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There are thousands of rare genetic diseases that could be treated with classical gene therapy strategies such as the addition of the defective gene via viral or non-viral delivery or by direct gene editing. However, several genetic defects are too complex for these approaches. These "genomic mutations" include aneuploidies, intra and inter chromosomal rearrangements, large deletions, or inversion and copy number variations. Chromosome transplantation (CT) refers to the precise substitution of an endogenous chromosome with an exogenous one. By the addition of an exogenous chromosome and the concomitant elimination of the endogenous one, every genetic defect, irrespective of its nature, could be resolved. In the current review, we analyze the state of the art of this technique and discuss its possible application to human pathology. CT might not be limited to the treatment of human diseases. By working on sex chromosomes, we showed that female cells can be obtained from male cells, since chromosome-transplanted cells can lose either sex chromosome, giving rise to 46,XY or 46,XX diploid cells, a modification that could be exploited to obtain female gametes from male cells. Moreover, CT could be used in veterinary biology, since entire chromosomes containing an advantageous locus could be transferred to animals of zootechnical interest without altering their specific genetic background and the need for long and complex interbreeding. CT could also be useful to rescue extinct species if only male cells were available. Finally, the generation of "synthetic" cells could be achieved by repeated CT into a recipient cell. CT is an additional tool for genetic modification of mammalian cells.

Background: The prevalence of hypothyroidism among older patients hospitalized for COVID-19 and its association with mortality is unclear. This study aims to investigate the prevalence of hypothyroidism in older COVID-19 inpatients and verify if this comorbidity is associated with a specific pattern of onset symptoms and a worse prognosis. Methods: COVID-19 inpatients aged ≥ 60 years, participating in the GeroCovid acute wards cohort, were included. The history of hypothyroidism was derived from medical records and the use of thyroid hormones. Sociodemographic data, comorbidities, symptoms/signs at the disease onset and inflammatory markers at ward admission were compared between people with vs without history of hypothyroidism. The association between hypothyroidism and in-hospital mortality was tested through Cox regression. Results: Of the 1245 patients included, 8.5% had a history of hypothyroidism. These patients were more likely to present arterial hypertension and obesity compared with those without an history of hypothyroidism. Concerning COVID-19 clinical presentation, patients with hypothyroidism had less frequently low oxygen saturation and anorexia but reported muscle pain and loss of smell more commonly than those without hypothyroidism. Among the inflammatory markers, patients with hypothyroidism had higher lymphocytes values. At Cox regression, hypothyroidism was associated with reduced in-hospital mortality only in the univariable model (HR = 0.66, 95% CI 0.45–0.96, p = 0.03); conversely, no significant result were observed after adjusting for potential confounders (HR = 0.69, 95% CI 0.47–1.03, p = 0.07). Conclusions: Hypothyroidism does not seem to substantially influence the prognosis of COVID-19 in older people, although it may be associated with peculiar clinical and biochemical features at the disease onset.

The aim of this study is to provide an estimate of the social costs of gambling in Italy. In line with other research on social costs, the present study estimates the consequences of gambling harm on public finances, focusing on the estimated costs to treat high-risk gamblers, costs associated with productivity losses, costs of unemployment, personal and family costs, crime and legal costs. We used two different approaches to calculate these costs. The first approach, used for health care costs, consists of using the lump sum spent to prevent the harm caused to high-risk gamblers. The second approach involves estimating the number of high-risk gamblers causing the cost, which is then multiplied with the average unit cost per person. Our estimates of the annual social costs of gambling in Italy – more than EUR 2.3 billion – demonstrate a substantial economic burden to society. However, the costs are a substantial underestimate, as they are limited to those of a public nature and do not take into consideration those costs borne by moderate and low-risk gamblers, as well as affected others.

Due to the recurrent pandemic outbreaks that occurred during the last century, Influenza A viruses are considered a serious potential danger to human health. Among the innate immune pathways in eukaryotes, RNA interference plays a significant role in the interaction between viruses and host cells. RNA interference is addressed by small dsRNA molecules produced by the host itself (miRNAs, i.e. "micro-RNAs") but can be triggered also by the administration of exogenous short RNAs (siRNAs, "short interfering RNAs"). In this work, artificial siRNA pools targeting NP and PB genomic regions of the Influenza virus were produced in engineered Escherichia coli, adapting a published protocol. In a MDCK cell in vitro model, these preparations were challenged against reporter vectors bearing viral genomic sequences. A strong and specific RNA interference activity was observed, and the details of this action were indagated.

