Publications by authors named "F Levi"

893 Publications

European cancer mortality predictions for the year 2021 with focus on pancreatic and female lung cancer.

Ann Oncol 2021 04 21;32(4):478-487. Epub 2021 Feb 21.

Department of Biomedical and Clinical Sciences, Università degli Studi di Milano, Milan, Italy.

Background: We predicted cancer mortality statistics for 2021 for the European Union (EU) and its five most populous countries plus the UK. We also focused on pancreatic cancer and female lung cancer.

Materials And Methods: We obtained cancer death certifications and population data from the World Health Organization and Eurostat databases for 1970-2015. We predicted numbers of deaths and age-standardised (world population) rates for 2021 for total cancers and 10 major cancer sites, using a joinpoint regression model. We calculated the number of avoided deaths over the period 1989-2021.

Results: We predicted 1 267 000 cancer deaths for 2021 in the EU, corresponding to age-standardised rates of 130.4/100 000 men (-6.6% since 2015) and 81.0/100 000 for women (-4.5%). We estimated further falls in male lung cancer rates, but still trending upward in women by +6.5%, reaching 14.5/100 000 in 2021. The breast cancer predicted rate in the EU was 13.3/100 000 (-7.8%). The rates for stomach and leukaemias in both sexes and for bladder in males are predicted to fall by >10%; trends for other cancer sites were also favourable, except for the pancreas, which showed stable patterns in both sexes, with predicted rates of 8.1/100 000 in men and 5.6/100 000 in women. Rates for pancreatic cancer in EU men aged 25-49 and 50-64 years declined, respectively, by 10% and 1.8%, while for those aged 65+ years increased by 1.3%. Rates fell for young women only (-3.4%). Over 1989-2021, about 5 million cancer deaths were avoided in the EU27 compared with peak rates in 1988.

Conclusion: Overall cancer mortality continues to fall in both sexes. However, specific focus is needed on pancreatic cancer, which shows a sizeable decline for young men only. Tobacco control remains a priority for the prevention of pancreatic and other tobacco-related cancers, which account for one-third of the total EU cancer deaths, especially in women, who showed less favourable trends.
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http://dx.doi.org/10.1016/j.annonc.2021.01.006DOI Listing
April 2021

Dose- and time-dependent tolerability and efficacy of organo-osmium complex FY26 and its tissue pharmacokinetics in hepatocarcinoma-bearing mice.

Metallomics 2021 02;13(2)

Chronotherapy Team, Division of Biomedical Sciences, Warwick Medical School, University of Warwick, Gibbett Hill Road, Coventry CV4 7AL, UK.

The organo-osmium complex [OsII(ɳ6-p-cym)(PhAzPy-NMe2)I]+ (FY26) exhibits promising in vitro antitumour activity against mouse hepatocarcinoma Hepa1-6 and other mouse or human cancer cell lines. Here, we drastically enhance water solubility of FY26 through the replacement of the PF6- counter-anion with chloride using a novel synthesis method. FY26⋅PF6 and FY26⋅Cl displayed similar in vitro cytotoxicity in two cancer cell models. We then show the moderate and late anticancer efficacy of FY26⋅PF6 and FY26⋅Cl in a subcutaneous murine hepatocarcinoma mouse model. Both efficacy and tolerability varied according to FY26 circadian dosing time in hepatocarcinoma tumour-bearing mice. Tumour and liver uptake of the drug were determined over 48 h following FY26⋅Cl administration at Zeitgeber time 6 (ZT6), when the drug is least toxic (in the middle of the light span when mice are resting). Our studies suggest the need to administer protracted low doses of FY26 at ZT6 in order to optimize its delivery schedule, for example through the use of chrono-releasing nanoparticles.
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http://dx.doi.org/10.1093/mtomcs/mfaa003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7853623PMC
February 2021

Trends in male breast cancer mortality: a global overview.

Eur J Cancer Prev 2021 Jan 18. Epub 2021 Jan 18.

Department of Clinical Sciences and Community Health Department of Biomedical and Clinical Sciences L. Sacco, Università degli Studi di Milano, Milan, Italy Department of Epidemiology and Health Services Research, Centre for Primary Care and Public Health (Unisanté), University of Lausanne, Lausanne, Switzerland Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy Stony Brook Cancer Center, Stony Brook University, Stony Brook, New York, USA.

Objectives: Recent trends in male breast cancer have been inadequately studied. We updated mortality trends in selected countries and regions worldwide using most recent available data and we predicted figures for 2020.

Methods: We extracted official death certification data for male breast cancer and population estimates from the WHO and the Pan American Health Organization databases, from 2000 to 2017. We computed age-standardized (world population) death rates for selected countries and regions worldwide. We used joinpoint regression analysis to identify significant changes in trends and to predict death numbers and rates for 2020.

Results: In 2015-2017, Central-Eastern Europe had a rate of 2.85/1 000 000, and Russia of 2.22, ranking among the highest. North-Western and Southern Europe, the European Union as a whole and the USA showed rates ranging between 1.5 and 2.0. Lower rates were observed in most Latin American countries, with values below 1.35/1 000 000, in Australia, 1.22, and Japan, 0.58. Between 2000-2004 and 2015-2017, age-adjusted death rates decreased between 10 and 40% in North-Western Europe, Russia, and the USA, and between 1.5 and 25% in the other areas under study, except Latin America (+0.8%). Except for Central-Eastern Europe, predicted rates for 2020 were favourable.

Conclusion: Advancements in management are likely the main drivers of the favourable trends in male breast cancer death rates over the last decades. Delayed diagnosis and limited access to effective care explain the higher mortality in some areas.
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http://dx.doi.org/10.1097/CEJ.0000000000000651DOI Listing
January 2021

Colorectal Cancer Mortality in Young Adults Is Rising in the United States, Canada, United Kingdom, and Australia but Not in Europe and Asia.

Gastroenterology 2021 Apr 6;160(5):1860-1862.e2. Epub 2021 Jan 6.

