Improved Constraints on Primordial Gravitational Waves using Planck, WMAP, and BICEP/Keck Observations through the 2018 Observing Season.

We present results from an analysis of all data taken by the BICEP2, Keck Array, and BICEP3 CMB polarization experiments up to and including the 2018 observing season. We add additional Keck Array observations at 220 GHz and BICEP3 observations at 95 GHz to the previous 95/150/220 GHz dataset. The Q/U maps now reach depths of 2.8, 2.8, and 8.8 µK_{CMB} arcmin at 95, 150, and 220 GHz, respectively, over an effective area of ≈600 square degrees at 95 GHz and ≈400 square degrees at 150 and 220 GHz. The 220 GHz maps now achieve a signal-to-noise ratio on polarized dust emission exceeding that of Planck at 353 GHz. We take auto- and cross-spectra between these maps and publicly available WMAP and Planck maps at frequencies from 23 to 353 GHz and evaluate the joint likelihood of the spectra versus a multicomponent model of lensed ΛCDM+r+dust+synchrotron+noise. The foreground model has seven parameters, and no longer requires a prior on the frequency spectral index of the dust emission taken from measurements on other regions of the sky. This model is an adequate description of the data at the current noise levels. The likelihood analysis yields the constraint r_{0.05}<0.036 at 95% confidence. Running maximum likelihood search on simulations we obtain unbiased results and find that σ(r)=0.009. These are the strongest constraints to date on primordial gravitational waves.

Internal Delensing of Cosmic Microwave Background Polarization B-Modes with the POLARBEAR Experiment.

Using only cosmic microwave background polarization data from the polarbear experiment, we measure B-mode polarization delensing on subdegree scales at more than 5σ significance. We achieve a 14% B-mode power variance reduction, the highest to date for internal delensing, and improve this result to 22% by applying for the first time an iterative maximum a posteriori delensing method. Our analysis demonstrates the capability of internal delensing as a means of improving constraints on inflationary models, paving the way for the optimal analysis of next-generation primordial B-mode experiments.

The POLARBEAR Fourier transform spectrometer calibrator and spectroscopic characterization of the POLARBEAR instrument.

We describe the Fourier Transform Spectrometer (FTS) used for in-field testing of the POLARBEAR receiver, an experiment located in the Atacama Desert of Chile which measures the cosmic microwave background (CMB) polarization. The POLARBEAR-FTS (PB-FTS) is a Martin-Puplett interferometer designed to couple to the Huan Tran Telescope (HTT) on which the POLARBEAR receiver is installed. The PB-FTS measured the spectral response of the POLARBEAR receiver with signal-to-noise ratio >20 for ∼69% of the focal plane detectors due to three features: a high throughput of 15.1 sr cm2, optimized optical coupling to the POLARBEAR optics using a custom designed output parabolic mirror, and a continuously modulated output polarizer. The PB-FTS parabolic mirror is designed to mimic the shape of the 2.5 m-diameter HTT primary reflector, which allows for optimum optical coupling to the POLARBEAR receiver, reducing aberrations and systematics. One polarizing grid is placed at the output of the PB-FTS and modulated via continuous rotation. This modulation allows for decomposition of the signal into different harmonics that can be used to probe potentially pernicious sources of systematic error in a polarization-sensitive instrument. The high throughput and continuous output polarizer modulation features are unique compared to other FTS calibrators used in the CMB field. In-field characterization of the POLARBEAR receiver was accomplished using the PB-FTS in April 2014. We discuss the design, construction, and operation of the PB-FTS and present the spectral characterization of the POLARBEAR receiver. We introduce future applications for the PB-FTS in the next-generation CMB experiment, the Simons Array.

Pregnancy-associated plasma protein-A truncation limits in antenatal screening for trisomy 18.

Upper and lower truncation limits are commonly applied to quantitative markers used in medical screening tests. We here examine data on 375 trisomy 18 and 522,081 unaffected singleton pregnancies, to determine if the lower truncation limit should be set below the previously specified 0.2 multiples of the median. A lower truncation limit of 0.15 would reduce the underestimation of the risk of having a trisomy 18 pregnancy in about 50% of affected pregnancies and would lead to an estimated 10 percentage point increase in the detection rate, with only a very small increase in the false-positive rate.

