now we are seeing this consistency across studies,” Kamil E. Barbour, PhD, MPH, MS, of the CDC, said. “Our association between the inflammatory markers and hip fracture was due in large part to poor renal function, so what is the possible biological mechanism for this? We know that the basic science literature shows glomerular injury may occur directly by cytokines or indirectly through mediation of immune cells. But we must acknowledge the mediation could be in the other direction where poor kidney function results in higher inflammation and subsequently results in higher fracture risk.”

 

From the Study of Osteoporotic Fractures (SOF) at year 10, researchers using data from the SOF analyzed the assays of 1,339 women (mean age, 80 years) and followed them for a median follow-up time of 6.3 years.

Researchers separated inflammatory marker levels into quartiles, showing that the HR of hip fracture and 95% CI for women in the highest quartile of inflammatory markers, as compared with those lowest quartile, was 1.7 (95% CI, 1.1-2.5) for interleukin-6, 1.5 (95% CI, 1.0-2.1) for IL-6 soluble receptor (SR), 2.0 (95% CI, 1.4-3.1) for tumor necrosis factor (TNF) SR1 and 1.2 (95% CI, 0.8-1.8) for TNF SR2.

Researchers separated inflammatory marker levels into quartiles, showing that the HR and 95% CI of hip fracture for women in the highest quartile of inflammatory markers, as compared with those in the lowestquartile, was 1.7 (95% CI, 1.1-2.5) for interleukin-6, 1.5 (95% CI, 1.0-2.1) for IL-6 soluble receptor (SR), 2.0 (95% CI, 1.4-3.1) for tumor necrosis factor (TNF) SR1 and 1.2 (95% CI, 0.8-1.8) for TNF SR2.

Women with two of the four inflammatory markers in the top quartile had an HR of hip fracture of 1.5 (95% CI, 1.1-2.1); women with three or more inflammatory markers in the top quartile had a hip fracture HR of 1.4 (95% CI, 0.9-2.3), in comparison with those women with zero or one marker (P trend=.03).

After adjusting for six potential mediators, cystatin C was most associated with the most attenuation of the dose-response relationship (P trend=.24), more so than bone mineral density (P trend=.16).

Based on this and other studies, Barbour said older women with high inflammatory markers have a higher risk for hip fracture due in large part to poor renal function.

Source: Endocrine Today.

Probiotics may save patients from deadly chemotherapy.


If you or someone you love is facing the possibility of cancer or chemotherapy, make sure they read this story. Breakthrough new science conducted at the University of Michigan and about to be published in the journal Nature reveals that intestinal health is the key to surviving chemotherapy.

 

The study itself is very difficult for laypeople to parse, however, so I’m going to translate into everyday language while also offering additional interpretations of the research that the original study author is likely unable to state due to the nutritional censorship of medical journals and universities, both of which have an anti-nutrition bias.

The upshot is this: A clinical study gave mice lethal injections of chemotherapy that would, pound for pound, kill most adult human beings, too. The study authors openly admit: “All tumors from different tissues and organs can be killed by high doses of chemotherapy and radiation, but the current challenge for treating the later-staged metastasized cancer is that you actually kill the [patient] before you kill the tumor.” (See sources below.)

Chemotherapy is deadly. It is the No. 1 cause of death for cancer patients in America, and the No. 1 side effect of chemo is more cancer. But certain mice in the study managed to survive the lethal doses of chemo. How did they do that? They were injected with a molecule that your own body produces naturally. It’s production is engineered right into your genes, and given the right gene expression in an environment of good nutrition (meaning the cellular environment), you can generate this substance all by yourself, 24 hours a day.

The substance is called “Rspo1″ or “R-spondon1.” It activates stem cell production within your own intestinal walls, and these stem cells are like super tissue regeneration machines that rebuild damaged tissues faster than the chemotherapy can destroy them, thereby allowing the patient to survive an otherwise deadly does of chemo poison.

As the study showed, 50 – 75 percent of the mice who were given R-spondon1 survived the fatal chemotherapy dose!

The cancer industry needs to find a way to stop killing all their customers

The problem with the cancer industry today is that all the conventional cancer treatments keep killing the patients. This is bad for business. So the purpose of research like the R-spondon1 research mentioned here — which was funded by a government grant — is to find ways to keep giving patients deadly doses of high-profit chemotherapy without actually killing them. You slap a patient with a dose of R-spondon1 (sold at $50,000 a dose as a patented “drug,” of course), dose ‘em up with a fatal injection of chemotherapy, and then thanks to the R-spondon1 you get a repeat cancer customers instead of a corpse.

