Publications by authors named "Silvia Rizzi"

26 Publications

  • Page 1 of 1

Engagement and Effectiveness of a Healthy-Coping Intervention via Chatbot for University Students During the COVID-19 Pandemic: Mixed Methods Proof-of-Concept Study.

JMIR Mhealth Uhealth 2021 05 28;9(5):e27965. Epub 2021 May 28.

Digital Health Lab, Fondazione Bruno Kessler, Trento, Italy.

Background: University students are increasingly reporting common mental health problems, such as stress, anxiety, and depression, and they frequently face barriers to seeking psychological support because of stigma, cost, and availability of mental health services. This issue is even more critical in the challenging time of the COVID-19 pandemic. Digital mental health interventions, such as those delivered via chatbots on mobile devices, offer the potential to achieve scalability of healthy-coping interventions by lowering cost and supporting prevention.

Objective: The goal of this study was to conduct a proof-of-concept evaluation measuring the engagement and effectiveness of Atena, a psychoeducational chatbot supporting healthy coping with stress and anxiety, among a population of university students.

Methods: In a proof-of-concept study, 71 university students were recruited during the COVID-19 pandemic; 68% (48/71) were female, they were all in their first year of university, and their mean age was 20.6 years (SD 2.4). Enrolled students were asked to use the Atena psychoeducational chatbot for 4 weeks (eight sessions; two per week), which provided healthy-coping strategies based on cognitive behavioral therapy, positive psychology, and mindfulness techniques. The intervention program consisted of conversations combined with audiovisual clips delivered via the Atena chatbot. Participants were asked to complete web-based versions of the 7-item Generalized Anxiety Disorder scale (GAD-7), the 10-item Perceived Stress Scale (PSS-10), and the Five-Facet Mindfulness Questionnaire (FFMQ) at baseline and postintervention to assess effectiveness. They were also asked to complete the User Engagement Scale-Short Form at week 2 to assess engagement with the chatbot and to provide qualitative comments on their overall experience with Atena postintervention.

Results: Participants engaged with the Atena chatbot an average of 78 (SD 24.8) times over the study period. A total of 61 out of 71 (86%) participants completed the first 2 weeks of the intervention and provided data on engagement (10/71, 14% attrition). A total of 41 participants out of 71 (58%) completed the full intervention and the postintervention questionnaires (30/71, 42% attrition). Results from the completer analysis showed a significant decrease in anxiety symptoms for participants in more extreme GAD-7 score ranges (t=0.94; P=.009) and a decrease in stress symptoms as measured by the PSS-10 (t=2.00; P=.05) for all participants postintervention. Participants also improved significantly in the describing and nonjudging facets, based on their FFMQ subscale scores, and asked for some improvements in the user experience with the chatbot.

Conclusions: This study shows the benefit of deploying a digital healthy-coping intervention via a chatbot to support university students experiencing higher levels of distress. While findings collected during the COVID-19 pandemic show promise, further research is required to confirm conclusions.
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http://dx.doi.org/10.2196/27965DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8166265PMC
May 2021

Short-term forecasts of expected deaths.

Proc Natl Acad Sci U S A 2021 04;118(15)

Interdisciplinary Centre on Population Dynamics, University of Southern Denmark, 5230 Odense M, Denmark

We introduce a method for making short-term mortality forecasts of a few months, illustrating it by estimating how many deaths might have happened if some major shock had not occurred. We apply the method to assess excess mortality from March to June 2020 in Denmark and Sweden as a result of the first wave of the coronavirus pandemic; associated policy interventions; and behavioral, healthcare, social, and economic changes. We chose to compare Denmark and Sweden because reliable data were available and because the two countries are similar but chose different responses to COVID-19: Denmark imposed a rather severe lockdown; Sweden did not. We make forecasts by age and sex to predict expected deaths if COVID-19 had not struck. Subtracting these forecasts from observed deaths gives the excess death count. Excess deaths were lower in Denmark than Sweden during the first wave of the pandemic. The later/earlier ratio we propose for shortcasting is easy to understand, requires less data than more elaborate approaches, and may be useful in many countries in making both predictions about the future and the past to study the impact on mortality of coronavirus and other epidemics. In the application to Denmark and Sweden, prediction intervals are narrower and bias is less than when forecasts are based on averages of the last 5 y, as is often done. More generally, later/earlier ratios may prove useful in short-term forecasting of illnesses and births as well as economic and other activity that varies seasonally or periodically.
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http://dx.doi.org/10.1073/pnas.2025324118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8053952PMC
April 2021

Risk of pre-term births and major birth defects resulting from paternal intake of COVID-19 medications prior to conception.

BMC Res Notes 2020 Nov 7;13(1):509. Epub 2020 Nov 7.

Male Reproductive Medicine and Surgery, Department of Urology and Obstetrics & Gynecology, Stanford University School of Medicine, 300 Pasteur Drive, S-287, Stanford, CA, USA.