Mortality from aortic stenosis: prospective study of serum calcium and phosphate.

PURPOSE: To investigate the associations between levels of serum calcium and phosphate and subsequent death from aortic stenosis, and the implications for prevention. METHODS: A prospective (nested case-control) analysis of serum calcium and phosphate levels was performed in stored samples from the British United Provident Association prospective study of 21 520 men aged 35-64, followed for up to 32 years. There were 49 men without baseline valvular heart disease who subsequently died of aortic stenosis. Each was matched, for age, duration of sample storage and number of freeze-thaw cycles, with four unaffected control subjects. Odds ratios for death from aortic stenosis were estimated by logistic regression. RESULTS: Mean serum calcium concentration was higher in men who died of aortic stenosis than in those who did not (2.44 vs. 2.39 mmol L-1 ; P = 0.01). The risk of death from aortic stenosis in the highest calcium tertile was 2.87-fold higher than in the lowest tertile (95% confidence interval 1.22-6.76). There was a continuous dose-response relationship; risk of death from aortic stenosis increased by 51% (11-105%) per 0.1 mmol L-1 increase in serum calcium, equivalent to a 34% (10-52%) lower risk per 0.1 mmol L-1 decrease. Serum phosphate was not significantly higher in men who died of aortic stenosis than in those who did not (1.0 vs. 0.99 mmol L-1 ; P = 0.76). CONCLUSIONS: The association between serum calcium and subsequent mortality from aortic stenosis is of potential preventive significance. If confirmed quantitatively in other similar cohort studies, the results suggest that a very small reduction in serum calcium (about 5%) could translate into a large (about one-third) reduction in aortic stenosis.

Infrared spectra of primary melanomas can predict response to chemotherapy: The example of dacarbazine.

Metastatic melanomas are highly aggressive and median survival is 6-9months for stage IV patients in the absence of treatment with anti-tumor activity. Dacarbazine is an alkylating agent that has been widely used in the treatment of metastatic melanomas and that could be still used in combination with targeted or immune therapies. Indeed, therapeutic benefits of these treatments in monotherapy are poor and one option to improve them is to combine drugs and/or to better anticipate the individual response to a defined treatment. To our best knowledge and to date, there is no test available to predict the response of a patient to dacarbazine. We show here that examination of melanoma histological sections by infrared micro-spectroscopy reveals the sensitivity of the cancer to dacarbazine. Unsupervised analysis of the FTIR spectra evidences spontaneous and significant clustering of infrared spectra into two groups that match the clinical responsiveness of the patients to dacarbazine used as a first-line treatment. A supervised model resulted in 83% of the patient status (responder/non-responder) being correctly identified. The spectra revealed a key modification in the nature and quantity of lipids in the cells of both groups.

Identification of melanoma cells and lymphocyte subpopulations in lymph node metastases by FTIR imaging histopathology.

While early stages of melanoma are usually cured by surgery, metastatic melanomas are difficult to treat because the widely available options have low response rates. Careful and precise diagnosis and staging are essential to determine patient's risk and to select appropriate treatments. Fortunately, the recent progress in immunotherapy is very encouraging. In this context, it is important to characterize the intratumoral infiltration of immune cells in each patient, which is however not done routinely due to the lack of standardized methods. In this study, we used Fourier transform infrared (FTIR) imaging combined with multivariate statistical analyses to investigate non-metastatic and metastatic lymph nodes from melanoma patients. Our results show that the different cell types have different infrared spectral features allowing automated identification of these cell types. High recognition rates were obtained using a supervised partial least square discriminant analysis (PLS-DA) model. Melanoma cells were recognized with 87.1% sensitivity and 85.7% specificity, showing that FTIR spectroscopy has similar detection power as immunohistochemistry. Besides, FTIR imaging could also distinguish lymphocyte subpopulations (B and T cells). Finally, we investigated the changes in lymphocytes due to the presence of metastases. Interestingly, specific features of spectra of lymphocytes present in metastatic or tumor-free lymph nodes could be evidenced by PCA. A PLS-DA model was capable of predicting whether lymphocytes originated from invaded or non-invaded lymph nodes. These data demonstrate that FTIR imaging is capable to distinguish known and also novel biological features in human tissues, with potential practical relevance for histopathological diagnosis and biomarker assessment.

