The high frequencies and pitch found in pop and rock music cause vibrations that enhanced energy generation in solar cells containing a cluster of ‘nanorods’, leading to a 40 per cent increase in efficiency of the solar cells.
The study has implications for improving energy generation from sunlight, particularly for the development of new, lower cost, printed solar cells.
The researchers grew billions of tiny rods (nanorods) made from zinc oxide, then covered them with an active polymer to form a device that converts sunlight into electricity.
Using the special properties of the zinc oxide material, the team was able to show that sound levels as low as 75 decibels (equivalent to a typical roadside noise or a printer in an office) could significantly improve the solar cell performance.
“After investigating systems for converting vibrations into electricity this is a really exciting development that shows a similar set of physical properties can also enhance the performance of a photovoltaic,” said Dr Steve Dunn, Reader in Nanoscale Materials from Queen Mary’s School of Engineering and Materials Science and co-author of the paper.
Scientists had previously shown that applying pressure or strain to zinc oxide materials could result in voltage outputs, known as the piezoelectric effect. However, the effect of these piezoelectric voltages on solar cell efficiency had not received significant attention before.
“We thought the soundwaves, which produce random fluctuations, would cancel each other out and so didn’t expect to see any significant overall effect on the power output,” said James Durrant, Professor of Photochemistry at Imperial College London, who co-led the study.
“We tried playing music instead of dull flat sounds, as this helped us explore the effect of different pitches. The biggest difference we found was when we played pop music rather than classical, which we now realise is because our acoustic solar cells respond best to the higher pitched sounds present in pop music,” he concluded.
The discovery could be used to power devices that are exposed to acoustic vibrations, such as air conditioning units or within cars and other vehicles.
Co-author Dr Joe Briscoe also from Queen Mary’s School of Engineering and Materials Science, commented: “The whole device extremely simple and inexpensive to produce as the zinc oxide was grown using a simple, chemical solution technique and the polymer was also deposited from a solution.”
Dr Dunn added: “The work highlights the benefits of collaboration to develop new and interesting systems and scientific understanding.”
Pilot Safety Study of a Novel Operator-Independent Ultrasound Device in Patients With Acute Ischemic Stroke
The Combined Lysis of Thrombus in Brain Ischemia With Transcranial Ultrasound and Systemic T-PA-Hands-Free (CLOTBUST-HF) study is a first-in-human, National Institutes of Health–sponsored, multicenter, open-label, pilot safety trial of tissue-type plasminogen activator (tPA) plus a novel operator-independent ultrasound device in patients with ischemic stroke caused by proximal intracranial occlusion.
All patients received standard-dose intravenous tPA, and shortly after tPA bolus, the CLOTBUST-HF device delivered 2-hour therapeutic exposure to 2-MHz pulsed-wave ultrasound. Primary outcome was occurrence of symptomatic intracerebral hemorrhage. All patients underwent pretreatment and post-treatment transcranial Doppler ultrasound or CT angiography. National Institutes of Health Stroke Scale scores were collected at 2 hours and modified Rankin scale at 90 days.
Summary characteristics of all 20 enrolled patients were 60% men, mean age of 63 (SD=14) years, and median National Institutes of Health Stroke Scale of 15. Sites of pretreatment occlusion were as follows: 14 of 20 (70%) middle cerebral artery, 3 of 20 (15%) terminal internal carotid artery, and 3 of 20 (15%) vertebral artery. The median (interquartile range) time to tPA at the beginning of sonothrombolysis was 22 (13.5–29.0) minutes. All patients tolerated the entire 2 hours of insonation, and none developed symptomatic intracerebral hemorrhage. No serious adverse events were related to the study device. Rates of 2-hour recanalization were as follows: 8 of 20 (40%; 95% confidence interval, 19%–64%) complete and 2 of 20 (10%; 95% confidence interval, 1%–32%) partial. Middle cerebral artery occlusions demonstrated the greatest complete recanalization rate: 8 of 14 (57%; 95% confidence interval, 29%–82%). At 90 days, 5 of 20 (25%, 95% confidence interval, 7%–49) patients had a modified Rankin scale of 0 to 1.