Objective: With the ongoing COVID-19 pandemic, large numbers of people will receive one of the several medications proposed to treat COVID-19, including patients of reproductive age. Given that some medications have shown adverse effects on sperm quality, there might be a transgenerational concern. We aim at examining the association between drugs proposed to treat COVID-19 when taken by the father around conception and any pre-term birth or major birth defects in offspring in a nation-wide cohort study using Danish registry data. Offspring whose father filled at least one prescription of the following medications in the 3 months preceding conception were considered exposed: chloroquine, hydroxychloroquine, losartan, azithromycin, naproxen, dexamethasone and prednisone.

Results: For azithromycin and naproxen, large numbers of offspring were exposed (> 1800 offspring), and we found no association with adverse birth outcomes. For chloroquine, losartan and dexamethasone, exposure was intermediate (~ 900 offspring), and there was no statistically significant association with birth defects. For hydroxychloroquine and prednisone, exposure was limited (< 300 offspring). Our evidence suggests that azithromycin and naproxen are safe with respect to pre-term birth and birth defects. For the other drugs investigated larger exposures are needed for conclusive statements.
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http://dx.doi.org/10.1186/s13104-020-05358-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7647878PMC
November 2020

Risk of pre-term births and major birth defects resulting from paternal intake of COVID-19 medications prior to conception.

Res Sq 2020 Aug 26. Epub 2020 Aug 26.

Stanford University School of Medicine.

Objective: With the ongoing COVID-19 pandemic, large numbers of people will receive one of the several medications proposed to treat COVID-19, including patients of reproductive age. Given that some medications have shown adverse effects on sperm quality, there might be a transgenerational concern. We aim at examining the association between drugs proposed to treat COVID-19 when taken by the father around conception and any pre-term birth or major birth defects in offspring in a nation-wide cohort study using Danish registry data. Offspring whose father filled at least one prescription of the following medications in the three months preceding conception were considered exposed: chloroquine, hydroxychloroquine, losartan, azithromycin, naproxen, dexamethasone and prednisone.

Results: For azithromycin and naproxen, large numbers of offspring were exposed (> 1800 offspring), and we found no association with adverse birth outcomes. For chloroquine, losartan and dexamethasone, exposure was intermediate (~ 900 offspring), and there was no statistically significant association with birth defects. For hydroxychloroquine and prednisone, exposure was limited (< 300 offspring). There is strong evidence that azithromycin and naproxen are safe with respect to pre-term birth and birth defects. With some caution, the other drugs investigated can be considered safe.
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http://dx.doi.org/10.21203/rs.3.rs-59420/v1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7457584PMC
August 2020

Age-specific cancer rates: a bird's-eye view on progress.

Ann Epidemiol 2020 08 6;48:51-54.e1. Epub 2020 May 6.

Unit of Epidemiology, Biostatistics and Biodemography, Department of Public Health, University of Southern Denmark, Odense, Denmark; Interdisciplinary Centre on Population Dynamics, University of Southern Denmark, Odense, Denmark.

Purpose: We aim to shed light on progress in cancer medicine through studying time trends in age-specific rates of cancer incidence and mortality over the last quarter century.

Methods: We analyzed age-specific incidence and mortality rates of all cancer sites combined using the high-quality population-based databases of Denmark, Finland, Norway, Sweden, and the Netherlands for the period 1990-2016.

Results: Over these 26 years, cancer incidence rates increased in all investigated countries irrespective of age by about 22%. By contrast, cancer mortality rates decreased across all ages, also by about 22%, except ages 80+ years in Denmark, Norway, and Sweden, where they remained unchanged. This pattern is consistent with earlier diagnoses and more effective treatments of cancer.

Conclusions: This bird's-eye view on cancer reveals substantive progress in cancer medicine.
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http://dx.doi.org/10.1016/j.annepidem.2020.04.007DOI Listing
August 2020

A Chatbot-Based Coaching Intervention for Adolescents to Promote Life Skills: Pilot Study.

JMIR Hum Factors 2020 Feb 14;7(1):e16762. Epub 2020 Feb 14.

eHealth Unit, Fondazione Bruno Kessler, Trento, Italy.

Background: Adolescence is a challenging period, where youth face rapid changes as well as increasing socioemotional demands and threats, such as bullying and cyberbullying. Adolescent mental health and well-being can be best supported by providing effective coaching on life skills, such as coping strategies and protective factors. Interventions that take advantage of online coaching by means of chatbots, deployed on Web or mobile technology, may be a novel and more appealing way to support positive mental health for adolescents.

Objective: In this pilot study, we co-designed and conducted a formative evaluation of an online, life skills coaching, chatbot intervention, inspired by the positive technology approach, to promote mental well-being in adolescence.

