Test ‘may predict altitude sickness’


Mountaineers in the French Alps

Scientists say they have developed a way of predicting who will develop altitude sickness.

The condition, otherwise known as acute mountain sickness, occurs when people have difficulty adapting to low oxygen levels at high altitude.

Most cases are mild – but in rare cases there can be a potentially fatal build-up of fluid on the brain and lungs.

Altitude sickness often affects skiers and mountaineers.

It affects people only when they go above 8,000ft (2,500m).

Around 30% experience a mild form of the condition. Between 1%-2% develop the more severe form of the disease.

It is not possible to get altitude sickness in the UK because the highest mountain – Ben Nevis in Scotland – is only 4,406ft (1,344m) high.

The condition usually causes relatively mild symptoms such as headaches, nausea and dizziness. But it can in rare cases cause fluid to build up on the lungs or brain.

Current advice is to aim to acclimatise slowly to higher altitudes to give the body a chance to adapt.

Drugs which can reduce the severity of symptoms are also available, but can have side-effects.

Ultrasound check

Details of the new test are being presented to the EuroEcho-Imaging conference in Istanbul.

The researchers looked at how the heart responds to hypoxia – low oxygen levels.

They studied cardiovascular function, using non-invasive, ultrasound-based techniques, in 34 healthy volunteers once at sea level and again after going by cable car up Aiguille de Midi, a mountain in the French Alps, to a height of 12,600 ft (3,842m).

“Start Quote

An increasing number of people of all ages go to high altitude, mainly for recreational purposes but also for working without being conscious of the potential risks”

Dr Rosa Maria Bruno, Researcher

Around a third of them had experienced severe altitude sickness previously.

Participants had oxygen saturation levels monitored and had an ultrasound check of their heart function, using a portable device, after four hours on the mountain.

After 24 hours at high altitude, 13 out of 34 volunteers developed moderate to severe symptoms.

They had lower oxygen saturation levels and the ultrasound showed poorer function in the systolic (pumping) ability in the right ventricle.

The changes were not seen in people who did not display altitude sickness symptoms.

Susceptibility

Dr Rosa Maria Bruno, who led the study, said: “If these results are confirmed by larger studies, it will be possible to identify vulnerable individuals and suggest particular behaviours and drugs.

“Thus we can limit drug use (and side-effects) only to those who will really need them, and give them special advice and recommendations such as avoiding high altitudes or spending more time ascending to allow time for acclimatisation.”

She added: “At the moment we don’t know exactly why some people can adapt successfully to high altitude and other people cannot, or how to identify susceptible individuals in whom preventative strategies may be applied.

“This can be an important problem since an increasing number of people of all ages go to high altitude, mainly for recreational purposes but also for working without being conscious of the potential risks.”

The test can now only be done once people have spent at least four hours at high altitude but the team hope it can be developed so it can work sooner.

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Sudden decline in male testosterone may cause Parkinson’s disease.


The results of a new study by neurological researchers at Rush University Medical Center show that a sudden decrease of testosterone, the male sex hormone, may cause Parkinson’s like symptoms in male mice. The findings were recently published in the Journal of Biological Chemistry.

One of the major roadblocks for discovering drugs against Parkinson’s disease is the unavailability of a reliable animal model for this disease.

old-man_0

“While scientists use different toxins and a number of complex genetic approaches to model Parkinson’s disease in mice, we have found that the sudden drop in the levels of testosterone following castration is sufficient to cause persistent Parkinson’s like pathology and symptoms in male mice,” said Dr. Kalipada Pahan, lead author of the study and the Floyd A. Davis endowed professor of neurology at Rush. “We found that the supplementation of testosterone in the form of 5-alpha dihydrotestosterone (DHT) pellets reverses Parkinson’s pathology in male mice.”

“In men, testosterone levels are intimately coupled to many disease processes,” said Pahan. Typically, in healthy males, testosterone level is the maximum in the mid-30s, which then drop about one percent each year. However, testosterone levels may dip drastically due to stress or sudden turn of other life events, which may make somebody more vulnerable to Parkinson’s disease.

“Therefore, preservation of testosterone in males may be an important step to become resistant to Parkinson’s disease,” said Pahan.

Understanding how the disease works is important to developing effective drugs that protect the brain and stop the progression of Parkinson’s disease. Nitric oxide is an important molecule for our brain and the body.

“However, when nitric oxide is produced within the brain in excess by a protein called inducible nitric oxide synthase, neurons start dying,” said Pahan.

“This study has become more fascinating than we thought,” said Pahan. “After castration, levels of inducible nitric oxide synthase (iNOS) and nitric oxide go up in the brain dramatically. Interestingly, castration does not cause Parkinson’s like symptoms in male mice deficient in iNOS gene, indicating that loss of testosterone causes symptoms via increased nitric oxide production.”

