Reduced Deadtime and Higher Rate Photon-Counting Detection using a Multiplexed Detector Array

We present a scheme for a photon-counting detection system that can be operated at incident photon rates higher than otherwise possible by suppressing the effects of detector deadtime. The method uses an array of N detectors and a 1-by-N optical switch with a control circuit to direct input light to live detectors. Our calculations and models highlight the advantages of the technique. In particular, using this scheme, a group of N detectors provides an improvement in operation rate that can exceed the improvement that would be obtained by a single detector with deadtime reduced by 1/N, even if it were feasible to produce a single detector with such a large improvement in deadtime. We model the system for continuous and pulsed light sources, both of which are important for quantum metrology and quantum key distribution applications.Comment: 6 figure

Avalanche Photo-Detection for High Data Rate Applications

Avalanche photo detection is commonly used in applications which require single photon sensitivity. We examine the limits of using avalanche photo diodes (APD) for characterising photon statistics at high data rates. To identify the regime of linear APD operation we employ a ps-pulsed diode laser with variable repetition rates between 0.5MHz and 80MHz. We modify the mean optical power of the coherent pulses by applying different levels of well-calibrated attenuation. The linearity at high repetition rates is limited by the APD dead time and a non-linear response arises at higher photon-numbers due to multiphoton events. Assuming Poissonian input light statistics we ascertain the effective mean photon-number of the incident light with high accuracy. Time multiplexed detectors (TMD) allow to accomplish photon- number resolution by photon chopping. This detection setup extends the linear response function to higher photon-numbers and statistical methods may be used to compensate for non-linearity. We investigated this effect, compare it to the single APD case and show the validity of the convolution treatment in the TMD data analysis.Comment: 16 pages, 5 figure

Descarga sólida em suspensão do sistema fluvial do Guaíba, RS, e sua variabilidade temporal

The suspended load of the Guaíba fluvial system and its temporal variability were assessed. A dataset was assembled gathering river discharge daily data from the main rivers that form the Guaíba (Jacuí, Sinos and Caí rivers), and water turbidity data from a water treatment plant of Water and Sewage Municipal Department (DMAE), recorded at 30 minutes interval. The turbidity data were converted to suspended sediment concentration (SSC) throughout calibration procedures with samples of suspended sediments from the Guaíba. The turbidity monitoring station was also validated for representativeness to the Guaíba waters, with synoptic sampling.  The turbidity data were reduced do mean daily values. The function of the SSC (kg.m-3 ) as function of river discharge (Q, m3 .s-1) was built given the rating curve SSC(Q) = 0.0057 + 0.00450,2884 Q with r2 = 0,68. The suspended load was directly obtained by the product of river discharge and SSC. The results indicated that the suspended load varies considerably along the time, mainly during short period discharge peaks. The major ity of suspended load is carried with river discharge between 1,000 and 3,000 m3 .s-1 , representing 47.2% of the total. The averaged suspended load to Patos Lagoon for the 2003-2006 period was of the order of 1,1 x 106 t/yr, or, of about 400.000 m of sediments (2650 kg/m3 ) from the Guaíba's drainage basin towards the lagoon depositional sites, and further the continental shelf.O presente trabalho apresenta uma avaliação da variação temporal da descarga sólida em suspensão no sistema fluvial do Guaíba. Foi utilizada uma base de dados históricos entre 2003 a 2006, constituída de vazões diárias dos rios afluentes (rios Jacuí, Sinos e Caí), e da turbidez da água monitorada em intervalos de 30 minutos na estação de tratamento de água do Departamento Municipal de Água e Esgoto (DMAE). Os dados de turbidez foram convertidos em concentração de sedimentos em suspensão (CSS) através da calibração do sensor de turbidez com amostras de sedimentos em suspensão coletadas no Guaíba. Também foi realizada uma validação da estação de monitoramento para verificar se os dados obtidos a partir da estação representavam as condições simultâneas no Guaíba. Os dados de turbidez foram reduzidos para médias diárias. Foi elaborada a curva chave de CSS (em kg.m-3) em função da vazão (Q em m3.s-1), representada por CSS(Q) = 0,0057 + 0,0045 Q 0,2884 com r2 = 0,68. A descarga sólida em suspensão foi obtida pelo produto simples entre a vazão e a CSS. Os resultados demonstraram que a descarga sólida em suspensão varia consideravelmente ao logo do tempo, principalmente durante eventos de alta vazão de curta duração. A maior parte dos sedimentos em suspensão é transportada com valores de vazões entre 1.000 e 3.000 m3.s-1 e representou 47,2% do total. O valor médio de descarga sólida transportada para a Lagoa dos Patos entre os períodos de 2003 a 2006 foi da ordem de 1,1 x 106 t/ano, o que representa uma exportação da ordem de 400.000 m3 de sedimentos (2.650 kg/m3) da bacia de drenagem do rio Guaíba para os sistemas deposicionais lagunares e, posteriormente a plataforma continental adjacente