Methods: We co-designed the first life skills coaching session of the CRI (for girls) and CRIS (for boys) chatbot with 20 secondary school students in a participatory design workshop. We then conducted a formative evaluation of the entire intervention-eight sessions-with a convenience sample of 21 adolescents of both genders (mean age 14.52 years). Participants engaged with the chatbot sessions over 4 weeks and filled in an anonymous user experience questionnaire at the end of each session; responses were based on a 5-point Likert scale.

Results: A majority of the adolescents found the intervention useful (16/21, 76%), easy to use (19/21, 90%), and innovative (17/21, 81%). Most of the participants (15/21, 71%) liked, in particular, the video cartoons provided by the chatbot in the coaching sessions. They also thought that a session should last only 5-10 minutes (14/21, 66%) and said they would recommend the intervention to a friend (20/21, 95%).

Conclusions: We have presented a novel and scalable self-help intervention to deliver life skills coaching to adolescents online that is appealing to this population. This intervention can support the promotion of coping skills and mental well-being among youth.
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http://dx.doi.org/10.2196/16762DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7055808PMC
February 2020

Progression of the smoking epidemic in high-income regions and its effects on male-female survival differences: a cohort-by-age analysis of 17 countries.

BMC Public Health 2020 Jan 10;20(1):39. Epub 2020 Jan 10.

Interdisciplinary Centre on Population Dynamics, University of Southern Denmark, Odense, Denmark.

Background: Of all lifestyle behaviours, smoking caused the most deaths in the last century. Because of the time lag between the act of smoking and dying from smoking, and because males generally take up smoking before females do, male and female smoking epidemiology often follows a typical double wave pattern dubbed the 'smoking epidemic'. How are male and female deaths from this epidemic differentially progressing in high-income regions on a cohort-by-age basis? How have they affected male-female survival differences?

Methods: We used data for the period 1950-2015 from the WHO Mortality Database and the Human Mortality Database on three geographic regions that have progressed most into the smoking epidemic: high-income North America, high-income Europe and high-income Oceania. We examined changes in smoking-attributable mortality fractions as estimated by the Preston-Glei-Wilmoth method by age (ages 50-85) across birth cohorts 1870-1965. We used these to trace sex differences with and without smoking-attributable mortality in period life expectancy between ages 50 and 85.

Results: In all three high-income regions, smoking explained up to 50% of sex differences in period life expectancy between ages 50 and 85 over the study period. These sex differences have declined since at least 1980, driven by smoking-attributable mortality, which tended to decline in males and increase in females overall. Thus, there was a convergence between sexes across recent cohorts. While smoking-attributable mortality was still increasing for older female cohorts, it was declining for females in the more recent cohorts in the US and Europe, as well as for males in all three regions.

Conclusions: The smoking epidemic contributed substantially to the male-female survival gap and to the recent narrowing of that gap in high-income North America, high-income Europe and high-income Oceania. The precipitous decline in smoking-attributable mortality in recent cohorts bodes somewhat hopeful. Yet, smoking-attributable mortality remains high, and therefore cause for concern.
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http://dx.doi.org/10.1186/s12889-020-8148-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6954612PMC
January 2020

UPRIGHT, a resilience-based intervention to promote mental well-being in schools: study rationale and methodology for a European randomized controlled trial.

BMC Public Health 2019 Oct 29;19(1):1413. Epub 2019 Oct 29.

Kronikgune Institute for Health Services Research, Torre del BEC, Ronda de Azkue 1, 48902, Barakaldo, Bizkaia, Basque Country, Spain.

Background: Adolescence is crucial period for laying the foundations for healthy development and mental well-being. The increasing prevalence of mental disorders amongst adolescents makes promotion of mental well-being and prevention interventions at schools important. UPRIGHT (Universal Preventive Resilience Intervention Globally implemented in schools to improve and promote mental Health for Teenagers) is designed as a whole school approach (school community, students and families) to promote a culture of mental well-being and prevent mental disorders by enhancing resilience capacities. The present article aims at describing the rationale, conceptual framework, as well as methodology of implementation and evaluation of the UPRIGHT intervention.

Methods: UPRIGHT project is a research and innovation project funded by the European Union's Horizon 2020 Research and Innovation programme under grant agreement No. 754919 (Duration: 48 months). The theoretical framework has been developed by an innovative and multidisciplinary approach using a co-creation process inside the UPRIGHT Consortium (involving seven institutions from Spain, Italy, Poland, Norway, Denmark, and Iceland). Resulted is the UPRIGHT programme with 18 skills related to 4 components: Mindfulness, Coping, Efficacy and Social and Emotional Learning. Among the five Pan-European regions, 34 schools have been currently involved (17 control; 17 intervention) and around 6000 adolescents and their families are foreseen to participate along a 3-year period of evaluation. Effectiveness of the intervention will be evaluated as a randomized controlled trial including quantitative and qualitative analysis in the five Pan-European regions representative of the cultural and socioeconomic diversity. The cost-effectiveness assessment will be performed by simulation modelling methods.

Discussion: We expect a short- to medium-term improvement of mental well-being in adolescents by enhancing resilience capacities. The study may provide robust evidence on intrapersonal, familiar and social environmental resilience factors promoting positive mental well-being.

