Respiratory symptoms and lung function in patients treated for pulmonary tuberculosis in Malawi a prospective cohort study

Rationale Pulmonary tuberculosis (PTB) can cause post-TB lung disease (PTLD) associated with respiratory symptoms, spirometric and radiological abnormalities. Understanding of the predictors and natural history of PTLD is limited. Objectives To describe the symptoms and lung function of Malawian adults up to 3 years following PTB-treatment completion, and to determine the evolution of PTLD over this period. Methods Adults successfully completing PTB treatment in Blantyre, Malawi were followed up for 3 years and assessed using questionnaires, post-bronchodilator spirometry, 6 min walk tests, chest X-ray and high-resolution CT. Predictors of lung function at 3 years were identified by mixed effects regression modelling. Measurement and main results We recruited 405 participants of whom 301 completed 3 years follow-up (mean (SD) age 35 years (10.2); 66.6% males; 60.4% HIV-positive). At 3 years, 59/301 (19.6%) reported respiratory symptoms and 76/272 (27.9%) had abnormal spirometry. The proportions with low FVC fell from 57/285 (20.0%) at TB treatment completion to 33/272 (12.1%), while obstruction increased from and 41/285 (14.4%) to 43/272 (15.8%) at 3 years. Absolute FEV1 and FVC increased by mean 0.03 L and 0.1 L over this period, but FEV1 decline of more than 0.1 L was seen in 73/246 (29.7%). Higher spirometry values at 3 years were associated with higher body mass index and HIV coinfection at TB-treatment completion. Conclusion Spirometric measures improved over the 3 years following treatment, mostly in the first year. However, a third of PTB survivors experienced ongoing respiratory symptoms and abnormal spirometry (with accelerated FEV1 decline). Effective interventions are needed to improve the care of this group of patients

Phase II TPDCV protocol for pediatric low-grade hypothalamic/chiasmatic gliomas: 15-year update

To report long-term results for children with low-grade hypothalamic/chiasmatic gliomas treated on a phase II chemotherapy protocol. Between 1984 and 1992, 33 children with hypothalamic/chiasmatic LGGs received TPDCV chemotherapy on a phase II prospective trial. Median age was 3.0 years (range 0.3–16.2). Twelve patients (36%) underwent STRs, 14 (42%) biopsy only, and seven (21%) no surgery. Twenty patients (61%) had pathologic JPAs, nine (27%) grade II gliomas, and four (12%) no surgical sampling. Median f/u for surviving patients was 15.2 years (range 5.3–20.7); 20 of the 23 surviving patients had 14 or more years of follow-up. Fifteen-year PFS and OS were 23.4 and 71.2%, respectively. Twenty-five patients progressed, of whom 13 are NED, two are AWD, and 10 have died. All children who died were diagnosed and first treated at age three or younger. Age at diagnosis was significantly associated with relapse and survival (P = 0.004 for PFS and P = 0.037 for OS). No PFS or OS benefit was seen with STR versus biopsy/no sampling (P = 0.58 for PFS, P = 0.59 for OS). For patients with JPAs and WHO grade II tumors, the 15-year PFS was 18.8 and 22.2% (P = 0.95) and 15-year OS was 73.7 and 55.6% (P = 0.17), respectively. Upfront TPDCV for children with hypothalamic/chiasmatic LGGs resulted in 15-year OS of 71.2% and 15-year PFS of 23.4%. No survival benefit is demonstrated for greater extent of resection. Age is a significant prognostic factor for progression and survival

Rescue of skeletal muscle α-actin–null mice by cardiac (fetal) α-actin

Skeletal muscle α-actin (ACTA1) is the major actin in postnatal skeletal muscle. Mutations of ACTA1 cause mostly fatal congenital myopathies. Cardiac α-actin (ACTC) is the major striated actin in adult heart and fetal skeletal muscle. It is unknown why ACTC and ACTA1 expression switch during development. We investigated whether ACTC can replace ACTA1 in postnatal skeletal muscle. Two ACTC transgenic mouse lines were crossed with Acta1 knockout mice (which all die by 9 d after birth). Offspring resulting from the cross with the high expressing line survive to old age, and their skeletal muscles show no gross pathological features. The mice are not impaired on grip strength, rotarod, or locomotor activity. These findings indicate that ACTC is sufficiently similar to ACTA1 to produce adequate function in postnatal skeletal muscle. This raises the prospect that ACTC reactivation might provide a therapy for ACTA1 diseases. In addition, the mouse model will allow analysis of the precise functional differences between ACTA1 and ACTC

Economic evaluation of shortened, bedaquiline-containing treatment regimens for rifampicin-resistant tuberculosis (STREAM stage 2): a within-trial analysis of a randomised controlled trial

