The ADHD Controversy.


ADHD was already a controversial diagnosis; are Jerome Kagan’s recent criticisms of it warranted?

Is attention deficit hyperactivity disorder (ADHD) a legitimate diagnosis or is it mostly a fraud? The answer has important implications for many individuals and for society. The diagnosis is accepted as legitimate by the psychiatric profession, but continues to have its vehement critics. Recently, noted psychologist Jerome Kagan has been giving tremendous weight to these criticisms by calling ADHD mostly a fraud. There are significant problems with his criticism, however.

What is ADHD?

ADHD was first described in children in 1902, and was understood as an impulse control disorder. It was not formally recognized as a diagnosis, however, until the second edition of the DSM in 1968. The first approved drug used to treat ADHD was benzedrine in 1936. Ritalin, which is still used to treat the disorder, was approved in 1955.

Here is the official DSM diagnosis:

  • A persistent pattern of inattention and/or hyperactivity-impulsivity that interferes with functioning or development
    • Six or more of the symptoms have persisted for at least six months to a degree that is inconsistent with developmental level and that negatively impacts directly on social and academic/occupational activities. Please note: The symptoms are not solely a manifestation of oppositional behaviour, defiance, hostility, or failure to understand tasks or instructions. For older adolescents and adults (age 17 and older), five or more symptoms are required
  • Several inattentive or hyperactive-impulsive symptoms were present prior to age 12 years
  • Several inattentive or hyperactive-impulsive symptoms are present in two or more settings (e.g. at home, school, or work; with friends or relatives; in other activities)
  • There is clear evidence that the symptoms interfere with, or reduce the quality of, social, academic or occupational functioning
  • The symptoms do not occur exclusively during the course of schizophrenia or another psychotic disorder and are not better explained by another mental disorder (e.g. mood disorder, anxiety disorder, dissociative disorder, personality disorder, substance intoxication or withdrawal)

There are a few aspects of this diagnosis worth pointing out. First, this is what we call a clinical diagnosis, it is based entirely on signs and symptoms without any objective diagnostic tests. You cannot see ADHD on an MRI scan of the brain, an EEG, or a blood test. This is not unusual in medicine, especially for brain disorders. The same is true, for example, of migraine headaches. It is entirely a clinical diagnosis.

This, by itself, should not call the diagnosis into question. Brain function relies not only on the health of the cells and the absence of identifiable anatomical or gross pathology. It also depends on the pattern of connections among brain cells, the density of their connections, and the details of their biochemistry. We are just starting to be able to image the brain at this level.

As an example, raise someone in a closet for 20 years and I guarantee you they will have a psychological disorder, but you would not be able to tell that from looking at their brain with any tool we currently have.

Because mood, thought, and behavior largely rely on brain function that cannot be imaged, psychiatrists have relied on elaborate schemes of clinical diagnoses to at least have a common language for thinking and talking about mental illness. It is imperfect, and extremely fuzzy around the edges, but it has its utility.

That fuzziness is partly based in the limits of our current technology and understanding. But it is also based in the fact that humans are neurologically heterogeneous and the fact that the brain is an extremely complex system. This means that the same end result (behavior, for example) might result from almost endless permutations of interactions among various systems in the brain and their interaction with the environment.

You can see this in the formal description of ADHD above. There is a sincere attempt to capture a real neurological phenomenon, and to filter out other factors that might contribute to or cause similar symptoms. Signs used to establish the diagnosis cannot be temporary, or isolated to only one environment, or related to other conditions or situations that might provoke them. You need to have many symptoms persistent over a long time without other identifiable causes and to a sufficient degree that they cause demonstrable harm.

There is also an attempt to separate out those who have a real disorder from the typical spectrum of human behavior. This is also a common problem in medicine. Many disorders, like high blood pressure, do not have a sharp demarcation line. The curves for normal blood pressure and hypertension overlap. Experts have to decide where to draw the line, either capturing more people with the disorder but also more people just at the upper range of normal, vs excluding those who are just at the upper range of normal but also then missing more people with the disorder.