Department of Clinical Sciences and Community Health, Università degli Studi di Milano, Milan, Italy. Electronic address:

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http://dx.doi.org/10.1053/j.gastro.2020.12.070DOI Listing
April 2021

Cancer mortality and predictions for 2020 in selected Australasian countries, Russia and Ukraine.

Eur J Cancer Prev 2021 Jan;30(1):1-14

Department of Clinical Sciences and Community Health.

Objectives: Predicted cancer mortality figures are useful for public health planning. We predicted cancer mortality rates in Israel, Hong Kong, Japan, the Philippines, Korea, Australia, Russia and Ukraine for the year 2020 using the most recent available data. We focused on breast cancer.

Methods: We obtained cancer death certification and population data from the WHO and the United Nations Population Division databases. We derived figures for 10 major cancer sites and total cancers over 1970-2017. We predicted numbers of deaths and age-standardized mortality rates for 2020 through joinpoint regression models. We calculated the number of avoided deaths from 1994-2020.

Results: Overall, total cancer mortality is predicted to decline. Russia had the highest all cancers rates in 2020, 151.9/100 000 men and 79.6 women; the Philippines had the lowest rate in men, 78.0/100 000, Korea in women, 47.5. Stomach cancer rates declined over the whole period in all countries considered, colorectal cancer since the late 1990s. Trends for pancreas were inconsistent. Predicted rates for lung and breast cancer were favourable; women from Hong Kong, Korea and Australia had lung cancer death rates higher than breast ones. Predicted rates for uterine, ovarian, prostate and bladder cancers and leukaemias were downward for most countries. Between 1994 and 2020, over 3.3 million cancer deaths were avoided in the considered countries, except for the Philippines where no reduction was observed.

Conclusion: Predicted cancer rates were lower than in the European Union and the USA, even though falls started later and were less marked.
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http://dx.doi.org/10.1097/CEJ.0000000000000639DOI Listing
January 2021

Efficacy and safety of chronomodulated irinotecan, oxaliplatin, 5-fluorouracil and leucovorin combination as first- or second-line treatment against metastatic colorectal cancer: Results from the International EORTC 05011 Trial.

Int J Cancer 2020 Dec 3. Epub 2020 Dec 3.

Division of Medical Oncology, San Camillo Forlanini Hospital, Rome, Italy.

The triplet combination of irinotecan, oxaliplatin and fluorouracil is an active frontline regimen in metastatic colorectal cancer, but scarce data exist on its use as salvage treatment. We aimed at assessing its safety and efficacy profiles with its circadian-based administration (chronoIFLO5) as either first- or second-line treatment, within the time-finding EORTC 05011 trial. Five-day chronoIFLO5 was administered every 3 weeks in patients with PS 0, 1 or 2. It consisted of chronomodulated irinotecan (180 mg/sqm), oxaliplatin (80 mg/sqm) and fluorouracil-leucovorin (2800 and 1200 mg/sqm, respectively). For our study, toxicity and antitumour activity were evaluated separately in first- and second-line settings. Primary endpoints included Grade 3-4 toxicity rates, best objective response rate (ORR), progression-free survival (PFS) and overall survival (OS). One-hundred forty-nine and 44 patients were treated in first-line and second-line settings, respectively, with a total of 1138 cycles with median relative dose intensities of about 90%. Demographics were comparable in the two groups. Thirty-six (24.7%) and 10 (22.2%) patients experienced at least one episode of severe toxicity in first line and second line, respectively. Frontline chronoIFLO5 yielded an ORR of 62.3% [95% CI: 54.2-70.4] and resulted in median PFS and OS of 8.7 months [7.5-9.9] and 19.9 months [15.4-24.5]. Corresponding figures in second line were 37.5% [22.5-52.5], 6.7 months [4.8-8.9] and 16.3 months [11.8-20.8]. International and prospective evaluation revealed the favourable safety and efficacy profiles of chronoIFLO5, both as frontline and as salvage treatment against metastatic colorectal cancer. In particular, encouraging activity in second line was observed, with limited haematological toxicity.
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http://dx.doi.org/10.1002/ijc.33422DOI Listing
December 2020

Dietary patterns and oesophageal cancer: a multi-country latent class analysis.

J Epidemiol Community Health 2020 Nov 17. Epub 2020 Nov 17.

Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy.

Background: The considerable differences in food consumption across countries pose major challenges to the research on diet and cancer, due to the difficulty to generalise and reproduce the dietary patterns identified in a specific population.

Methods: We analysed data from a multicentric case-control study on oesophageal squamous cell carcinoma (ESCC) carried out between 1992 and 2009 in three Italian areas and in the Canton of Vaud, Switzerland, which included 505 cases and 1259 hospital controls. Dietary patterns were derived applying LCA on 24 food groups, controlling for country membership, and non-alcoholic energy intake. A multiple logistic regression model was used to derive odds ratio (ORs) and corresponding 95% CIs for ESCC according to the dietary patterns identified, correcting for classification error.

Results And Conclusion: We identified three dietary patterns. The 'Prudent' pattern was distinguished by a diet rich in fruits and vegetables. The 'Western' pattern was characterised by low consumption of these food groups and higher intakes of sugar. The 'Lower consumers-combination pattern' exhibited a diet poor in most of the nutrients, preferences for fish, potatoes, meat and a few specific types of vegetables. Differences between Italy and Switzerland emerged for pattern sizes and for specific single food preferences. Compared to the 'Prudent' pattern, the 'Western' and the 'Lower consumers-combination' patterns were associated with an increased risk of ESCC (OR=3.04, 95% CI=2.12-4.38 and OR=2.81, 95% CI=1.65-4.76).
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http://dx.doi.org/10.1136/jech-2020-214882DOI Listing
November 2020

Pregnancy outcomes and risk of endometrial cancer: A pooled analysis of individual participant data in the Epidemiology of Endometrial Cancer Consortium.

Int J Cancer 2021 May 17;148(9):2068-2078. Epub 2020 Nov 17.

Population Health Department, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.