The main purpose of the Divertor Tokamak Test facility (DTT) [1], whose construction is starting in Frascati, Italy, is to study solutions to mitigate the issue of power exhaust in conditions relevant for ITER and DEMO. DTT will be equipped with a significant amount of auxiliary heating power (45 MW) to reach PSEP/R = 15 MW m-1 required to be DEMO-relevant [2]. DDT is characterized by high flexibility for the assembling and testing of divertor components and for the different magnetic configurations to address the integrated physics and technology problems. The current conceptual design of the beamline for the DTT Neutral Beam Heating system is here presented, with a particular focus on the effect on the DTT plasma and on the technical solutions adopted to maximize the RAMI indexes (Reliability, Availability, Maintainability and Inspectability) and minimize complexity and costs. Various design options were considered, and a comprehensive set of simulations was carried out using several physics and engineering codes to drive the choice of the most suitable design options and optimize them, aiming at finding a good compromise among different requirements. This paper describes the design of the main components of the DTT NBI beamline, explaining the motivations for the main design choices.

OBJECTIVES: The purpose of this study was to create, standardize, and validate a new instrument, named 4-DSD, and determine its diagnostic accuracy in the diagnosis of delirium in subjects with moderate to severe dementia.DESIGN: Multicenter cross-sectional observational study.SETTING AND PARTICIPANTS: Older patients consecutively admitted to acute and rehabilitation hospital wards.MEASURES: The DSM-5 was used as the reference standard delirium assessment. The presence and severity of dementia was defined using the AD8 and the Global Deterioration Scale (GDS). The 4-DSD is a 4-item tool that ranges from 0 to 12. Item 1 measures alertness, item 2 altered function, item 3 attention, and item 4 acute change or fluctuation in mental status.RESULTS: A total of 134 patients were included in the study. Most of the patients were enrolled in acute hospital wards (60%), with 40% in rehabilitation settings. A minority of the patients were categorized with moderate dementia, with a GDS score of 5 (4%). Most of the patients were in the moderate-severe stage with a GDS score ≤6 (77%); 19% were classed as severe, with a GDS score of 7. A 4-DSD cutoff score ≥5 had a sensitivity of 80% and specificity of 80% with a positive predictive value (PPV) of 67% and a negative predictive value (NPV) of 89%. In the subgroup with moderate-severe dementia (n=108), the sensitivity and the specificity were 79% and 82%, respectively, with a PPV and NPV of 62% and 92%. In the subgroup with severe dementia (n=26) the sensitivity was 82% and the specificity 56% with a PPV of 78% and a NPV of 63%.CONCLUSIONS AND IMPLICATIONS: The availability of a specific tool to detect delirium in patients with moderate-severe dementia has important clinical and research implications, allowing all health care providers to improve their ability to identify it.

Clostridium tyrobutyricum represents the main spoiling agent responsible for late blowing defects (LBD) in hard and semi-hard cheeses. Its spores are resistant to manufacturing procedures and can germinate during the long ripening process, causing the burst of the cheese paste with a consequent undesirable taste. The lower quality of blown cheeses leads to considerable financial losses for the producers. The early identification of spore contaminations in raw milk samples thus assumes a pivotal role in industrial quality control. Herein, we developed a point of care (POC) testing method for the sensitive detection of C. tyrobutyricum in milk samples, combining fast DNA extraction (with no purification steps) with a robust colorimetric loop-mediated isothermal amplification (LAMP) technique. Our approach allows for the sensitive and specific detection of C. tyrobutyricum spores (limit of detection, LoD: ~2 spores/mL), with the advantage of a clear naked-eye visualization of the results and a potential semi-quantitative discrimination of the contamination level. In addition, we demonstrated the feasibility of this strategy using a portable battery-operated device that allowed both DNA extraction and amplification steps, proving its potential for on-site quality control applications without the requirement of sophisticated instrumentation and trained personnel.