UK Lung Cancer RCT Pilot Screening Trial: baseline findings from the screening arm provide evidence for the potential implementation of lung cancer screening.

BACKGROUND: Lung cancer screening using low-dose CT (LDCT) was shown to reduce lung cancer mortality by 20% in the National Lung Screening Trial. METHODS: The pilot UK Lung Cancer Screening (UKLS) is a randomised controlled trial of LDCT screening for lung cancer versus usual care. A population-based questionnaire was used to identify high-risk individuals. CT screen-detected nodules were managed by a pre-specified protocol. Cost effectiveness was modelled with reference to the National Lung Cancer Screening Trial mortality reduction. RESULTS: 247 354 individuals aged 50-75 years were approached; 30.7% expressed an interest, 8729 (11.5%) were eligible and 4055 were randomised, 2028 into the CT arm (1994 underwent a CT). Forty-two participants (2.1%) had confirmed lung cancer, 34 (1.7%) at baseline and 8 (0.4%) at the 12-month scan. 28/42 (66.7%) had stage I disease, 36/42 (85.7%) had stage I or II disease. 35/42 (83.3%) had surgical resection. 536 subjects had nodules greater than 50 mm(3) or 5 mm diameter and 41/536 were found to have lung cancer. One further cancer was detected by follow-up of nodules between 15 and 50 mm(3) at 12 months. The baseline estimate for the incremental cost-effectiveness ratio of once-only CT screening, under the UKLS protocol, was £8466 per quality adjusted life year gained (CI £5542 to £12 569). CONCLUSIONS: The UKLS pilot trial demonstrated that it is possible to detect lung cancer at an early stage and deliver potentially curative treatment in over 80% of cases. Health economic analysis suggests that the intervention would be cost effective-this needs to be confirmed using data on observed lung cancer mortality reduction. TRIAL REGISTRATION: ISRCTN 78513845.

Prevention of neural tube defects in the UK: a missed opportunity.

OBJECTIVE: In 1991, the Medical Research Council (MRC) Vitamin Study demonstrated that folic acid taken before pregnancy and in early pregnancy reduced the risk of a neural tube defect (NTD). We aimed to estimate the number of NTD pregnancies that would have been prevented if flour had been fortified with folic acid in the UK from 1998 as it had been in the USA. DESIGN: Estimates of NTD prevalence, the preventive effect of folic acid and the proportion of women taking folic acid supplements before pregnancy were used to predict the number of NTD pregnancies that would have been prevented if folic acid fortification had been implemented. SETTING: Eight congenital anomaly registers in England and Wales. MAIN OUTCOME MEASURES: The prevalence of pregnancies with an NTD in the UK and the number of these pregnancies that would have been prevented if folic acid fortification had been implemented. RESULTS: From 1991 to 2012, the prevalence of NTD pregnancies was 1.28 (95% CI 1.24 to 1.31) per 1000 total births (19% live births, 81% terminations and 0.5% stillbirths and fetal deaths ≥20 weeks' gestation). If the USA levels of folic acid fortification from 1998 onwards had been adopted in the UK, an estimated 2014 fewer NTD pregnancies would have occurred. CONCLUSIONS: Failure to implement folic acid fortification in the UK has caused, and continues to cause, avoidable terminations of pregnancy, stillbirths, neonatal deaths and permanent serious disability in surviving children.

Presentation of meta-analysis plots.

Meta-analysis (forest) plots are widely used to show the results from multiple individual randomized trials or observational studies that address the same question, including the assessment of screening markers. They show the between study spread of results and provide a summary estimate of the results from all the studies combined. We here illustrate the advantage of ordering study results by the magnitude of the effect and including a vertical shaded band encompassing the summary 95% confidence interval of the summary estimate to emphasize the uncertainty of the estimate in a way that is more prominent than only displaying a "diamond" around its value.

An infrared spectral signature of human lymphocyte subpopulations from peripheral blood.

