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Treatment of young adults with colorectal cancer (CRC) represents an unmet clinical need, especially as diagnosis in this population might lead to the greatest loss of years of life. Since 1994, CRC incidence in individuals younger than 50 years has been increasing by 2% per year. The surge in CRC incidence in young adults is particularly alarming as the overall CRC frequency has been decreasing. Early‐onset CRC are characterized by a more advanced stage at diagnosis, poorer cell differentiation, higher prevalence of signet ring cell histology, and left colon‐sided location of the primary tumor. Among EO‐CRC, approximately 30% of patients are affected by tumors harboring mutations causing hereditary cancer predisposing syndromes, and 20% have familial CRC. Most notably, the remaining 50% of EO‐CRC patients have neither hereditary syndromes nor familial CRC, thus representing a formidable challenge for research. In this review article we summarize epidemiology, clinical and molecular features, heredity and outcome of treatments of EO‐CRC, and provide considerations for future perspectives. The prevalence of hereditary syndromes, familial syndromes and neither hereditary or familial (‘terra incognita’) syndromes among early‐onset colorectal cancer in young individuals. Figures are derived from studies in the text.

Brugada syndrome (BrS) is a genetic disorder marked by a characteristic electrocardiogram (ECG) pattern of ST-segment elevation and T-wave inversion in right precordial leads, which is associated with an increased risk of ventricular fibrillation in the absence of structural heart disease. Despite advancements in understanding its epidemiology, pathophysiology, and treatment, there is considerable variability in how sports cardiologists approach BrS. This expert opinion by the Italian Society of Sports Cardiology (SICSPORT) aim to review the current definition, diagnosis, epidemiology, genetics, risk stratification, and treatment of BrS and provide guidance for sport eligibility provides guidance for sports doctors and cardiologists in assessing competitive sports eligibility in athletes with BrS. A multiparametric approach to diagnosis and risk stratification is recommended, noting that the presence of a Brugada ECG pattern (BrP) does not confirm a BrS diagnosis. The risk of sudden cardiac death (SCD) is low in asymptomatic individuals with type 1 BrP, especially those with a drug-induced pattern. Pharmacological testing is not required for type 2 or 3 patterns without other risk factors. Low-risk individuals do not require therapy, while intermediate or high-risk patients may need pharmacological treatment, ICD implantation, or ablation. Asymptomatic individuals with type 2 or 3 BrP, no family history of SCD, and no other risk factors may be eligible for competitive sports, as well as asymptomatic type 1 BrP without risk factors and negative electrophysiological study. Conversely, sports eligibility should be denied in patients with BrS who have a history of syncope or cardiac arrest (high-risk subjects), regardless of ICD presence.

The need for greener and cleaner aviation has accelerated the transition towards more electric systems on the More Electric Aircraft. One of the key challenges related to the increasing number of electrical devices onboard is the control of bidirectional power converters. In this work, stability analysis and control of a buck–boost converter for aeronautic applications are presented. Firstly, stability of the buck–boost converter in the Lyapunov sense is proven by resorting to input-to-state stability notions. Then, a novel control design based on second order sliding mode control and uniting control, aimed at overcoming the difficulties generated by the nonlinear input gain function of the system not being sign definite, is presented. Extensive and detailed simulations, designed to emulate one of the possible energy management policies onboard a More Electric Aircraft, confirm the correctness of the theoretical analysis both in buck and in boost mode.

We present protocols to generate arbitrary photonic graph states from quantum emitters that are in principle deterministic. We focus primarily on two-dimensional cluster states of arbitrary size due to their importance for measurement-based quantum computing. Our protocols for these and many other types of two-dimensional graph states require a linear array of emitters in which each emitter can be controllably pumped, rotated about certain axes, and entangled with its nearest neighbors. We show that an error on one emitter produces a localized region of errors in the resulting graph state, where the size of the region is determined by the coordination number of the graph. We describe how these protocols can be implemented for different types of emitters, including trapped ions, quantum dots, and nitrogen-vacancy centers in diamond.