Background: Lung cancer mortality in men has been declining since the late 1980s in most European countries. In women, although rates are still appreciably lower than those for men, steady upward trends have been observed in most countries. To quantify the current and future lung cancer epidemic in European women, trends in lung cancer mortality in women over the last four decades were analyzed, with specific focus on the young. Patients and methods: Age-standardized (world standard) lung cancer mortality rates per 100 000 women—at all ages, and truncated 35-64 and 20-44 years—were derived from the WHO for the European Union (EU) as a whole and for 33 separate European countries. Joinpoint regression analysis was used to identify points where a significant change in trends occurred. Results: In the EU overall, female lung cancer mortality rates rose by 23.8% between 1980-1981 and 1990-1991 (from 7.8 to 9.6/100 000), and by 16.1% thereafter, to reach the value of 11.2/100 000 in 2000-2001. Increases were smaller in the last decade in several countries. Only in England and Wales, Latvia, Lithuania, Russia and Ukraine did female lung cancer mortality show a decrease over the last decade. In several European countries, a decline in lung cancer mortality in young women (20-44 years) was observed over the last decade. Conclusions: Although female lung cancer mortality is still increasing in most European countries, the more favorable trends in young women over recent calendar years suggest that if effective interventions to control tobacco smoking in women are implemented, the lung cancer epidemic in European women will not reach the levels observed in the USA

After long-term rises, over the last decade age-standardised mortality from most common cancer sites has fallen in the European Union (EU). For males, the fall was 11% for lung and intestines, 12% for bladder, 6% for oral cavity and pharynx, and 5% for oesophagus. For females, the fall was 7% for breast and 21% for intestines. There were also persisting declines in stomach cancer (30% in both sexes), uterus (mainly cervix, -26%) and leukaemias (-10%). Mortality rates for other common neoplasms, including pancreas for both sexes, prostate and ovary, tended to stabilise. The only unfavourable trends were observed for female lung cancer (+15%). Lung cancer rates in women from the EU are approximately one-third of those in the USA, and 50% lower than breast cancer rates in the EU. Lung cancer rates in European women have also tended to stabilise below the age of 75 years. Thus, effective interventions on tobacco control could, in principle, avoid a major lung cancer epidemic in European women

Sviluppato nel corso dei tre anni in cui si articola il Dottorato di Ricerca in Sociologia Applicata e Metodologia della Ricerca Sociale dell’Università degli Studi di Milano Bicocca, il progetto di chi scrive, alla luce degli sviluppi della letteratura dedicata al gioco d’azzardo, alle sue ricadute individuali e sociali e alle eventuali degenerazioni, mira ad acquisire un quadro conoscitivo del fenomeno, analizzando i tratti socio-economici dei giocatori problematici e il loro grado di accettazione e ricerca del rischio. Per dare risposta agli interrogativi di ricerca, si è ricorso all’analisi dei dati emergenti dallo studio Italian Population Survey on Alcohol and other Drugs (Ipsad), che, realizzato dall’Istituto di Fisiologia Clinica (Ifc) del Consiglio Nazionale delle Ricerche (Cnr) di Pisa, indaga il consumo di alcol, l’uso di sostanze psicoattive e la messa in atto di comportamenti a rischio. Ipsad segue le linee guida fornite dall’European Monitoring Centre for Drug and Drug Abuse (Emcdda) di Lisbona. Chi scrive ha avuto la preziosa opportunità di essere coinvolto nello studio e di contare sulla disponibilità dei dati raccolti (circa 30mila casi, età 15-64 anni) per sviluppare le opportune analisi e verificare la correttezza delle ipotesi avanzate. In primo luogo, seguendo alcune delle evidenze emerse in letteratura, è stata verificata l’ipotesi secondo cui i comportamenti di gioco eccessivo, tali da connotare un profilo di gioco problematico, siano più diffusi tra le fasce della popolazione con uno status socio-economico più basso. In secondo luogo, è stata sottoposta a verifica l’ipotesi secondo cui i comportamenti di gioco eccessivo siano una specifica manifestazione di una più generale propensione al rischio. Nel primo capitolo del presente lavoro di tesi, viene inquadrato il fenomeno del gioco d’azzardo e presentate le sue derive problematiche. Nel secondo, viene proposta una rassegna della letteratura relativa all’associazione tra condizione, Developed during a PhD in Applied Sociology and Social Research Methodology (University of Milano- Bicocca), the project – starting from a review of the literature on gambling and problem gambling – aimed to analyze the socio-economic status of problem gamblers and their risk-taking propensity. To address the research questions (What is the association between socio-economic status and gambling behaviour? What is the association between risk-taking propensity and gambling behaviour?), it has been performed an analysis of the data emerging from the study Italian Population Survey on Alcohol and other Drugs (IPSAD). Realized by the Institute of Clinical Physiology (IFC) of the National Research Council (CNR) in Pisa (Italy), IPSAD investigates the consumption of alcohol, the use of psychoactive substances, and the attitude towards risky behaviour. IPSAD follows the guidelines provided by the European Monitoring Centre for Drug and Drug Abuse (EMCDDA) in Lisbon. The writer had the opportunity to be involved in the study and to take advantage of the collected data (roughly 30,000 cases; aged 15-64 years). Firstly, it has been scrutinized the hypothesis that problem gambling is more prevalent among sections of the population with lower socio-economic status. Secondly, it has been tested the hypothesis that excessive gambling behaviour is a specific manifestation of a more general risk-taking propensity. In the first chapter of this thesis, we discuss the concepts of gambling, gambling behaviour, and problem gambling. In the second chapter, we present a review of the literature on the association between socio-economic status, risk-taking propensity and problem gambling. In the third chapter, we highlight objectives, hypotheses, research questions, population and sample, detailing the operationalization procedures. In the fourth chapter, we explicit analytical strategy and results, then discussed (Chapter 5) also in the light of the limitations of the study (Chapter 6). B