Metastatic melanomas are frequently refractory to most adjuvant therapies such as chemotherapies and radiotherapies. Recently, immunotherapies have shown good results in the treatment of some metastatic melanomas. Immune cell infiltration in the tumor has been associated with successful immunotherapy. More generally, tumor infiltrating lymphocytes (TILs) in the primary tumor and in metastases of melanoma patients have been demonstrated to correlate positively with favorable clinical outcomes. Altogether, these findings suggest the importance of being able to identify, quantify and characterize immune infiltration at the tumor site for a better diagnostic and treatment choice. In this paper, we used Fourier Transform Infrared (FTIR) imaging to identify and quantify different subpopulations of T cells: the cytotoxic T cells (CD8+), the helper T cells (CD4+) and the regulatory T cells (T reg). As a proof of concept, we investigated pure populations isolated from human peripheral blood from 6 healthy donors. These subpopulations were isolated from blood samples by magnetic labeling and purities were assessed by Fluorescence Activated Cell Sorting (FACS). The results presented here show that Fourier Transform Infrared (FTIR) imaging followed by supervised Partial Least Square Discriminant Analysis (PLS-DA) allows an accurate identification of CD4+ T cells and CD8+ T cells (>86%). We then developed a PLS regression allowing the quantification of T reg in a different mix of immune cells (e.g. Peripheral Blood Mononuclear Cells (PBMCs)). Altogether, these results demonstrate the sensitivity of infrared imaging to detect the low biological variability observed in T cell subpopulations.

Infrared imaging of primary melanomas reveals hints of regional and distant metastases.

Melanoma is the deadliest form of skin cancer. Metastatic melanomas are resistant to almost all existing adjuvant therapies such as chemotherapy and radiotherapy, so detection of metastases remains a challenge, and no biomarkers are currently available to detect primary tumors with the highest risk of metastasis. Results presented in this paper show that Fourier Transform Infrared (FTIR) imaging of histological sections followed by supervised partial least squares discriminant analysis (PLS-DA) can accurately (>90%) identify the main cell types commonly found in melanoma tumors. Here we define six cell types: melanoma cells, erythrocytes, connective tissue (includes blood vessel walls, dermis and collagen regions), keratinocytes, lymphocytes and necrotic cells. Interestingly, more than 98% of the melanoma cells are correctly identified. The spectra of the cells identified as melanomas were then further analyzed. First, we compared melanoma cells in primary tumors (from 26 patients) with melanoma cells from metastases (from 25 patients). Neither supervised nor unsupervised analyses revealed any significant difference. Similarly, we found no significant correlation between the infrared spectra of melanoma cells and the number of proliferative cells assessed by Ki67 immunostaining. Finally, we compared the infrared spectra of primary tumors from patients diagnosed at different stages of the disease. Infrared spectroscopy was capable of pointing out differences between primary tumors of patients at stage I or II and patients at stage III or IV, even by unsupervised analysis. We then developed a supervised PLS-DA model capable of predicting whether tumor cells belonged to one of the two aggregated disease stage groups. The model predicted a high rate of true positives (sensitivity of 88.9%) and a good rate of true negatives (specificity of 70.6%) in external validation. These results demonstrate that infrared spectroscopy can be used to help identify melanoma characteristics related to the cells' invasive capability.

Is the area under an ROC curve a valid measure of the performance of a screening or diagnostic test?

OBJECTIVES: The area under a receiver operating characteristic (ROC) curve (the AUC) is used as a measure of the performance of a screening or diagnostic test. We here assess the validity of the AUC. METHODS: Assuming the test results follow Gaussian distributions in affected and unaffected individuals, standard mathematical formulae were used to describe the relationship between the detection rate (DR) (or sensitivity) and the false-positive rate (FPR) of a test with the AUC. These formulae were used to calculate the screening performance (DR for a given FPR, or FPR for a given DR) for different AUC values according to different standard deviations of the test result in affected and unaffected individuals. RESULTS: The DR for a given FPR is strongly dependent on relative differences in the standard deviation of the test variable in affected and unaffected individuals. Consequently, two tests with the same AUC can have a different DR for the same FPR. For example, an AUC of 0.75 has a DR of 24% for a 5% FPR if the standard deviations are the same in affected and unaffected individuals, but 39% for the same 5% FPR if the standard deviation in affected individuals is 1.5 times that in unaffected individuals. CONCLUSION: The AUC is an unreliable measure of screening performance because in practice the standard deviation of a screening or diagnostic test in affected and unaffected individuals can differ. The problem is avoided by not using AUC at all, and instead specifying DRs for given FPRs or FPRs for given DRs.