In February 2021, the spread of a new variant of SARS-CoV-2 in the Lombardy Region, Italy caused concerns about school-aged children as a source of contagion, leading local authorities to adopt an extraordinary school closure measure. This generated a debate about the usefulness of such an intervention in light of the trade-off between its related benefits and costs (e.g. delays in educational attainment, impact on children and families' psycho-physical well-being). This article analyses the epidemiological impact of the school closure intervention in the Milan metropolitan area. Data from the Agency for Health Protection of the Metropolitan City of Milan allowed analysing the trend of contagion in different age classes before and after the intervention, adopting an interrupted times series design, providing a quasi-experimental counterfactual scenario. Segmented Poisson regression models of daily incident cases were performed separately for the 3-11-year-old, the 12-19-year-old, and the 20+-year-old age groups, examining the change in the contagion curves after the intervention, adjusting for time-varying confounders. Kaplan-Meier survival curves and Cox regression were used to assess the equality of survival curves in the three age groups before and after the intervention. Net of time-varying confounders, the intervention produced a daily reduction of the risk of contagion by 4% in those aged 3-11 and 12-19 (IRR = 0·96) and by 3% in those aged 20 or more (IRR = 0·97). More importantly, there were differences in the temporal order of contagion decrease between the age groups, with the epidemic curve lowering first in the school-aged children directly affected by the intervention, and only subsequently in the adult population, which presumably indirectly benefitted from the reduction of contagion among children. Though it was not possible to completely discern the effect of school closures from concurrent policy measures, a substantial decrease in the contagion curves was clearly detected after the intervention. The extent to which the slowdown of infections counterbalanced the social costs of the policy remains unclear.

The assessment of ctDNA has emerged as a minimally invasive avenue for molecular diagnosis and real-time tracking of tumor progression in NSCLC. However, the evaluation of ctDNA by amplicon-based NGS has been not endorsed by all the healthcare systems and remains to be fully integrated into clinical routine practice. To compare tissue single-gene with plasma multiplexed testing, we retrospectively evaluated 120 plasma samples from 12 consecutive patients with advanced non-squamous NSCLC who were part of a prospective study enrolling treatment-naïve patients and in which tissue samples were evaluated using a single-gene testing approach. While the plasma ctDNA detection of EGFR and BRAF mutations had an acceptable level of concordance with the archival tissue (85%), discordance was seen in all the patients in whom ALK alterations were only detected in tissue samples. Among six responders and six non-responders, early ctDNA mutant allelic frequency (MAF) reduction seemed to predict radiologic responses and longer survival, whereas increasing MAF values with the emergence of co-mutations like BRAF V600E , KRAS G12V or TP53 M237I seemed to be an early indicator of molecular and radiologic progression. This report using an amplicon-based NGS assay on ctDNA underscores the real-life need for plasma and tissue genotyping as complementary tools in the diagnostic and therapeutic decision-making process.

Background In the winter of 2016–2017, the number of deaths recorded in the north-west Europe was significantly higher than that in previous years. This spike in mortality was attributed principally to an influenza epidemic, but the contribution of air pollution and cold temperature has not been investigated. Information on the combined effect of low temperatures, influenza epidemic, and air pollution on mortality is inadequate. The objective of this study was to estimate the excess mortality in the winter of 2016–2017 in the metropolitan area of Milan, and to evaluate the independent short-term effect of 3 risk factors: low temperatures, the influenza epidemic, and air pollution. Methods We used a case-crossover, time-stratified study design. Mortality data were collected on all people aged > 65 years who died of natural causes, due to respiratory diseases or cardiovascular diseases, between December 1, 2016 and February 15, 2017. Environmental data were extracted from the Regional Environmental Protection Agency. The National Surveillance Network provided data on influenza epidemic. Results Among the 7590 natural deaths in people aged > 65 years, 965 (13%) were caused by respiratory conditions, and 2688 (35%) were caused by cardiovascular conditions. There were statistically significant associations between the minimum recorded temperature and deaths due to natural causes (OR = 0.966, 95% CI: 0.944–0.989), and cardiovascular conditions (OR = 0.961, 95% CI: 0.925–0.999). There were also statistically significant association between the influenza epidemic and deaths due to natural causes (OR = 1.198, 95% CI: 1.156–1.241), cardiovascular conditions (OR = 1.153, 95% CI: 1.088–1.223), and respiratory conditions (OR = 1.303, 95% CI: 1.166–1.456). High levels of PM10 (60 and 70 μg/m 3 ) were associated with a statistically significant increase in natural and cause-specific mortality. There were statistically significant interactions between PM10 and influenza for cardiovascular-related mortality, and between influenza and temperature for deaths due to natural causes. Conclusions Excess of mortality in Milan during winter 2016–2017 was associated with influenza epidemic and concomitant environmental exposures, specifically, the combined effect of air pollution and low temperatures. Policies mitigating the effects of environmental risk factors should be implemented to prevent future excess mortality.