“Further research must be conducted to see how we could potentially target testosterone levels in human males in order to find a viable treatment,” said Pahan.S

Source: http://machineslikeus.com

 

Everolimus treatment of abdominal lymphangioleiomyoma in five women with sporadic lymphangioleiomyomatosis.


Abstract

Objective: Lymphangioleiomyomatosis (LAM) is a rare systemic disease of young women arising from mutations in the tuberous sclerosis complex (TSC) genes, TSC1 or TSC2. This disrupts the mammalian target of rapamycin (mTOR) pathway, affecting cellular proliferation and growth. mTOR inhibitors are a promising novel therapy in LAM. The mTOR inhibitor sirolimus is reported to produce resolution of lymphatic abnormalities in LAM, but the efficiacy of the mTOR inhibitor everolimus has not been assessed. We aimed to examine the efficacy of everolimus on lymphatic abnormalities in LAM.

Design, setting and participants: Open-label treatment of five patients with sporadic LAM (sLAM) and abdominopelvic and lung involvement at the outpatient LAM clinic of a tertiary city teaching hospital. Clinical data were collected during treatment of the women and included regular clinical reviews, everolimus levels, lung function and computed tomography assessment before and after 6 months of everolimus treatment.

Main outcome measures: Symptoms and level of resolution of lymphangioleiomyomas.

Results: All five women experienced significant shrinkage or complete resolution of the lymphangioleiomyomas during treatment. In one woman, cessation of everolimus resulted in recurrence of symptoms. Adverse events were compatible with the known side-effect profile of everolimus, but overall the drug was well tolerated.

Conclusions: This is the first report to suggest that everolimus has efficacy in the treatment of lymphangioleiomyoma and chylous ascites in sLAM.

Discussion

Although LAM frequently presents with respiratory symptoms, abdominal involvement occurs in up to 70% of cases,14 with abdominal lymphangioleiomyomas in 16% of cases.2 Women may present with abdominal pain and swelling, and refractory chylous ascites, or with non-specific signs such as infertility or perimenstrual abdominal discomfort.4Treatment is generally unsatisfactory, with medical therapies ineffective, and repeated abdominocentesis resulting in fluid reaccumulation, protein loss and potential infection.

The use of mTOR therapy in LAM is a targeted approach to an abnormality arising from a genetic mutation affecting multiple systems. The 2011 MILES trial showed that treatment with sirolimus in LAM was associated with a slower decline in lung function, improvement in quality of life and shrinkage of renal AMLs, but abdominal LAM was not the focus of that trial.3 To date, single-case reports and one observational series have documented regression of abdominal lymphangioleiomyomas with sirolimus or temsirolimus treatment,69,11 but there are no reports on everolimus. Our case series suggests that the efficacy of mTOR inhibitors extends to everolimus, and that this has good effect on abdominal LAM, which has been very difficult to treat in the past. Previous studies have shown that mTOR inhibitor treatment needs to be continued in TSC, but longitudinal data in LAM are limited.3,7 This is the first study to report everolimus treatment for LAM for several years, with all five women continuing on everolimus therapy. This is significant because the efficacy of mTOR inhibitors appears to rely on sustained therapy.3,11

Everolimus is a derivative of sirolimus and has a very similar side-effect profile. It has a shorter elimination half-life (about 30 hours) and greater relative bioavailability, compared with sirolimus.15 We used a lower dose of everolimus than the dose of sirolimus that was used in the MILES trial. The everolimus dose we used was consistent with the lower range of doses used in lung transplantation in our centre, with the aim of producing fewer side effects. Overall, everolimus was well tolerated and side effects, although significant, were within its described profile.

In summary, all women with sLAM showed a good response to treatment, with disappearance or shrinkage of abdominal lymphangioleiomyomas in four of five of cases, and clinical resolution of the lymphangioleiomyoma in the fifth. Abdominal symptoms resolved. Cessation of the therapy in one patient resulted in recurrence of ascites, and reinstitution of treatment resulted in resolution again. This is similar to the MILES trial, in which continued treatment was required.3 We suggest that everolimus treatment may be an effective long-term therapy for lymphangioleiomyomas and chylous ascites, which requires further evaluation in an appropriately designed controlled trial.

Source: MJA

 

 

 

 

Adverse respiratory effects associated with cadmium exposure in small-scale jewellery workshops in India.


Abstract

Background Cadmium (Cd) is an important metal with both common occupational and environmental sources of exposure. Although it is likely to cause adverse respiratory effects, relevant human data are relatively sparse.

Methods A cross-sectional study of 133 workers in jewellery workshops using Cd under poor hygienic conditions and 54 referent jewellery sales staffs was performed. We assessed symptoms, performed spirometry, measured urinary Cd levels in all study subjects and quantified airborne total oxidant contents for 35 job areas in which the studied workforce was employed. We tested the association of symptoms with exposure relative to the unexposed referents using logistic regression analysis, and tested the association between urinary Cd levels and lung function using multiple regression analysis, adjusting for demographics, smoking and area-level airborne oxidants.

