Shortened Lung Clearance Index is a repeatable and sensitive test in children and adults with cystic fibrosis

Background: Lung clearance index (LCI) derived from sulfur hexafluoride (SF6) multiple breath washout (MBW) is a sensitive measure of lung disease in people with cystic fibrosis (CF). However, it can be time-consuming, limiting its use clinically. Aim: To compare the repeatability, sensitivity and test duration of LCI derived from washout to 1/30th (LCI1/30), 1/20th (LCI1/20) and 1/10th (LCI1/10) to ‘standard’ LCI derived from washout to 1/40th initial concentration (LCI1/40). Methods: Triplicate MBW test results from 30 clinically stable people with CF and 30 healthy controls were analysed retrospectively. MBW tests were performed using 0.2% SF6 and a modified Innocor device. All LCI end points were calculated using SimpleWashout software. Repeatability was assessed using coefficient of variation (CV%). The proportion of people with CF with and without abnormal LCI and forced expiratory volume in 1 s (FEV1) % predicted was compared. Receiver operating characteristic (ROC) curve statistics were calculated. Test duration of all LCI end points was compared using paired t tests. Results: In people with CF, LCI1/40 CV% (p=0.16), LCI1/30 CV%, (p=0.53), LCI1/20 CV% (p=0.14) and LCI1/10 CV% (p=0.25) was not significantly different to controls. The sensitivity of LCI1/40, LCI1/30 and LCI1/20 to the presence of CF was equal (67%). The sensitivity of LCI1/10 and FEV1% predicted was lower (53% and 47% respectively). Area under the ROC curve (95% CI) for LCI1/40, LCI1/30, LCI1/20, LCI1/10 and FEV1% predicted was 0.89 (0.80 to 0.97), 0.87 (0.77 to 0.96), 0.87 (0.78 to 0.96), 0.83 (0.72 to 0.94) and 0.73 (0.60 to 0.86), respectively. Test duration of LCI1/30, LCI1/20 and LCI1/10 was significantly shorter compared with the test duration of LCI1/40 in people with CF (p<0.0001) equating to a 5%, 9% and 15% time saving, respectively. Conclusions: In this study, LCI1/20 was a repeatable and sensitive measure with equal diagnostic performance to LCI1/40. LCI1/20 was shorter, potentially offering a more feasible research and clinical measure.

Pupillary and visual thresholds in young children as an index of population vitamin A status

A prototype scotopic sensitivity machine was used to evaluate pupillary and visual thresholds for 295 Indonesian children aged 1-5 y, most of whom were initially vitamin A-deficient. Subjects were tested 6 and 9 mo after receiving a high dose of vitamin A. A group of 136 older children was tested at 6 mo after dosing; all subjects underwent testing at 9 mo. After testing at 9 mo, children randomly received either a second high dose of vitamin A or placebo and were tested a final time 2 wk later. Children with abnormal pupillary thresholds had significantly higher relative dose responses (RDRs) (P < 0.01) and significantly lower serum retinol values (P = 0.05) than did normal children. The mean pupillary threshold rose (eg, retinal sensitivity fell) as vitamin A status deteriorated between 6 and 9 mo after initial dosing, and was significantly different from a group of normal American children tested previously (P < 0.001). After placebo-controlled dosing, the decline in pupillary and visual thresholds (rise in retinal sensitivity) was significant for children receiving vitamin A but not for children receiving placebo.

Pupillary threshold as an index of population vitamin A status among children in India

Two hundred seven vitamin A-deficient southern Indian children aged 1-7 y (mean age: 56.9 mo) underwent testing of dark-adapted visual and pupillary thresholds in their village setting according to a previously reported protocol. One hundred thirty (62.8%) of the children also underwent serum retinol testing, and 178 (86.0%) participated in a randomized, placebo-controlled vitamin A dosing trial with pre- and postdose testing of dark-adaptation threshold. Most subjects (184 of 207, 88.9%) were able to complete pupillary testing, an objective sign requiring minimal cooperation, including a high proportion of the youngest children (72.2% of subjects aged 2 y). The proportion of children completing visual threshold testing, which requires greater understanding and cooperation, was significantly smaller than that able to complete pupillary testing (131 of 207, 63.3%; P < 0.0001, chi square). At baseline (predosing), the mean serum retinol concentration declined in linear fashion with a higher pupillary threshold (0.73 mumol/L with a score < or = 4; 0.47 mumol/L with a score > or = 8; P < 0.01). The mean pupillary threshold for these highly vitamin A-deficient Indian children (-0.622 log cd/m2) was significantly higher than that for 136 more moderately deficient Indonesian children (-0.985 log cd/m2; P < 0.001, two-sample t test) and 56 normal American children (-1.335 log cd/m2; P < 0.0001, two-sample t test). The improvement in pupillary dark-adaptation testing was not significant for children receiving vitamin A or placebo, though there was a nonsignificant trend toward greater improvement in children receiving vitamin A (P = 0.2, two-sample t test). Pupillary threshold testing represents a new, noninvasive, practical, and seemingly valid approach to assessing the vitamin A status of a moderately to severely deficient preschool population.