Eventually such clinical questions evolve from, “Who has the disorder” to “Who benefits from treatment for the disorder.” That is the real question.

Neuroanatomical Correlates

Despite the fact that ADHD is a fuzzy clinical entity, we have made progress in understanding what is happening in the brain of most people with ADHD. The current consensus is that ADHD is a deficit of executive functions. The frontal lobes carry out many critical functions, some considered executive functions: they include being able to focus your attention, maintain focus, switch among tasks, filter out distractions, and impulse control. Executive function includes the ability to weigh the probable outcomes of your behavior and then make high-level decisions about how you will behave.

As an adult neurologist I see patients with executive function disorder frequently, usually from head trauma. Car accidents in particular result in frontal lobe damage as it is common to hit your head against the windshield during many types of accidents. Patients frequently develop the symptoms of ADHD after frontal head trauma. They have poor focus, and poor impulse control. In one dramatic case a patient’s entire personality changed. She lost all ability to control or moderate her behavior (as have others). Often these patients respond favorably to the same stimulants we use to treat ADHD.

When we look at the brains of those who meet the clinical diagnosis of ADHD with our modern imaging techniques, such as fMRI and EEG, we find a similar pattern of brain dysfunction:

Convergent data from neuroimaging, neuropsychology, genetics and neurochemical studies consistently point to the involvement of the frontostriatal network as a likely contributor to the pathophysiology of ADHD. This network involves the lateral prefrontal cortex, the dorsal anterior cingulate cortex, the caudate nucleus and putamen. Moreover, a growing literature demonstrates abnormalities affecting other cortical regions and the cerebellum.

At this point there is no reasonable disagreement about the fact that ADHD is a disorder of brain function. Children who meet the strict diagnostic criteria are demonstrably different, in consistent and predictable ways, than children who do not (controlling for other possible factors). They have impaired executive functions, and we can see this in changes to the relevant parts of the brain. We still have a lot to learn (again, the brain is complex) but a consistent picture is emerging.

Jerome Kagan’s criticism

Jerome Kagan is a preeminent psychologist. This gives his opinions about a psychological topic a great deal of weight. The press loves him because he has a sensational story to tell and he has impeccable credential. Articles about Kagan often spend an entire paragraph or two touting those credentials.

Unfortunately this is a common mistake that mainstream journalists make when discussing scientific topics. They confuse the expertise of an individual with scientific authority. No individual ever represents the consensus of scientific opinion, they can only represent their own quirky opinions (which may or may not be in line with the consensus).

This is a classic example of this error. Kagan’s opinions do not conform to the current consensus of scientific opinion, but he is presented as an unimpeachable authority. Further, all reporting that I have seen on Kagan’s opinions regarding ADHD fail to put his expertise into a reasonable context. Kagan is a psychologist. He is not a psychiatrist, nor a neuroscientist.

Often related fields covering the same question have different opinions. Geologists and paleontologists disagree about the relative contribution of a meteor impact to the extinction of the dinosaurs at the K-Pg boundary. If a reporter talked only to a geologist they would not capture the true state of the broader scientific opinion.

Many psychologists have opinions about psychiatry that do not reflect the consensus of psychiatric opinion. In essence, even though Kagan has relevant expertise, he is not a clinician, and therefore is an outsider when it comes to the practice of psychiatry. He also does not seem to be up to date on the neuroscience of ADHD.

Yet his recent interview with Spiegel is being widely reports as definitive criticism of the diagnosis and treatment of ADHD. Here are some of the highlights: He says:

Let’s go back 50 years. We have a 7-year-old child who is bored in school and disrupts classes. Back then, he was called lazy. Today, he is said to suffer from ADHD (Attention Deficit Hyperactivity Disorder). That’s why the numbers have soared.

We are familiar with a similar criticism of autism diagnoses. Yes, diagnostic practices have changed. Awareness of the diagnosis has changed. The implication here is that the 1950s diagnosis (a bored child) was better than the current diagnosis of ADHD.