That’s called “good business practices” in the cancer industry, which is so far best known for turning patients into body bags rather than actually curing cancer.

(Yes, there is a reason why most oncologists would never undergo chemotherapy themselves. They know it doesn’t work on 98% of all cancers.)

Probiotics are likely the key to generating your own R-spondon1

Before I discuss why these findings are so important for followers of natural health and nutrition, let me first offer a disclaimer. The research mentioned here was conducted on mice, not humans, so it isn’t full proof that the same mechanism works in humans. Nevertheless, the reason mice are used for such research is because they are nearly identical to humans in terms of biology, gene expression, endocrine system function and more.

Furthermore, even though this study used an injection of R-spondon1 as the “activator” of gene expression in endothelial cells of the intestinal lining, in truth your cells already possess the blueprint to produce R-spondon1 on their own. In fact, human intestines are coated with a layer of epithelial cells that are regenerated every 4-5 days in a healthy person. This is only possible through the activation and continued operation of intestinal stem cells, a normal function for a healthy human.

And what determines the health of those stem cells more than anything else? Their local environment which is predominantly determined by gut bacteria. If your gut bacteria are in balance, the gene expression of your epithelial cells is normal and healthy. If your gut bacteria are out of whack, so to speak, the gene expression of your epithelial cells will be suppressed, thereby slowing or halting the regenerative potential of your intestinal cells. This is why people who have imbalanced intestinal flora also suffer from inflammatory intestinal conditions such as Crohn’s, IBS and so on.

Thus, probiotics are a key determining factor in the ability of your intestines to maintain the appropriate gene expression for the very kind of rapid cellular regeneration that can help your body survive a fatal dose of chemotherapy.

Meat and dairy cause devastating gut flora imbalances that may increase susceptibility to chemotherapy drugs

This may also explain why people who eat large quantities of processed meat, cheese and dead, pasteurized dairy products — especially when combined with starchy carbohydrates and processed sugars — are far more likely to die from chemotherapy than people who eat more plant-based diets. (There isn’t yet a source to substantiate this claim, but it’s something I’ve noted from considerable personal observation. You may have noticed it too among your own family members who have undergone chemotherapy treatments. Those with the worst diets seem to have far higher fatality rates.)

Those who consume processed meat and dead dairy have their intestines filled with fiber-less, difficult-to-digest proteins that are putrefied and sit in the intestines for 2 – 5 days, typically. Dietary sugars and carbohydrates then feed the bacteria fermentation process, resulting in the rapid growth and replication of sugar-feeding bacteria that displace the kind of healthy flora which best protect intestinal wall cells.

This imbalance, I suggest, increases susceptibility to chemotherapy toxicity while simultaneously impairing the ability of the patient to absorb key nutrients that protect healthy cells from the toxicity of chemo drugs. This may explain why patients who heavily consume meat, cheese and dairy diets tend to die so easily when exposed to chemotherapy.

But there’s something even more alarming about all this that everyone needs to know…

Antibiotics may also set you up to be killed by chemo

Although the research did not directly address this question, its findings seem to indicate that the kind of gut bacteria “wipeout” caused by antibiotics could prove fatal to a chemotherapy patient.

This is especially worrisome because many cancer patients are simultaneously prescribed antibiotics as they undergo chemotherapy. This could be a death sentence in disguise. While neither the antibiotics nor the chemo directly kill the patient, the combination of sterilized gut bacteria and highly-toxic chemotherapy drugs could multiply the toxicity and prove fatal. The death certificate, however, will say the patient died from “cancer,” not from the chemotherapy which is usually the actual cause of death.

And yet, every single day in America, patients who are taking antibiotics are subjected to multiple courses of chemotherapy. This may quite literally be a death sentence for those patients.

There’s also a self-fulfilling death spiral at work in all this: following the first round of chemotherapy, many patients suffer from weakened immune system that result in symptomatic infections. Physicians respond to this by prescribing antibiotics, resulting in the patient undergoing subsequent rounds of chemotherapy with “wiped out” gut flora. So the chemo causes the problem in the first place, and then the response to the problem by western doctors makes the next round of chemo fatal. This is a self-fulfilling death spiral of failed medicine.