Trial Registration: ClinicalTrials.gov Identifier: NCT03951376 . Registered 15 May 2019.
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http://dx.doi.org/10.1186/s12889-019-7759-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6820972PMC
October 2019

Correction to: The private healthcare market and the sustainability of an innovative community nurses programme based on social entrepreneurship - CoNSENSo project.

BMC Health Serv Res 2018 10 11;18(1):771. Epub 2018 Oct 11.

Direzione Sanità - Regione Piemonte, Torino, Italy.

Following publication of the original article [1], the author reported that their first names and last names were swapped. The original article has been corrected.
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http://dx.doi.org/10.1186/s12913-018-3597-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6180619PMC
October 2018

How to estimate mortality trends from grouped vital statistics.

Int J Epidemiol 2019 04;48(2):571-582

Institute of Public Health, Unit of Epidemiology, Biostatistics and Biodemography, University of Southern Denmark, Odense, Denmark.

Background: Mortality data at the population level are often aggregated in age classes, for example 5-year age groups with an open-ended interval for the elderly aged 85+. Capturing detailed age-specific mortality patterns and mortality time trends from such coarsely grouped data can be problematic at older ages, especially where open-ended intervals are used.

Methods: We illustrate the penalized composite link model (PCLM) for ungrouping to model cancer mortality surfaces. Smooth age-specific distributions from data grouped in age classes of adjacent calendar years were estimated by constructing a two-dimensional regression, based on B-splines, and maximizing a penalized likelihood. We show the applicability of the proposed model, analysing age-at-death distributions from cancers of all sites in Denmark from 1980 to 2014. Data were retrieved from the Danish Cancer Society and the Human Mortality Database.

Results: The main trends captured by PCLM are: (i) a decrease in cancer mortality rates after the 1990s for ages 50-75; (ii) a decrease in cancer mortality in later cohorts for young ages, especially, and very advanced ages. Comparing the raw data by single year of age, with the PCLM-ungrouped distributions, we clearly illustrate that the model fits the data with a high level of accuracy.

Conclusions: The PCLM produces detailed smooth mortality surfaces from death counts observed in coarse age groups with modest assumptions, that is Poisson distributed counts and smoothness of the estimated distribution. Hence, the method has great potential for use within epidemiological research when information is to be gained from aggregated data, because it avoids strict assumptions about the actual distributional shape.
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http://dx.doi.org/10.1093/ije/dyy183DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6469310PMC
April 2019

The private healthcare market and the sustainability of an innovative community nurses programme based on social entrepreneurship - CoNSENSo project.

BMC Health Serv Res 2018 Sep 5;18(1):689. Epub 2018 Sep 5.

Direzione Sanità - Regione Piemonte, Torino, Italy.

Background: CoNSENSo is a project funded by the European Union, which is aimed at developing an innovative care model based on community nurses to support active ageing in mountain areas. The planned sustainability of this innovative approach relies on social entrepreneurship on the healthcare market, and this work highlights the necessary conditions for the successful implementation of these entrepreneurial initiatives.

Methods: Considering municipalities in the Piedmont Region and those aged 65 or older as target population, the authors propose several negative binomial regression models to estimate the effectiveness of current private healthcare services in supporting the active aging process. Such effectiveness may represent the ex-ante (positive) reputation of these new social entrepreneurial initiatives on the market.

Results: According to our results, the private supply of healthcare services can effectively support the aging process. Indeed, given that the other predictor variables in the model are held constant, there are statistically significant negative relations between the number of hip fractures and the private supply of healthcare services by dental practitioners and psychologists (p-value < 0.05), as well as the private supply of opportunities for social interaction by coffee bars (p-value < 0.05).

Conclusions: The authors expect a favourable environment for the entrepreneurial initiatives of community nurses in mountain areas. Accordingly, policy makers cannot reject the hypothesis that the goals reached by the CoNSENSo project may be maintained for the sake of the future generations, avoiding its collapse as soon as public funding shifts to new programmes.
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http://dx.doi.org/10.1186/s12913-018-3513-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6125879PMC
September 2018

The sustainability of a community nurses programme aimed at supporting active ageing in mountain areas.

Int J Health Plann Manage 2018 Oct 27;33(4):e1100-e1111. Epub 2018 Jul 27.

Piedmont Region, Italy.

Background: Community Nurse Supporting Elderly iN a changing SOciety is a project funded by the European Union, which is aimed at developing an innovative care model based on community nurses to support active ageing in mountain areas. The planned sustainability of this innovative approach relies on social entrepreneurship, and this work highlights the necessary conditions for the existence of these entrepreneurial initiatives on the market, with community nurses' services purchased by the public health care system.

Methods: The authors propose a sustainability framework for this project based on three relevant dimensions (ie, health, organisation, and context), highlighting the necessary conditions for continued provision of health services beyond project conclusion. Then, considering the Piedmont Region and those aged 65 or older as target population, health outcomes are analysed, proposing a break-even analysis to calculate expected levels.