A full-term pregnancy is associated with reduced endometrial cancer risk; however, whether the effect of additional pregnancies is independent of age at last pregnancy is unknown. The associations between other pregnancy-related factors and endometrial cancer risk are less clear. We pooled individual participant data from 11 cohort and 19 case-control studies participating in the Epidemiology of Endometrial Cancer Consortium (E2C2) including 16 986 women with endometrial cancer and 39 538 control women. We used one- and two-stage meta-analytic approaches to estimate pooled odds ratios (ORs) for the association between exposures and endometrial cancer risk. Ever having a full-term pregnancy was associated with a 41% reduction in risk of endometrial cancer compared to never having a full-term pregnancy (OR = 0.59, 95% confidence interval [CI] 0.56-0.63). The risk reduction appeared the greatest for the first full-term pregnancy (OR = 0.78, 95% CI 0.72-0.84), with a further ~15% reduction per pregnancy up to eight pregnancies (OR = 0.20, 95% CI 0.14-0.28) that was independent of age at last full-term pregnancy. Incomplete pregnancy was also associated with decreased endometrial cancer risk (7%-9% reduction per pregnancy). Twin births appeared to have the same effect as singleton pregnancies. Our pooled analysis shows that, while the magnitude of the risk reduction is greater for a full-term pregnancy than an incomplete pregnancy, each additional pregnancy is associated with further reduction in endometrial cancer risk, independent of age at last full-term pregnancy. These results suggest that the very high progesterone level in the last trimester of pregnancy is not the sole explanation for the protective effect of pregnancy.
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http://dx.doi.org/10.1002/ijc.33360DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7969437PMC
May 2021

Undetectable -Mutant Clones in Plasma: Possible Implication for Anti-EGFR Therapy and Prognosis in Patients With -Mutant Metastatic Colorectal Cancer.

JCO Precis Oncol 2020 16;4. Epub 2020 Sep 16.

Oncogenetics Department, Assistance Publique-Hôpitaux de Paris, Paul Brousse Hospital, Université Paris-Saclay, Villejuif, France.

Purpose: Combining cetuximab with chemotherapy provides clinical benefit to 60% of the patients with wild-type (-wt) metastatic colorectal cancer (mCRC). This pilot study investigated the efficacy of cetuximab-based chemotherapy in a sample of patients (40%) with mutation (-mt) in their primary tumor whose circulating tumor DNA (ctDNA) was -wt.

Materials And Methods: The occurrence of Kirsten rat sarcoma viral oncogene homolog (), neuroblastoma rat sarcoma viral oncogene homolog (NRAS), V-raf murine sarcoma viral oncogene homolog B1 (), and mutations was determined in ctDNA by using a new ultrasensitive analysis based on mass spectrometry detection. All consenting patients with confirmed -mt mCRC had disease progression on previous chemotherapy that contained no anti-epidermal growth factor receptor (EGFR). The patients with -wt ctDNA received cetuximab + fluorouracil, leucovorin, and irinotecan (FOLFIRI), whereas those with -mt ctDNA were treated with the oncologist's choice of therapy.

Results: Of 16 registered patients, 11 were male and five female. They were age 48 to 81 years, and they had unresectable metastatic adenocarcinoma from the colon (n = 11) or rectum (n = 5), with a median of two metastatic sites. They had received a median number of three previous chemotherapy protocols. Plasma genotyping identified -mt in seven patients (44%) and -wt in nine patients (56%). In the patients with wt ctDNA, objective tumor response rate was 50.0%, including one complete response and four partial responses after a median number of 6 courses of cetuximab + FOLFIRI (range, 1 to 16 courses). Two of the nine patients had stable disease, and two had progressive disease. No grade 3 to 4 toxicities were encountered. One-year survival rates were 60.0% for the patients with -wt ctDNA and 17.9% for those with -mt ctDNA. Median overall survival times were not reached and 4.7 months, respectively.

Conclusion: Patients with -mt mCRC whose plasma biopsies contained -wt could benefit from cetuximab-based therapy, a hypothesis to be tested in a prospective randomized trial.
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http://dx.doi.org/10.1200/PO.19.00400DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7529530PMC
September 2020

Kr-Based Buffer Gas for Rb Vapor-Cell Clocks.

IEEE Trans Ultrason Ferroelectr Freq Control 2021 Apr 26;68(4):1442-1447. Epub 2021 Mar 26.

Optically pumped Rb vapor cell clocks are by far the most used devices for timekeeping in all ground and space applications. The compactness and the robustness of this technology make Rb clocks extremely well fit to a large number of applications, including GNSS, telecommunication, and network synchronization. Many efforts are devoted to improve the stability of Rb clocks and reduce their environmental sensitivity. In this article, we investigate the use of a novel mixture of buffer gas based on Kr and N, capable of reducing by more than one order of magnitude the barometric and temperature sensitivities of the clock, with possible improvement of their long-term stability.
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http://dx.doi.org/10.1109/TUFFC.2020.3026220DOI Listing
April 2021

Alcohol drinking and head and neck cancer risk: the joint effect of intensity and duration.

Br J Cancer 2020 10 24;123(9):1456-1463. Epub 2020 Aug 24.

Branch of Medical Statistics, Biometry and Epidemiology "G. A. Maccacaro", Department of Clinical Sciences and Community Health, Università degli Studi di Milano, Milano, Italy.

Background: Alcohol is a well-established risk factor for head and neck cancer (HNC). This study aims to explore the effect of alcohol intensity and duration, as joint continuous exposures, on HNC risk.

Methods: Data from 26 case-control studies in the INHANCE Consortium were used, including never and current drinkers who drunk ≤10 drinks/day for ≤54 years (24234 controls, 4085 oral cavity, 3359 oropharyngeal, 983 hypopharyngeal and 3340 laryngeal cancers). The dose-response relationship between the risk and the joint exposure to drinking intensity and duration was investigated through bivariate regression spline models, adjusting for potential confounders, including tobacco smoking.

Results: For all subsites, cancer risk steeply increased with increasing drinks/day, with no appreciable threshold effect at lower intensities. For each intensity level, the risk of oral cavity, hypopharyngeal and laryngeal cancers did not vary according to years of drinking, suggesting no effect of duration. For oropharyngeal cancer, the risk increased with durations up to 28 years, flattening thereafter. The risk peaked at the higher levels of intensity and duration for all subsites (odds ratio = 7.95 for oral cavity, 12.86 for oropharynx, 24.96 for hypopharynx and 6.60 for larynx).

