After curative radiotherapy (RT) or chemoradiation (CRT), there is no validated tool to accurately identify patients for adjuvant therapy in nasopharyngeal carcinoma (NPC). Post-RT circulating plasma ...Epstein–Barr virus (EBV) DNA can detect minimal residual disease and is associated with recurrence and survival independent of TNM (tumor–lymph node–metastasis) stage. We aimed to develop and validate a risk model for stratification of NPC patients after completion of RT/CRT to observation or adjuvant therapy.
The prospective multicenter 0502 EBV DNA screening cohort (Hong Kong NPC Study Group 0502 trial) enrolled from 2006 to 2015 (n = 745) was used for model development. For internal validation, we pooled independent patient cohorts from prospective clinical studies enrolled from 1997 to 2006 (n = 340). For external validation, we used retrospective cohort of NPC patients treated at Sun Yat-sen University Cancer Center from 2009 to 2012 (n = 837). Eligible patients had histologically confirmed NPC of Union for International Cancer Control (UICC) 7th Edition stage II–IVB who completed curative RT/CRT with or without neoadjuvant chemotherapy, had post-RT EBV DNA tested within 120 days after RT and received no adjuvant therapy. The primary end point was overall survival (OS). We used recursive-partitioning analysis (RPA) to classify patients into groups of low, intermediate, and high risk of death.
Combining post-RT EBV DNA level (0, 1–49, 50–499, and ≥500 copies/ml) and TNM stage (II, III, IVAB), RPA model classified patients into low-, intermediate-, and high-risk groups with 5-year OS of 89.4%, 78.5% and 37.2%, respectively. The RPA low-risk group had comparable OS to TNM stage II (5-year OS 88.5%) but identified more patients (64.8% versus stage II 28.1%) that could potentially be spared adjuvant therapy toxicity. The RPA model (c-index 0.712) showed better risk discrimination than either the TNM stage (0.604) or post-RT EBV DNA alone (0.675) with improved calibration and consistence. These results were validated in both internal and external cohorts.
Combining post-RT EBV DNA and TNM stage improved risk stratification in NPC.
•Integrating postradiotherapy plasma Epstein–Barr virus (EBV) DNA and tumor–lymph node–metastasis (TNM) stage improves the risk stratification of nasopharyngeal carcinoma.•Postradiotherapy plasma EBV DNA is a better predictor of early death in nasopharyngeal carcinoma than TNM stage.•The low-risk group by recursive partitioning model can spare more patients from unnecessary toxicity of adjuvant therapy.
Background: Patients with mild to moderate obstructive sleep apnoea (OSA) may be managed with different treatment options. This study compared the effectiveness of three commonly used non-surgical ...treatment modalities. Methods: Subjects with mild to moderate OSA were randomised to one of three treatment groups for 10 weeks: conservative measures (sleep hygiene) only, continuous positive airways pressure (CPAP) in addition to conservative measures or an oral appliance in addition to conservative measures. All overweight subjects were referred to a weight-reduction class. OSA was assessed by polysomnography. Blood pressure was recorded in the morning and evening in the sleep laboratory. Daytime sleepiness was assessed with the Epworth Sleepiness Scale. Health-related quality of life (HRQOL) was assessed with the 36-Item Short-Form Health Survey (SF-36) and Sleep Apnoea Quality of Life Index (SAQLI). Results: 101 subjects with a mean (SEM) apnoea–hypopnoea index (AHI) of 21.4 (1.1) were randomised to one of the three groups. The severity of sleep-disordered breathing was decreased in the CPAP and oral appliance groups compared with the conservative measures group, and the CPAP group was significantly better than the oral appliance group. Relief from sleepiness was significantly better in the CPAP group. CPAP was also better than the oral appliance or conservative measures in improving the “bodily pain” domain, and better than conservative measures in improving the “physical function” domain of SF-36. Both CPAP and the oral appliance were more effective than conservative measures in improving the SAQLI, although no difference was detected between the CPAP and oral appliance groups. CPAP and the oral appliance significantly lowered the morning diastolic blood pressure compared with baseline values, but there was no difference in the changes in blood pressure between the groups. There was also a linear relationship between the changes in AHI and body weight. Conclusion: CPAP produced the best improvement in terms of physiological, symptomatic and HRQOL measures, while the oral appliance was slightly less effective. Weight loss, if achieved, resulted in an improvement in sleep parameters, but weight control alone was not uniformly effective.