But, if you recall the diagnostic criteria from above, displaying ADHD behavior in school alone is not sufficient to establish the diagnosis. So, Kagan’s example is simply wrong. The child in his example should not be diagnosed with ADHD.

Being generous, he may be implying only that doctors are overdiagnosing ADHD and not following their own diagnostic criteria. This is a real issue, but here is a far more nuanced discussion from an actual clinician:

ADHD is real—it’s not made up. But it exists on a continuum. There’s no marker or white line that says you’re in the “definite” or “highly likely” group. There’s almost unanimous agreement that five or six percent clearly have enough of these symptoms for an ADHD diagnosis. Then there’s the next group, where the diagnosis is more of a judgment call, and for these kids, behavioral therapy might work. And then there’s a third group, on the borderline. These are the ones we’re worried about being pushed into an inaccurate diagnosis.

The real issue is – are schools pushing for more kids in the gray zone to be diagnosed because of funding and regulation issues? Also, there is a real “demarcation problem” with the diagnosis, and we have to carefully consider the risks and benefits of using looser or tighter criteria. These discussions are happening within the profession, and are very evidence-based and nuanced. Kagan’s criticism, by comparison, is shooting from the hip and simplistic. (I will add the caveat that the interview may not reflect the full depth of his opinion, but he is responsible for how he communicates to the public, especially given how widely his opinions have been spread.)

He continues:

SPIEGEL: Experts speak of 5.4 million American children who display the symptoms typical of ADHD. Are you saying that this mental disorder is just an invention?

Kagan: That’s correct; it is an invention. Every child who’s not doing well in school is sent to see a pediatrician, and the pediatrician says: “It’s ADHD; here’s Ritalin.” In fact, 90 percent of these 5.4 million kids don’t have an abnormal dopamine metabolism. The problem is, if a drug is available to doctors, they’ll make the corresponding diagnosis.

That characterization, while you might dismiss it as hyperbole, is irresponsible. “Every” child? Again, this does not meet the official diagnostic criteria for ADHD which requires more than just not doing well in school. His reference to “dopamine metabolism” is just weird. It is true that some studies show some children with ADHD have impaired reward system function. This may be playing a role in some subtypes of ADHD. It is not a core feature of ADHD, however, and the evidence is still very preliminary. Invoking what is essentially a preliminary side point about the neuroanatomical correlates of ADHD as reason to doubt the diagnosis is, to be kind, highly problematic.

Kagan then broadens his criticism to encompass psychiatry in general:

We could get philosophical and ask ourselves: “What does mental illness mean?” If you do interviews with children and adolescents aged 12 to 19, then 40 percent can be categorized as anxious or depressed. But if you take a closer look and ask how many of them are seriously impaired by this, the number shrinks to 8 percent. Describing every child who is depressed or anxious as being mentally ill is ridiculous. Adolescents are anxious, that’s normal. They don’t know what college to go to. Their boyfriend or girlfriend just stood them up. Being sad or anxious is just as much a part of life as anger or sexual frustration.

This is a typical anti-mental illness statement. This is simply a straw man of what psychiatry does.

He is saying that we should not confuse the normal range of behavior with a disorder, as if this is a huge insight. This understanding has already been incorporated into clinical thinking. As I pointed out above – there are great pains taken when defining mental disorders to separate true disorders from the healthy range of human behavior.

Further, being “seriously impaired” is already part of the diagnosis, so what is he talking about?

He goes on to argue that some people are depressed in response to a life event. Right – psychiatrists call this a “reactive depression” because it is already recognized, and not confused with a chronic depression. That is why the diagnosis of clinical depression excludes depression that follows a major trigger, and must continue for greater than six months to be considered a disorder.

From reading the entire interview I am left wondering, exactly what Kagan is criticizing? He is certainly not criticizing the standard of care within psychiatry. He seems to be tilting at a straw man of the worst possible malpractice that deviates from that standard. He is raising issues as if these are not already part of a vigorous evidence-based discussion within psychiatry itself.