Conclusions: Present results further encourage the reduction of alcohol intensity to mitigate HNC risk.
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http://dx.doi.org/10.1038/s41416-020-01031-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7592048PMC
October 2020

Loaded Microwave Cavity for Compact Vapor-Cell Clocks.

IEEE Trans Ultrason Ferroelectr Freq Control 2021 Mar 25;68(3):872-879. Epub 2021 Feb 25.

Vapor-cell devices based on microwave interrogation provide a stable frequency reference with a compact and robust setup. Further miniaturization must focus on optimizing the physics package, containing the microwave cavity and atomic reservoir. In this article, we present a compact cavity-cell assembly based on a dielectric-loaded cylindrical resonator. The loaded cavity resonating at 6.83 GHz has an external volume of only 35 cm and accommodates a vapor cell with 0.9-cm inner volume. The proposed design aims at strongly reducing the core of the atomic clock, maintaining, at the same time, high-performing short-term stability ( σ(τ) ≤ 5×10 τ standard Allan deviation). The proposed structure is characterized in terms of microwave field uniformity and atom-field coupling with the aid of finite-element calculations. The thermal sensitivity is also analyzed and experimentally characterized. We present preliminary spectroscopy results by integrating the compact cavity within a rubidium clock setup based on the pulsed optically pumping technique. The obtained clock signals are compatible with the targeted performances. The loaded-cavity approach is, thus, a viable design option for miniaturized microwave clocks.
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http://dx.doi.org/10.1109/TUFFC.2020.3011604DOI Listing
March 2021

Cohort Analysis of Epithelial Cancer Mortality Male-to-Female Sex Ratios in the European Union, USA, and Japan.

Int J Environ Res Public Health 2020 07 23;17(15). Epub 2020 Jul 23.

Department of Clinical Sciences and Community Health, Universitá degli Studi di Milano, 20133 Milan, Italy.

Objective: To illustrate trends in sex ratios in epithelial cancer mortality in the EU, USA, and Japan, with a focus on age-specific and cohort patterns.

Methods: We obtained certified deaths and resident populations from the World Health Organisation for the period of 1970-2014 for the USA, Japan, and the EU for 12 epithelial cancer sites. From these, we calculated both the age-specific and age-standardised male-to-female mortality sex ratios. We applied an age-period-cohort model to the sex ratios in order to disentangle the effects of age, period of death, and birth cohort.

Results: Age-standardised mortality sex ratios were found to be unfavourable to males, apart from thyroid cancer. The highest standardised rates were in laryngeal cancer: 7·7 in the 1970s in the USA, 17·4 in the 1980s in the EU, and 16·8 in the 2000s in Japan. Cohort patterns likely to be due to excess smoking (1890 cohort) and drinking (1940 cohort) in men were identified in the USA, and were present but less defined in the EU and Japan for the oral cavity, oesophagus, liver, pancreas, larynx, lung, bladder, and kidney.

Conclusion: Mortality sex ratio patterns are partly explained by the differences in exposure to known and avoidable risk factors. These are mostly tobacco, alcohol, and obesity/overweight, as well as other lifestyle-related factors.
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http://dx.doi.org/10.3390/ijerph17155311DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7432705PMC
July 2020

Tele-Monitoring of Cancer Patients' Rhythms during Daily Life Identifies Actionable Determinants of Circadian and Sleep Disruption.

Cancers (Basel) 2020 Jul 17;12(7). Epub 2020 Jul 17.

Cancer Chronotherapy Team, Warwick Medical School, Coventry CV4 7AL, UK.

The dichotomy index (I < O), a quantitative estimate of the circadian regulation of daytime activity and sleep, predicted overall cancer survival and emergency hospitalization, supporting its integration in a mHealth platform. Modifiable causes of I < O deterioration below 97.5%-(I < O)-were sought in 25 gastrointestinal cancer patients and 33 age- and sex-stratified controls. Rest-activity and temperature were tele-monitored with a wireless chest sensor, while daily activities, meals, and sleep were self-reported for one week. Salivary cortisol rhythm and dim light melatonin onset (DLMO) were determined. Circadian parameters were estimated using Hidden Markov modelling, and spectral analysis. Actionable predictors of (I < O) were identified through correlation and regression analyses. Median compliance with protocol exceeded 95%. Circadian disruption-(I < O)-was identified in 13 (52%) patients and four (12%) controls ( = 0.002). Cancer patients with (I < O) had lower median activity counts, worse fragmented sleep, and an abnormal or no circadian temperature rhythm compared to patients with I < O exceeding 97.5%-(I < O)-( < 0.012). Six (I < O) patients had newly-diagnosed sleep conditions. Altered circadian coordination of rest-activity and chest surface temperature, physical inactivity, and irregular sleep were identified as modifiable determinants of (I < O). Circadian rhythm and sleep tele-monitoring results support the design of specific interventions to improve outcomes within a patient-centered systems approach to health care.
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http://dx.doi.org/10.3390/cancers12071938DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7409071PMC
July 2020

Tunable UV spectrometer for Doppler broadening thermometry of mercury.

Opt Lett 2020 Jul;45(13):3693-3696

We realized a UV laser spectrometer at 253.7 nm for Doppler broadening thermometry on the - intercombination line in mercury vapors. Our setup is based on the two-stage duplication of a 1014.8 nm diode laser in a fiber-coupled periodically poled lithium niobate waveguide crystal and a beta-barium borate crystal in enhancement cavity, and we exploit injection locking of a 507.4 nm diode laser to boost the available optical power after the first duplication. Our setup addresses spectroscopic features that allow the thermodynamic temperature determination of the atomic sample from the absorption profile with 10 accuracy. The realized UV laser source has 1×10 relative intensity stability, Gaussian shape, and over 10 GHz mode-hop-free tunable range. These features are crucial for the practical realization of the kelvin in the new International System of Units through a spectroscopic technique.
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http://dx.doi.org/10.1364/OL.393793DOI Listing
July 2020

Childhood cancer mortality trends in Europe, 1990-2017, with focus on geographic differences.