Results Exposed workers had 10 times higher urinary Cd values than referents (geometric mean 5.8 vs 0.41 µg/dl; p<0.01). Of the exposed subjects, 75% reported respiratory tract symptoms compared with 33% of the referents (OR=3.1, 95% CI 1.4 to 7.3). Forced vital capacity (FVC) and forced expiratory volume in 1 s (FEV1) were also lower among the exposed workers than the referents (>600 ml decrement for each, p<0.001). For every 1 µg increase in urinary Cd there was a 34 ml decrement in FVC and a 39 ml decrement in FEV1(p<0.01), taking into account other covariates including workplace airborne oxidant concentrations.

Conclusions This cohort of heavily exposed jewellery workers experienced frequent respiratory symptoms and manifested a marked deficit in lung function, demonstrating a strong response to Cd exposure.

Source: Thorax

Cooking fuels and prevalence of asthma: a global analysis of phase three of the International Study of Asthma and Allergies in Childhood (ISAAC).


Background

Indoor air pollution from a range of household cooking fuels has been implicated in the development and exacerbation of respiratory diseases. In both rich and poor countries, the effects of cooking fuels on asthma and allergies in childhood are unclear. We investigated the association between asthma and the use of a range of cooking fuels around the world.

Methods

For phase three of the International Study of Asthma and Allergies in Childhood (ISAAC), written questionnaires were self-completed at school by secondary school students aged 13—14 years, 244 734 (78%) of whom were then shown a video questionnaire on wheezing symptoms. Parents of children aged 6—7 years completed the written questionnaire at home. We investigated the association between types of cooking fuels and symptoms of asthma using logistic regression. Adjustments were made for sex, region of the world, language, gross national income, maternal education, parental smoking, and six other subject-specific covariates. The ISAAC study is now closed, but researchers can continue to use the instruments for further research.

Findings

Data were collected between 1999 and 2004. 512 707 primary and secondary school children from 108 centres in 47 countries were included in the analysis. The use of an open fire for cooking was associated with an increased risk of symptoms of asthma and reported asthma in both children aged 6—7 years (odds ratio [OR] for wheeze in the past year, 1·78, 95% CI 1·51—2·10) and those aged 13—14 years (OR 1·20, 95% CI 1·06—1·37). In the final multivariate analyses, ORs for wheeze in the past year and the use of solely an open fire for cooking were 2·17 (95% CI 1·64—2·87) for children aged 6—7 years and 1·35 (1·11—1·64) for children aged 13—14 years. Odds ratios for wheeze in the past year and the use of open fire in combination with other fuels for cooking were 1·51 (1·25—1·81 for children aged 6—7 years and 1·35 (1·15—1·58) for those aged 13—14 years. In both age groups, we detected no evidence of an association between the use of gas as a cooking fuel and either asthma symptoms or asthma diagnosis.

Interpretation

The use of open fires for cooking is associated with an increased risk of symptoms of asthma and of asthma diagnosis in children. Because a large percentage of the world population uses open fires for cooking, this method of cooking might be an important modifiable risk factor if the association is proven to be causal.

Source: Lancet

Are inhaled longacting β2 agonists detrimental to asthma?


Possible adverse effects of adrenergic bronchodilators in asthma have been the subject of discussion for more than half a century, with recent intense debate about the safety of longacting β agonists (LABAs). In this Debate, we consider the issues of bronchodilator and bronchoprotective tolerance resulting from the frequent use of bronchodilators, which is noted particularly with shortacting drugs, but has also been shown to occur quicker and to a greater extent with LABAs. Increased allergen responsiveness and masking allowing inflammation to increase, while symptoms and lung function remain apparently controlled, have also been observed. Studies in which LABAs were used as monotherapy were associated with increased mortality. However, several studies have shown the benefits of adding LABAs to inhaled corticosteroids (ICS). Meta-analyses of asthma clinical trials involving LABAs showed that, when given with mandatory ICS, LABAs were not associated with an increased risk of death, intubations, or hospital admission for exacerbations when compared with use of the same dose of ICS only. Withdrawal of LABA therapy once symptom control is achieved is often associated with subsequent loss of symptom control. When used for appropriate indications, LABAs should be combined with ICS in one inhaler so that monotherapy is not possible.

Source: lancet

 

Gamma Knife surgery for the treatment of patients with asymptomatic meningiomas.


Abstract

OBJECT

Increasingly, meningiomas are detected incidentally, prior to symptom development. While these lesions are traditionally managed conservatively until symptoms develop or lesion growth occurs, it is conceivable that patients at high risk for symptom development may benefit from earlier intervention prior to the appearance of symptoms. However, little research has been performed to determine whether Gamma Knife surgery (GKS) can alter the rate of symptom development in such patients.