Has VZV epidemiology changed in Italy? Results of a seroprevalence study

The aim of the study was to evaluate if and how varicella prevalence has changed in Italy. In particular a seroprevalence study was performed, comparing it to similar surveys conducted in pre-immunization era. During 2013–2014, sera obtained from blood samples taken for diagnostic purposes or routine investigations were collected in collaboration with at least one laboratory/center for each region, following the approval of the Ethics Committee. Data were stratified by sex and age. All samples were processed in a national reference laboratory by an immunoassay with high sensitivity and specificity. Statutory notifications, national hospital discharge database and mortality data related to VZV infection were analyzed as well. A total of 3707 sera were collected and tested. In the studied period both incidence and hospitalization rates decreased and about 5 deaths per year have been registered. The seroprevalence decreased in the first year of life in subjects passively protected by their mother, followed by an increase in the following age classes. The overall antibody prevalence was 84%. The comparison with surveys conducted with the same methodology in 1996–1997 and 2003–2004 showed significant differences in age groups 1–19 y. The study confirms that in Italy VZV infection typically occurs in children. The impact of varicella on Italian population is changing. The comparison between studies performed in different periods shows a significant increase of seropositivity in age class 1–4 years, expression of vaccine interventions already adopted in some regions

Surgical impact on brain tumor invasion: A physical perspective

It is conventional strategy to treat highly malignant brain tumors initially with cytoreductive surgery followed by adjuvant radio- and chemotherapy. However, in spite of all such efforts, the patients' prognosis remains dismal since residual glioma cells continue to infiltrate adjacent parenchyma and the tumors almost always recur. On the basis of a simple biomechanical conjecture that we have introduced previously, we argue here that by affecting the 'volume-pressure' relationship and minimizing surface tension of the remaining tumor cells, gross total resection may have an inductive effect on the invasiveness of the tumor cells left behind. Potential implications for treatment strategies are discussed

A multivariable prognostic score to guide systemic therapy in early-stage HER2-positive breast cancer: a retrospective study with an external evaluation

Background: In early-stage HER2-positive breast cancer, escalation or de-escalation of systemic therapy is a controversial topic. As an aid to treatment decisions, we aimed to develop a prognostic assay that integrates multiple data types for predicting survival outcome in patients with newly diagnosed HER2-positive breast cancer. Methods: We derived a combined prognostic model using retrospective clinical–pathological data on stromal tumour-infiltrating lymphocytes, PAM50 subtypes, and expression of 55 genes obtained from patients who participated in the Short-HER phase 3 trial. The trial enrolled patients with newly diagnosed, node-positive, HER2-positive breast cancer or, if node negative, with at least one risk factor (ie, tumour size >2 cm, histological grade 3, lymphovascular invasion, Ki67 >20%, age ≤35 years, or hormone receptor negativity), and randomly assigned them to adjuvant anthracycline plus taxane-based combinations with either 9 weeks or 1 year of trastuzumab. Trastuzumab was administered intravenously every 3 weeks (8 mg/kg loading dose at first cycle, and 6 mg/kg thereafter) for 18 doses or weekly (4 mg/kg loading dose in the first week, and 2 mg/kg thereafter) for 9 weeks, starting concomitantly with the first taxane dose. Median follow-up was 91·4 months (IQR 75·1–105·6). The primary objective of our study was to derive and evaluate a combined prognostic score associated with distant metastasis-free survival (the time between randomisation and distant recurrence or death before recurrence), an exploratory endpoint in Short-HER. Patient samples in the training dataset were split into a training set (n=290) and a testing set (n=145), balancing for event and treatment group. The training set was further stratified into 100 iterations of Monte-Carlo cross validation (MCCV). Cox proportional hazard models were fit to MCCV training samples using Elastic-Net. A maximum of 92 features were assessed. The final prognostic model was evaluated in an independent combined dataset of 267 patients with early-stage HER2-positive breast cancer treated with different neoadjuvant and adjuvant anti-HER2-based combinations and from four other studies (PAMELA, CHER-LOB, Hospital Clinic, and Padova) with disease-free survival outcome data. Findings: From Short-HER, data from 435 (35%) of 1254 patients for tumour size (T1 vs rest), nodal status (N0 vs rest), number of tumour-infiltrating lymphocytes (continuous variable), subtype (HER2-enriched and basal-like vs rest), and 13 genes composed the final model (named HER2DX). HER2DX was significantly associated with distant metastasis-free survival as a continuous variable (p<0·0001). HER2DX median score for quartiles 1–2 was identified as the cutoff to identify low-risk patients; and the score that distinguished quartile 3 from quartile 4 was the cutoff to distinguish medium-risk and high-risk populations. The 5-year distant metastasis-free survival of the low-risk, medium-risk, and high-risk populations were 98·1% (95% CI 96·3–99·9), 88·9% (83·2–95·0), and 73·9% (66·0–82·7), respectively (low-risk vs high-risk hazard ratio [HR] 0·04, 95% CI 0·0–0·1, p<0·0001). In the evaluation cohort, HER2DX was significantly associated with disease-free survival as a continuous variable (HR 2·77, 95% CI 1·4–5·6, p=0·0040) and as group categories (low-risk vs high-risk HR 0·27, 0·1–0·7, p=0·005). 5-year disease-free survival in the HER2DX low-risk group was 93·5% (89·0–98·3%) and in the high-risk group was 81·1% (71·5–92·1). Interpretation: The HER2DX combined prognostic score identifies patients with early-stage, HER2-positive breast cancer who might be candidates for escalated or de-escalated systemic treatment. Future clinical validation of HER2DX seems warranted to establish its use in different scenarios, especially in the neoadjuvant setting. Funding: Instituto Salud Carlos III, Save the Mama, Pas a Pas, Fundación Científica, Asociación Española Contra el Cáncer, Fundación SEOM, National Institutes of Health, Agenzia Italiana del Farmaco, International Agency for Research on Cancer, and the Veneto Institute of Oncology, and Italian Association for Cancer Research