Oncologists seem to have no awareness whatsoever of the importance of gut bacteria in allowing patients to protect their own healthy cells from the devastating effects of chemotherapy drugs. Many oncologists, in fact, actively discourage their patients from taking any sort of supplements during chemotherapy out of an irrational, anti-scientific fear that such supplements may “interfere” with the chemo and make the treatment fail.

This is one of the many ways in which oncologists get cancer patients killed.

Takeaway points from this article:

• New research shows that a substance generated by intestinal stem cells allows subjects to survive an otherwise fatal dose of toxic chemotherapy.

• Healthy gene expression of intestinal cells allows them to naturally produce protective molecules that support and boost cell regeneration.

• Probiotics may protect and support the intestinal stem cells that help cancer patients survive toxic chemotherapy. (More studies needed to explore this and document the impact.)

• Antibiotics may be a death sentence when followed by chemotherapy.

• Oncologists need to consider the risks and benefits of postponing chemotherapy in patients who are simultaneously taking antibiotics. The combination may be deadly. Conversely, they need to consider the benefits of encouraging chemotherapy patients to take probiotic supplements before beginning chemotherapy treatment.

Source: naturalnews.com

Ground Breaking Study Could Spell the End For GMOs.


It sounds like science fiction or even quackery. However the results of this latest study conducted by Warrenstown Horticultural College and the Chemical & Environmental Science Dept., University of Limerick, Ireland, say otherwise.

This 35 page report tested the effects of “Vi-Aqua,” a system that electro-magnetically charges water, on a cross-section of vegetation from Rye Grass to ornamental plants of various species. The plant experiment confirmed enhanced vigor of growth and stronger plant structure, which increased damage resistance in the treated specimens.

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The 
study explains, “All vegetation-derived energy on this planet is solar in origin. Only approximately 1% of the solar energy, which impinges on the Earth, is captured. This is through the agency of Chlorophyll in most forms of plant life. Animal life on this planet is critically dependent upon the continued availability of energy donating vegetation for its survival. Since all living organisms have evolved in the presence of a strong natural geomagnetic field the possible influence of magnetic fields on living organisms increasingly has become the subject of research endeavors. The possibility of enhancing plant growth utilizing a natural activity such as magnetism has stimulated research over at least the past six decades.”

The study highlights the effects of the 
changes of the plants. “Sophisticated tests which measure hydrogen bonding properties indicated that EM radiation reduced the size of hydrogen bonded water networks. In particular the changes in the hydrogen bonding networks affected the solution of naturally dissolved gases in the water. This hydrogen bonding modification slowly decayed to undetectable levels several hours after the treatment was stopped. Modifying hydrogen bonding has had several possible consequences for live plants loosening the hydrogen bonding in cell walls permitted the faster growth of plants due to reduced resistance to cells elongating during the growth process.”

The implications for this technology are optimistic to say the least. If this study can be replicated we could see a major decline in the proliferation of GMOs, because this system can produce very similar resistance in plants simply by making them healthier, hardier and less prone to damage from insects and drought.

Money Isn’t a Dirty Word: How to Use Money to Serve Your Purpose.


“What we really want to do is what we are really meant to do. When we do what we are meant to do, money comes to us, doors open for us, we feel useful, and the work we do feels like play to us.” ~ Julia Cameron

So many of us cringe at the image of a person who loves money. We tend to think it’s tacky, greedy, and not noble to strive to be rich. And for those of us who want to do work that serves the world in a positive way, money can start to feel like a dirty word.

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And I’m here to change that.

I don’t believe money is the root of all evil. Nor do I believe money can buy happiness. But I do believe that when we can get rid of our hang-ups around money, it allows us to serve the world in a bigger way. Especially if your career is centered around doing good in the world, it’s important for you to embrace making money as a part of your making-a-difference strategy.

It’s time to stop shaming yourself for wanting to make money in your career or your passion-based business. You might think it’s noble to work for free or low cost and help the less fortunate, but there is nothing noble about not being able to pay your rent.

In order to do good in the world, you must be able to take care of yourself first. And when you do that, you stop playing small and you can fully step into what you were put here to do – fulfill your purpose through your work.

Here’s how you can start shifting your money mindset right now:

1. Acknowledge that what you do has value

And even more than that, acknowledge that who you are has value. All of us have our own unique gifts that we don’t think are that remarkable, when in fact, these are the very traits that others admire in us. The more you can play up who you are at your core, the more you will see the value that you bring to the world around you. And the more value you can find in your own self worth, just the way you are, the easier it is to see why people would pay you for these qualities. You are different and special, and you deserve to be paid well for doing that special thing that only you can do.