METHODS

A retrospective case study was performed by screening the University of Virginia GKS database for patients treated for asymptomatic meningiomas. From the patient’s medical records, pertinent demographic and treatment information was obtained. Yearly follow-up MRI had been performed to assess tumor control and detect signs of radiation-induced injury. Clinical follow-up via neurological examination had been performed to assess symptom development.

RESULTS

Forty-two patients, 33 females (78.6%) and 9 males (21.4%), with 42 asymptomatic meningiomas were included in the analysis. The median age at GKS was 53 years. The most common lesion location was the cerebral convexities (10 lesions [23.8%]), and the median lesion size was 4.0 ml. The median duration of imaging and clinical follow-ups was 59 and 76 months, respectively. During the follow-up period, 1 tumor (2.4%) increased in size, 2 patients (4.8%) demonstrated symptoms, and 1 patient (2.4%) exhibited possible signs of radiation-induced injury. Thus, actuarial tumor control rates were 100%, 95.7%, and 95.7% for 2, 5, and 10 years, respectively. Actuarial symptom control at 5 and 10 years was 97% and 93.1%, respectively. Overall progression-free survival was 91.1% and 77.8% at 5 and 10 years, respectively.

CONCLUSIONS

Compared with published rates of symptom development in patients with untreated meningiomas, results in this study indicated that patients with asymptomatic lesions may benefit from prophylactic radiosurgery prior to the appearance of symptoms. Additionally, GKS is a treatment option that offers low morbidity.

Source: :  journal of neurosurgery

 

 

The Effect of Dexlansoprazole MR on Nocturnal Heartburn and GERD-Related Sleep Disturbances in Patients With Symptomatic GERD.


OBJECTIVES:

 

Nocturnal heartburn and related sleep disturbances are common among patients with gastroesophageal reflux disease (GERD). This study evaluated the efficacy of dexlansoprazole MR 30mg in relieving nocturnal heartburn and GERD-related sleep disturbances, improving work productivity, and decreasing nocturnal symptom severity in patients with symptomatic GERD.

METHODS:

 

Patients (N=305) with frequent, moderate-to-very severe nocturnal heartburn and associated sleep disturbances were randomized 1:1 in a double-blind fashion to receive dexlansoprazole MR or placebo once daily for 4 weeks. The primary end point was the percentage of nights without heartburn. Secondary end points were the percentage of patients with relief of nocturnal heartburn and of GERD-related sleep disturbances over the last 7 days of treatment. At baseline and week 4/final visit, patients completed questionnaires that assessed sleep quality, work productivity, and the severity and impact of nocturnal GERD symptoms.

RESULTS:

 

Dexlansoprazole MR 30mg (n=152) was superior to placebo (n=153) in median percentage of nights without heartburn (73.1 vs. 35.7%, respectively; P<0.001). Dexlansoprazole MR was significantly better than placebo in percentage of patients with relief of nocturnal heartburn and GERD-related sleep disturbances (47.5 vs. 19.6%, 69.7 vs. 47.9%, respectively; P<0.001), and led to significantly greater improvements in sleep quality and work productivity and decreased nocturnal symptom severity. Adverse events were similar across treatment groups.

CONCLUSIONS:

 

In patients with symptomatic GERD, dexlansoprazole MR 30mg is significantly more efficacious than placebo in providing relief from nocturnal heartburn, in reducing GERD-related sleep disturbances and the consequent impairments in work productivity, and in improving sleep quality/quality of life.

DISCUSSION

Dexlansoprazole MR 30 mg daily was significantly better than placebo in improving symptoms of nocturnal heartburn in symptomatic GERD patients with frequent, moderate-to-very severe nocturnal heartburn leading to improved sleep quality, and decreased symptom severity and impact on morning activities. Dexlansoprazole MR 30 mg was also effective in increasing work productivity and reducing activity impairment. It should be noted that patients enrolled in this study had to be responsive to acid-suppression therapy. This inclusion criterion was used to limit the number of functional heartburn patients enrolled in the study.

During this study, the median percentage of nights without heartburn over 4 weeks for the intent-to-treat patients receiving dexlansoprazole MR 30 mg was 73.1%. In a previous dexlansoprazole MR phase 3 study, which assessed efficacy and safety among patients with non-erosive reflux disease, this value was 80.8%(vs. 51.7% for placebo; P<0.00001) (23), supporting the results of our study. Furthermore, the therapeutic gain, or the difference between active study drug and placebo, seen in this current nocturnal heartburn study was greater than that observed in a previous phase 3 symptomatic GERD trial (37 vs. 29%) (23).