Sonothrombolysis using a novel, operator-independent device, in combination with systemic tPA, seems safe, and recanalization rates warrant evaluation in a phase III efficacy trial.
Therapeutic hypothermia is now the standard of care for hypoxic-ischemic encephalopathy. Treatment should be started early, and it is often necessary to transfer the infant to a regional NICU for ongoing care. There are no large studies reporting outcomes from infants cooled passively compared with active (servo-controlled) cooling during transfer. Our goal was to review data from a regional transport service, comparing both methods of cooling.
This was a retrospective observational study of 143 infants referred to a regional NICU for ongoing therapeutic hypothermia. Of the 134 infants transferred, the first 64 were cooled passively, and 70 were subsequently cooled after purchase of a servo-controlled mattress. Key outcome measures were time to arrival at the regional unit, temperature at referral and arrival at the regional unit, and temperature stability during transfer.
The age cooling was started was significantly shorter in the actively cooled group (46 [0–352] minutes vs 120 [0–502] minutes; <.01). The median (range) stabilization time (153 [60–385] minutes vs 133 [45–505] minutes; = .04) and age at arrival at the regional unit (504 [191–924] minutes vs 452 [225–1265]) minutes; = .01) were significantly shorter in the actively cooled group. Only 39% of infants passively cooled were within the target temperature range at arrival to the regional unit compared with 100% actively cooled.
Servo-controlled active cooling has been shown to improve temperature stability and is associated with a reduction in transfer time.
Narrow-spectrum antibiotics have similar efficacy and cost-effectiveness as broad-spectrum antibiotics in the treatment of pediatric community-acquired pneumonia (CAP), according to the findings of a retrospective study.
“The 2011 Pediatric Infectious Diseases Society/Infectious Diseases Society of America…guideline for the management of children with [CAP] recommends narrow-spectrum antimicrobial therapy for most hospitalized children,” the authors write. “Nevertheless, few studies have directly compared the effectiveness of narrow-spectrum agents to the broader spectrum third-generation cephalosporins commonly used among hospitalized children with CAP.”
Therefore, the researchers used the Pediatric Health Information System database to assess the hospital length of stay (LOS) and associated healthcare costs of children aged 6 months to 18 years who were diagnosed with pneumonia between July 2005 and June 2011 and treated with either narrow-spectrum or broad-spectrum antibiotics. The authors excluded children with potentially severe pneumonia, those at risk for healthcare-associated infections, and those with mild disease requiring less than 2 days of hospitalization.
Narrow-spectrum therapy consisted of the exclusive use of penicillin or ampicillin, whereas broad-spectrum treatment was defined as the exclusive use of parenteral ceftriaxone or cefotaxime.
The median LOS for the entire study population (n = 15,564) was 3 days (interquartile range, 3 – 4 days), and LOS was not significantly different between the narrow-spectrum and broad-spectrum treatment groups (adjusted difference [aD], 0.12 days; P = .11), after adjustments for covariates including age, sex, and ethnicity.
Similarly, the investigators found no differences in the proportion of children requiring intensive care unit admission in the first 2 days of hospitalization (adjusted odds ratio [aOR], 0.85; 95% CI, 0.25 – 2.73) or hospital readmission within 14 days (aOR, 0.85; 95% CI, 0.45 – 1.63) were noted between the groups.
Narrow-spectrum treatment was also linked to a similar cost of hospitalization (aD, −$14.4; 95% CI, −$177.1 to $148.3) and cost per episode of illness (aD, −$18.6; 95% CI, −$194 to $156.9) as broad-spectrum therapy.
The researchers note that the limitations of the study were mostly related to its retrospective nature, including potential confounding by indication, the absence of etiologic and other clinical data, and a relative lack of objective outcome measures.