Results: According to our results, in order to care for 191 977 elderly people for 3 years, a successful pro-active approach is needed to prevent 1657 falls with hip fracture, reducing the prevalence of this adverse outcome by 36%. These are the expected health outcome levels for the existence of a social market, which can be achieved through the successful involvement of local public health organisations and stakeholders.

Conclusions: Policy makers need clear information on the economic impact of extending this new intervention to the whole target population and on the required preconditions for its financial sustainability in terms of health outcomes. However, a participatory process involving all relevant local stakeholders and organisations is crucial to extend current achievements beyond project conclusion.
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http://dx.doi.org/10.1002/hpm.2591DOI Listing
October 2018

Comparison of cognitive and physical functioning of Europeans in 2004-05 and 2013.

Int J Epidemiol 2018 10;47(5):1518-1528

Interdisciplinary Center for Research and Education on Population Change, University of Southern Denmark, Odense, Denmark.

Background: Adult mortality has been postponed over time to increasingly high ages. However, evidence on past and current health trends has been mixed, and little is known about European disability trends.

Methods: In a cross-sectional setting, we compared cognitive and physical functioning in same-aged Europeans aged 50+ between 2004-05 (wave 1; n = 18 757) and 2013 (wave 5 refresher respondents; n = 16 696), sourced from the Survey of Health, Ageing and Retirement in Europe (SHARE).

Results: People in 2013 had better cognitive function compared with same-aged persons in 2004-05, with an average difference of approximately one-third standard deviation. The same level of cognitive function in 2004-05 at age 50 was found in 2013 for people who were 8 years older. There was an improvement in cognitive function in all European regions. Mean grip strength showed an improvement in Northern Europe of 1.00 kg [95% confidence interval (CI) 0.65; 1.35] and in Southern Europe of 1.68 kg (95% CI 1.14; 2.22), whereas a decrease was found in Central Europe (-0.80 kg; 95% CI -1.16; -0.44). We found no overall differences in activities of daily living (ADL), but small improvements in instrumental activities of daily living (IADL) in Northern and Southern Europe, with an improvement in both ADL and IADL from age 70 in Northern Europe.

Conclusions: Our results indicate that later-born Europeans have substantially better cognitive functioning than earlier-born cohorts. For physical functioning, improvements were less clear, but for Northern Europe there was an improvement in ADL and IADL in the oldest age groups.
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http://dx.doi.org/10.1093/ije/dyy094DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6208267PMC
October 2018

Why did Danish women's life expectancy stagnate? The influence of interwar generations' smoking behaviour.

Eur J Epidemiol 2016 12 16;31(12):1207-1211. Epub 2016 Sep 16.

Max-Planck Odense Center on the Biodemography of Aging, University of Southern Denmark, J.B. Winsløws Vej 9B, 5000, Odense C, Denmark.

The general health status of a population changes over time, generally in a positive direction. Some generations experience more unfavourable conditions than others. The health of Danish women in the interwar generations is an example of such a phenomenon. The stagnation in their life expectancy between 1977 and 1995 is thought to be related to their smoking behaviour. So far, no study has measured the absolute effect of smoking on the mortality of the interwar generations of Danish women and thus the stagnation in Danish women's life expectancy. We applied a method to estimate age-specific smoking-attributable number of deaths to examine the effect of smoking on the trends in partial life expectancy of Danish women between age 50 and 85 from 1950 to 2012. We compared these trends to those for women in Sweden, where there was no similar stagnation in life expectancy. When smoking-attributable mortality was excluded, the gap in partial life expectancy at age 50 between Swedish and Danish women diminished substantially. The effect was most pronounced in the interwar generations. The major reason for the stagnation in Danish women's partial life expectancy at age 50 was found to be smoking-related mortality in the interwar generations.
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http://dx.doi.org/10.1007/s10654-016-0198-7DOI Listing
December 2016

Comparison of non-parametric methods for ungrouping coarsely aggregated data.

BMC Med Res Methodol 2016 05 23;16:59. Epub 2016 May 23.

Max Planck Odense Center on the Biodemography of Aging, J.B. Winsløws Vej 9, Odense, 5000, Denmark.

Background: Histograms are a common tool to estimate densities non-parametrically. They are extensively encountered in health sciences to summarize data in a compact format. Examples are age-specific distributions of death or onset of diseases grouped in 5-years age classes with an open-ended age group at the highest ages. When histogram intervals are too coarse, information is lost and comparison between histograms with different boundaries is arduous. In these cases it is useful to estimate detailed distributions from grouped data.

Methods: From an extensive literature search we identify five methods for ungrouping count data. We compare the performance of two spline interpolation methods, two kernel density estimators and a penalized composite link model first via a simulation study and then with empirical data obtained from the NORDCAN Database. All methods analyzed can be used to estimate differently shaped distributions; can handle unequal interval length; and allow stretches of 0 counts.