Stratification of the primary end point by baseline mean nocturnal symptom severity reveals that patients with the most severe symptoms experience the greatest therapeutic gain. Although the median percentage of nights free of nocturnal heartburn declined with increasing baseline severity, the therapeutic gain increased. The therapeutic gain experienced by patients receiving dexlansoprazole MR with severe-to-very severe baseline nocturnal symptoms is more than twice that experienced by patients with mild-to-moderate or moderate-to-severe baseline nocturnal symptoms. Patients in the severe-to-very severe group who received placebo experienced a median of 0% heartburn-free nights, while the 34 patients in the dexlansoprazole MR group reported a median of 66%of their nights as heartburn free during the 4 weeks of the trial. This could be explained by the finding that patients with more severe non-erosive reflux disease (NERD; as determined by pH testing) are more responsive to PPI therapy than patients with less severe NERD (24). This is in contrast to the response of erosive esophagitis patients receiving anti-reflux treatment (25).

During the last 7 days of the study, 48 and 70% of patients receiving dexlansoprazole MR reported relief of nocturnal heartburn and GERD-related sleep disturbances, respectively, which were significantly greater than with placebo (P<0.001 for each comparison). A similar pattern was observed by Johnson et al.(26), where patients receiving esomeprazole, 20 or 40 mg, reported higher rates of relief from GERD-related sleep disturbances from nocturnal heartburn during the last 7 days of a 4-week study.

A significantly lower frequency of GERD-related sleep disturbances was observed in the dexlansoprazole MR group. Dexlansoprazole MR resulted in a significantly lower frequency of the different types of sleep disturbances attributed to nocturnal heartburn. Of note, the percentage of nights with sleep disturbances due to other causes did not differ significantly between treatment groups. Taken together, these results suggest that patients taking dexlansoprazole MR 30 mg can expect a reduction in or relief from nocturnal heartburn symptoms and therefore better sleep quality.

Recording daily symptoms via diaries is common in clinical trials where symptom relief is a primary outcome (27). However, the limitations of this approach, particularly with paper diaries, include non-adherence (skipping entries) and “hoarding” (the retrospective completion of entries), which can lead to recall errors (28,29). Objective analyses of paper diary use have shown high rates of both non-adherence and hoarding (29). Electronic diaries, such as those used during this study, do not allow for hoarding beyond 24 h before the scheduled entry. Compliance with diary entries was high: ≥90% in 87% of patients.

The efficacy of dexlansoprazole MR for the relief of nocturnal heartburn and relief from GERD-related sleep disturbances is further supported by the improvements seen in the patient-reported outcomes. Patients receiving dexlansoprazole MR reported significantly greater improvements from baseline in sleep quality compared with placebo, which manifested as greater decreases in PSQI scores. Decreases in overall and subscale N-GSSIQ scores also showed greater efficacy for dexlansoprazole MR 30 mg compared with placebo in decreasing symptom severity, next morning impact of nocturnal symptoms, and concern regarding nocturnal GERD among the patients, thus demonstrating improvements in HRQoL. Significant improvements in HRQoL due to treatment of heartburn, both daytime and nocturnal, have been documented previously (23,26,30,31).

Accompanying these improvements in sleep quality, decreased symptom severity, and reduced impact the following morning were decreases in impairments in work productivity, as demonstrated by decreases in the WPAI scores. Treatment with dexlansoprazole MR was more effective than placebo in decreasing impairment while working and improving overall work productivity and functionality during regular activities. Furthermore, this treatment was more effective in reducing the number of work hours missed due to GERD-related sleep disturbances. These results are not unexpected when one considers the connection between repeated lack of sleep during the night and daytime sleepiness (9), as well as reduced HRQoL and work productivity (11). The negative impact of nocturnal GERD on HRQoL and work productivity is well recognized (7,8,10).

A recent survey of over 600 GERD patients on various PPI therapies found that the majority of patients continued to experience heartburn, with 83% experiencing nocturnal symptoms and almost a quarter of these patients reporting severe or very severe nocturnal symptoms (32). Daily dosing of dexlansoprazole MR 30 mg may reduce the likelihood of persistent nocturnal symptoms due to its extended duration of plasma drug levels (33); however, additional studies are needed to determine if this property equates to improved clinical outcomes.

In the above-mentioned survey (32), only approximately one-half of the patients surveyed took their PPI within the recommended 1 h to 30 min before breakfast. Poor compliance with PPI therapy is likely the most common cause for PPI failure (25). In this study, patients were to take the study drug in the morning, without regard to food. Comparable acid suppression with dexlansoprazole MR dosing has been demonstrated regardless of the timing of food intake (fasting, before or after breakfast) (34) or the time of day (before breakfast, lunch, dinner, or evening snack) (35). Although additional studies are needed to assess the impact of various dosing timings of dexlansoprazole MR on GERD symptoms, it is not unreasonable to suggest that increased flexibility in administration, and therefore increased compliance, would lead to reduced symptoms, particularly at night.

Dexlansoprazole MR 30 mg was well tolerated by patients in this current trial. Rates of treatment-emergent AEs were low and similar between the dexlansoprazole MR and placebo groups, including the premature discontinuation due to AEs. Recent analyses of pooled safety data from the phase 3 pivotal trials demonstrated that the safety profile of dexlansoprazole MR 30 mg was comparable to that of lansoprazole 30 mg (36).