Cancer mortality rates and trends over the period 1980-2000 for accession countries to the European Union (EU) in May 2004, which include a total of 75 million inhabitants, were abstracted from the World Health Organization (WHO) database, together with, for comparative purposes, those of the current EU. Total cancer mortality for men was 166/100 000 in the EU, but ranged between 195 (Lithuania) and 269/100 000 (Hungary) in central and eastern European accession countries. This excess related to most cancer sites, including lung and other tobacco-related neoplasms, but also stomach, intestines and liver, and a few neoplasms amenable to treatment, such as testis, Hodgkin's disease and leukaemias. Overall cancer mortality for women was 95/100 000 in the EU, and ranged between 100 and 110/100 000 in several central and eastern European countries, and up to 120/100 000 in the Czech Republic and 138/100 000 in Hungary. The latter two countries had a substantial excess in female mortality for lung cancer, but also for several other sites. Furthermore, for stomach and especially (cervix) uteri, female rates were substantially higher in central and eastern European accession countries. Over the last two decades, trends in mortality were systematically less favourable in accession countries than in the EU. Most of the unfavourable patterns and trends in cancer mortality in accession countries are due to recognised, and hence potentially avoidable, causes of cancer, including tobacco, alcohol, dietary habits, pollution and hepatitis B, plus inadequate screening, diagnosis and treatment. Consequently, the application of available knowledge on cancer prevention, diagnosis and treatment may substantially reduce the disadvantage now registered in the cancer mortality of central and eastern European accession countries

Background: Cancer mortality peaked in the European Union (EU) in the late 1980s and declined thereafter. Materials and methods: We analyzed EU cancer mortality data provided by the World Health Organization in 1970-2003, using joinpoint analysis. Results: Overall, cancer mortality levelled off in men since 1988 and declined in 1993-2003 (annual percent change, APC = −1.3%). In women, a steady decline has been observed since the early 1970s. The decline in male cancer mortality has been driven by lung cancer, which levelled off since the late 1980s and declined thereafter (APC = 2.7% in 1997-2003). Recent decreases were also observed for other tobacco-related cancers, as oral cavity/pharynx, esophagus, larynx and bladder, as well as for colorectal (APC = −0.9% in 1992-2003) and prostate cancers (APC = −1.0% in 1994-2003). In women, breast cancer mortality levelled off since the early 1990s and declined thereafter (APC = −1.0% in 1998-2003). Female mortality declined through the period 1970-2003 for colorectal and uterine cancer, while it increased over the last three decades for lung cancer (APC = 4.6% in 2001-2003). In both sexes, mortality declined in 1970-2003 for stomach cancer and for a few cancers amenable to treatment. Conclusion: This update analysis of the mortality from cancer in the EU shows favorable patterns over recent years in both sexes