Results: The methods show similar performance when the grouping scheme is relatively narrow, i.e. 5-years age classes. With coarser age intervals, i.e. in the presence of open-ended age groups, the penalized composite link model performs the best.

Conclusion: We give an overview and test different methods to estimate detailed distributions from grouped count data. Health researchers can benefit from these versatile methods, which are ready for use in the statistical software R. We recommend using the penalized composite link model when data are grouped in wide age classes.
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http://dx.doi.org/10.1186/s12874-016-0157-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4877978PMC
May 2016

Efficient estimation of smooth distributions from coarsely grouped data.

Am J Epidemiol 2015 Jul 16;182(2):138-47. Epub 2015 Jun 16.

Ungrouping binned data can be desirable for many reasons: Bins can be too coarse to allow for accurate analysis; comparisons can be hindered when different grouping approaches are used in different histograms; and the last interval is often wide and open-ended and, thus, covers a lot of information in the tail area. Age group-specific disease incidence rates and abridged life tables are examples of binned data. We propose a versatile method for ungrouping histograms that assumes that only the underlying distribution is smooth. Because of this modest assumption, the approach is suitable for most applications. The method is based on the composite link model, with a penalty added to ensure the smoothness of the target distribution. Estimates are obtained by maximizing a penalized likelihood. This maximization is performed efficiently by a version of the iteratively reweighted least-squares algorithm. Optimal values of the smoothing parameter are chosen by minimizing Akaike's Information Criterion. We demonstrate the performance of this method in a simulation study and provide several examples that illustrate the approach. Wide, open-ended intervals can be handled properly. The method can be extended to the estimation of rates when both the event counts and the exposures to risk are grouped.
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http://dx.doi.org/10.1093/aje/kwv020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4493979PMC
July 2015

The BRAF V600E mutation in hairy cell leukemia and other mature B-cell neoplasms.

Blood 2012 Jan 9;119(1):188-91. Epub 2011 Nov 9.

Departments of Hematology Oncology, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico Policlinico San Matteo & University of Pavia, Pavia, Italy.

The somatically acquired V600E mutation of the BRAF gene has been recently described as a molecular marker of hairy cell leukemia (HCL). We developed an allele-specific PCR for this mutation and studied 62 patients with HCL, 1 with HCL variant, 91 with splenic marginal zone lymphoma, 29 with Waldenström macroglobulinemia, and 57 with B-cell chronic lymphoproliferative disorders. The BRAF V600E mutation was detected in all HCL cases and in only 2 of the remaining 178 patients. These 2 subjects had B-cell chronic lymphoproliferative disorders that did not fulfill the diagnostic criteria for HCL. Despite the positive PCR finding, the mutation could not be detected by Sanger sequencing in these 2 cases, suggesting that it was associated with a small subclone. We conclude that the BRAF V600E mutation is present in all patients with HCL and that, in combination with clinical and morphologic features, represents a reliable molecular marker for this condition.
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http://dx.doi.org/10.1182/blood-2011-08-368209DOI Listing
January 2012

Distinctive clinical and histological features of Waldenström's macroglobulinemia and splenic marginal zone lymphoma.

Clin Lymphoma Myeloma Leuk 2011 Feb;11(1):103-5

Division of Hematology, Department of Oncohematology, University of Pavia Medical School, Fondazione IRCCS Policlinico San Matteo, Italy.

We studied 122 patients with Waldenström's macroglobulinemia (WM) and 98 with splenic marginal zone lymphoma (SMZL); 29 SMZL patients (30%) had a serum MC (IgM in 17 patients). SMZL differed from WM for female prevalence, abdominal and superficial adenopathy, spleen and liver involvement, positive HCV. The median MC level was 2.0 g/dL in WM and 0.95 g/dL in SMZL (P<.001). On BM histology, SMZL was characterized by sinusoidal infiltration (70% of cases) and by a more frequent nodular pattern (P<.01) while WM had a higher incidence of interstitial BM localization. After a median follow-up of 5.3 years, median OS was not reached for SMZL and was 12 years for WM (P=.23; 14 years for asymptomatic WM, 8 years for symptomatic WM). In conclusion, despite similar outcomes of these 2 entities, SMZL appears as a disease with distinct clinical features and BM histology and a peculiar association with HCV infection.
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http://dx.doi.org/10.3816/CLML.2011.n.020DOI Listing
February 2011

Plerixafor and G-CSF for PBSC mobilization in patients with lymphoma who failed previous attempts with G-CSF and chemotherapy: a REL (Rete Ematologica Lombarda) experience.

Leuk Res 2011 Jun 26;35(6):712-4. Epub 2011 Jan 26.

Division of Hematology, Department of Oncohematology, University of Pavia Medical School, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy.