The economic implications of this study are readily apparent. The favorable effect of improvement for work productivity has significant implications to payers and employers. For the patients receiving dexlansoprazole MR compared with placebo, there was an apparent work productivity advantage—$38 for the fourth week ($227 vs. $189). If these savings were extrapolated over the 4-week study, the advantage would be $152/treated patient. This type of modeling allows for the development of a business plan for payers–employers to evaluate the cost benefits of effective therapy. By this type of analysis, the “investment” cost of therapy can be analyzed against the returns of improved work productivity.

This study has several limitations, the first being the lack of an active comparator, another PPI. Although direct comparisons of efficacy results from different trials cannot be made, a recent review comparing the efficacy of various PPIs (not including dexlansoprazole MR) in relieving or resolving nocturnal heartburn in a clinical trial setting found no outstanding differences in efficacy between comparable doses (37). Placebo has been the standard comparator used in other studies assessing the efficacy of a PPI for nocturnal heartburn and in all studies of GERD-related sleep disturbances (23,26,38).

A second limitation is the lack of pH monitoring to document the level of acid suppression or to distinguish symptomatic non-erosive reflux from functional heartburn. It is difficult to attribute any symptom to reflux without direct esophageal monitoring. The primary reason for no pH monitoring during this study was the potential sleep disruption caused by an intra-esophageal pH electrode. However, to mitigate lack of pH monitoring, inclusion criteria mandated previous response to acid-suppression therapy. We also did not utilize sleep labs for an objective assessment of sleep quality, which could be considered another limitation. Because a sleep lab is an artificial environment, it is likely that many patients would not have slept the same way there as they would at home. Changes in sleep quality are subjective, whether as reported in the daily diaries or in the PSQI and N-GSSIQ.

A third limitation is the assessment of response for productivity analysis limited to the fourth week of therapy. Questions remain as to what the effect is on a weekly basis beyond the early therapy effect on these particular measurements. Furthermore, an area of further research is to evaluate whether these favorable effects persist, wane, or continue to improve with extended therapy.

In summary, dexlansoprazole MR 30 mg was significantly more efficacious in providing relief from nocturnal heartburn and in reducing GERD-related sleep disturbances compared with placebo in symptomatic GERD patients with moderate-to-very severe nocturnal heartburn. This study also demonstrated significantly greater improvements in sleep quality, HRQoL, and work productivity for patients receiving dexlansoprazole MR compared with those receiving placebo.

Furthermore, there were notable economic implications with favorable advantages evident for patients treated with dexlansoprazole MR—allowing for estimates of a calculable rate of return on investment for effective therapy.

Source: Nature/AJG

 

patients presenting to primary care with acute cough: diagnostic study.


Abstract

Objectives To quantify the diagnostic accuracy of selected inflammatory markers in addition to symptoms and signs for predicting pneumonia and to derive a diagnostic tool.

Design Diagnostic study performed between 2007 and 2010. Participants had their history taken, underwent physical examination and measurement of C reactive protein (CRP) and procalcitonin in venous blood on the day they first consulted, and underwent chest radiography within seven days.

Setting Primary care centres in 12 European countries.

Participants Adults presenting with acute cough.

Main outcome measures Pneumonia as determined by radiologists, who were blind to all other information when they judged chest radiographs.

Results Of 3106 eligible patients, 286 were excluded because of missing or inadequate chest radiographs, leaving 2820 patients (mean age 50, 40% men) of whom 140 (5%) had pneumonia. Re-assessment of a subset of 1675 chest radiographs showed agreement in 94% (κ 0.45, 95% confidence interval 0.36 to 0.54). Six published “symptoms and signs models” varied in their discrimination (area under receiver operating characteristics curve (ROC) ranged from 0.55 (95% confidence interval 0.50 to 0.61) to 0.71 (0.66 to 0.76)). The optimal combination of clinical prediction items derived from our patients included absence of runny nose and presence of breathlessness, crackles and diminished breath sounds on auscultation, tachycardia, and fever, with an ROC area of 0.70 (0.65 to 0.75). Addition of CRP at the optimal cut off of >30 mg/L increased the ROC area to 0.77 (0.73 to 0.81) and improved the diagnostic classification (net reclassification improvement 28%). In the 1556 patients classified according to symptoms, signs, and CRP >30 mg/L as “low risk” (<2.5%) for pneumonia, the prevalence of pneumonia was 2%. In the 132 patients classified as “high risk” (>20%), the prevalence of pneumonia was 31%. The positive likelihood ratio of low, intermediate, and high risk for pneumonia was 0.4, 1.2, and 8.6 respectively. Measurement of procalcitonin added no relevant additional diagnostic information. A simplified diagnostic score based on symptoms, signs, and CRP >30 mg/L resulted in proportions of pneumonia of 0.7%, 3.8%, and 18.2% in the low, intermediate, and high risk group respectively.