A kernel of truth

We often take a sharply critical approach to medical science here at SBM. Self-criticism is critical to improvement. That is the essence of science itself, it is designed for error correction through self-criticism.

Our nuanced position is that science basically works, but there is a lot of room for improvement. Enemies of science, however, or those with a specific ideological axe to grind, use the same evidence to argue that the institution of science is fatally flawed and can be comfortably dismissed or ignored.

I find the same is true of much of the public criticism of psychiatry. There is a lot to criticize in the profession (as in medicine in general), and a lot of room for improvement. Some of that is just the current status of the science. We don’t know everything, and yet medicine (including psychiatry) is an applied science. We have to make important decisions with limited information.

There are also many issues of quality control. Medicine is hard, and keeping quality standards high is challenging.

So there are many legitimate criticisms of ADHD and psychiatry, but that does not mean ADHD is a fraud. The scientific evidence, both clinical and neuroscience, is robust. Kagan’s criticisms are mostly greatly exaggerated, or they are straw men because they are already incorporated into the standard of care.

Unfortunately, you will not be exposed to any of that from reading any of the popular press breathlessly reporting that ADHD is a fraud.

Source:https://sciencebasedmedicine.org

Building the Evidence Base of Blood-Based Biomarkers for Early Detection of Cancer: A Rapid Systematic Mapping Review


 There are a large number of biomarkers with potential utility for early cancer detection from blood samples

Few biomarkers have been studied sufficiently with clinical validation to allow their use in combination for screening in the general population.

We used an iterative mapping review of 20,000 references, retrieving 3,990 relevant papers, and identified 788 markers in blood of potential use

Screening for cancer can save lives, but it is difficult to justify individual screening programmes for many cancer types. However, cancers of different types share many attributes, and markers of cancer biology found in the blood. We surveyed the literature to identify known biomarkers using a new mapping approach. With nearly 20,000 papers on the subject, we retrieved 3990 papers, and identified 788 markers in blood of potential use. Most have not been studied enough to justify their use in clinical practice. This evidence based approach should help us to develop a blood-based cancer screening test in the general population.

Abstract

Background

The Early Cancer Detection Consortium is developing a blood-test to screen the general population for early identification of cancer, and has therefore conducted a systematic mapping review to identify blood-based biomarkers that could be used for early identification of cancer.

Methods

A mapping review with a systematic approach was performed to identify biomarkers and establish their state of development. Comprehensive searches of electronic databases Medline, Embase, CINAHL, the Cochrane library and Biosis were conducted in May 2014 to obtain relevant literature on blood-based biomarkers for cancer detection in humans. Screening of retrieved titles and abstracts was performed using an iterative sifting process known as “data mining”. All blood based biomarkers, their relevant properties and characteristics, and their corresponding references were entered into an inclusive database for further scrutiny by the Consortium, and subsequent selection of biomarkers for rapid review. This systematic review is registered with PROSPERO (no. CRD42014010827).

Findings

The searches retrieved 19,724 records after duplicate removal. The data mining approach retrieved 3990 records (i.e. 20% of the original 19,724), which were considered for inclusion. A list of 814 potential blood-based biomarkers was generated from included studies. Clinical experts scrutinised the list to identify miss-classified and duplicate markers, also volunteering the names of biomarkers that may have been missed: no new markers were identified as a result. This resulted in a final list of 788 biomarkers.

Interpretation

This study is the first to systematically and comprehensively map blood biomarkers for early detection of cancer. Use of this rapid systematic mapping approach found a broad range of relevant biomarkers allowing an evidence-based approach to identification of promising biomarkers for development of a blood-based cancer screening test in the general population.