Breast cancer and melanoma cell line identification by FTIR imaging after formalin-fixation and paraffin-embedding.

Over the past few decades, Fourier transform infrared (FTIR) spectroscopy coupled to microscopy has been recognized as an emerging and potentially powerful tool in cancer research and diagnosis. For this purpose, histological analyses performed by pathologists are mostly carried out on biopsied tissue that undergoes the formalin-fixation and paraffin-embedding (FFPE) procedure. This processing method ensures an optimal and permanent preservation of the samples, making FFPE-archived tissue an extremely valuable source for retrospective studies. Nevertheless, as highlighted by previous studies, this fixation procedure significantly changes the principal constituents of cells, resulting in important effects on their infrared (IR) spectrum. Despite the chemical and spectral influence of FFPE processing, some studies demonstrate that FTIR imaging allows precise identification of the different cell types present in biopsied tissue, indicating that the FFPE process preserves spectral differences between distinct cell types. In this study, we investigated whether this is also the case for closely related cell lines. We analyzed spectra from 8 cancerous epithelial cell lines: 4 breast cancer cell lines and 4 melanoma cell lines. For each cell line, we harvested cells at subconfluence and divided them into two sets. We first tested the "original" capability of FTIR imaging to identify these closely related cell lines on cells just dried on BaF2 slides. We then repeated the test after submitting the cells to the FFPE procedure. Our results show that the IR spectra of FFPE processed cancerous cell lines undergo small but significant changes due to the treatment. The spectral modifications were interpreted as a potential decrease in the phospholipid content and protein denaturation, in line with the scientific literature on the topic. Nevertheless, unsupervised analyses showed that spectral proximities and distances between closely related cell lines were mostly, but not entirely, conserved after FFPE processing. Finally, PLS-DA statistical analyses highlighted that closely related cell lines are still successfully identified and efficiently distinguished by FTIR spectroscopy after FFPE treatment. This last result paves the way towards identification and characterization of cellular subtypes on FFPE tissue sections by FTIR imaging, indicating that this analysis technique could become a potential useful tool in cancer research.

Improvements in antenatal screening for Down's syndrome.

OBJECTIVES: To estimate improvements to four antenatal screening tests for Down's syndrome (first trimester Combined, second trimester Quadruple, and first and second trimester Integrated and Serum Integrated tests) based on adding ductus venosus pulsatility index (DVPI), fetal nasal bone examination (NBE) and serum placental growth factor (PlGF). SETTING: Statistical analysis of data from several sources modelled using the maternal age distribution of live births in England and Wales from 2006 to 2008. METHODS: Monte Carlo simulation carried out to estimate the screening performance of tests with the addition of combinations of DVPI, NBE and PlGF. RESULTS: At a 95% detection rate (DR), with first trimester markers measured at 11 completed weeks' gestation, the addition of DVPI, NBE and PlGF decreased the false-positive rate (FPR) of the Combined test from 16.1% to 3.0%, the addition of PlGF to the Quadruple test decreased the FPR from 15.7% to 15.3%, the addition of DVPI, NBE and PlGF to the Integrated test decreased the FPR from 4.1% to 0.6% and the addition of PlGF to the Serum Integrated test decreased the FPR from 15.1% to 11.1%. At a 90% detection rate, the reductions in the FPR were from 6.8% to 0.8%, 7.7% to 7.4%, 1.2% to 0.1% and 6.2% to 4.8%, respectively. CONCLUSIONS: The addition of DVPI, NBE and PlGF to the Combined and Integrated tests significantly improves screening performance, reducing the FPRs by over 80%. The Integrated test with DVPI, NBE and PlGF is significantly better than the Combined test with DVPI, NBE and PlGF.

Direct and indirect tasks on assessment of dose and time distributions and thresholds of acute radiation exposure.