Plerixafor has been previously reported to improve PBSC collection in pts undergoing PBSC mobilization. Aim of the study was to assess the efficacy of plerixafor and G-CSF in pts with lymphoma who failed previous attempts of PBSC mobilization with conventional schemes of chemotherapy+G-CSF. 35 heavily pre-treated lymphoma pts (29 NHL, 6 HL) classified as "poor mobilizers" were enrolled in a program of compassionate use of plerixafor in 7 Italian centres of REL (Rete Ematologica Lombarda). Median number of previous lines of therapy was 3 and median number of previous attempts of mobilizations was 2. The median number of circulating CD34+ cells/μL following plerixafor was 11/μL. It was ≥10/μL in 17 pts and ≥20/μL in 10 pts; 13 were able to collect ≥2×10(6) CD34+ cells/kg with a median of 1 apheresis procedure; 4 pts collected ≥4×10(6) CD34+ cells/kg. A total of 6 pts had proceeded to transplant at the time of analysis. The median dose of PBSCs infused was 4×10(6)/kg and hematopoietic recovery was regular. In conclusion, plerixafor combined with G-CSF allows a collection of adequate number of PBSC in approximately 40% of cases of poor mobilizer, heavily pre-treated pts with lymphoma, who need consolidation with ASCT.
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http://dx.doi.org/10.1016/j.leukres.2010.12.036DOI Listing
June 2011

Assessment of bone marrow involvement in non-Hodgkin's lymphomas: comparison between histology and flow cytometry.

Eur J Haematol 2010 Nov;85(5):405-15

Department of Oncohematology, Fondazione IRCCS Policlinico S. Matteo, University of Pavia, Italy.

Bone marrow (BM) examination is essential in the staging of non-Hodgkin's lymphoma (NHL) patients. Few studies have compared BM histologic findings with results of flow cytometric (FC) analysis. We analyzed the incidence and patterns of histologic BM involvement in a series of 753 patients with NHL. For 498 patients, a concurrent FC analysis on BM was available. Histologic involvement was detected at diagnosis in 311/753 (41%) patients. By FC, BM involvement was clearly detected in 150/498 (30%). After excluding 12 cases with equivocal histology, concordance between the two methods was detected in 411 (85%) cases (27% BMB+/FC+; 58% BMB-/FC-), while discordance was present in 75 (15%) (P < 0.001): 58 cases (12%) were BMB+/FC- and 17 (3%) were BMB-/FC+. Discordance was more frequent in FL and in lymphoplasmacytic lymphoma (LPL). These data demonstrate that the two methods are comparable in qualitative assessment of BM involvement in NHL, with the exception of FL and LPL. In FL, diffuse large B-cell lymphoma (DLBCL) and LPL, FC underestimates the extent of infiltrate with respect to histology.
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http://dx.doi.org/10.1111/j.1600-0609.2010.01503.xDOI Listing
November 2010

Stereotyped patterns of B-cell receptor in splenic marginal zone lymphoma.

Haematologica 2010 Oct 29;95(10):1792-6. Epub 2010 May 29.

Division of Hematology, Department of Oncohematology, Fondazione IRCCS Policlinico San Matteo, University of Pavia, Viale Golgi 19, Pavia, Italy.

Antigen stimulation may be important for splenic marginal zone lymphoma pathogenesis. To address this hypothesis, the occurrence of stereotyped B-cell receptors was investigated in 133 SMZL (26 HCV+) compared with 4,414 HCDR3 sequences from public databases. Sixteen SMZL (12%) showed stereotyped BCR; 7 of 86 (8%) SMZL sequences retrieved from public databases also belonged to stereotyped HCDR3 subsets. Three categories of subsets were identified: i) "SMZL-specific subsets" (n=5), composed only of 12 SMZL (9 HCV-from our series); ii) "Non-Hodgkin's lymphoma-like subsets" (n=5), comprising 5 SMZL (4 from our series) clustering with other indolent lymphomas; iii) "CLL-like subsets" (n=6), comprising 6 SMZL (3 from our series) that belonged to known CLL subsets (n=4) or clustered with public CLL sequences. Immunoglobulin 3D modeling of 3 subsets revealed similarities in antigen binding regions not limited to HCDR3. Overall, data suggest that the pathogenesis of splenic marginal zone lymphoma may involve also HCV-unrelated epitopes or an antigenic trigger common to other indolent lymphomas.
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http://dx.doi.org/10.3324/haematol.2010.025437DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2948108PMC
October 2010

Impact of treatment-related liver toxicity on the outcome of HCV-positive non-Hodgkin's lymphomas.

Am J Hematol 2010 Jan;85(1):46-50

Divison of Hematology, Fondazione IRCCS Policlinico S. Matteo, University of Pavia, Viale Golgi 19, Pavia, Italy.