Source:http://www.ebiomedicine.com

The epidemiology, pathogenesis, transmission, diagnosis, and management of multidrug-resistant, extensively drug-resistant, and incurable tuberculosis


Summary

Global tuberculosis incidence has declined marginally over the past decade, and tuberculosis remains out of control in several parts of the world including Africa and Asia. Although tuberculosis control has been effective in some regions of the world, these gains are threatened by the increasing burden of multidrug-resistant (MDR) and extensively drug-resistant (XDR) tuberculosis. XDR tuberculosis has evolved in several tuberculosis-endemic countries to drug-incurable or programmatically incurable tuberculosis (totally drug-resistant tuberculosis). This poses several challenges similar to those encountered in the pre-chemotherapy era, including the inability to cure tuberculosis, high mortality, and the need for alternative methods to prevent disease transmission. This phenomenon mirrors the worldwide increase in antimicrobial resistance and the emergence of other MDR pathogens, such as malaria, HIV, and Gram-negative bacteria. MDR and XDR tuberculosis are associated with high morbidity and substantial mortality, are a threat to health-care workers, prohibitively expensive to treat, and are therefore a serious public health problem. In this Commission, we examine several aspects of drug-resistant tuberculosis. The traditional view that acquired resistance to antituberculous drugs is driven by poor compliance and programmatic failure is now being questioned, and several lines of evidence suggest that alternative mechanisms—including pharmacokinetic variability, induction of efflux pumps that transport the drug out of cells, and suboptimal drug penetration into tuberculosis lesions—are likely crucial to the pathogenesis of drug-resistant tuberculosis. These factors have implications for the design of new interventions, drug delivery and dosing mechanisms, and public health policy. We discuss epidemiology and transmission dynamics, including new insights into the fundamental biology of transmission, and we review the utility of newer diagnostic tools, including molecular tests and next-generation whole-genome sequencing, and their potential for clinical effectiveness. Relevant research priorities are highlighted, including optimal medical and surgical management, the role of newer and repurposed drugs (including bedaquiline, delamanid, and linezolid), pharmacokinetic and pharmacodynamic considerations, preventive strategies (such as prophylaxis in MDR and XDR contacts), palliative and patient-orientated care aspects, and medicolegal and ethical issues.

Conclusion

MDR tuberculosis, XDR tuberculosis, and resistance beyond XDR tuberculosis remains a major threat to global tuberculosis control because of the increasing burden it creates on health-care systems, economies, and societies, the threat to health-care workers in tuberculosis-endemic countries, the high mortality, and the unsustainably high costs of treating drug-resistant tuberculosis. Additionally, the development of totally drug-resistant or programmatically incurable tuberculosis has raised several ethical and medicolegal challenges. The global epidemiology of drug-resistant tuberculosis shows a worrying increase in the prevalence and incidence of drug-resistant tuberculosis in several countries and regions. Also, the proportion of cases of tuberculosis that are MDR and fluoroquinolone-resistant or aminoglycoside-resistant—ie, pre-XDR—or that are programmatically incurable has increased greatly. New molecular tools such as next-generation whole-genome sequencing are shedding further light on the transmission, diagnosis, and pathogenesis of drug-resistant tuberculosis.522Particularly, several lines of evidence challenge the traditional view that resistance is acquired through non-adherence promoted by poor programmatic functioning. Although adherence is clearly important for the prevention of drug-resistant tuberculosis, several other factors that promote pharmacokinetic mismatch drive the acquisition of drug-resistant tuberculosis even when adherence is good. However, newer methods to enable whole-genome sequencing directly from sputum and to assess its effect on clinical outcomes are needed.

Furthermore, a paradigm shift is required to take testing from the clinical setting into the community, thus promoting active case finding, and the detection of the undiagnosed and unsuspected cases of community-based drug-resistant tuberculosis. Newer drugs have improved the efficacy of the treatment of MDR and XDR tuberculosis, and therefore the prognosis, but resistance amplification will need to be minimised through strengthening tuberculosis programmes and other innovative approaches to prevent pharmacokinetic mismatch. Novel ways to reduce or eliminate the transmission of drug-resistant tuberculosis and to understand the fundamental biology of transmission are urgently required. These key messages are summarised in panel 11, and timeline-orientated research priorities and goals for drug-resistant tuberculosis are shown in table 15. All these priorities will need to be urgently addressed in tandem with the strengthening of health systems, reduction of poverty, and changing of political will.