BACKGROUND: The STREAM stage 2 trial assessed two bedaquiline-containing regimens for rifampicin-resistant tuberculosis: a 9-month all-oral regimen and a 6-month regimen containing an injectable drug for the first 2 months. We did a within-trial economic evaluation of these regimens. METHODS: STREAM stage 2 was an international, phase 3, non-inferiority randomised trial in which participants with rifampicin-resistant tuberculosis were randomly assigned (1:2:2:2) to the 2011 WHO regimen (terminated early), a 9-month injectable-containing regimen (control regimen), a 9-month all-oral regimen with bedaquiline (oral regimen), or a 6-month regimen with bedaquiline and an injectable for the first 2 months (6-month regimen). We prospectively collected direct and indirect costs and health-related quality of life data from trial participants until week 76 of follow-up. Cost-effectiveness of the oral and 6-month regimens versus control was estimated in four countries (oral regimen) and two countries (6-month regimen), using health-related quality of life for cost-utility analysis and trial efficacy for cost-effectiveness analysis. This trial is registered with ISRCTN, ISRCTN18148631. FINDINGS: 300 participants were included in the economic analyses (Ethiopia, 61; India, 142; Moldova, 51; Uganda, 46). In the cost-utility analysis, the oral regimen was not cost-effective in Ethiopia, India, Moldova, and Uganda from either a provider or societal perspective. In Moldova, the oral regimen was dominant from a societal perspective. In the cost-effectiveness analysis, the oral regimen was likely to be cost-effective from a provider perspective at willingness-to-pay thresholds per additional favourable outcome of more than US$4500 in Ethiopia,$1900 in India, $3950 in Moldova, and$7900 in Uganda, and from a societal perspective at thresholds of more than $15 900 in Ethiopia,$3150 in India, and $4350 in Uganda, while in Moldova the oral regimen was dominant. In Ethiopia and India, the 6-month regimen would cost tuberculosis programmes and participants less than the control regimen and was highly likely to be cost-effective in both cost-utility analysis and cost-effectiveness analysis. Reducing the bedaquiline price from$1·81 to $1·00 per tablet made the oral regimen cost-effective in the provider-perspective cost-utility analysis in India and Moldova and dominate over the control regimen in the provider-perspective cost-effectiveness analysis in India. INTERPRETATION: At current costs, the oral bedaquiline-containing regimen for rifampicin-resistant tuberculosis is unlikely to be cost-effective in many low-income and middle-income countries. The 6-month regimen represents a cost-effective alternative if injectable use for 2 months is acceptable. FUNDING: USAID and Janssen Research & Development

Grey matter in shadow banking: international organizations and expert strategies in global financial governance

Who controls global policy debates on shadow banking regulation? We show how experts secured control over how issues in shadow banking regulation are treated by examining the policy recommendations of the Bank of International Settlements, the International Monetary Fund and the Financial Stability Board. The evidence suggests that IO experts embedded a bland reformism opposed to both strong and ‘light touch’ regulation at the core of the emerging regulatory regime. Technocrats reinforced each other's expertise, excluded some potential competitors (legal scholars), co-opted others (select Fed and elite academic economists), and deployed measurement, mandate, and status strategies to assert issue control. In the field of shadow banking regulation, academic economists’ influence came from their credibility as arbitrageurs between several professional fields rather than their intellectual output. The findings have important implications for how we study the relationship between IO technocrats and experts from other professional field

Neurodevelopmental Correlates of True and False Recognition

The Deese/Roediger–McDermott (DRM) false-memory effect has been extensively documented in psychological research. People falsely recognize critical lures or nonstudied items that are semantically associated with studied items. Behavioral research has provided evidence for age-related increases in the DRM false-recognition effect. The present event-related functional magnetic resonance imaging study was aimed at investigating neurodevelopmental changes in brain regions associated with true- and false-memory recognition in 8-year olds, 12-year olds, and adults. Relative to 8-year olds, adults correctly endorsed more studied items as “old” but also mistakenly endorsed more critical lures. Age-related increases in recollection were associated with changes in the medial temporal lobe (MTL) activation profile. Additionally, age-related increases in false alarms (FAs) to semantically related lures were associated with changes in the activation profile of left ventrolateral prefrontal cortex, a region associated with semantic processing. Additional regions exhibiting age-related changes include posterior parietal and anterior prefrontal cortices. In summary, concomitant changes in the MTL, prefrontal cortex, and parietal cortex underlie developmental increases in true and false recognition during childhood and adolescence

A Specific and Rapid Neural Signature for Parental Instinct

Darwin originally pointed out that there is something about infants which prompts adults to respond to and care for them, in order to increase individual fitness, i.e. reproductive success, via increased survivorship of one's own offspring. Lorenz proposed that it is the specific structure of the infant face that serves to elicit these parental responses, but the biological basis for this remains elusive. Here, we investigated whether adults show specific brain responses to unfamiliar infant faces compared to adult faces, where the infant and adult faces had been carefully matched across the two groups for emotional valence and arousal, as well as size and luminosity. The faces also matched closely in terms of attractiveness. Using magnetoencephalography (MEG) in adults, we found that highly specific brain activity occurred within a seventh of a second in response to unfamiliar infant faces but not to adult faces. This activity occurred in the medial orbitofrontal cortex (mOFC), an area implicated in reward behaviour, suggesting for the first time a neural basis for this vital evolutionary process. We found a peak in activity first in mOFC and then in the right fusiform face area (FFA). In mOFC the first significant peak (p<0.001) in differences in power between infant and adult faces was found at around 130 ms in the 10–15 Hz band. These early differences were not found in the FFA. In contrast, differences in power were found later, at around 165 ms, in a different band (20–25 Hz) in the right FFA, suggesting a feedback effect from mOFC. These findings provide evidence in humans of a potential brain basis for the “innate releasing mechanisms” described by Lorenz for affection and nurturing of young infants. This has potentially important clinical applications in relation to postnatal depression, and could provide opportunities for early identification of families at risk