Cancer Epidemiol 2020 08 24;67:101768. Epub 2020 Jun 24.

Department of Biomedical and Clinical Sciences L. Sacco, Università degli Studi di Milano, Milan, Italy.

Aim: To monitor trends in childhood cancer mortality in Europe.

Methods: We calculated age-standardized mortality rates per 100,000 children (age 0-14 years) from 1990 to the last available calendar year, for all neoplasms and six main cancers in childhood, in selected European countries and geographic areas, plus the European Union (EU), using data from the World Health Organization database. We carried out a joinpoint regression analysis of mortality trends for all neoplasms, leukaemia and tumours of the nervous system. Results of the joinpoint regression were summarized through annual percent change (APC) for each identified linear segment, and weighted average APC (AAPC) over the whole period.

Results: From 1990 to 2015, childhood total cancer mortality rates dropped by 2.8% per year in the EU, to reach 2.6/100,000 in the latest available calendar years. The greatest declines were in central-eastern countries (AAPCs -3% to -4%). Recent rates ranged between 1.7 and 4.3 deaths/100,000, with the highest values in central-eastern Europe. Leukaemia mortality rates in the EU decreased from 1.6 to 0.6/100,000 in the latest calendar years (AAPC -4%). The deepest declines were registered in central-eastern countries, though they still showed the highest rates (0.9). The lowest leukaemia mortality rates were in northern-western Europe (0.5/100,000), but also in the Czech Republic and Poland. Southern European countries showed comparatively high rates (0.8). Nervous system tumours showed relatively modest falls (AAPC: -1.7% in the EU).

Conclusions: Childhood cancer mortality continued to decline steady in Europe, though geographic differences persist. Further efforts are required to fill the gap, by promoting widespread and rational adoption of currently available treatment protocols.
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http://dx.doi.org/10.1016/j.canep.2020.101768DOI Listing
August 2020

Hepatic metastases resection after cetuximab: are we missing something?

Lancet Oncol 2020 05;21(5):e228

Centre Hépato-Biliaire, Assistance Publique-Hopitaux de Paris, Paul Brousse Hospital, 94800 Villejuif, France; INSERM U935 Campus CNRS, Villejuif, France.

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http://dx.doi.org/10.1016/S1470-2045(20)30144-3DOI Listing
May 2020

European cancer mortality predictions for the year 2020 with a focus on prostate cancer.

Ann Oncol 2020 05 19;31(5):650-658. Epub 2020 Apr 19.

Department of Clinical Sciences and Community Health, Universitá degli Studi di Milano, Milan, Italy.

Background: Current cancer mortality figures are important for disease management and resource allocation. We estimated mortality counts and rates for 2020 in the European Union (EU) and for its six most populous countries.

Materials And Methods: We obtained cancer death certification and population data from the World Health Organization and Eurostat databases for 1970-2015. We estimated projections to 2020 for 10 major cancer sites plus all neoplasms and calculated the number of avoided deaths over 1989-2020.

Results: Total cancer mortality rates in the EU are predicted to decline reaching 130.1/100 000 men (-5.4% since 2015) and 82.2 in women (-4.1%) in 2020. The predicted number of deaths will increase by 4.7% reaching 1 428 800 in 2020. In women, the upward lung cancer trend is predicted to continue with a rate in 2020 of 15.1/100 000 (higher than that for breast cancer, 13.5) while in men we predicted further falls. Pancreatic cancer rates are also increasing in women (+1.2%) but decreasing in men (-1.9%). In the EU, the prostate cancer predicted rate is 10.0/100 000, declining by 7.1% since 2015; decreases for this neoplasm are ∼8% at age 45-64, 14% at 65-74 and 75-84, and 6% at 85 and over. Poland is the only country with an increasing prostate cancer trend (+18%). Mortality rates for other cancers are predicted to decline further. Over 1989-2020, we estimated over 5 million avoided total cancer deaths and over 400 000 for prostate cancer.

Conclusion: Cancer mortality predictions for 2020 in the EU are favourable with a greater decline in men. The number of deaths continue to rise due to population ageing. Due to the persistent amount of predicted lung (and other tobacco-related) cancer deaths, tobacco control remains a public health priority, especially for women. Favourable trends for prostate cancer are largely attributable to continuing therapeutic improvements along with early diagnosis.
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http://dx.doi.org/10.1016/j.annonc.2020.02.009DOI Listing
May 2020

Sex-dependent least toxic timing of irinotecan combined with chronomodulated chemotherapy for metastatic colorectal cancer: Randomized multicenter EORTC 05011 trial.

Cancer Med 2020 06 22;9(12):4148-4159. Epub 2020 Apr 22.

Division of Biomedical Sciences, Cancer Chronotherapy Team, Cancer Research Centre, Warwick Medical School, Coventry, United Kingdom.

The least toxic time (LTT) of irinotecan varied by up to 8 hours according to sex and genetic background in mice. The translational relevance was investigated within a randomized trial dataset, where no LTT stood out significantly in the whole population. 130 male and 63 female eligible patients with metastatic colorectal cancer were randomized to receive chronomodulated Irinotecan with peak delivery rate at 1 of 6 clock hours staggered by 4 hours on day 1, then fixed-time chronomodulated Fluorouracil-Leucovorin-Oxaliplatin for 4 days, q3 weeks. The sex-specific circadian characteristics of grade (G) 3-4 toxicities were mapped with cosinor and time*sex interactions confirmed with Fisher's exact test. Baseline characteristics of male or female patients were similar in the six treatment groups. Main grade 3-4 toxicities over six courses were diarrhea (males vs females, 39.2%; vs 46.0%), neutropenia (15.6% vs 15.0%), fatigue (11.5% vs 15.9%), and anorexia (10.0% vs 7.8%). They were reduced following irinotecan peak delivery in the morning for males, but in the afternoon for females, with statistically significant rhythms (P < .05 from cosinor) and sex*timing interactions (Fisher's exact test, diarrhea, P = .023; neutropenia, P = .015; fatigue, P = .062; anorexia, P = .032). Irinotecan timing was most critical for females, with grades 3-4 ranging from 55.2% of the patients (morning) to 29.4% (afternoon) for diarrhea, and from 25.9% (morning) to 0% (afternoon) for neutropenia. The study results support irinotecan administration in the morning for males and in the afternoon for females, in order to minimize adverse events without impairing efficacy.
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http://dx.doi.org/10.1002/cam4.3056DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7300418PMC
June 2020

Adherence to the World Cancer Research Fund/American Institute for Cancer Research Recommendations and the Risk of Breast Cancer.