Key messages

  • Resistance to antituberculosis drugs is a global problem of considerable public health importance that threatens to derail efforts to eradicate the disease. Advocacy is needed in national and transnational fora to ensure the urgency of the situation is understood and that appropriate funding is made available.

  • Practices for the management of individual patients in settings with a high tuberculosis burden are not sufficient to prevent the emergence, amplification, and spread of drug-resistant tuberculosis. These practices include empirical treatment with standardised second-line drug regimens for people who are found to have rifampicin-resistant tuberculosis.

  • Access to drug resistance testing is scarce in most countries and urgently needs to be expanded to allow curative second-line treatment regimens to be implemented.

  • Knowledge regarding the safe use—including dose and length of treatment—of new and repurposed drugs must be improved through clinical trials.

  • Models of care for people with drug-resistant tuberculosis, including programmatically incurable disease, must ensure that the rights and dignity of individual patients are respected.

  • Assessment of the performance, health effects, and potential economic benefits of molecular tools such as genome sequencing for detecting resistance, must be accelerated to facilitate effective implementation.

  • Greater investment is needed in the development of new drugs and diagnostics.

Source:Lancet

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

Influence of Body Mass Index on Survival in Veterans With Multiple Myeloma.


Abstract

Purpose. We investigated the association between body mass index (BMI) at the time of multiple myeloma (MM) diagnosis and overall survival in a cohort of patients within the Veterans Health Administration system. We also evaluated the association between weight loss in the year prior to diagnosis and survival.

Patients and Methods. Prospective analysis was performed on a retrospectively assembled cohort of 2,968 U.S. veterans diagnosed and treated for MM between September 1, 1999, and September 30, 2009, with follow-up information through October 22, 2011. Cox modeling controlling for patient- and disease-related prognostic variables was used to analyze the data.

Results. Underweight patients (BMI <18.5 kg/m2) had increased mortality, whereas patients who were overweight (BMI 25–29.9 kg/m2) and obese (BMI ≥30 kg/m2) had lower mortality compared with healthy-weight patients (BMI 18.5–24.9 kg/m2). Weight loss ≥10% of baseline in the year before diagnosis was also associated with increased mortality and made the association between increased BMI and survival nonsignificant.

Conclusion. Disease-related weight loss may be an important and heretofore unknown indicator of poor prognosis in MM. Assessment of weight loss prior to MM diagnosis should become a standard component of the clinical history in patients with newly diagnosed MM. Further research may identify relationships between disease-related weight loss and currently used prognostic factors in MM, further defining the role of this clinical factor in prognostic stratification.

 

Source: The Oncologist.

Imaging in Mental Health And Improving the Diagnostic Process.


 What are some of the most troubling numbers in mental health? Six to 10 — the number of years it can take to properly diagnose a mental health condition. Dr. Elizabeth Osuch, a Researcher at Lawson Health Research Institute and a Psychiatrist at London Health Sciences Centre and the Department of Psychiatry at Western University, is helping to end misdiagnosis by looking for a ‘biomarker’ in the brain that will help diagnose and treat two commonly misdiagnosed disorders.

Major Depressive Disorder (MDD), otherwise known as Unipolar Disorder, and Bipolar Disorder (BD) are two common disorders. Currently, diagnosis is made by patient observation and verbal history. Mistakes are not uncommon, and patients can find themselves going from doctor to doctor receiving improper diagnoses and prescribed medications to little effect.

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Dr. Osuch looked to identify a ‘biomarker’ in the brain which could help optimize the diagnostic process. She examined youth who were diagnosed with either MDD or BD (15 patients in each group) and imaged their brains with an MRI to see if there was a region of the brain which corresponded with the bipolarity index (BI). The BI is a diagnostic tool which encompasses varying degrees of bipolar disorder, identifying symptoms and behavior in order to place a patient on the spectrum.