Abstract
We report results from continued timing observations of PSR J0740+6620, a high-mass, 2.8 ms radio pulsar in orbit with a likely ultracool white dwarf companion. Our data set consists of ...combined pulse arrival-time measurements made with the 100 m Green Bank Telescope and the Canadian Hydrogen Intensity Mapping Experiment telescope. We explore the significance of timing-based phenomena arising from general relativistic dynamics and variations in pulse dispersion. When using various statistical methods, we find that combining ∼1.5 yr of additional, high-cadence timing data with previous measurements confirms and improves on previous estimates of relativistic effects within the PSR J0740+6620 system, with the pulsar mass
m
p
=
2.08
−
0.07
+
0.07
M
⊙
(68.3% credibility) determined by the relativistic Shapiro time delay. For the first time, we measure secular variation in the orbital period and argue that this effect arises from apparent acceleration due to significant transverse motion. After incorporating contributions from Galactic differential rotation and off-plane acceleration in the Galactic potential, we obtain a model-dependent distance of
d
=
1.14
−
0.15
+
0.17
kpc (68.3% credibility). This improved distance confirms the ultracool nature of the white dwarf companion determined from recent optical observations. We discuss the prospects for future observations with next-generation facilities, which will likely improve the precision on
m
p
for J0740+6620 by an order of magnitude within the next few years.
To study the dynamic changes in plasma Epstein-Barr virus (pEBV) DNA after radiotherapy in nasopharyngeal cancer (NPC).
We conducted a randomized controlled trial of adjuvant chemotherapy versus ...observation in patients with NPC who had detectable pEBV DNA at 6 weeks post-radiotherapy. Randomized patients had a second pEBV DNA checked at 6 months post-randomization. The primary endpoint was progression-free survival (PFS).
We prospectively enrolled 789 patients. Baseline post-radiotherapy pEBV DNA was undetectable in 573 (72.6%) patients, and detectable in 216 (27.4%) patients, of whom 104 (13.2%) patients were eligible for randomization to adjuvant chemotherapy (
= 52) versus observation (
= 52). The first post-radiotherapy pEBV DNA had a sensitivity of 0.48, specificity of 0.81, area under receiver-operator characteristics curve (AUC) of 0.65, false positive (FP) rate of 13.8%, and false negative (FN) rate of 14.4% for disease progression. The second post-radiotherapy pEBV DNA had improved sensitivity of 0.81, specificity of 0.75, AUC of 0.78, FP rate of 14.3%, and FN rate of 8.1%. Patients with complete clearance of post-radiotherapy pEBV DNA (51%) had survival superior to that of patients without post-radiotherapy pEBV DNA clearance (5-year PFS, 85.5% vs. 23.3%; HR, 9.6;
< 0.0001), comparable with patients with initially undetectable post-radiotherapy pEBV DNA (5-year PFS, 77.1%), irrespective of adjuvant chemotherapy or observation.
Patients with NPC with detectable post-radiotherapy pEBV DNA who experienced subsequent pEBV DNA clearance had superior survival comparable with patients with initially undetectable post-radiotherapy pEBV DNA. Post-radiotherapy pEBV DNA clearance may serve as an early surrogate endpoint for long-term survival in NPC.
Vancomycin-resistant enterococci (VRE) are one of the leading causes of nosocomial infections in health care facilities around the globe. In particular, infections caused by vancomycin-resistant ...Enterococcus faecium are becoming increasingly common. Comparative and functional genomic studies of E. faecium isolates have so far been limited owing to the lack of a fully assembled E. faecium genome sequence. Here we address this issue and report the complete 3.0-Mb genome sequence of the multilocus sequence type 17 vancomycin-resistant Enterococcus faecium strain Aus0004, isolated from the bloodstream of a patient in Melbourne, Australia, in 1998. The genome comprises a 2.9-Mb circular chromosome and three circular plasmids. The chromosome harbors putative E. faecium virulence factors such as enterococcal surface protein, hemolysin, and collagen-binding adhesin. Aus0004 has a very large accessory genome (38%) that includes three prophage and two genomic islands absent among 22 other E. faecium genomes. One of the prophage was present as inverted 50-kb repeats that appear to have facilitated a 683-kb chromosomal inversion across the replication terminus, resulting in a striking replichore imbalance. Other distinctive features include 76 insertion sequence elements and a single chromosomal copy of Tn1549 containing the vanB vancomycin resistance element. A complete E. faecium genome will be a useful resource to assist our understanding of this emerging nosocomial pathogen.