Mathematical methods were developed to construct dose and time distributions and their associated risks and threshold values for lethal and non-lethal effects of acute radiation exposure to include mortality and incidence, prodromal vomiting, and agranulocytosis. A new distribution (T-model) was obtained to describe time parameters of acute radiation syndrome such as the latency period, time to onset of vomiting, and time to initiation of agranulocytosis. Based on the dose and time distributions, the parameter translation method was defined using an orthogonal regression, which allows one to solve for these distributions in the case of acute radiation exposure. The assessment of threshold doses was performed for some effects of acute radiation syndrome: for the latency period, ∼6-8 Gy absorbed dose and ∼0.7-0.9 h time to onset of vomiting; and for incidence (agranulocytosis), ∼2-3 Gy absorbed dose and ∼2-3 h time to onset of vomiting. The obtained new formula for assessment of radiation risk is applicable to the time parameters of acute radiation syndrome.

Search for a new gauge boson in electron-nucleus fixed-target scattering by the APEX experiment.

We present a search at the Jefferson Laboratory for new forces mediated by sub-GeV vector bosons with weak coupling α' to electrons. Such a particle A' can be produced in electron-nucleus fixed-target scattering and then decay to an e + e- pair, producing a narrow resonance in the QED trident spectrum. Using APEX test run data, we searched in the mass range 175-250 MeV, found no evidence for an A'→ e+ e- reaction, and set an upper limit of α'/α ~/= 10(-6). Our findings demonstrate that fixed-target searches can explore a new, wide, and important range of masses and couplings for sub-GeV forces.

UK Lung Screen (UKLS) nodule management protocol: modelling of a single screen randomised controlled trial of low-dose CT screening for lung cancer.

The UK Lung Screen (UKLS) is a randomised controlled trial of the use of low-dose multidetector CT for lung cancer screening. It completed the Health Technology Appraisal (HTA)-funded feasibility stage in October 2009 and the pilot UKLS will be initiated in early 2011. The pilot will randomise 4000 subjects to either low-dose CT screening or no screening. The full study, due to start in September 2012, if progression criteria are met, will randomise a further 28,000 subjects from seven centres in the UK. Subjects will be selected if they have sufficient risk of developing lung cancer according to the Liverpool Lung Project risk model. The UKLS employs the 'Wald Single Screen Design', which was modelled in the UKLS feasibility study. This paper describes the modelling of nodule management in UKLS by using volumetric analysis with a single initial screen design and follow-up period of 10 years. This modelling has resulted in the development and adoption of the UKLS care pathway, which will be implemented in the planned CT screening trial in the UK.

Distribution of nuchal translucency in antenatal screening for Down's syndrome.

OBJECTIVE: To determine whether the standard deviation of nuchal translucency (NT) measurements has decreased over time and if so to revise the estimate and assess the effect of revising the estimate of the standard deviation on the performance of antenatal screening for Down's syndrome. SETTING: Data from a routine antenatal screening programme for Down's syndrome comprising 106 affected and 22,640 unaffected pregnancies. METHODS: NT measurements were converted into multiple of the median (MoM) values and standard deviations of log(10) MoM values were calculated in affected and unaffected pregnancies. The screening performance of the Combined and Integrated tests (that include NT measurement) were compared using previous and revised estimates of the standard deviation. RESULTS: The standard deviation of NT in unaffected pregnancies has reduced over time (from 1998 to 2008) (e.g. from 0.1329 to 0.1105 [log(10) MoM] at 12-13 completed weeks of pregnancy, reducing the variance by about 30%). This was not observed in affected pregnancies. Compared with results from the serum, urine and ultrasound screening study (SURUSS), use of the revised NT standard deviations in unaffected pregnancies resulted in an approximate 20% decrease in the false-positive rate for a given detection rate; for example, from 2.1% to 1.7% (a 19% reduction) at a 90% detection rate using the Integrated test with first trimester markers measured at 11 completed weeks' gestation and from 4.4% to 3.5% (a 20% reduction) at an 85% detection rate using the Combined test at 11 completed weeks. CONCLUSIONS: The standard deviation of NT has declined over time and using the revised estimates improves the screening performance of tests that incorporate an NT measurement.