Background: The different spread of tobacco smoking across European countries has caused a substantial variability in lung cancer mortality. The objective of this investigation was to analyse the trends in lung cancer mortality rates in three broad European regions (Northern and Western countries, Eastern countries, and Mediterranean countries) during the second half of the 20th century. Patients and methods: Mortality data were obtained from the World Health Organisation database. Lung cancer mortality rates were age-standardised by the direct method to the world standard population. Trends from 1955 to 1997 were assessed by means of joinpoint regression analysis. Results: In men, rates in Eastern Europe increased to reach in the 1990s the highest values ever registered, while downward trends were observed in Northern and Western Europe since 1979, and in Mediterranean countries since the 1990s. In women, upward trends were observed in the three regions considered for the whole period. Conclusions: Different smoking prevalences over time explain the shift of almost one decade in the trends in Mediterranean men as compared with Northern and other Western European men. The persisting upward trends in women in the three regions are of concern

Mortality rates from kidney cancer increased throughout Europe up until the late 1980s or early 1990s. Trends in western European countries, the European Union (EU) and selected central and eastern European countries have been updated using official death certification data for kidney cancer abstracted from the World Health Organisation (WHO) database over the period 1980-1999. In EU men, death rates increased from 3.92 per 100 000 (age standardised, world standard) in 1980-81 to 4.63 in 1994-95, and levelled off at 4.15 thereafter. In women, corresponding values were 1.86 in 1980-81, 2.04 in 1994-95 and 1.80 in 1998-99. Thus, the fall in kidney cancer mortality over the last 5 years was over 10% for both sexes in the EU. The largest falls were in countries with highest mortality in the early 1990s, such as Germany, Denmark and the Netherlands. Kidney cancer rates levelled off, but remained very high, in the Czech Republic, Baltic countries, Hungary, Poland and other central European countries. Thus, in the late 1990s, a greater than three-fold difference in kidney cancer mortality was observed between the highest rates in the Czech Republic, the Baltic Republics and Hungary, and the lowest ones in Romania, Portugal and Greece. Tobacco smoking is the best recognised risk factor for kidney cancer, and the recent trends in men, mainly in western Europe, can be related to a reduced prevalence of smoking among men. Tobacco, however, cannot account for the recent trends registered in women

Background: To update the pattern of cancer mortality in Europe. Materials and methods: We analysed cancer mortality in 34 European countries during 2000-2004, with an overview of trends in 1975-2004 using data from the World Health Organization. Results: From 1990-1994 to 2000-2004, overall cancer mortality in the European Union declined from 185.2 to 168.0/100 000 (world standard, −9%) in men and from 104.8 to 96.9 (−8%) in women, with larger falls in middle age. Total cancer mortality trends were favourable, though to a variable degree, in all major European countries, including Russia, but not in Romania. The major determinants of these favourable trends were the decline of lung (−16%) and other tobacco-related cancers in men, together with the persistent falls in gastric cancer, and the recent appreciable falls in colorectal cancer. In women, relevant contributions came from the persistent decline in cervical cancer and the recent falls in breast cancer mortality, particularly in northern and western Europe. Favourable trends were also observed for testicular cancer, Hodgkin lymphomas, leukaemias, and other neoplasms amenable to treatment, though the reductions were still appreciably smaller in eastern Europe. Conclusion: This updated analysis of cancer mortality in Europe showed a persistent favourable trend over the last years

Background: Hodgkin lymphoma (HL) is a largely curable disease and its mortality had steadily declined in western Europe since the late 1960s. Only modest declines were, however, observed in central/eastern Europe. Materials and methods: We updated trends in mortality from HL in various European areas up to 2004 and analyzed patterns in incidence for selected European countries providing national data. Results: In most western European countries, HL mortality continued to steadily decline up to the mid 2000s. More recent reductions were also observed in eastern European countries. Overall, mortality from HL declined from 1.17/100 000 (age-standardized, world population) in 1980-1989 to 1.42/100 000 in 2000-2004 in men from the 15 member states of the European Union (EU) from western and northern Europe. In the EU 10 accession countries of central and eastern Europe, male mortality from HL was 1.42/100 000 in 1980-1984, 1.32 in 1990-1994, and declined to 0.76 in 2000-2004. Similar trends were observed in women. No consistent patterns were found for HL incidence. Conclusions: The present work confirms the persistent declines in HL mortality in western European countries, and shows favorable patterns over more recent calendar years in central/eastern ones, where rates, however, are still at levels observed in western Europe in the early 1990s