In this paper, we describe the International Pulsar Timing Array second data release, which includes recent pulsar timing data obtained by three regional consortia: the European Pulsar Timing Array, ...the North American Nanohertz Observatory for Gravitational Waves, and the
Parkes Pulsar Timing Array. We analyse and where possible combine high-precision timing data for 65 millisecond pulsars which are regularly observed by these groups. A basic noise analysis, including the processes which are both correlated and uncorrelated in time, provides noise models and timing ephemerides for the pulsars. We find that the timing precisions of pulsars are generally improved compared to the previous data release, mainly due to the addition of new data in the combination. The main purpose of this work is to create the most up-to-date IPTA data release. These data are publicly available for searches for low-frequency gravitational waves and other pulsar science.
Objective The objective of this first population‐based study in Hong Kong was to assess the impact of psychological abuse by an intimate partner on the mental health of pregnant women.
Design ...Survey.
Setting Antenatal clinics in seven public hospitals in Hong Kong.
Population Three thousand two hundred and forty‐five pregnant women.
Methods The Abuse Assessment Screen (AAS) and demographic questionnaires were administered face‐to‐face at 32–36 weeks of gestation. At 1 week postpartum, the AAS, Edinburgh Postnatal Depression Scale and SF‐12 Health Survey were administered by telephone.
Main outcome measures Intimate partner violence, postnatal depression and health‐related quality of life.
Results Two hundred and ninety six (9.1%) of the participants reported abuse by an intimate partner in the past year. Of those abused, 216 (73%) reported psychological abuse only and 80 (27%) reported physical and/or sexual abuse. Forty six (57.5%) in the physical and/or sexual abuse group also reported psychological abuse. Women in the psychological abuse only group had a higher risk of postnatal depression compared with nonabused women (adjusted OR: 1.84, 95% CI: 1.12–3.02). They were also at a higher risk of thinking about harming themselves (adjusted OR: 3.50, 95% CI: 1.49–8.20) and had significantly poorer mental health‐related quality of life (P < 0.001). The higher risks of postnatal depression and thinking of harming themselves were not observed in the physical and/or sexual abuse group although significantly poorer mental health‐related quality of life (P < 0.001) was observed.
Conclusions Psychological abuse by an intimate partner against pregnant women has a negative impact on their mental health postdelivery. Furthermore, psychological abuse in the absence of physical and/or sexual abuse can have a detrimental effect on the mental health of abused women. The findings underscore the importance of screening pregnant women for abuse by an intimate partner and the need for developing, implementing and evaluating interventions to address psychological abuse.
Complete surgical removal of the prostate, radical prostatectomy, is the most frequently used treatment option for men with localised prostate cancer. The use of laparoscopic (keyhole) and ...robot-assisted surgery has improved operative safety but the comparative effectiveness and cost-effectiveness of these options remains uncertain.
This study aimed to determine the relative clinical effectiveness and cost-effectiveness of robotic radical prostatectomy compared with laparoscopic radical prostatectomy in the treatment of localised prostate cancer within the UK NHS.
MEDLINE, MEDLINE In-Process & Other Non-Indexed Citations, EMBASE, BIOSIS, Science Citation Index and Cochrane Central Register of Controlled Trials were searched from January 1995 until October 2010 for primary studies. Conference abstracts from meetings of the European, American and British Urological Associations were also searched. Costs were obtained from NHS sources and the manufacturer of the robotic system. Economic model parameters and distributions not obtained in the systematic review were derived from other literature sources and an advisory expert panel.
Evidence was considered from randomised controlled trials (RCTs) and non-randomised comparative studies of men with clinically localised prostate cancer (cT1 or cT2); outcome measures included adverse events, cancer related, functional, patient driven and descriptors of care. Two reviewers abstracted data and assessed the risk of bias of the included studies. For meta-analyses, a Bayesian indirect mixed-treatment comparison was used. Cost-effectiveness was assessed using a discrete-event simulation model.