A BRCA1 deficient, NFκB driven immune signal predicts good outcome in triple negative breast cancer

Triple negative (TNBCs) and the closely related Basal-like (BLBCs) breast cancers are a loosely defined collection of cancers with poor clinical outcomes. Both show strong similarities with BRCA1-mutant breast cancers and BRCA1 dysfunction, or 'BRCAness', is observed in a large proportion of sporadic BLBCs. BRCA1 expression and function has been shown in vitro to modulate responses to radiation and chemotherapy. Exploitation of this knowledge in the treatment of BRCA1-mutant patients has had varying degrees of success. This reflects the significant problem of accurately detecting those patients with BRCA1 dysfunction. Moreover, not all BRCA1 mutations/loss of function result in the same histology/pathology or indeed have similar effects in modulating therapeutic responses. Given the poor clinical outcomes and lack of targeted therapy for these subtypes, a better understanding of the biology underlying these diseases is required in order to develop novel therapeutic strategies.We have discovered a consistent NFκB hyperactivity associated with BRCA1 dysfunction as a consequence of increased Reactive Oxygen Species (ROS). This biology is found in a subset of BRCA1-mutant and triple negative breast cancer cases and confers good outcome. The increased NFκB signalling results in an anti-tumour microenvironment which may allow CD8+ cytotoxic T cells to suppress tumour progression. However, tumours lacking this NFκB-driven biology have a more tumour-promoting environment and so are associated with poorer prognosis. Tumour-derived gene expression data and cell line models imply that these tumours may benefit from alternative treatment strategies such as reprogramming the microenvironment and targeting the IGF and AR signalling pathways.

Trends in adult body-mass index in 200 countries from 1975 to 2014: a pooled analysis of 1698 population-based measurement studies with 19·2 million participants

Background: Underweight and severe and morbid obesity are associated with highly elevated risks of adverse health outcomes. We estimated trends in mean body-mass index (BMI), which characterises its population distribution, and in the prevalences of a complete set of BMI categories for adults in all countries.

Methods: We analysed, with use of a consistent protocol, population-based studies that had measured height and weight in adults aged 18 years and older. We applied a Bayesian hierarchical model to these data to estimate trends from 1975 to 2014 in mean BMI and in the prevalences of BMI categories (<18·5 kg/m2 [underweight], 18·5 kg/m2 to <20 kg/m2, 20 kg/m2 to <25 kg/m2, 25 kg/m2 to <30 kg/m2, 30 kg/m2 to <35 kg/m2, 35 kg/m2 to <40 kg/m2, ≥40 kg/m2 [morbid obesity]), by sex in 200 countries and territories, organised in 21 regions. We calculated the posterior probability of meeting the target of halting by 2025 the rise in obesity at its 2010 levels, if post-2000 trends continue.
Findings: We used 1698 population-based data sources, with more than 19·2 million adult participants (9·9 million men and 9·3 million women) in 186 of 200 countries for which estimates were made. Global age-standardised mean BMI increased from 21·7 kg/m2 (95% credible interval 21·3–22·1) in 1975 to 24·2 kg/m2 (24·0–24·4) in 2014 in men, and from 22·1 kg/m2 (21·7–22·5) in 1975 to 24·4 kg/m2 (24·2–24·6) in 2014 in women. Regional mean BMIs in 2014 for men ranged from 21·4 kg/m2 in central Africa and south Asia to 29·2 kg/m2 (28·6–29·8) in Polynesia and Micronesia; for women the range was from 21·8 kg/m2 (21·4–22·3) in south Asia to 32·2 kg/m2 (31·5–32·8) in Polynesia and Micronesia. Over these four decades, age-standardised global prevalence of underweight decreased from 13·8% (10·5–17·4) to 8·8% (7·4–10·3) in men and from 14·6% (11·6–17·9) to 9·7% (8·3–11·1) in women. South Asia had the highest prevalence of underweight in 2014, 23·4% (17·8–29·2) in men and 24·0% (18·9–29·3) in women. Age-standardised prevalence of obesity increased from 3·2% (2·4–4·1) in 1975 to 10·8% (9·7–12·0) in 2014 in men, and from 6·4% (5·1–7·8) to 14·9% (13·6–16·1) in women. 2·3% (2·0–2·7) of the world's men and 5·0% (4·4–5·6) of women were severely obese (ie, have BMI ≥35 kg/m2). Globally, prevalence of morbid obesity was 0·64% (0·46–0·86) in men and 1·6% (1·3–1·9) in women.

Interpretation: If post-2000 trends continue, the probability of meeting the global obesity target is virtually zero. Rather, if these trends continue, by 2025, global obesity prevalence will reach 18% in men and surpass 21% in women; severe obesity will surpass 6% in men and 9% in women. Nonetheless, underweight remains prevalent in the world's poorest regions, especially in south Asia.