Background: Processed meat has been related to the risk of digestive tract neoplasms but the evidence remains inconclusive. We examined data from a network of case-control studies conducted between 1992 and 2002 in the Swiss Canton of Vaud. Patients and methods: We studied 316 patients with incident, histologically confirmed oral and pharyngeal cancer, 138 patients with oesophageal cancer, 91 patients with laryngeal cancer and 323 patients with colorectal cancer. Controls were 1271 subjects admitted to the same hospital for a wide spectrum of acute non-neoplastic conditions, unrelated to long-term modification of diet. Results: There were strong direct trends in risk between consumption of processed meat and the various neoplasms considered: the multivariate odds ratios for the highest quartile of intake compared to the lowest were 4.7 for oral and pharyngeal cancer, 4.5 for oesophageal cancer, 3.4 for laryngeal cancer and 2.5 for colorectal cancer. The association was stronger in younger subjects, in moderate drinkers and in non-smokers. Conclusion: Processed meat represents a strong indicator of unfavourable diet for digestive tract and laryngeal cancer risk in this population

Summary Background: Trends in cancer mortality for the elderly have long been unfavourable. Materials and methods: Mortality from 12 major cancer sites, plus total cancer mortality at age 65-84 in 23 European countries, the US and Japan was analyzed. Results: Between the late 1980s and the late 1990s total cancer mortality at age 65 to 84 has been declining in the European Union (UE) (−5.5% in males, −4.5% in females), in United States (US) males (−2.3%), but not females (+4.4%), and in Japanese females (−5.6%), but not males (+6.3%). Cancer mortality in the elderly rose for both sexes in eastern Europe. Gastric cancer mortality declined in all the areas. Lung cancer rates declined over the last decade by 8.5% in males in the EU, and by 0.9% in the US. Rates were still increasing in eastern Europe, in Japanese males and in females in all areas. Pancreatic mortality rates were increasing in both sexes in the EU and Japan up to the late 1980s, and in eastern Europe up to the 1990s, whereas rates for US males have been declining over recent years. Breast cancer mortality has declined over the last decade by 8% in the US and by 3% in the EU, while it has risen in eastern Europe and in Japan. Mortality from breast and prostate as well as ovarian cancer remained however low in elderly Japanese. Prostate cancer mortality declined in the EU and in the US, whereas it rose in eastern Europe and in Japan. Mortality from lymphomas and multiple myeloma rose in both sexes and various geographic areas, but improved diagnosis and certification may have played a role in these trends. Mortality from leukemia in the elderly increased in eastern Europe and Japan, but was stable in the US and the EU. Conclusions: Cancer mortality in the elderly has stopped systematically rising, and is on the decline in males since the late 1980s

Background A role of energy and various nutrients, including protein, sugar, saturated and unsaturated fats, in colorectal cancer risk has been suggested, but should be better defined. Patients and methods The association between dietary intake of various macronutrients and colorectal cancer risk was analysed using data from a case-control study conducted between 1992 and 2000 in the Swiss Canton of Vaud. The study comprised 286 case subjects (174 males, 112 females; median age 65 years) with incident, histologically confirmed colon (n = 149) or rectal (n = 137) cancer, and 550 control subjects (269 males, 281 females; median age 59 years) admitted to the same University Hospital for a wide spectrum of acute non-neoplastic conditions. Dietary habits were investigated using a validated food frequency questionnaire, including questions on 79 foods or recipes and on individual fat intake pattern. Multivariate odds ratios (OR) were obtained after allowance for age, sex, education, physical activity and energy intake. Results The risk of colon and rectal cancer increased with total energy intake (OR in highest and lowest tertile, 2.0 and 2.2, respectively). There was no significant relation with starches or proteins, a significant inverse relation with sugars (OR for the highest tertile, 0.5), a direct trend in risk of borderline significance for saturated fats (OR = 1.4 for the highest tertile), and significant inverse trends for monounsaturated (OR = 0.6) and polyunsaturated fats (OR = 0.6). Conclusions These findings confirm that energy intake is directly related to colorectal cancer risk, and that different types of fat may have different roles in colorectal carcinogenesis