2. Start to love money

Like, really love it. Part of this practice is being grateful for all the things that money helps you do in your life. With money, you can buy yourself healthy organic food, you can support your local charities, you can give your kids an education. When you start to realize how the money you make is able to be filtered back into your life s a source of growth, you start to become grateful for every penny you earn, because you know it allows you to give back to yourself and your community.

3. Stop discounting money as something you don’t need

Stop discounting money as something you don’t need, and imagine a life where money flows freely. Recognize that you DO need money to live, and pay attention to how it would feel to no longer have to be penny pinching, or budgeting carefully every month. Imagine a life where you had all the money you wanted, more than you knew what to do with. How would you spend it? What would you do with it? Imagine the possibilities of how you could use that extra money as a force for good in the world, how many lives you could shape with it, how many of the world’s problems you could solve by re-investing it back into your community.  Start thinking of money as possibility instead of burden, and notice how much energy that brings to your purpose in the world. Money could help you build that school in Africa, or support your local animal shelter, or run the women’s group you volunteer at. Money is essential in helping support your purpose and passions.

When you stop fearing money and start allowing yourself to fall in love with it, doors open for you like you might never have imagined. Making money is not a sin and wanting money is not a sin. Money gives you the gift of taking care of yourself and those around you, which allows you to live a life that lets you help the world in a bigger way.

Money can be used as a force of good in the world. You just have to let it in.

Do you believe money is the root of all evil? What are some of the limiting beliefs you borrowed from others when it comes to money? Share your insights by joining the conversation in the comment section bellow.

Source:Purpose fairy

Stars’ twinkle reveals their character.


In 1806, English poet Jane Taylor famously lamented that a little star’s twinkle left her wondering what it was.

Fast-forward 207 years and a new analysis of starlight collected by NASA’s Kepler space telescope shows patterns in the flicker that are directly tied to the amount of boiling taking place on a star’s surface, a key indicator of its size, mass and evolutionary state.

That information, in turn, reveals volumes about any orbiting planets, including those fortuitously positioned from their parent stars for liquid surface water, apparently a key ingredient for life.

“Everything you know about planets is tied to what you know about the host star,” says Fabienne Bastien, an astronomy graduate student at Vanderbilt University.

“We don’t observe the planets directly. We observe the stars and the influence that the planets have on their stars. So in order to make any conclusions about the size of the planet or the mass of the planet as it’s pulling on the star when it’s moving, you need to know the size and the mass of the star very well.”

“That directly impacts whether or not you can claim that you have an Earth-like planet,” she says.

Bastien, who is working on a doctoral dissertation, was analysing archived Kepler data for a totally different reason when she and colleagues chanced upon strange patterns in the data that they didn’t understand.

“It was a complete surprise,” says Bastien.

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Boiling surfaces

It turns out the pattern provides a quick and relatively reliable way to determine a star’s evolutionary state.

Stars like the Sun, which is about 4.6 billion years old, eventually will evolve into red giants as they run out of fuel for nuclear fusion. The new study shows the surfaces of younger dwarf stars boiling more vigorously than older giants.

“What we are looking at here is the gravitational acceleration in the stellar outer layers, what we often call the atmosphere,” says astronomer Joergen Christensen-Dalsgaard, with Aarhus University in Denmark.

“The typical methods used have uncertainties up to 150 per cent. That very imprecise method is the easiest to do, and especially if you’re dealing with 150,000 stars and you need to characterise them all, that’s what you go to because it takes the least amount of resources. Our technique lets us beat that down to 25 per cent, which is very, very good for this field,” added Bastien.

Kepler, which collected data from about 120,000 target stars between May 2009 and May 2013, was designed to search for Earth-like planets in stars’ habitable zones,

For Bastien’s study, which appears in this week’s edition of Nature, astronomers analysed a few thousand stars in the Kepler data archive.

“If you have a large enough sample, then you start to pick out patterns in the way stars of different evolutionary states behave,” she says.

While the study is based on eight-hour flicker patterns in the visible light coming from target stars, scientists translated the data into corresponding audio wavelengths, a poignant conceptualisation that no doubt would have intrigued, and delighted, poet Taylor.

Source: http://www.abc.net.au