The Baltic Dry Index: cyclicalities, forecasting and hedging strategies

The cyclical properties of the Baltic Dry Index (BDI) and their implications for forecasting performance are investigated. We find that changes in the BDI can lead to permanent shocks to trade of major exporting economies. In our forecasting exercise, we show that commodities and trigonometric regression can lead to improved predictions and then use our forecasting results to perform an investment exercise and to show how they can be used for improved risk management in the freight sector.

Selective Multi-Carrier Index Keying OFDM: Error Propagation Rate with Moment Generating Function

We propose a new selective multi-carrier index keying in orthogonal frequency division multiplexing (OFDM) systems that opportunistically modulate both a small subset of sub-carriers and their indices. Particularly, we investigate the performance enhancement in two cases of error propagation sensitive and compromised deviceto-device (D2D) communications. For the performance evaluation, we focus on analyzing the error propagation probability (EPP) introducing the exact and upper bound expressions on the detection error probability, in the presence of both imperfect and perfect detection of active multi-carrier indices. The average EPP results in closedform are generalized for various fading distribution using the moment generating function, and our numerical results clearly show that the proposed approach is desirable for reliable and energy-efficient D2D applications.

Fetal umbilical artery Doppler pulsatility index and childhood neurocognitive outcome at 12 years

OBJECTIVE: To determine whether an elevated fetal umbilical artery Doppler (UAD) pulsatility index (PI) at 28 weeks' gestation, in the absence of fetal growth restriction (FGR) and prematurity, is associated with adverse neurocognitive outcome in children aged 12 years.

METHODS: Prospective cohort study, comparing children with a normal fetal UAD PI (<90th centile) (n=110) and those with an elevated PI (≥90th centile) (n=40). UAD was performed at 28, 32 and 34 weeks gestation. At 12 years of age, all children were assessed under standardised conditions at Queen's University, Belfast, UK to determine cognitive and behavioural outcomes using the British Ability Score-II and Achenbach Child Behavioural Checklist Parent Rated Version under standardised conditions. Regression analysis was performed, controlling for confounders such as gender, socioeconomic status and age at assessment.

RESULTS: The mean age of follow-up was 12.4 years (±0.5 SD) with 44% of children male (n=63). When UAD was assessed at 28 weeks, the elevated fetal UAD group had lower scores in cognitive assessments of information processing and memory. Parameters included (1) recall of objects immediate verbal (p=0.002), (2) delayed verbal (p=0.008) and (3) recall of objects immediate spatial (p=0.0016). There were no significant differences between the Doppler groups at 32 or 34 weeks' gestation.

CONCLUSIONS: An elevated UAD PI at 28 weeks' gestation in the absence of FGR or prematurity is associated with lower scores of declarative memory in children aged 12 years. A potential explanation for this is an element of placental insufficiency in the presence of the appropriately grown fetus, which affects the development of the fetal hippocampus and information processing and memory long-term. These findings, however, had no impact on overall academic ability, mental processing and reasoning or overall behavioural function.

The value of adjuvant radiotherapy on survival and recurrence in triple-negative breast cancer: a systematic review and meta-analysis of 5,507 patients

BACKGROUND: The value of adjuvant radiotherapy in triple negative breast cancer (TNBC) remains unclear. A systematic review and meta-analysis was conducted in TNBC patients to assess survival and recurrence outcomes associated with radiotherapy following either breast conserving therapy (BCT) or post-mastectomy radiotherapy (PMRT). METHODS: Four electronic databases were searched from January 2000 to November 2015 (PubMed, MEDLINE, EMBASE and Web of Science). Studies investigating overall survival and/or recurrence in TNBC patients according to radiotherapy administration were included. A random effects meta-analysis was conducted using mastectomy only patients as the reference.  RESULTS: Twelve studies were included. The pooled hazard ratio (HR) for locoregional recurrence comparing BCT and PMRT to mastectomy only was 0.61 (95% confidence interval [CI] 0.41-0.90) and 0.62 (95% CI 0.44-0.86), respectively. Adjuvant radiotherapy was not significantly associated with distant recurrence. The pooled HR for overall survival comparing BCT and PMRT to mastectomy only was 0.57 (95% CI 0.36-0.88) and HR 1.12 (95% CI 0.75, 1.69). Comparing PMRT to mastectomy only, tests for interaction were not significant for stage (p=0.98) or age at diagnosis (p=0.85). However, overall survival was improved in patients with late-stage disease (T3-4, N2-3) pooled HR 0.53 (95% CI 0.32-0.86), and women <40 years, pooled HR 0.30 (95% CI 0.11-0.82). CONCLUSIONS: Adjuvant radiotherapy was associated with a significantly lower risk of locoregional recurrence in TNBC patients, irrespective of the type of surgery. While radiotherapy was not consistently associated with an overall survival gain, benefits may be obtained in women with late-stage disease and younger patients.