The searches identified 2722 potentially relevant titles and abstracts, from which 914 reports were selected for full-text eligibility screening. Of these, data were included from 19,064 patients across one RCT and 57 non-randomised comparative studies, with very few studies considered at low risk of bias. The results of this study, although associated with some uncertainty, demonstrated that the outcomes were generally better for robotic than for laparoscopic surgery for major adverse events such as blood transfusion and organ injury rates and for rate of failure to remove the cancer (positive margin) (odds ratio 0.69; 95% credible interval 0.51 to 0.96; probability outcome favours robotic prostatectomy = 0.987). The predicted probability of a positive margin was 17.6% following robotic prostatectomy compared with 23.6% for laparoscopic prostatectomy. Restriction of the meta-analysis to studies at low risk of bias did not change the direction of effect but did decrease the precision of the effect size. There was no evidence of differences in cancer-related, patient-driven or dysfunction outcomes. The results of the economic evaluation suggested that when the difference in positive margins is equivalent to the estimates in the meta-analysis of all included studies, robotic radical prostatectomy was on average associated with an incremental cost per quality-adjusted life-year that is less than threshold values typically adopted by the NHS (£30,000) and becomes further reduced when the surgical capacity is high.
The main limitations were the quantity and quality of the data available on cancer-related outcomes and dysfunction.
This study demonstrated that robotic prostatectomy had lower perioperative morbidity and a reduced risk of a positive surgical margin compared with laparoscopic prostatectomy although there was considerable uncertainty. Robotic prostatectomy will always be more costly to the NHS because of the fixed capital and maintenance charges for the robotic system. Our modelling showed that this excess cost can be reduced if capital costs of equipment are minimised and by maintaining a high case volume for each robotic system of at least 100-150 procedures per year. This finding was primarily driven by a difference in positive margin rate. There is a need for further research to establish how positive margin rates impact on long-term outcomes.
The National Institute for Health Research Health Technology Assessment programme.
We have constructed a new time-scale, TT(IPTA16), based on observations of radio pulsars presented in the first data release from the International Pulsar Timing Array (IPTA). We used two analysis ...techniques with independent estimates of the noise models for the pulsar observations and different algorithms for obtaining the pulsar time-scale. The two analyses agree within the estimated uncertainties and both agree with TT(BIPM17), a post-corrected time-scale produced by the Bureau International des Poids et Mesures (BIPM). We show that both methods could detect significant errors in TT(BIPM17) if they were present. We estimate the stability of the atomic clocks from which TT(BIPM17) is derived using observations of four rubidium fountain clocks at the US Naval Observatory. Comparing the power spectrum of TT(IPTA16) with that of these fountain clocks suggests that pulsar-based time-scales are unlikely to contribute to the stability of the best time-scales over the next decade, but they will remain a valuable independent check on atomic time-scales. We also find that the stability of the pulsar-based time-scale is likely to be limited by our knowledge of solar-system dynamics, and that errors in TT(BIPM17) will not be a limiting factor for the primary goal of the IPTA, which is to search for the signatures of nano-Hertz gravitational waves.
Owing to the increasing prevalence of obesity and diabetes in Asia, and the paucity of studies, we examined the influence of raised blood glucose and diabetes on cancer mortality risk.
Thirty-six ...cohort Asian and Australasian studies provided 367361 participants (74% from Asia); 6% had diabetes at baseline. Associations between diabetes and site-specific cancer mortality were estimated using time-dependent Cox models, stratified by study and sex, and adjusted for age.
During a median follow-up of 4.0 years, there were 5992 deaths due to cancer (74% Asian; 41% female). Participants with diabetes had 23% greater risk of mortality from all-cause cancer compared with those without: hazard ratio (HR) 1.23 95% confidence interval (CI) 1.12, 1.35. Diabetes was associated with mortality due to cancer of the liver (HR 1.51; 95% CI 1.19, 1.91), pancreas (HR 1.78; 95% CI 1.20, 2.65), and, less strongly, colorectum (HR 1.32; 95% CI 0.98, 1.78). There was no evidence of sex- or region-specific differences in these associations. The population attributable fractions for cancer mortality due to diabetes were generally higher for Asia compared with non-Asian populations.
Diabetes is associated with increased mortality from selected cancers in Asian and non-Asian populations.
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