In order to achieve the high-fidelity quantum control needed for a broad range of quantum information technologies, reducing the effects of noise and system inhomogeneities is an essential task. It is well known that a system can be decoupled from noise or made insensitive to inhomogeneous dephasing dynamically by using carefully designed pulse sequences based on square or delta-function waveforms such as Hahn spin echo or CPMG. However, such ideal pulses are often challenging to implement experimentally with high fidelity. Here, we uncover a new geometrical framework for visualizing all possible driving fields, which enables one to generate an unlimited number of smooth, experimentally feasible pulses that perform dynamical decoupling or dynamically corrected gates to arbitrarily high order. We demonstrate that this scheme can significantly enhance the fidelity of single-qubit operations in the presence of noise and when realistic limitations on pulse rise times and amplitudes are taken into account.

MUTYH gene is involved in the base excision repair (BER) mechanism and its pathogenic alterations are associated with colorectal polyposis and cancer. MUTYH -associated polyposis (MAP) is a condition which is inherited in an autosomal recessive manner. MAP patients, beyond colorectal cancer (CRC), may develop other types of tumors, including duodenal, breast, ovarian, pancreatic, bladder and skin cancers. Carriers of biallelic MUTYH likely pathogenic/pathogenic variants exhibit a high lifetime risk of CRC, though cancer risk evidence becomes less clear when monoallelic carriers and extraintestinal tumors are considered. However, several studies recently reported an increased genetic susceptibility to cancer also for carriers of germline monoallelic MUTYH mutations. Moreover, experimental evidence highlighted the MUTYH involvement in many other biological functions. In future, MUTYH mutation carriers might benefit from new target therapies involving the use of PD-1 or KRAS inhibitors. Therefore, “ MUTYH -associated tumor syndrome” might be the most appropriate term, due to the multiplicity of tumors observed in MAP patients and different biological contexts in which MUTYH acts as a “playmaker”. In this Review, we will investigate the impact of germline mono- and biallelic MUTYH mutations on cancer risk, providing a proposal for clinical surveillance of mutation carriers.

The treatment of metastatic non-small cell lung cancer (NSCLC) has undergone a paradigm shift over the last decade. Better molecular characterization of the disease has led to the rapid improvement of personalized medicine and the prompt delivery of targeted therapies to patients with NSCLC. The discovery of the EML4-ALK fusion gene in a limited subset of patients affected by NSCLC and the subsequent clinical development of crizotinib in 2011 has been an impressive milestone in lung cancer research. Unfortunately, acquired resistances regularly develop, hence disease progression occurs. Afterward, modern tyrosine kinase inhibitors (TKIs), such as ceritinib, alectinib, brigatinib, and lorlatinib, have been approved by the Food and Drug Administration (FDA) for the management of anaplastic lymphoma kinase (ALK)-positive NSCLCs. Several compounds are currently under investigation to achieve the optimal strategy of therapy. Additionally, the results of ongoing clinical trials with novel-generation TKI will provide more evidence on the best sequence in the treatment of ALK-positive NSCLC patients. In this review, we provide a comprehensive overview of the state-of-the-art targeted therapy options in ALK-positive NSCLCs. Resistance, potential therapeutic strategies to overcome drug resistance, and future perspectives for this subset of patients are critically analyzed and summarized.