We studied 160 Hepatitis C virus (HCV)-positive patients with NHL (59 indolent NHL, 101 aggressive). Median age was 67 years. HCV-RNA was present in 146. HBsAg was positive in seven patients. At diagnosis, ALT value was above UNL in 67 patients. One hundred and twenty patients received an anthracycline-based therapy, alkylators, 28 received chemotherapy plus rituximab. Cytotoxic drugs dose was reduced in 63 patients. Among 93 patients with normal ALT at presentation, 16 patients developed WHO grade II-III liver toxicity. Among 67 patients with abnormal ALT, eight patients had a 3.5 times elevation during treatment. Among 28 patients treated with rituximab and chemotherapy, five patients (18%) developed liver toxicity. Thirty four patients (21%) did not complete treatment (eight for liver toxicity). Median progression-free survival (PFS) for patients who experienced liver toxicity is significantly shorter than median PFS of patients without toxicity (respectively, 2 years and 3.7 years, P = 0.03). After a median F-UP of 2 years, 32 patients died (three for hepatic failure). A significant proportion of patients with HCV+ NHL develop liver toxicity often leading to interruption of treatment. This could be a limit to the application of immunochemotherapy programs. HCV+ lymphomas represent a distinct clinical subset of NHL that deserves specific clinical approach to limit liver toxicity and ameliorate survival.
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http://dx.doi.org/10.1002/ajh.21564DOI Listing
January 2010

High-resolution genome-wide array comparative genomic hybridization in splenic marginal zone B-cell lymphoma.

Hum Pathol 2009 Nov 3;40(11):1628-37. Epub 2009 Aug 3.

Department of Human end Hereditary Pathology, Section of Medical Genetics, University of Pavia, Pavia 27100, Italy.

Splenic marginal zone B-cell lymphoma is characterized by high genetic heterogeneity, and hepatitis C virus infection seems to be involved in a subset of patients. The aims of the analysis were to identify potential genetic alterations related to hepatitis C virus status, IgV(H) gene mutational status, and prognostic categories identified in a multicenter study (Blood 2006;107:4643). Genome-wide array comparative genomic hybridization at a 100-kilobase (kb) resolution was performed in 34 patients with splenic marginal zone B-cell lymphoma, 12 of whom were hepatitis C virus positive. Array-comparative genomic hybridization experiments revealed no copy number alterations in 10 patients (4 were hepatitis C virus positive). A median of 5.6 and 3.8 copy number alterations were detected in hepatitis C virus-positive and in hepatitis C virus-negative patients, respectively. The most frequent copy number alterations involved chromosomes 7 and 17 (21% and 24%, respectively). Except for Xp gain (P = .01), no differences in common alterations were found between hepatitis C virus-positive and hepatitis C virus-negative cases. Unmutated status of the IgV(H) gene was related to del(7q) (P = .04) and dup(12q) (P = .03). The high-risk group identified according to the new splenic marginal zone B-cell lymphoma prognostic score was associated with del(7q) (P = .01) and del(17p) (P = .02). Hepatitis C virus-positive splenic marginal zone B-cell lymphoma patients have no specific chromosome alterations. Patients with poor prognosis are characterized by distinctive imbalances.
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http://dx.doi.org/10.1016/j.humpath.2009.01.025DOI Listing
November 2009

Splenic marginal zone lymphoma: Clinical clustering of immunoglobulin heavy chain repertoires.

Blood Cells Mol Dis 2009 May-Jun;42(3):286-91. Epub 2009 Feb 27.

Division of Hematology, Fondazione IRCCS Policlinico San Matteo, University of Pavia - Viale C. Golgi 19, 27100 Pavia, Italy.

Immunoglobulin gene usage and somatic mutation patterns were studied in 59 patients with splenic marginal zone lymphoma and were correlated with clinical characteristics. Fifty-nine IGHV rearrangements were amplified. IGHV1, IGHV3, and IGHV4 subgroups accounted for 30%, 56%, and 14% of sequences, respectively. IGHV genes most frequently used were IGHV1-2 (n=12), IGHV3-23 (n=15), IGHV3-30 (n=7) and IGHV4-34 (n=5). IGHV was unmutated in 25%. Villous lymphocytes >10% were detected in 50% of patients belonging to the IGHV1-2 group, in 21% of the IGHV3-23 group, and in no patient of the IGHV3-30 group (p=0.05). Liver involvement was present in 50% of the IGHV3-30 group, in 9% of the IGHV3-23 group, and in no patient of the IGHV1-2 group (p=0.04). HCV-serology was positive in 50% of the IGHV3-30 group, in 7% of the IGHV3-23 group, and in 17% of the IGHV1-2 group (p=0.04). The proportion of intermediate and high risk patients according to the SMZL score was higher in the unmutated respect to the mutated group (69% vs 32%, p=0.05). In conclusion, IGHV rearrangement analysis in splenic marginal zone B-cell lymphoma reveals a non-random preference for use of IGHV1-2, IGHV3-23 and IGHV3-30 genes, whose presence differs according to clinical features and prognostic category.
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http://dx.doi.org/10.1016/j.bcmd.2009.01.004DOI Listing
August 2009