Oestrogen receptor activity in hormone-dependent breast cancer during chemotherapy: ER activity in pre-menopausal HR+ breast cancer during CT

Background: Chemotherapy efficacy in early-stage hormone receptor-positive (HR+) breast cancer (BC) according to menopausal status needs a biological explanation. Methods: We compared early-stage HR+ BC biological features before and after (neo)adjuvant chemotherapy or endocrine therapy (ET), and assessed oestrogen receptor (ER) pathway activity in both pre- and post-menopausal patients. The nCounter platform was used to detect gene expression levels. Findings: In 106 post-menopausal patients with HR+/HER2-negative BC randomized to neoadjuvant chemotherapy or ET (letrozole+ribociclib), a total of 19 oestrogen-regulated genes, including progesterone receptor (PGR), were found downregulated in the ET-based arm-only. We confirmed this finding in an independent dataset of 20 letrozole-treated post-menopausal patients and found, conversely, an up-regulation of the same signature in HR+/HER2-negative MCF7 cell line treated with estradiol. PGR was found down-regulated by 2 weeks of ET+anti-HER2 therapy in pre-/post-menopausal patients with HR+/HER2-positive (HER2+) BC, while anti-HER2 therapy alone increased PGR expression in HR-negative/HER2+ BC. In 88 pre- and post-menopausal patients with newly diagnosed HR+/HER2-negative BC treated with chemotherapy, the 19 oestrogen-regulated genes were found significantly downregulated only in pre-menopausal patients. In progesterone receptor (PR)+/HER2-negative BC treated with neoadjuvant chemotherapy (n=40), tumours became PR-negative in 69.2% of pre-menopausal patients and 14.8% of post-menopausal patients (p=0.001). Finally, a mean decrease in PGR levels was only observed in pre-menopausal patients undergoing anti-HER2-based multi-agent chemotherapy. Interpretation: Chemotherapy reduces the expression of ER-regulated genes in pre-menopausal women suffering from hormone-dependent BC by supressing ovarian function. Further studies should test the value of chemotherapy in this patient population when ovarian function is suppressed by other methods. Funding: Instituto de Salud Carlos III, Breast Cancer Now, the Breast Cancer Research Foundation, the American Association for Cancer Research, Fundació La Marató TV3, the European Union's Horizon 2020 Research and Innovation Programme, Pas a Pas, Save the Mama, Fundación Científica Asociación Española Contra el Cáncer, PhD4MDgrant of “Departament de Salut”, exp SLT008/18/00122, Fundación SEOM and ESMO. Any views, opinions, findings, conclusions, or recommendations expressed in this material are those solely of the author(s

Medical treatment of prolactinomas.

Prolactinomas, the most prevalent type of neuroendocrine disease, account for approximately 40% of all pituitary adenomas. The most important clinical problems associated with prolactinomas are hypogonadism, infertility and hyposexuality. In patients with macroprolactinomas, mass effects, including visual field defects, headaches and neurological disturbances, can also occur. The objectives of therapy are normalization of prolactin levels, to restore eugonadism, and reduction of tumor mass, both of which can be achieved in the majority of patients by treatment with dopamine agonists. Given their association with minimal morbidity, these drugs currently represent the mainstay of treatment for prolactinomas. Novel data indicate that these agents can be successfully withdrawn in a subset of patients after normalization of prolactin levels and tumor disappearance, which suggests the possibility that medical therapy may not be required throughout life. Nevertheless, multimodal therapy that involves surgery, radiotherapy or both may be necessary in some cases, such as patients who are resistant to the effects of dopamine agonists or for those with atypical prolactinomas. This Review reports on efficacy and safety of pharmacotherapy in patients with prolactinomas