Conclusions A clinical rule based on symptoms and signs to predict pneumonia in patients presenting to primary care with acute cough performed best in patients with mild or severe clinical presentation. Addition of CRP concentration at the optimal cut off of >30 mg/L improved diagnostic information, but measurement of procalcitonin concentration did not add clinically relevant information in this group.

 

What is already known on this topic

  • Studies have evaluated the diagnostic accuracy of signs and symptoms for pneumonia, but there is limited evidence applicable to primary care
  • The added diagnostic value of C reactive protein (CRP) and procalcitonin concentrations to clinical signs and symptoms is unknown
  • Symptoms and signs (absence of runny nose and presence of breathlessness, crackles and diminished breath sounds on auscultation, tachycardia, and fever) have moderate diagnostic accuracy for pneumonia in patients who present in primary care with acute cough
  • CRP concentration at the optimal threshold of >30 mg/L adds some diagnostic information by increasing diagnostic certainty in the patients when doubt remains after history and physical examination
  • Procalcitonin concentration adds no clinically relevant information in primary care

What this study adds

 

Source: BMJ

Use of serum C reactive protein and procalcitonin concentrations in addition to symptoms and signs to predict pneumonia in patients presenting to primary care with acute cough: diagnostic study.


Abstract

Objectives To quantify the diagnostic accuracy of selected inflammatory markers in addition to symptoms and signs for predicting pneumonia and to derive a diagnostic tool.

Design Diagnostic study performed between 2007 and 2010. Participants had their history taken, underwent physical examination and measurement of C reactive protein (CRP) and procalcitonin in venous blood on the day they first consulted, and underwent chest radiography within seven days.

Setting Primary care centres in 12 European countries.

Participants Adults presenting with acute cough.

Main outcome measures Pneumonia as determined by radiologists, who were blind to all other information when they judged chest radiographs.

Results Of 3106 eligible patients, 286 were excluded because of missing or inadequate chest radiographs, leaving 2820 patients (mean age 50, 40% men) of whom 140 (5%) had pneumonia. Re-assessment of a subset of 1675 chest radiographs showed agreement in 94% (κ 0.45, 95% confidence interval 0.36 to 0.54). Six published “symptoms and signs models” varied in their discrimination (area under receiver operating characteristics curve (ROC) ranged from 0.55 (95% confidence interval 0.50 to 0.61) to 0.71 (0.66 to 0.76)). The optimal combination of clinical prediction items derived from our patients included absence of runny nose and presence of breathlessness, crackles and diminished breath sounds on auscultation, tachycardia, and fever, with an ROC area of 0.70 (0.65 to 0.75). Addition of CRP at the optimal cut off of >30 mg/L increased the ROC area to 0.77 (0.73 to 0.81) and improved the diagnostic classification (net reclassification improvement 28%). In the 1556 patients classified according to symptoms, signs, and CRP >30 mg/L as “low risk” (<2.5%) for pneumonia, the prevalence of pneumonia was 2%. In the 132 patients classified as “high risk” (>20%), the prevalence of pneumonia was 31%. The positive likelihood ratio of low, intermediate, and high risk for pneumonia was 0.4, 1.2, and 8.6 respectively. Measurement of procalcitonin added no relevant additional diagnostic information. A simplified diagnostic score based on symptoms, signs, and CRP >30 mg/L resulted in proportions of pneumonia of 0.7%, 3.8%, and 18.2% in the low, intermediate, and high risk group respectively.

Conclusions A clinical rule based on symptoms and signs to predict pneumonia in patients presenting to primary care with acute cough performed best in patients with mild or severe clinical presentation. Addition of CRP concentration at the optimal cut off of >30 mg/L improved diagnostic information, but measurement of procalcitonin concentration did not add clinically relevant information in this group.

Discussion

Main findings

Pneumonia was diagnosed by chest x radiography in 140 (5%) of the 2820 patients presenting to primary care with acute cough. The optimal combination of symptoms and signs for predicting pneumonia was absence of runny nose and presence of breathlessness, crackles and diminished breath sounds on auscultation, tachycardia, and fever. Signs and symptoms were useful in correctly identifying patients with a “low” (<2.5%) or “high” (>20%) diagnostic risk in 26% of patients. In the 74% of patients in whom diagnostic doubt remained (estimated risk 2.5%-20%), measurement of C reactive protein (CRP) concentration helped to correctly exclude pneumonia. A simplified diagnostic score based on symptoms, signs, and CRP concentration resulted in proportions of pneumonia of 0.7%, 4%, and 18% in the low, intermediate, and high risk group, respectively. Measurement of procalcitonin concentration had no clinically relevant added value in this setting.