Nutrients 2020 Feb 26;12(3). Epub 2020 Feb 26.

Department of Clinical Sciences and Community Health, Università degli studi di Milano, Via A. Vanzetti 5, 20133 Milan, Italy.

The World Cancer Research Fund/American Institute for Cancer Research (WCRF/AICR) introduced in 2007, and updated in 2018, nutrition-related recommendations for cancer prevention. Previous studies generally reported inverse associations of breast cancer with the 2007 recommendations, while no study has yet evaluated the association with the 2018 guidelines. We investigated the association between adherence to the 2018 WCRF/AICR recommendations and breast cancer risk in a case-control study from Italy and Switzerland (1991-2008) including 3034 incident histologically-confirmed breast cancer cases and 3392 hospital controls. Adherence to the 2018 guidelines was summarized through a score incorporating eight recommendations (body fatness, physical activity, consumption of wholegrains/vegetables/fruit/beans, "fast foods" and other processed foods high in fat, starches, or sugars, red/processed meat, sugar-sweetened drinks, alcohol, breastfeeding), with higher scores indicating higher adherence. Odds ratios (OR) were estimated using multiple logistic regression models. We also conducted a meta-analysis including 15 additional studies using random-effects models. In our case-control study, adherence to the 2018 WCRF/AICR guidelines was inversely associated with breast cancer, with ORs of 0.60 (95% confidence interval (CI), 0.51-0.70) for a score ≥5.5 vs. ≤4.25, and of 0.83 (95% CI, 0.79-0.88) for a 1-point increment. In our study, 25% of breast cancers were attributable to low-to-moderate guideline adherence. In the meta-analysis, the pooled relative risks (RRs) were 0.73 (95% CI, 0.65-0.82, p heterogeneity among studies< 0.001) for the highest vs. the lowest WCRF/AICR score category, and 0.91 (95% CI, 0.88-0.94, p heterogeneity < 0.001) for a 1-point increment. This work provides quantitative evidence that higher adherence to the WCRF/AICR recommendations reduces the risk of breast cancer, thus opening perspectives for prevention.
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http://dx.doi.org/10.3390/nu12030607DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7146587PMC
February 2020

Optimizing circadian drug infusion schedules towards personalized cancer chronotherapy.

PLoS Comput Biol 2020 01 27;16(1):e1007218. Epub 2020 Jan 27.

INSERM and Paris Sud university, UMRS 935, Team "Cancer Chronotherapy and Postoperative Liver Functions", Campus CNRS, Villejuif, F-94807, France. & Honorary position, University of Warwick, UK.

Precision medicine requires accurate technologies for drug administration and proper systems pharmacology approaches for patient data analysis. Here, plasma pharmacokinetics (PK) data of the OPTILIV trial in which cancer patients received oxaliplatin, 5-fluorouracil and irinotecan via chronomodulated schedules delivered by an infusion pump into the hepatic artery were mathematically investigated. A pump-to-patient model was designed in order to accurately represent the drug solution dynamics from the pump to the patient blood. It was connected to semi-mechanistic PK models to analyse inter-patient variability in PK parameters. Large time delays of up to 1h41 between the actual pump start and the time of drug detection in patient blood was predicted by the model and confirmed by PK data. Sudden delivery spike in the patient artery due to glucose rinse after drug administration accounted for up to 10.7% of the total drug dose. New model-guided delivery profiles were designed to precisely lead to the drug exposure intended by clinicians. Next, the complete mathematical framework achieved a very good fit to individual time-concentration PK profiles and concluded that inter-subject differences in PK parameters was the lowest for irinotecan, intermediate for oxaliplatin and the largest for 5-fluorouracil. Clustering patients according to their PK parameter values revealed patient subgroups for each drug in which inter-patient variability was largely decreased compared to that in the total population. This study provides a complete mathematical framework to optimize drug infusion pumps and inform on inter-patient PK variability, a step towards precise and personalized cancer chronotherapy.
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http://dx.doi.org/10.1371/journal.pcbi.1007218DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7004559PMC
January 2020

Dietary glycaemic index, glycaemic load and head and neck cancer risk: a pooled analysis in an international consortium.

Br J Cancer 2020 03 13;122(6):745-748. Epub 2020 Jan 13.

Department of Clinical Sciences and Community Health, Università degli Studi di Milano, via Venezian, 1, 20133, Milano, Italy.

High dietary glycaemic index (GI) and glycaemic load (GL) may increase cancer risk. However, limited information was available on GI and/or GL and head and neck cancer (HNC) risk. We conducted a pooled analysis on 8 case-control studies (4081 HNC cases; 7407 controls) from the International Head and Neck Cancer Epidemiology (INHANCE) consortium. We estimated the odds ratios (ORs) and 95% confidence intervals (CIs) of HNC, and its subsites, from fixed- or mixed-effects logistic models including centre-specific quartiles of GI or GL. GI, but not GL, had a weak positive association with HNC (OR = 1.16; 95% CI = 1.02-1.31). In subsites, we found a positive association between GI and laryngeal cancer (OR = 1.60; 95% CI = 1.30-1.96) and an inverse association between GL and oropharyngeal cancer (OR = 0.78; 95% CI = 0.63-0.97). This pooled analysis indicates a modest positive association between GI and HNC, mainly driven by laryngeal cancer.
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http://dx.doi.org/10.1038/s41416-019-0702-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7078183PMC
March 2020

Intensity Detection Noise in Pulsed Vapor-Cell Frequency Standards.