What she found was the activation of the putamen correlated positively with BD. This is the region of the brain that controls motor skills, and has a strong link to reinforcement and reward. This speaks directly to the symptoms of bipolar disorder. “The identification of the putamen in our positive correlation may indicate a potential trait marker for the symptoms of mania in bipolar disorder,” states Dr. Osuch.

In order to reach this conclusion, the study approached mental health research from a different angle. “The unique aspect of this research is that, instead of dividing the patients by psychiatric diagnoses of bipolar disorder and unipolar depression, we correlated their functional brain images with a measure of bipolarity which spans across a spectrum of diagnoses.” Dr. Osuch explains, “This approach can help to uncover a ‘biomarker’ for bipolarity, independent of the current mood symptoms or mood state of the patient.”

Moving forward Dr. Osuch will repeat the study with more patients, seeking to prove that the activation of the putamen is the start of a trend in large numbers of patients. The hope is that one day there could be a definitive biological marker which could help differentiate the two disorders, leading to a faster diagnosis and optimal care.

In using a co-relative approach, a novel method in the field, Dr. Osuch uncovered results in patients that extend beyond verbal history and observation. These results may go on to change the way mental health is diagnosed, and subsequently treated, worldwide.

Strongyloides stercoralis infection.


Summary points

  • Strongyloidiasis is endemic in the tropics and subtropics and anyone who has travelled to, or lived in, these areas is at risk
  • Unlike most other intestinal parasite infections, strongyloidiasis may be life long
  • The infection is often asymptomatic and may only be indicated by a peripheral blood eosinophilia
  • Diagnosis is important as immunosuppression in patients with chronic infection can precipitate a life threatening hyperinfection syndrome
  • Serology is the investigation of choice for diagnosis and follow-up, as stool microscopy has a low sensitivity
  • Treatment is with 2×200 μg/kg doses of oral ivermectin given two weeks apart

Strongyloides stercoralis is an intestinal helminth that infects humans through contact with soil containing the larvae. Between 30 and 100 million people are infected worldwide.1 In the United Kingdom, strongyloidiasis is seen predominantly in migrants and returning travellers from endemic areas in the tropics and subtropics. Strongyloidiasis may present with cutaneous or gastrointestinal symptoms but is asymptomatic in over 60% of cases and only indicated by a raised blood eosinophil count.2 Diagnosis is important as the infection may persist for decades.3Immunosuppressed patients with chronic strongyloidiasis are at high risk of developing strongyloides hyperinfection syndrome, a life threatening complication whereby larval proliferation leads to systemic sepsis and multiorgan failure. If strongyloidiasis is diagnosed early, however, it is easily treatable with oral antihelmintic drugs. In this article we review the epidemiology and common symptoms of strongyloidiasis and strongyloides hyperinfection syndrome, discuss the appropriate investigations, and summarise the evidence on treatment.

Source: BMJ

FDA allows marketing for HbA1c assay to diagnose diabetes.


The FDA has announced they will allow the marketing of the COBAS INTEGRA 800 Tina-quant HbA1cDx assay for the diagnosis of diabetes by health care professionals, according to a press release.

Investigators analyzed 141 blood samples and found a difference of <6% in accuracy between the Tina-quant HbA1cDx assay (Roche) and results from standard reference for HbA1c analysis, according to the release.

Clinical laboratories will be permitted to use the Tina-quant HbA1cDX assay to diagnose patients with diabetes and monitor glucose control. The assay should not be used to diagnose diabetes during pregnancy or used to diagnose or monitor diabetes in patients with hemoglobin variant hemoglobin F. Furthermore, it should not be used to monitor diabetes in patients with hemoglobinopathy, hereditary spherocytosis, malignancies, or severe chronic, hepatic and renal disease, according to the release.

Source: Endocrine today

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