Strengths and limitations

This is the first study to quantify the independent diagnostic value of symptoms, signs, and additional diagnostic value of inflammatory markers for pneumonia in patients presenting with acute cough in primary care that included an adequate number of cases of pneumonia. All blood samples were analysed in the same laboratory with standardised procedures. Serum CRP and procalcitonin concentrations were measured by conventional venous blood tests in a diagnostic laboratory and not with a point of care test. The added value of CRP might be different and could be lower when measured with a point of care test in general practice. Nonetheless, agreement between point of care test results and a conventional reference test has been shown to be good.44

Given how common lower respiratory tract infections are, many more eligible patients presented during the recruitment period than were approached about participation in this study, and therefore we probably did not achieve the goals of recruiting all consecutive, eligible patients. Nevertheless, we do not believe that there was important clinical selection bias because feedback from recruiting clinicians during and after the study was that the time required to recruit and assess each patient made sequential recruitment of every eligible patient impossible.

Chest radiographs were examined by local radiologists. We attempted to increase uniformity in assessment by implementing a protocol for reporting. While there was some variability between observers, the moderate unweighted κ of 0.45 was similar to that reported in other studies.18 20

We did not attempt to distinguish between bacterial and viral pneumonia as this is not feasible in routine primary care.14 45 All available relevant guidelines advocate identification of patients with pneumonia and treatment with antibiotics without further aetiological testing.14

Comparison with other studies

Absence of a runny nose and presence of dry cough, breathlessness, chest pain, diarrhoea, fever, and crackles have previously been found to have diagnostic value for pneumonia in primary care populations.7 9 “Tachycardia” and “diminished vesicular breathing” have diagnostic value in secondary care populations.3 6 8 11 We were able to confirm the predictive value of most of these items, apart from chest pain and diarrhoea. Differences between our findings and those from previous studies could relate to the difference in prevalence of pneumonia, inclusion criteria, and outcome definition.

Our finding that CRP concentration can be low in people with pneumonia is not new. Flanders and colleagues reported on a small subgroup of patients with pneumonia who had a CRP of less than 11 mg/L.3 In the 54 patients with pneumonia with low CRP in our study, the estimated diagnostic risk of pneumonia was high (n=3) or intermediate (n=51) based on history and physical examination results as defined in our model. These findings emphasise that CRP test results should be interpreted together with clinical findings.

Of the factors known to lower CRP—such as steroid use46 and duration of disease47—only steroid use (including both oral and inhaled steroids) was significantly more prevalent in the group of patients with pneumonia with low CRP concentration. Exclusion of all steroid users from our analyses resulted in a similar association between CRP concentration and pneumonia.

Procalcitonin concentrations in our study were higher in patients with pneumonia and comparable with previous findings in patients with lower respiratory tract infection in primary care.17 48 They did not, however, add meaningful diagnostic information. Holm and colleagues showed a clear association between procalcitonin concentration and radiographic pneumonia as well as bacterial infection,17 but the positive predictive value was too low to be useful in clinical practice. Our findings support this conclusion. Moreover, Holm and colleagues studied a population with a higher prevalence of pneumonia (13%) and did not combine history and physical examination with procalcitonin test results.17

Implications for practice and conclusions

Although the diagnostic “symptoms and signs” model presented in this study assigned an intermediate diagnostic risk of pneumonia to most patients, history taking and physical examination alone enabled general practitioners to correctly identify a small group of patients at high risk. Chest radiography and/or (empirical) antibiotic treatment should therefore be considered in these patients. In these more severely ill patients, point of care tests, including CRP, do not seem to be useful. In patients with a low risk of pneumonia based on symptoms and signs, it seems justified to withhold further diagnostic investigation and not to treat with antibiotics.

CRP has additional diagnostic value in patients with an intermediate diagnostic risk of pneumonia as determined by symptoms and signs alone, especially in appropriately excluding pneumonia. Procalcitonin has no additional diagnostic value in primary care.

The simplified score derived from the regression models is more suitable for uptake in daily care than the regression models. The downside of the simplified score is that it is less precise and contains less diagnostic information. To determine whether our diagnostic model improves clinical outcomes in everyday practice would require an implementation study in which general practitioners use point of care CRP testing with outcomes such as patient recovery and the unnecessary prescription of antibiotics. Further research should also determine the performance of CRP in other settings where pneumonia is more prevalent or where patients are more severely ill.

What is already known on this topic

  • Studies have evaluated the diagnostic accuracy of signs and symptoms for pneumonia, but there is limited evidence applicable to primary care
  • The added diagnostic value of C reactive protein (CRP) and procalcitonin concentrations to clinical signs and symptoms is unknown
  • Symptoms and signs (absence of runny nose and presence of breathlessness, crackles and diminished breath sounds on auscultation, tachycardia, and fever) have moderate diagnostic accuracy for pneumonia in patients who present in primary care with acute cough
  • CRP concentration at the optimal threshold of >30 mg/L adds some diagnostic information by increasing diagnostic certainty in the patients when doubt remains after history and physical examination
  • Procalcitonin concentration adds no clinically relevant information in primary care

What this study adds

Source: BMj