IEEE Trans Ultrason Ferroelectr Freq Control 2020 05 3;67(5):1074-1079. Epub 2019 Dec 3.

Laser intensity noise is currently recognized as one of the main factors limiting the short-term stability of vapor-cell clocks. In this article, we propose a signal theory approach to estimate the contribution of the laser intensity fluctuations to the short-term stability of vapor-cell clocks working in a pulsed regime. Specifically, given the laser intensity noise spectrum, an analytical expression is derived to evaluate its impact on the clock Allan deviation (ADEV). The theory has been tested for two intensity noise spectra of interest in clock applications: white frequency noise and flicker noise. The predicted results turn out to be in good agreement with experiments performed with a prototype of pulsed optically pumped Rb-cell clock, and can be extended to other compact clocks.
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http://dx.doi.org/10.1109/TUFFC.2019.2957418DOI Listing
May 2020

Cancer mortality predictions for 2019 in Latin America.

Int J Cancer 2020 08 27;147(3):619-632. Epub 2019 Nov 27.

Department of Biomedical and Clinical Sciences, L. Sacco, Università degli Studi di Milano, Milan, Italy.

We estimated mortality figures for 2019 in seven Latin American countries, with focus on breast cancer. We retrieved cancer death certification and population data from the WHO and PAHO databases. We obtained mortality statistics for Argentina, Brazil, Chile, Colombia, Cuba, Mexico and Venezuela for 1970-2015. We predicted current death numbers and age-standardised (world population) mortality rates using joinpoint regression models. Total cancer mortality is predicted to decline in all countries and both sexes, except Argentinian women. Cuba had the highest all cancer rates for 2019, 136.9/100,000 men and 90.4 women, while Mexico showed the lowest ones, 63.8/100,000 men and 61.9 women. Stomach cancer showed favourable trends over the whole period, while colorectal cancer only recently. Lung cancer rates declined in men, while in women they decreased slightly over the most recent years, only. In Cuban women, lung cancer rates overtook breast cancer ones. Breast cancer showed overall favourable trends, but rates are rising in young women. Prostate and uterine cancer had favourable trends. Pancreas, ovary, bladder and leukaemias showed slightly decreasing trends. Between 1990 and 2019, mortality from all neoplasms is predicted to fall by about 18% in Argentina, 26% in Chile, 14% in Colombia, 17% in Mexico and 13% in Venezuela, corresponding to almost 0.5 million avoided cancer deaths. No decline was observed in Brazil and Cuba. Of concern, the persisting high rates of (cervix) uterus cancer, the high lung cancer rates in Cuba, the possible increases in breast cancer in young women, and the lack of overall declines in Brazil, Cuba and Venezuelan men.
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http://dx.doi.org/10.1002/ijc.32749DOI Listing
August 2020

Age at start of using tobacco on the risk of head and neck cancer: Pooled analysis in the International Head and Neck Cancer Epidemiology Consortium (INHANCE).

Cancer Epidemiol 2019 12 3;63:101615. Epub 2019 Oct 3.

Division of Public Health, Department of Family & Preventive Medicine, University of Utah School of Medicine, and Huntsman Cancer Institute, Salt Lake City, UT, United States. Electronic address:

Background: Tobacco use is a well-established risk factor for head and neck cancer (HNC). However, less is known about the potential impact of exposure to tobacco at an early age on HNC risk.

Methods: We analyzed individual-level data on ever tobacco smokers from 27 case-control studies (17,146 HNC cases and 17,449 controls) in the International Head and Neck Cancer Epidemiology (INHANCE) consortium. Adjusted odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using random-effects logistic regression models.

Results: Without adjusting for tobacco packyears, we observed that younger age at starting tobacco use was associated with an increased HNC risk for ever smokers (OR: 1.64, 95% CI: 1.35, 1.97). However, the observed association between age at starting tobacco use and HNC risk became null after adjusting for tobacco packyears (OR: 0.97, 95% CI: 0.80, 1.19). In the stratified analyses on HNC subsites by tobacco packyears or years since quitting, no difference in the association between age at start and HNC risk was observed.

Conclusions: Results from this pooled analysis suggest that increased HNC risks observed with earlier age at starting tobacco smoking are largely due to longer duration and higher cumulative tobacco exposures.
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http://dx.doi.org/10.1016/j.canep.2019.101615DOI Listing
December 2019

Predictability of individual circadian phase during daily routine for medical applications of circadian clocks.

JCI Insight 2019 09 19;4(18). Epub 2019 Sep 19.

Medical School, Warwick University, Coventry, United Kingdom.

BACKGROUNDCircadian timing of treatments can largely improve tolerability and efficacy in patients. Thus, drug metabolism and cell cycle are controlled by molecular clocks in each cell and coordinated by the core body temperature 24-hour rhythm, which is generated by the hypothalamic pacemaker. Individual circadian phase is currently estimated with questionnaire-based chronotype, center-of-rest time, dim light melatonin onset (DLMO), or timing of core body temperature (CBT) maximum (acrophase) or minimum (bathyphase).METHODSWe aimed at circadian phase determination and readout during daily routines in volunteers stratified by sex and age. We measured (a) chronotype, (b) every minute (q1min) CBT using 2 electronic pills swallowed 24 hours apart, (c) DLMO through hourly salivary samples from 1800 hours to bedtime, and (d) q1min accelerations and surface temperature at anterior chest level for 7 days, using a teletransmitting sensor. Circadian phases were computed using cosinor and hidden Markov modeling. Multivariate regression identified the combination of biomarkers that best predicted core temperature circadian bathyphase.RESULTSAmong the 33 participants, individual circadian phases were spread over 5 hours, 10 minutes (DLMO); 7 hours (CBT bathyphase); and 9 hours, 10 minutes (surface temperature acrophase). CBT bathyphase was accurately predicted, i.e., with an error less than 1 hour for 78.8% of the subjects, using a new digital health algorithm (INTime), combining time-invariant sex and chronotype score with computed center-of-rest time and surface temperature bathyphase (adjusted R2 = 0.637).CONCLUSIONINTime provided a continuous and reliable circadian phase estimate in real time. This model helps integrate circadian clocks into precision medicine and will enable treatment timing personalization following further validation.FUNDINGMedical Research Council, United Kingdom; AP-HP Foundation; and INSERM.
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http://dx.doi.org/10.1172/jci.insight.130423DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6795290PMC
September 2019

Medicine in the Fourth Dimension.