“Clinical outcomes and costs for children hospitalized with CAP are not different when empirical treatment is with narrow-spectrum compared with broad-spectrum therapy,” the authors write. “Programs promoting guideline implementation and targeting judicious antibiotic selection for CAP are needed to optimize management of childhood CAP in the United States.”
Nearly half of pediatric influenza deaths occur in otherwise healthy children, according to an 8-year Centers for Disease Control and Prevention study published online October 28 in Pediatrics.
“[T]hese data, which reveal that any child can be at risk of influenza-associated death regardless of age or high-risk medical conditions, support the recommendation that all children ≥6 months of age receive annual vaccination,” Karen K. Wong, MD, MPH, from the Epidemic Intelligence Service assigned to the Influenza Division, Centers for Disease Control and Prevention, Atlanta, Georgia, and colleagues write. They note that the national coverage rate (52% in 2011-2012) remains far below the Healthy People 2010 objective of 80%.
The investigators reviewed data for 830 pediatric influenza-related deaths that occurred between October 2004 and September 2012. Of the 794 children with an available medical record, 341 (43%) had no high-risk medical conditions such as neurologic disorders, asthma, or diseases of the heart, kidney, liver, or immune system, and 453 (57%) did. Among the entire study population, the median age of death was 7 years (interquartile range [IQR], 1 – 12 years), with 35% of cases occurring before hospital admission.
As expected, the study data confirmed the increased risk for complications, including mortality, among children with comorbidities: 33% of high-risk deaths occurred in children with neurologic disorders, and 12% had genetic or chromosomal disorders.
However, researchers also found that otherwise healthy children were almost twice as likely to die before hospital admission as their high-risk counterparts (relative risk [RR], 1.9; 95% confidence interval [CI], 1.6 – 2.4) and were 1.6 times more likely to die within 3 days of symptom onset (95% CI, 1.3 – 2.0).Although the cause remains unclear, a doubled prevalence of bacterial coinfection may have factored in the observed acceleration of clinical course (relative risk [RR], 2.0; 95% CI, 1.5 – 2.5), the authors write.
Otherwise healthy children were also more likely to be younger than 5 years (RR, 1.3; 95% CI, 1.1 – 1.6; P < .001), with a median age of 5 years (interquartile range [IQR], 1 – 11 years), compared with 8 years (IQR, 3 – 13 years) in the high-risk group.
According to the authors, the findings underscore the need for clinicians to be more aggressive with antiviral therapy.
“[I]influenza antiviral medications can reduce the severity of illness and complications associated with influenza virus infection…. [H]owever, antiviral treatment was reported in less than half of the children who died during the 2010-2011 and 2011-2012 seasons in this study,” the authors point out.
Children with signs or symptoms of severe or progressive illness and those who are hospitalized should be started on antivirals without waiting for laboratory results, even if they have no other risk factors for influenza-related complications, the authors write. Oseltamivir can be used in infants as young as 2 weeks, they note. In addition, antivirals are recommended regardless of illness severity for children younger than 2 years and for those with high-risk medical conditions.
“The potential for severe outcomes from influenza should be recognized in all children, both those with conditions that place them at higher risk of influenza-associated complications as well as healthy children,” the authors conclude.
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.
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*
Responder Rate (%)
Proportion of Seizure-Free Patients (%)
Weeks 5 to 16
Weeks 17 to 28
Weeks 29 to 40
Weeks 41 to 52
*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.
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.
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.”
1. The more positive your thoughts are, the happier your life gets
2. People will raise and lower at the level of your expectations
3. The value of Self Love
4. A musician must make music, an artist must paint and a poet must write
5. The importance of being present and engaged in the now
6. Be a first rate version of yourself and not a second rate version of someone else
7. Never get your sense of worth from outside yourself.
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.
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.
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 . 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 . Published data include only small numbers of microbiologically proven TBM cases (range of 0 to 23) –, 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 ,–. 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 –. 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 . We did not find a correlation between TTP and Xpert MTB/RIF CT values, as has been shown in sputum . In contrast to previous PCR-based studies ,, 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 . 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.