Cell Metab 2019 08;30(2):238-250

Experimental Audiology, Department of Physiology and Pharmacology, Karolinska Institutet, 171 77 Stockholm, Sweden. Electronic address:

The importance of circadian biology has rarely been considered in pre-clinical studies, and even more when translating to the bedside. Circadian biology is becoming a critical factor for improving drug efficacy and diminishing drug toxicity. Indeed, there is emerging evidence showing that some drugs are more effective at nighttime than daytime, whereas for others it is the opposite. This suggests that the biology of the target cell will determine how an organ will respond to a drug at a specific time of the day, thus modulating pharmacodynamics. Thus, it is now time that circadian factors become an integral part of translational research.
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http://dx.doi.org/10.1016/j.cmet.2019.06.019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6881776PMC
August 2019

Sex-, feeding-, and circadian time-dependency of P-glycoprotein expression and activity - implications for mechanistic pharmacokinetics modeling.

Sci Rep 2019 07 19;9(1):10505. Epub 2019 Jul 19.

Division of Biomedical Sciences, Warwick Medical School, University of Warwick, Coventry, UK.

P-glycoprotein (P-gp) largely influences the pharmacokinetics (PK) and toxicities of xenobiotics in a patient-specific manner so that personalized drug scheduling may lead to significant patient's benefit. This systems pharmacology study investigated P-gp activity in mice according to organ, sex, feeding status, and circadian time. Sex-specific circadian changes were found in P-gp ileum mRNA and protein levels, circadian amplitudes being larger in females as compared to males. Plasma, ileum and liver concentrations of talinolol, a pure P-gp substrate, significantly differed according to sex, feeding and circadian timing. A physiologically-based PK model was designed to recapitulate these datasets. Estimated mesors (rhythm-adjusted mean) of ileum and hepatic P-gp activity were higher in males as compared to females. Circadian amplitudes were consistently higher in females and circadian maxima varied by up to 10 h with respect to sex. Fasting increased P-gp activity mesor and dampened its rhythm. Ex-vivo bioluminescence recordings of ileum mucosae from transgenic mice revealed endogenous circadian rhythms of P-gp protein expression with a shorter period, larger amplitude, and phase delay in females as compared to males. Importantly, this study provided model structure and parameter estimates to refine PK models of any P-gp substrate to account for sex, feeding and circadian rhythms.
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http://dx.doi.org/10.1038/s41598-019-46977-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6642159PMC
July 2019

The day after: correlates of patient-reported outcomes with actigraphy-assessed sleep in cancer patients at home (inCASA project).

Sleep 2019 10;42(10)

Cancer Chronotherapy Team, Cancer Research Centre, Division of Biomedical Sciences, Warwick Medical School, Coventry, UK.

Subjective sleep assessment in cancer patients poorly correlates with actigraphy parameters that usually encompass multiple nights. We aimed to determine the objective actigraphy measures that best correlated with subjective sleep ratings on a night-by-night basis in cancer patients. Thirty-one cancer patients daily self-rated sleep disturbances using the single dedicated item of the MD Anderson Symptom Inventory (0-10 scale) with 18 other items, and continuously wore a wrist actigraph for 30 days. Objective sleep parameters were computed from the actigraphy nighttime series, and correlated with subjective sleep disturbances reported on the following day, using repeated measures correlations. Multilevel Poisson regression analysis was performed to identify the objective and subjective parameters that affected subjective sleep rating. Poor subjective sleep score was correlated with poor sleep efficiency (rrm = -0.13, p = 0.002) and large number of wake episodes (rrm = 0.12, p = 0.005) on the rated night. Multilevel analysis demonstrated that the expected sleep disturbance score was affected by the joint contribution of the wake episodes (exp(β) = 1.01, 95% confidence interval = 1.00 to 1.02, p = 0.016), fatigue (exp(β) = 1.35, 95% confidence interval = 1.15 to 1.55, p < 0.001) and drowsiness (exp(β) = 1.70, 95% confidence interval = 1.19 to 2.62, p = 0.018), self-rated the following evening, and sleep disturbance experienced one night before (exp(β) = 1.77, 95% confidence interval = 1.41 to 2.22, p < 0.001). The night-by-night approach within a multidimensional home tele-monitoring framework mainly identified the objective number of wake episodes computed from actigraphy records as the main determinant of the severity of sleep complaint in cancer patients on chemotherapy. This quantitative information remotely obtained in real time from cancer patients provides a novel framework for streamlining and evaluating interventions toward sleep improvement in cancer patients.
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http://dx.doi.org/10.1093/sleep/zsz146DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7587155PMC
October 2019

Bayesian Model Search for Nonstationary Periodic Time Series.

J Am Stat Assoc 2019 Jul 9;115(531):1320-1335. Epub 2019 Jul 9.

School of Life Sciences, University of Warwick, Coventry, UK.

We propose a novel Bayesian methodology for analyzing nonstationary time series that exhibit oscillatory behavior. We approximate the time series using a piecewise oscillatory model with unknown periodicities, where our goal is to estimate the change-points while simultaneously identifying the potentially changing periodicities in the data. Our proposed methodology is based on a trans-dimensional Markov chain Monte Carlo algorithm that simultaneously updates the change-points and the periodicities relevant to any segment between them. We show that the proposed methodology successfully identifies time changing oscillatory behavior in two applications which are relevant to e-Health and sleep research, namely the occurrence of ultradian oscillations in human skin temperature during the time of night rest, and the detection of instances of sleep apnea in plethysmographic respiratory traces. Supplementary materials for this article are available online.
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http://dx.doi.org/10.1080/01621459.2019.1623043DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7984273PMC
July 2019